Conditions: Pancreatitis, Acute Necrotizing
Keywords: 3-hydroxykynurenine Acute pancreatitis Dose-escalation Healthy subjects GSK3335065
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 18
Healthy volunteers: yes

Brief summary:
GSK3335065 is being developed as a treatment for acute pancreatitis with the intent of reducing 3-hydroxykynurenine (3HK) levels to the normal range (or lower) and maintaining them at this level throughout the treatment period. This study will utilize an adaptive design and is divided into 3 parts. Part A will consist of 8 cohorts (1-8) and is Single Ascending Dose (SAD) of GSK3335065 by IV bolus in males. Part B will be initiated after completion of dosing in Part A. It will involve ascending IV bolus doses of GSK3335065 followed by IV constant infusion for 7 days in males and will consist of four cohorts (9-12). Part C consists of a single dose of GSK3335065 by IV bolus (cohort 13), and a single dose followed by continuous infusion over 7 days (cohort 14) in females of non-child bearing potential (WONCBP). Total 64 subjects will be evaluated in the study of which Part A will include 16 healthy male subjects, Part B will include 32 healthy male subjects and Part C will include 16 WONCBP. In Part A, cohorts 1 and 2 will last up to 19 weeks and cohorts 3 to 8 will last up to 7 weeks and Part B will last up to 13 weeks. In Part C cohort 7 will last up to 7 weeks and cohort 8 will last for 13 weeks.

Detailed description:

Arms:
arm 1: Male subjects will be assigned to Cohorts 1 to 8. In each cohort, six subjects will be randomized to receive alternating and escalated doses of GSK3335065. arm 2: Male subjects will be assigned to Cohort 1 and 2. In each cohort, two subjects will be randomized to receive placebo. arm 3: Male subjects will be assigned to one of four cohorts (9, 10, 11 or 12). In each cohort, six subjects will be randomized to receive GSK3335065. In all cohorts each dose level will consist of an IV bolus on Day 1 subsequently followed by a continuous IV infusion for seven days. arm 4: Male subjects will be assigned to one of four cohorts (9, 10, 11 or 12). In each cohort, two subjects will be randomized to receive placebo. arm 5: WONCBP will be assigned to cohort 13. Six subjects will be randomized to receive a single IV dose of GSK3335065. arm 6: WONCBP will be assigned to cohort 13. Two subjects will be randomized to receive placebo. arm 7: WONCBP will be assigned to cohort 14. Six subjects will be randomized to receive a continuous IV infusion over 7 days of GSK3335065. arm 8: WONCBP will be assigned to cohort 14. Two subjects will be randomized to receive placebo.

Interventions: intervention 1: GSK3335065 intervention 2: Placebo
Intervention descriptions: intervention 1: GSK3335065 is being developed as a treatment for acute pancreatitis with the intent of reducing 3-hydroxykynurenine (3HK) levels to the normal range (or lower) and maintaining them at this level. GSK3335065 is a solution and will be administered as intravenous injection and infusion with dose strength of 5 milligram (mg)/mL that may be diluted in 0.9% weight by volume (w/v) sodium chloride. intervention 2: Placebo solution to match GSK3335065 will be given as intravenous injection and infusion.

Protocol document:
Prot_000.pdf: 
2015N261138_03
CONFIDENTIAL
GlaxoSmithKline group of companies
201570
1
TITLE PAGE
Protocol Title: Randomized, Double-blind, Placebo Controlled Dose Escalation Study to 
Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single Doses 
(Intravenous bolus) and constant intravenous infusion over 7 Days of GSK3335065 in 
Healthy Adult Subjects
Protocol Number: 201570
Short Title: Safety, Tolerability Pharmacokinetics, and Pharmacodynamics investigation 
of GSK3335065 (IV) in healthy adults
Compound Number:
GSK3335065
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
Primary 
Medical 
Monitor 
 
 M.D.
Day time: 
After hours:
1250 South Collegeville 
Road
MS: UP 1110, Collegevile 
PA, 19426, USA
Secondary 
Medical 
Monitor
 
 M.D.
Gunnels Wood Road,
Stevenage, Hertfordshire,
SG1 2NY, UK
Regulatory Agency Identifying Number(s):EudraCT number - 2016-001303-22
Approval Date: 29-Nov-2017
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD
PPD
PPD
PPD


PPD
PPD
PPD


2015N261138_03
CONFIDENTIAL
201570
3
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 03
29-Nov-2017
Amendment 02
21-August 2017
Amendment 01
11-July-2017
Original Protocol
14 June 2017
Amendment 03 29-November-2017
Overall Rationale for the Amendment: Change in post dose safety observation period, 
PK and PD assessment time points based on emerging PK data.


2015N261138_03
CONFIDENTIAL
201570
4
Section # and Name
Description of Change
Brief Rationale
Synopsis
Changes described in main 
sections of the protocol below
As below
Section 2.1 Schedule of 
Activities
Table updated with cohorts 
for parts A, B and C with 
corresponding new 
timepoints 
To ensure consistency following 
the additional timepoints
Discharge from clinical unit 
and brief physical 
examination has been 
changed from Day 4 to Day 8
in the remainder of Part A 
and Part C (Cohort 13)
To increase domiciling period 
and safety observation period 
based on emerging PK data
Section 2.2 Schedule of 
Activities: Part B and C (Cohort 
14)
Discharge from clinical unit 
and brief physical 
examination has been 
changed from Day 11 to Day 
15
To increase domiciling period 
and safety observation period 
based on emerging PK data.
Section 5.1 Overall Design

Revised Part A study 
Schematic has been 
included 
Operational feasibility due to the 
increase in domiciling period.
Section 5.1.1 and Section 
10.2.1
Part A will have Cohorts 3 to 
8 with changed duration from 
19 weeks to 7 weeks and 
design change from cross-
over to parallel.
Operational feasibility due to 
the increase in domiciling 
period
Section 5.1.2 Part B, Section 
5.4.2, Section 9.5.1, Section 
12.3

Part B will have 
Cohorts 9 to 12

Subjects will be 
admitted in the unit
from the day prior to 
dosing until Day 15

To ensure consistency 
following changes to 
Part A
Section 5.2 Number of 
Participants, Section 10.2.1
Number of evaluable subjects 
has been increased from 64 
to 112. Also number of 
subjects for Part A has been 
increased from 16 to 64.
This is a consequence 
of the change to the 
study design in Part A


2015N261138_03
CONFIDENTIAL
201570
5
Section # and Name
Description of Change
Brief Rationale
Section 7.3 Method of 
Treatment Assignment
Method of treatment 
assignment has been 
changed from randomization 
in sequences in each session 
to randomization of either 
active or placebo at the start 
of each cohort.
Study design in Part A 
was changed to parallel 
design for operational 
feasibility.
Section 9.7 
Biomarkers/Pharmacodynamics 
Include a short 
(approximately 12-14 hours) 
run-in PD sampling period 
prior to dosing.
To improve the 
understanding of the 
variability and to allow 
better interpretation of 
the PD markers in 
relation to study drug


2015N261138_03
CONFIDENTIAL
201570
6
TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS...............................................................................................................9
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................11
2.1.
Part A & C – Cohort 1, 2, 3, 4, 5, 6, 7, 8 & 13, single bolus dose, 
healthy volunteer subjects ..........................................................................12
2.2.
Part B & C – Cohorts 9, 10, 11, 12 & cohort 14, single bolus dose 
plus 7 day infusion, healthy volunteer subjects ...........................................16
3.
INTRODUCTION....................................................................................................22
3.1.
Study Rationale ..........................................................................................22
3.2.
Background ................................................................................................22
3.3.
Benefit/Risk Assessment ............................................................................24
3.3.1.
Risk Assessment .........................................................................25
3.3.2.
Benefit Assessment.....................................................................32
3.3.3.
Overall Benefit:Risk Conclusion...................................................32
4.
OBJECTIVES AND ENDPOINTS...........................................................................32
5.
STUDY DESIGN ....................................................................................................33
5.1.
Overall Design ............................................................................................33
5.1.1.
Part A: Single Ascending Dose (IV Bolus) in males .....................37
5.1.2.
Part B: Multiple Ascending Dose (IV Bolus followed by an
IV Infusion over 7 days) in Males .................................................39
5.1.3.
Part C: IV Bolus followed by an IV Infusion over 7 days in
WONCBP ....................................................................................40
5.2.
Number of Participants ...............................................................................41
5.3.
Participant and Study Completion...............................................................41
5.4.
Dose Justification........................................................................................42
5.4.1.
Starting dose for Part A................................................................42
5.4.2.
Starting dose for Part B................................................................46
5.4.3.
Maximum dose/exposure in Part B ..............................................47
5.4.4.
Part C: .........................................................................................48
6.
STUDY POPULATION...........................................................................................48
6.1.
Inclusion Criteria.........................................................................................48
6.2.
Exclusion Criteria........................................................................................49
6.3.
Lifestyle Restrictions...................................................................................51
6.3.1.
Meals and Dietary Restrictions ....................................................51
6.3.2.
Caffeine, Alcohol, and Tobacco ...................................................51
6.3.3.
Activity .........................................................................................51
6.3.4.
Exposure to UV............................................................................51
6.4.
Screen Failures...........................................................................................51
7.
TREATMENTS.......................................................................................................52
7.1.
Treatments Administered............................................................................52
7.2.
Dose Modification .......................................................................................53


2015N261138_03
CONFIDENTIAL
201570
7
7.3.
Method of Treatment Assignment ...............................................................53
7.4.
Blinding.......................................................................................................55
7.5.
Preparation/Handling/Storage/Accountability..............................................56
7.6.
Treatment Compliance................................................................................56
7.7.
Concomitant Therapy..................................................................................57
7.8.
Prohibited Medications and Non-Drug Therapies........................................57
7.9.
Treatment after the End of the Study ..........................................................57
8.
DISCONTINUATION CRITERIA.............................................................................58
8.1.
Discontinuation of Study Treatment ............................................................58
8.1.1.
Liver Chemistry Stopping Criteria ................................................58
8.1.2.
QTc Stopping Criteria ..................................................................58
8.1.3.
Rechallenge.................................................................................58
8.1.3.1.
Study Treatment Restart or Rechallenge....................58
8.1.4.
Additional Stopping Criteria .........................................................59
8.2.
Withdrawal from the Study..........................................................................61
8.3.
Lost to Follow Up........................................................................................61
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................62
9.1.
Efficacy Assessments.................................................................................63
9.2.
Adverse Events...........................................................................................63
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................63
9.2.2.
Method of Detecting AEs and SAEs.............................................63
9.2.3.
Follow-up of AEs and SAEs.........................................................64
9.2.4.
Regulatory Reporting Requirements for SAEs .............................64
9.3.
Treatment of Overdose...............................................................................64
9.4.
Safety Assessments ...................................................................................65
9.4.1.
Physical Examinations.................................................................65
9.4.2.
Vital Signs....................................................................................65
9.4.3.
Electrocardiograms......................................................................65
9.4.4.
Continuous ECG monitoring ........................................................66
9.4.5.
Echocardiogram...........................................................................66
9.4.6.
Clinical Safety Laboratory Assessments ......................................66
9.4.7.
Suicidal Risk and Cognitive Safety Monitoring .............................66
9.4.7.1.
Columbia Suicide Severity Rating Scale (C-
SSRS) ........................................................................67
9.4.7.2.
Possible Suicide Related Adverse Event(s) 
(PSRAE).....................................................................67
9.4.7.3.
Neuropsychiatric Inventory (NPI)................................68
9.4.7.4.
Six-Item Cognitive Impairment Test (6-CIT)................68
9.4.7.5.
Finger Tapping Test (FTT)..........................................68
9.4.8.
Assessment at infusion site .........................................................68
9.5.
Pharmacokinetics .......................................................................................68
9.5.1.
Blood Sample Collection..............................................................68
9.5.2.
Urine Sample Collection ..............................................................70
9.6.
Enterotest – Bile Sample Collection............................................................71
9.6.1.
Sample Analysis ..........................................................................71
9.7.
Biomarker(s)/Pharmacodynamics Markers .................................................71
9.7.1.
Sample Analysis ..........................................................................72
9.8.
Genetics .....................................................................................................72


2015N261138_03
CONFIDENTIAL
201570
8
9.9.
Health Economics OR Medical Resource Utilization and Health 
Economics..................................................................................................73
10. STATISTICAL CONSIDERATIONS........................................................................73
10.1.
Hypotheses.................................................................................................73
10.2.
Sample Size Considerations.......................................................................73
10.2.1.
Sample Size Assumptions ...........................................................73
10.2.2.
Sample Size Sensitivity................................................................73
10.2.3.
Sample Size Re-estimation or Adjustment...................................73
10.3.
Data Analysis Considerations .....................................................................74
10.3.1.
Analysis Populations....................................................................74
10.3.2.
Treatment Comparisons ..............................................................74
10.3.2.1.
Primary Comparisons of Interest ................................74
10.3.2.2.
Other Comparisons of Interest....................................74
10.3.3.
Interim Analysis ...........................................................................74
10.3.4.
Key Elements of Analysis Plan ....................................................75
10.3.5.
Safety Analyses...........................................................................75
10.3.5.1.
Extent of Exposure .....................................................75
10.3.5.2.
Adverse Events ..........................................................75
10.3.5.3.
Clinical Laboratory Evaluation ....................................76
10.3.5.4.
Other Safety Measures...............................................76
10.3.6.
Pharmacokinetic Analyses...........................................................76
10.3.7.
Pharmacodynamic Analyses........................................................77
10.3.8.
Pharmacokinetics/Pharmacodynamics Analyses .........................77
10.3.9.
Exploratory Analyses ...................................................................77
11. REFERENCES.......................................................................................................78
12. APPENDICES........................................................................................................79
12.1.
Appendix 1: Abbreviations and Trademarks................................................79
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................82
12.3.
Appendix 3: Study Governance Considerations..........................................83
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................89
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................94
12.6.
Appendix 6: Genetics..................................................................................96
12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................97
12.8.
Appendix 8: Cognitive Assessments...........................................................99
12.8.1.
Columbia Severity Suicide Rating scale.......................................99
12.8.2.
Neuropsychiatric Inventory (NPI) .................................................99
12.8.3.
Six-item Cognitive Impairment Test (6-CIT) .................................99
12.8.4.
Finger Tapping Test (FTT............................................................99
12.9.
Appendix 9: Telemetry Assessments........................................................100
12.10. Appendix 10: Protocol Amendment History...............................................101


2015N261138_03
CONFIDENTIAL
201570
9
1.
SYNOPSIS
Protocol Title: Randomized, Double-blind, Placebo-controlled Dose Escalation Study to 
Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single Doses 
(intravenous bolus) and constant intravenous infusion over 7 Days of GSK3335065 in 
Healthy Adult Subjects
Short Title: Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics
investigation of GSK3335065 (IV) in healthy adults
Rationale: GSK3335065 is being developed as a treatment for acute pancreatitis with the 
intent of reducing 3-hydroxykynurenine (3HK) levels to the normal range (or lower) and 
maintaining them at this level throughout the 7-day treatment period.
Objectives and Endpoints:
Objective
Endpoint
Primary

To determine the safety and tolerability of 
GSK3335065 administered as a single IV 
bolus (Part A and C), and as a constant IV 
infusion over 7 days (Part B and C) in 
healthy volunteers

Adverse event / Serious Adverse event 
monitoring 

Laboratory parameters (hematology, clinical 
chemistry,urinalysis)

12-lead ECG parameters (PR, QRS, QT, 
QTcF, etc.)

Vital signs (systolic and diastolic blood 
pressure, heart rate)
Secondary

To determine the pharmacokinetic 
characteristics of GSK3335065 
administered as a single IV bolus (Part A 
and C), and as a  constant IV infusion over 
7 days (Part B and C) in healthy volunteers

Determine dose/exposure effects of 
GSK3335065 on KMO inhibition 
(pharmacodynamics) in healthy volunteers 
(All Parts)

Pharmacokinetic Parameters: AUC(0 – t), 
AUC(0 – ∞), tlast, Cmax, Cavg, tmax, CL, V, t½

Evaluate changes in levels of TRP 
metabolites (3HK and KYN) 
Overall Design: This is a phase I, first time in human (FTIH), three part, randomized, 
placebo-controlled dose escalation study that will utilize an adaptive design for 
combining Single Ascending Dose (SAD) by IV bolus (Part A) with Ascending Doses by 
intravenous (IV) continuous infusion dosing for 7 days (Part B) in healthy males. Part C 
will recruit women of non-child bearing potential (WONCBP) only, and a single dose by 


2015N261138_03
CONFIDENTIAL
201570
10
IV bolus will be investigated prior to multiple dose (7 day) being investigated. The 
decision to proceed to the next dose level in Part A will be based on safety and 
tolerability data obtained up to 8 days post dose from at least 6 subjects at the prior dose 
level.
Number of Participants: 112 evaluable subjects. Part A will comprise of 64 healthy 
male subjects (Cohorts 1 to 8). Part B of 32 healthy male subjects (Cohorts 9 to 12). Part 
C will comprise of 16 women of non child bearing potential (Cohorts 13 to 14).
Treatment Groups and Duration:
Part A will last up to approximately 7 weeks from screening to follow-up. Part A was
initiated using an interlocking four period crossover design with two cohorts and the
intention that all participants will receive four ascending IV bolus doses of GSK3335065.
Subjects in cohorts 1 and 2 received a single dose of 0.1 mg and 0.25 mg GSK3335065,
respectively. All subjects from cohorts 1 and 2 will be discontinued from the study.
For operational feasibility, the design of Part A will be changed to a parallel cohort
design and dosing will be continued at the third dose level (1.3  mg) (Amendment 3). For
each subsequent dose level, a cohort of 8 subjects will receive a single dose of
GSK3335065.
Prior to initiation of Parts B and C, a review of all available safety, tolerability, PK and 
PD data from Part A will be conducted and potential changes to the dosing paradigm, 
safety observation period and assessments will be communicated in a future amendment 
to the protocol as appropriate.
Part B will last up to approximately 13 weeks from screening to follow-up. Particpants 
will receive one IV bolus dose of GSK3335065 immediately follwed by an IV infusion 
over seven days.
Part C cohort 7 will last approximately 7 weeks and Part C cohort 8 up to 13 weeks from 
screening to follow-up. Cohort 7 will comprise of a single IV bolus. Cohort 8 will mirror 
Part B.


2015N261138_03
CONFIDENTIAL
201570
11
2.
SCHEDULE OF ACTIVITIES (SOA)

The timing and number of planned study assessments, including safety, 
pharmacokinetic, pharmacodynamic/biomarker or other assessments may be 
altered during the course of the study based on newly available data (e.g., to 
obtain data closer to the time of peak plasma concentrations) to ensure 
appropriate monitoring. 

Any changes in the timing or addition of time points for any planned study 
assessments must be documented and approved by the relevant study team 
member and then archived in the sponsor and site study files, but will not 
constitute a protocol amendment. The Institutional Review Boards (IRB)/
Independent Ethics Committees (IEC) will be informed of any safety issues that 
require alteration of the safety monitoring scheme or amendment of the 
Informed Consent Form (ICF).


2015N261138_03
CONFIDENTIAL
201570
12
2.1.
Part A & C – Cohort 1, 2, 3, 4, 5, 6, 7, 8 & 13, single bolus dose, healthy volunteer subjects
Procedure
Screening 
(within 28 
days of 
Day 1)
Study Period (Days)
Follow-up
(7-14  days 
following 
discharge)
Notes
-
1
1
2
3
4
5
6
7
8
Outpatient Visit
X
X
Admission to Clinical Unit
X
Inpatient Stay at Clinical 
Unit
----------------------------------------------------------------
Discharge from Clinical 
Unit
X
Following completion of all 
assessments
Informed consent
X
Inclusion and exclusion 
criteria
X
X
Demography
X
Full physical exam incl 
height and weight
X
Brief Physical
X
X
X
Brief physical upon discharge from 
every cohort
(Day 8)
Medical history (includes 
substance usage)
X
Substances: Drugs, Alcohol, 
tobacco and caffeine
Clinical Safety Laboratory 
Assessments (HIV, Hep 
B and Hep C Screen at 
screening only1)
X
X
X
X
X
X
Screening and day -1 safety labs 
must be in fasted state.
1If test otherwise performed within 
3 months prior to first dose of study 
treatment, testing at screening is 
not required.
LFTs (ALT, AST, AP, 
direct and indirect 
Bilirubin)
X
X
X
X
X
X
X


2015N261138_03
CONFIDENTIAL
201570
13
Procedure
Screening 
(within 28 
days of 
Day 1)
Study Period (Days)
Follow-up
(7-14  days 
following 
discharge)
Notes
-
1
1
2
3
4
5
6
7
8
cTnI & BNP
X
X
X2
X
X
X
2 6hrs post-dose
FSH
X
Females only, if required
Urine Drug/Alcohol 
Breath Test
X
X
X3
3 Alcohol breath test only
12-lead ECG 
X
X
X
X
X
X
X
X
X
Triplicate ECGs will be obtained at 
screening and predose.
Single measurements at 30min, 
6hr, 12hr, 24hr, 72hr, 120hr, 
168hrpost-dose. ECG times may 
be adjusted once initial PK data is 
available.


2015N261138_03
CONFIDENTIAL
201570
14
Procedure
Screening 
(within 28 
days of 
Day 1)
Study Period (Days)
Follow-up
(7-14  days 
following 
discharge)
Notes
-
1
1
2
3
4
5
6
7
8
Continuous ECG 
monitoring
X
Continuous monitoring from -1 
hour pre-dose to 24hours post 
dose.
Based on preclinical data levels of 
parent compound and tryptophan 
metabolites are expected to reach 
peak levels within a few hours of 
the start of dosing. A review of 
telemetry data will therefore be 
performed after 24 hours for 
clinically relevant alerts (see 
Appendix 9 for guidance). In the 
absence of such a signal, 
monitoring will revert to regular 
ECG assessments. In case 
clinically relevant changes are 
observed telemetry will be 
continued as long as deemed 
appropriate by the investigator. At 
the investigator’s discretion and in 
consultation with the medical 
monitor telemetry could be 
reinitiated at any time during the 
study should any potential signals 
in regular ECG assessments 
emerge. 
Transthoracic 
Echocardiogram
X
Additional echocardiograms may 
be performed if increases in cTNI 
or BNP are observed (see Section 
8 for details), or at any time at the 
discretion of the investigator


2015N261138_03
CONFIDENTIAL
201570
15
Procedure
Screening 
(within 28 
days of 
Day 1)
Study Period (Days)
Follow-up
(7-14  days 
following 
discharge)
Notes
-
1
1
2
3
4
5
6
7
8
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
VS assessments will be performed 
in triplicate at screening and at pre-
dose. All post dose assessments 
will beperformed as single 
measurements at 30 min and 1 hr, 
6hr, 24hr, 48hr, 72hr, 96hr, 120hr, 
144hr, 168hr post-dose as outlined 
in Section 9.4.2. VS times may be 
adjusted based on emerging PK 
data.
Study Treatment
X
Assessment of infusion 
site
----------------------------------------------------------------------
------
Up to day 8
Blood (PK) 
-----For sampling time points, see Section 9.5.1-----------------------
-------
X
Additional blood PK samples may 
be collected other than those 
timepoints specified in Section 
9.5.1 or on additional days based 
on emerging data
Urine (metabolism)
X
X
Equivalent to admission on day -1 
to pre-dose day 1 and 0-24 hours 
post-dose as outlined in Section 
9.5.2. Part A Cohorts Only.
Blood (PD)
-----For sampling time points, see Section 9.7--------------------------------

X
Additional 3HK and PD Biomarker 
samples may be collected other 
than those timepoints specified in 
Section 9.7 or on additional days 
based on emerging data 


2015N261138_03
CONFIDENTIAL
201570
16
Procedure
Screening 
(within 28 
days of 
Day 1)
Study Period (Days)
Follow-up
(7-14  days 
following 
discharge)
Notes
-
1
1
2
3
4
5
6
7
8
PGx Sample
X
Pre-dose if possible. Informed 
consent for optional genetics 
research must be obtained before 
collecting a sample
AE/SAE review
------------------============================----------
-----
X
Concomitant medication 
review
X
---------------------------------------------------------------------------
------
X
2.2.
Part B & C – Cohorts 9, 10, 11, 12 & cohort 14, single bolus dose plus 7 day infusion, healthy 
volunteer subjects
Procedure
Screening 
(within 28 
days of 
Day 0)
Study Period (Days)
Follow-
up
(Day 
32 
± 2 
days)
Notes
-
1
1
2
3
4
5
6
7
8 9 10 11
12
13
14
15
LFT 
Follow-
up
(Day 
62 ±2 
days)
Outpatient Visit
X
X
X
Admission to Clinical 
Unit
X
Inpatient Stay at 
Clinical Unit
---------------------------------------------------------------------------------------------

Discharge from 
Clinical Unit
X
Following completion of all 
assessments
Informed consent
X
Inclusion and 
exclusion criteria
X
X


2015N261138_03
CONFIDENTIAL
201570
17
Procedure
Screening 
(within 28 
days of 
Day 0)
Study Period (Days)
Follow-
up
(Day 
32 
± 2 
days)
Notes
-
1
1
2
3
4
5
6
7
8 9 10 11
12
13
14
15
LFT 
Follow-
up
(Day 
62 ±2 
days)
Demography
X
Full physical exam 
incl height and weight
X
Brief Physical
X
X
X
Medical history 
(includes substance 
usage)
X
Substances: Drugs, Alcohol, tobacco 
and caffeine
Clinical Safety 
Laboratory 
Assessments (HIV, 
Hep B and Hep C 
Screen at screening 
only2)
X
X
X
X
X
X
X
X
X
X
Screening and day -1 safety labs must 
be in fasted state.
2If test otherwise performed within 3 
months prior to first dose of study 
treatment, testing at screening is not 
required
LFTs (ALT, AST, AP, 
direct and indirect 
Bilirubin)
X
X
X
X
X
X
X
X
X
X X
X
X
X
X
X
X
cTnI / BNP
X
X
X
X
X
X
X
X
X
6hrs, 24hrs and 72hrs post dose. D7 
immediately after end of infusion. D10, 
D13 and D15 anytime.
Urine Drug/Alcohol 
Breath Test
X
X
X3
X3
3Alcohol Breath test only
FSH
X
Females only, if required


2015N261138_03
CONFIDENTIAL
201570
18
Procedure
Screening 
(within 28 
days of 
Day 0)
Study Period (Days)
Follow-
up
(Day 
32 
± 2 
days)
Notes
-
1
1
2
3
4
5
6
7
8 9 10 11
12
13
14
15
LFT 
Follow-
up
(Day 
62 ±2 
days)
12-lead ECG 
X
X
X
X
X
X
X
X
X
X X
X
X
X
X
X
X
X
Triplicate ECGs will be obtained at 
screening and predose. 
Single measurements 30min and 6hr, 
12hr, 24hr, and on Days 3-15 post-
dose (equivalent to 36hr, 48hr, 72hr, 
96hr, 120hr, 144hr, 168hr, 192hr, 
216hr, 240hr, 264hr, 288hr, 312hr,
336hr, 360hr post-dose). ECG times 
may be adjusted once initial PK data is 
available.


2015N261138_03
CONFIDENTIAL
201570
19
Procedure
Screening 
(within 28 
days of 
Day 0)
Study Period (Days)
Follow-
up
(Day 
32 
± 2 
days)
Notes
-
1
1
2
3
4
5
6
7
8 9 10 11
12
13
14
15
LFT 
Follow-
up
(Day 
62 ±2 
days)
Continuous ECG 
Monitoring
X
Continuous monitoring from -1 hour 
pre-dose to 24hours post dose.
Based on preclinical data levels of 
parent compound and tryptophan 
metabolites are expected to reach 
peak levels within a few hours of the 
start of dosing. A review of telemetry 
data will therefore be performed after 
24 hours for clinically relevant alerts
(see Appendix 9 for guidance). In the 
absence of such a signal, monitoring 
will revert to regular ECG 
assessments. In case clinically 
relevant changes are observed 
telemetry will be continued as long as 
deemed appropriate by the 
investigator. At the investigator’s 
discretion and in consultation with the 
medical monitor telemetry could be 
reinitiated at any time during the study 
should any potential signals in regular 
ECG assessments emerge.
Transthoracic 
Echocardiogram
X
Additional echocardiograms may be 
performed if increases in cTN or BNP 
are observed (see Section 8 for 
details), or at any time at the discretion 
of the investigator


2015N261138_03
CONFIDENTIAL
201570
20
Procedure
Screening 
(within 28 
days of 
Day 0)
Study Period (Days)
Follow-
up
(Day 
32 
± 2 
days)
Notes
-
1
1
2
3
4
5
6
7
8 9 10 11
12
13
14
15
LFT 
Follow-
up
(Day 
62 ±2 
days)
Vital Signs
X
X
X
X
X
X
X
X
X
X X
X
X
X
X
X
X
X
VS assessments will be performed in 
triplicate at screening and pre-dose. 
Single measurement at 30 min and 1 
hr, 6hr, 24hr, and on Days 3-15  post-
dose as outlined in Section 9.4.2. VS 
times may be adjusted based on initial 
PK data.
Columbia Suicide 
Severity Rating Scale 
(C-SSRS)
X
X
X
X
X
Cognitive 
Assessments (6-CIT, 
fingertapping test and 
NPI)
X
X
X
Study Treatment
---------------------------------------

Assessment of 
infusion site
-------------------------------------
Up to 36 hrs post-start of infusion
Blood (PK) 
-------For sampling time points, Section 9.5.1-----------------------------------
Additional blood PK samples may be 
collected other than those timepoints 
specified in Section 9.5.1 or on 
additional days based on emerging 
data 
Urine (metabolite)
X
X
Equivalent to admission on day -1 to 
pre-dose day 1 and 48-72 hours post-
dose. PART B Cohorts Only.


2015N261138_03
CONFIDENTIAL
201570
21
Procedure
Screening 
(within 28 
days of 
Day 0)
Study Period (Days)
Follow-
up
(Day 
32 
± 2 
days)
Notes
-
1
1
2
3
4
5
6
7
8 9 10 11
12
13
14
15
LFT 
Follow-
up
(Day 
62 ±2 
days)
Blood (PD)
------For sampling time points, Section 9.7---------------------------------------
Additional 3HK and PD Biomarker  
samples may be collected other than 
those timepoints specified in Section 
9.7 or on additional days based on 
emerging data 
Bile  Sampling 
(enterotest)
X
Only to be performed at highest dose 
administered. Part B only
PGx Sample
X
Pre-dose if possible. Informed consent 
for optional genetics research must be 
obtained before collecting a sample
AE/SAE/PSRAE 
review
------------------------------------------------------------------------------------------
X
Concomitant 
medication review
X
------------------------------------------------------------------------------------------
X


2015N261138_03
CONFIDENTIAL
201570
22
3.
INTRODUCTION
3.1.
Study Rationale
GSK3335065 is being developed as a treatment for acute pancreatitis with the intent of 
reducing 3-hydroxykynurenine (3HK) levels to the normal range (or lower) and 
maintaining them at this level throughout the treatment period. It is envisaged that it will
be given intravenously (IV) as an initial bolus followed by continuous infusion over a 7 
day period.
This first time in human trial is primarily designed to determine the safety, tolerability 
pharmacokinetics, and pharmacodynamics of GSK3335065 in healthy male and female 
(women of non child bearing potential, WONCBP) volunteers. Additionally, the study 
will employ a biomarker strategy for establishing proof of mechanism and assist in dose 
finding for future studies. It has been designed to determine a well tolerated single bolus 
dose and constant IV infusion dose regimen to achieve a minimum of 85% reduction in 
3HK levels in healthy volunteers over 7 days of drug administration.
The study will employ an adaptive design comprised of three Parts: 
Part A: Single Ascending Dose (SAD) by IV bolus in males 
Part B: Ascending Doses by IV constant infusion for 7 days in males after single 
IV bolus in males
Part C: Single dose by IV bolus in females of non-child bearing potential 
(WONCBP), and continuous infusion over 7 days in WONCBP.
The study population is comprised of healthy male (Parts A and B) and female 
(WONCBP) (Part C) subjects. Women of child bearing potential are not included in this 
study due to the limited assessment of GSK3335065 on reproduction. Inclusion of 
females in the study will serve two main purposes: to generate safety/tolerability data in 
females prior to inclusion of females in a future Proof Of Concept study, and to rule out 
potential clinically relevant pharmacokinetics (PK) differences between males and 
females prior to inclusion of females in the POC study. Gender differences are currently 
not expected based on preclinical findings.
3.2.
Background
The peripheral metabolism of Tryptophan (TRP) occurs preferentially via the kynurenine 
(KYN) pathway (Figure 1). TRP metabolism is increased in a range of inflammatory 
conditions following induction of expression of indole dioxygenases (IDO) by cytokines 
such as interferon-. This results in increased production of downstream metabolites 
including 3-hydroxykynurenine (3HK) which is known to cause oxidative stress and be 
cytotoxic. A recent prospective study undertaken as a collaboration between GSK and the 
University of Edinburgh showed a strong association between disease severity and the 
plasma concentrations of 3-HK in patients diagnosed with acute pancreatitis (Skouras et 
al, 2016). 3HK is formed exclusively through the action of kynurenine-3-monooxygenase 
(KMO). There is no evidence of upregulation of KMO in disease, and as depletion of 


2015N261138_03
CONFIDENTIAL
201570
23
TRP is also observed, the increase in 3HK probably results directly from the increased 
flux through the pathway as a result of upregulation of IDO. Genetic or pharmacological 
inhibition of KMO protects rodents from kidney and lung damage when subjected to a 
model of pancreatic injury driven secondary organ dysfunction (Mole et al, 2016). 
GSK3335065 is being developed as an intravenously administered inhibitor of KMO 
which will reduce the production of 3HK and thereby limit damage to secondary organs 
during an attack of acute pancreatitis.
Figure 1
Kynurenine Monooxygenase (KMO) is a branchpoint in the 
Kynurenine Pathway of Tryptophan metabolism
Inhibition of KMO in vivo in preclinical species results in an accumulation in both the 
substrate (kynurenine (KYN) and in the products of the alternative metabolic routes 
(kynurenic acid (KYNA) and anthranillic acid (AA)). Of these, KYNA is of particular 
note as it may act on receptors within the central nervous system (CNS). However, to 
date no adverse effects relating to this metabolic diversion have been observed during the 
preclinical studies. 
Detailed information relating to non-clinical pharmacology, safety pharmacology, PK 
and metabolism, toxicology and other pre-clinical data can be found in the GSK3335065 
Investigators Brochure [GlaxoSmithKline Document Number 2016N273923_01].


2015N261138_03
CONFIDENTIAL
201570
24
3.3.
Benefit/Risk Assessment
The current study represents the first administration of GSK3335065 to healthy subjects.  
Considerations for safety monitoring are derived primarily from non-clinical data. 
Preliminary data from the first two dose levels (0.1 mg and 0.25 mg) in Part A (SAD) of 
this study is available (see below for details). The following section (Section 3.3.1) 
outlines the risk assessment and mitigation strategy for this protocol. More detailed 
information about the known and expected benefits and risks and reasonably expected 
adverse events of GSK3335065 may be found in the Investigator’s Brochure.
Summary of preliminary clinical data from 0.1 mg and 0.25 mg single doses in Part 
A (SAD)
No SAEs have been reported.
In cohort 1 period 1 (0.1 mg Single dose), six subjects reported a total of 7 AEs (back 
pain, epistaxis, contusion, headache, infusion site erythema, tachycardia, upper 
respiratory tract infection). All events were mild to moderate in intensity and are 
considered not related to the study medication based on the blinded review of the 
investigator. In this cohort a total of 5 subjects were withdrawn from the study, of which 
1 subject (subject 
 was withdrawn due to an AE. This subject developed a 11-beat 
run of broad complex tachycardia for 4 seconds approximately 20 hrs post dose. At the 
time of the event the subject was asleep and remained asymptomatic until discharge from 
the unit. This event was considered abnormal and clinically significant by the investigator 
but not related to the study medication. Four subjects 
 and 
 
were withdrawn from the study for logistical reasons.
In cohort 2 period 1 (0.25 mg SD), two subjects reported a total of 3 AEs (back pain, 
contact dermatitis secondary to cannula dressing, vessel puncture bruise). All events were 
considered mild to moderate in intensity and are considered not related to the study 
medication based on the blinded review of the investigator.
Except for subject # 
(see above) no clinically significant safety signals were 
observed in any of the subjects during physical examinations, 12 lead ECGs, cardiac 
telemetry, vital signs and laboratory tests at any dose level.
PPD
PPD
PPD
PPD


2015N261138_03
CONFIDENTIAL
201570
25
3.3.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [GSK 3335065]
Because cardiovascular (CV) changes were 
observed in rat safety assessments studies, 
there is a risk of cardiac-related adverse events 
being observed in man
In a rat preliminary dose range finding study via 
continuous infusion, increases in cardiac 
troponin I (cTnl) and N-terminal brain natriuretic 
peptide (NT-proANP) concentrations and 
degenerative and/or inflammatory changes in the 
heart were seen in rats given 300 mg/kg/day.
In a rat preliminary dose range finding study via 
oral gavage, myocardial necrosis and 
inflammatory cell infiltrate were seen in the 
hearts of rats given 400 mg/kg/day (with no 
changes in cardiac biomarkers).
The CV changes observed in rats were only 
noted at exposures 128-fold higher than the 
highest exposure predicted in this study and at 
concentrations 232-fold higher than those 
predicted in this study and were accompanied by 
changes in cardiac biomarkers that can be 
monitored (cTnI and brain natriuretic peptide 
[BNP]):
Subjects with cTN or BNP > ULN will be 
excluded (Exclusion criterion # 5) 
Monitoring for cTn and BNP in all parts of the 
study (Section 2, Time and Events Table)
Stopping criteria based on cTn and BNP 
increases (Section 8.1.4)
Continuous ECG minitoring during the first 24hr 
after initiation of dosing, followed by 12-lead 
ECG assessments
The NOAEL for this effect is 75-fold the highest 
exposures and 177 times the concentration 
proposed in this study. 


2015N261138_03
CONFIDENTIAL
201570
26
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Haemodynamic changes
In a screening cardiovascular study in the rat, 
there were increases in blood pressure 
(maximum 12 mmHg), pulse pressure (maximum 
5 mmHg), heart rate (maximum 63 bpm) and 
body temperature (0.7C), and decreases in QA 
interval (maximum 5 msec).
No effect concentration in the rat (16.8g/mL) 
was 4200-fold higher than the targeted 
concentration at starting dose (0.004µg/mL).
Regular Vital Sign (BP and HR) assessments 
during the study (Section 2 Time and Events 
Table)
Stopping criteria based on Vital Sign changes 
(Section 8.1.4)
Continuous ECG monitoring during initial 24hrs 
after initiation of dosing, followed by 12-lead 
ECG assessments.
Liver changes
In rats, there was centrilobular hepatocyte 
hypertrophy and increased liver weight at 
140 mg/kg/day; and additional liver pathology 
changes and increases in aspartate 
aminotransferase, alanine aminotransferase 
activity and total bilirubin concentrations at 
300 mg/kg/day.
GSK3335065 is a carboxylic acid and has the 
potential to form reactive acyl glucuronide 
metabolites which could contribute to 
idiosyncratic liver toxicity. An in vitro assay in 
human liver microsomes showed there was no 
turnover of GSK3335065 in microsomes and no 
acyl glucuronides were detected. However, an 
Subjects with ALT or bilirubin >1.5xULN prior to 
dosing will be excluded (isolated bilirubin 
>1.5xULN is acceptable if bilirubin is fractionated 
and direct bilirubin <35%). (Exclusion Criterion 
#1).
Subjects with current or chronic history of liver 
disease, or known hepatic or biliary 
abnormalities (with the exception of Gilbert's 
syndrome or asymptomatic gallstones) will be 
excluded (Exclusion Criterion #2). 
Monitoring for ALT, AST, alkaline phosphatase 
and bilirubin at each dose level (Section 2 Time 


2015N261138_03
CONFIDENTIAL
201570
27
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
acyl glucuronide with a measured half-life of 2 
hrs was detected in rat plasma following 7 days 
continuous infusion. Therefore there is a risk that 
this metabolite may be formed in humans.  This 
might be of clinical concern if the total daily dose 
exceeds 100 mg.
and Events Table)
Stopping criteria based on LFT increases 
(Section 8).
The NOAEL for these effects is 75-fold the 
highest exposures proposed in this study.
The highest dose proposed in this study is 
73.4 mg total dose on day 1 followed by 50.4 mg 
total dose/day (Above signals are considered an 
increased concern if daily dose is 100 mg). 
Selected plasma PK samples generated during 
Part A will be subjected to additional analysis in 
order to determine if any acyl glucuronides are 
present. In addition, plasma, urine and bile 
samples will be used to generate full metabolic 
profiles in samples taken during the study.
Haematological changes
Decreases in haemoglobin concentration, 
packed cell volume, red blood cell count and 
reticulocyte counts were seen in rats at 
≥36 mg/kg/day.
In the spleen, increased levels of haemopoiesis 
were seen in rats at 140 mg/kg/day, and 
vacuolation was seen in rats at 180 mg/kg/day.
The NOAEL for these effects is 75-fold the 
highest exposures proposed in this study.
Haematology parameters will be monitored 
during the study.


2015N261138_03
CONFIDENTIAL
201570
28
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Inflammatory changes
In rats, inflammatory cell foci were seen in the 
harderian gland (140 mg/kg/day), prostate 
(6 mg/kg/day), urinary bladder (15 mg/kg/day)
and testes (15 mg/kg/day).
Increases in neutrophil, lymphocyte, monocyte 
and total white blood cell counts in rats at 
180 mg/kg/day.
The NOAEL for this effect is 75-fold the highest 
exposures proposed in this study.
Haematology parameters will be monitored 
during the study.
Study Procedures
Intravenous Dosing – Pain, irritation and 
inflammation at the injection site
General concern in giving IV medication
In 14-day infusion studies in rats and dogs, no 
irritancy was seen at the dosing sites. 
In vitro hemolysis assessment of GSK3335065 
showed no evidence of haemolytic potential or 
incompatibility with plasma in humans.
The infusion site will be assessed at various 
times up to 36 hours post-dose using a 0–3 scale 
as follows: Grade 0=none; Grade 1=pain or 
itching or erythema; Grade 2=pain or swelling, 
with inflammation or phlebitis; Grade 
3=ulceration or necrosis


2015N261138_03
CONFIDENTIAL
201570
29
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Entero-Test
Streaks of blood on the string due to local 
irritation have been infrequently noted. Rarely, a 
patient will be unable to swallow the capsule 
because of gagging or will vomit after doing so. 
Gagging upon retrieval of the string can occur. 
On a few occasions, an entire string has been 
swallowed without ill effects and passes out from 
the body in the faeces.
The use of Entero-Test has been approved by 
the FDA (510(k), Summary of safety and 
effectiveness). The string will be securely taped 
in place during the collection time to minimize 
risk of swallowing the entire string. Any subject 
incapable of swallowing the capsule will be 
allowed to participate in the study without 
duodenal bile collection.
Other
Central Nervous System effects (off-target) due 
to metabolic diversion. Inhibition of KMO may 
result in increased KYNA levels in humans, 
which theoretically might affect suicidal ideation 
and behaviour, and cause cognitive and/ or 
behavioural effects.
GSK3335065 increases KYNA levels in the brain 
in rats. No behavioural signs were noted during 
14 day infusion studies in rats and dogs, and no 
effects were observed in the bespoke IRWIN 
test. 
Subjects with a history or current evidence of 
depression, bipolar disorder, suicidal ideation 
and behaviour, or a lifetime history of suicide 
attempt will be excluded (Exclusion criterion #4)
Subjects will be closely monitored in a domiciled 
environment. 
Sentinel dosing approach will be adopted in 
Parts A and B.
In line with FDA guidance, assessment of 
suicidal ideation and behaviour occurrence will 
be conducted in subjects who receive continuous 
infusion of GSK3335065 (Section 2 Time and 
Events Table) 


2015N261138_03
CONFIDENTIAL
201570
30
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Assessments of cognitive safety will be 
performed in subjects with continuous infusion of 
GSK3335065 (Section 2 Time and Events Table)
Stopping criteria based on assessments of 
suicidal ideation and behaviour, and cognitive 
safety (Section 8.1.4)
Adverse effects due to reduction of 3 
hydroxykynurenine (3HK) levels below the 
physiological range.
KMO deficient mice have undetectable levels of 
3HK and elevation of metabolites, such as 
kynurenine (KYN), kynurenic acid (KYNA) and 
anthranilic acid (AA), but are viable and healthy. 
Robust increases in KYN, KYNA, AA and 
decreases in xanthurenic acid (XA)
and 
quinolinic (QA) were measured in both rats and 
dogs in the 7-day dose rang finding studies. 
Additionally a robust decrease in 3HK was 
observed in the dog study. 3HK levels could not 
be determined in the rat study. However the mid 
dose used in this rat study had previously been 
shown to reduce 3HK levels  on the first day of 
dosing in a pharmacology study. Any adverse 
effects of changes in any of the TRP metabolites, 
including 3HK, would have been noted in these 
studies. 
No information on the dynamics of the pathway 
after KMO inhibition in man is available and 
specific data on the rate of recovery of 
tryptophan metabolites, including 3HK, after 
General safety monitoring will be conducted 
throughout the study, dose escalation criteria 
and stopping criteria (summarized in Appendix 3, 
Dose Escalation Committee), and a sentinel 
dosing approached (Section 5.1.1 and Section 
5.1.2) have been outlined in the protocol.
Based on preliminary PK data from the initial two 
dose levels in Part A (SAD) a conservative safety 
observation period of 168 hours after single 
bolus infusion and after cessation of dosing in 
the 7-day continuous infusion study in a 
domiciled setting was chosen; 3HK data from 
humans is not available yet.
The safety 
observation period will be reassessed based on 
emerging safety, PK and PD data during the trial. 
Additional 3HK samples may be collected based 
on emerging data.


2015N261138_03
CONFIDENTIAL
201570
31
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
treatment with GSK3335065 is not available from 
preclinical studies. Published studies with related 
KMO inhibitors have shown that recovery of 
metabolites typically occurs within 24-48hr after 
a bolus dose in rats (Mole et al 2016; Liddle et al, 
2017 although 3HK itself was not measured in 
these studies. 


2015N261138_03
CONFIDENTIAL
201570
32
3.3.2.
Benefit Assessment
There will be no benefits demonstrated in this study and there will be no clinical benefits 
to the participants.
3.3.3.
Overall Benefit:Risk Conclusion
Taking into account the measures that will be implemented to minimize the risk to 
subjects participating in the clinical study, the potential risks associated with the 
administration of GSK3335065 are considered to be justified by the potential benefits 
that may be afforded to patients with AP if the hypothesis that activation of the KMO 
pathway is a major driver of the disease is confirmed. This information could provide a 
breakthrough in the knowledge of the disease pathology which could facilitate the clinical 
development efforts for future therapies.
4.
OBJECTIVES AND ENDPOINTS
Objective
Endpoint
Primary

To determine the safety and tolerability of 
GSK3335065 administered as a single IV 
bolus (Part A and C), and as a constant IV 
infusion over 7 days (Part B and C) in 
healthy volunteers

Adverse event / Serious Adverse event 
monitoring 

Laboratory parameters (hematology, clinical 
chemistry, urinalysis)

12-lead ECG parameters (PR, QRS, QT, 
QTcF, etc.)

Vital signs (systolic and diastolic blood 
pressure, heart rate)
Secondary

To determine the pharmacokinetic 
characteristics of GSK3335065 
administered as a single IV bolus (Part A 
and C), and as a constant IV infusion over 7 
days (Part B and C) in healthy volunteers

Determine dose/exposure effect of 
GSK3335065 on KMO inhibition
(pharmacodynamics) in healthy volunteers 
(All Parts)

Pharmacokinetic Parameters: AUC(0 – t), 
AUC(0 – ∞), tlast, Cmax, Cavg, tmax, CL, V, t½

Evaluate changes in levels of TRP 
metabolites (3HK and KYN) 


2015N261138_03
CONFIDENTIAL
201570
33
Objective
Endpoint
Exploratory

Determine the effect of KMO inhibition on 
other components of the KYN pathway of 
TRP metabolism (All Parts)

To investigate the plasma, urinary ) and 
biliary (Part B) metabolic pathways of 
GSK3335065 in healthy subjects

Evaluate changes in TRP, KYNA, AA, 3-
HAT,
XA, 
QA 
and 
other 
pathway 
components.

GSK335065-related material in plasma, 
urine and bile
5.
STUDY DESIGN
5.1.
Overall Design
This is a phase 1 first time in human (FTIH), three part, randomized, placebo-controlled 
dose escalation study that will utilize an adaptive design for combining Single Ascending 
Dose (SAD) by IV bolus (Part A) with Ascending Doses by IV constant infusion dosing 
for 7 days (Part B) in males. Part C will recruit WONCBP only, and a single dose by IV 
bolus will be investigated prior to multiple dose (7 day) being investigated.
Constant infusion dosing in Part B will be initiated after completion of dosing in Part A
using an initial dose level that is considered safe and well tolerated and expected not to 
exceed the highest exposures safely achieved in Part A. Prior to initiation of Parts B and 
C, a review of all available safety, tolerability, PK and PD data from Part A will be 
conducted and potential changes to the dosing paradigm, safety observation period and 
assessments will be communicated in a future amendment to the protocol as appropriate.
The single and repeat doses administered in Part C will be ones that have already been 
administered to males in Part A and B (respectively) and are considered safe and well-
tolerated.
Pharmacologic activity will be determined by assessing levels of product and substrate of 
KMO activity (3HK, KYN) at each dose level.  The impact of compound on the broader 
components of the TRP metabolic pathway (Figure 1) will also be assessed.
Dose response/escalation will be assessed as outlined in Appendix 3 by:
a) Safety and tolerability as determined by adverse events, clinical laboratory 
assessment and vital signs (Parts A and B)
b) Pharmacokinetic data and modelling to remain below NOAEL (Parts A & B), 
c) The effect on 3HK and KYN
Bile will be collected via the Entero-Test (Guiney et al, 2011) at the time points indicated 
in Section 9.6 . It is anticipated that only subjects that receive the highest dose in Part B 


2015N261138_03
CONFIDENTIAL
201570
34
will also participate in the exploratory study of biliary secretion of GSK3335065 and/or 
its metabolites.  
Figure 2
Part A Study Schematic
Figure 2 
Revised Part A Study Schematic


2015N261138_03
CONFIDENTIAL
201570
35
Table 1
Part A Predicted Doses for Single Ascending Dose (NOTE: actual 
doses may change based on emerging data.
Cohort
Period 1
Period 2
Period 3
Period 4
1
0.1 mg 
(MABEL)
1.3 
mg
5.5 mg
35 mg
2
0.25 mg
2.6 
mg
12 mg
54 mg
Table 2
Part A Predicted Doses for Single Ascending Dose (NOTE: actual 
doses may change based on emerging data).
Cohort
Dose (mg)
3
1.3
4
2.6
5
5.5
6
12
7
35
8
54
The 0.1 mg and 0.25 mg doses have been completed. For operational reasons, dosing in 
Part A will be continued using a parallel design and dosing will continue at the third dose 
level (1.3 mg).


2015N261138_03
CONFIDENTIAL
201570
36
Figure 3
Part B Study Schematic
Table 3
Part B Predicted Doses for Multiple Ascending Dose (NOTE: actual 
doses may change based on emerging data). 4 ascending doses are 
planned in Part B to characterize the 3HK dose response curve.
Cohort
Minimum Dose
Middle Doses
Maximum Dose
9
IVB 0.14 mg + IV Inf. 0.012 
mg/h
(0.44 mg cumulative dose on 
day 1 followed by 
0.29 mg/day on days 2-7)
10
IVB 7.5 mg + IV
Inf. 0.63 mg/h
(22.6 mg cumulative dose 
on day 1 followed by 15.1 
mg/day on days 2-7)
11
IVB 12 mg + IV
Inf. 1.1 mg/h
(38.4 mg cumulative dose
on day 1 followed by 26.4 
mg/day on days 2-7)
12
IVB 23 mg + IV
Inf. 2.1 mg/h
(73.4 mg cumulative dose 
on day 1 followed by 50.4 
mg/day on days 2-7)


2015N261138_03
CONFIDENTIAL
201570
37
Figure 4
Part C Study Schematic
5.1.1.
Part A: Single Ascending Dose (IV Bolus) in males
Part A is a randomized, double-blind (Sponsor unblinded), placebo-controlled, single
intravenous ascending dose study to evaluate the safety, tolerability, pharmacokinetics
and pharmacodynamics of GSK3335065 in healthy male subjects. Part A was initiated
using an interlocking crossover design. 8 Healthy male subjects (6 active, 2 Placebo)
were assigned to one of two cohorts (Cohorts 1 and 2). Subjects in cohorts 1  received a
single dose of 0.1 mg GSK3335065, and subjects in cohort 2  received a single dose of


2015N261138_03
CONFIDENTIAL
201570
38
0.25 mg GSK3335065. All subjects from cohorts 1 and 2 will be discontinued from the
study.
To facilitate subject recruitment, the design of Part A will be changed to a parallel cohort
design and dosing will be continued at the third dose level (1.3 mg). For each cohort of 8
subjects at each dose, 6 subjects will receive active drug and 2 subjects will receive
placebo using a predefined allocation schedule. Hence, each subject in cohorts 3-8 will
receive one active dose strengths or placebo in a parallel study design according to the
dose escalation scheme described in a latter section.
Characterization of the GSK3335065 PK relationship will be performed based on 
emerging data from lower dose levels to ensure that anticipated exposures will not exceed 
an approximately 75-fold exposure margin in terms of AUC to the rat NOAEL.
Characterization of the PD response to GSK3335065 may be performed on an ongoing 
basis or reviewed at the completion of Part A.
Sentinel dosing: In Part A, the first 2 subjects in each cohort will act as sentinels. One of 
these subjects will be randomized to active treatment, and the other will receive placebo. 
At least 24 hours will elapse (relative to the start of dosing) before administration of
GSK3335065 to the subsequent subjects at the same dose level to allow for assessment of 
potential adverse experiences. This assessment will include evaluation of safety 
parameters including physical examination findings, 12-lead Electrocardiogram (ECGs), 
clinical laboratory tests and clinical monitoring for adverse events. If there are no 
clinically relevant safety or tolerability concerns, the remaining 6 subjects in the same 
dosing session will receive the dose. 
Table 4
Study Duration of Cohorts 1 and 2 (Part A)
Screening
All screening assessments to be completed within 28 days prior to the 
first dose. 
Treatment Period
For Cohorts 1 and 2, each subject will take part in four dosing session. 
During each study period subjects will be in-house from the day prior to 
dosing until Day 4 post dose when they will be discharged after post dose 
assessments have been completed. Subjects in Cohorts 1 and 2 will 
return to the unit approximately 3 weeks later to be dosed again on the 
following day. Following the completion of period 4, subjects will return as 
out-patients for any post-dose assessments. 
Washout Period
Approximately 10 to 21 days between dosesa.
Follow-up
7-14 days after final study drug administration in the Cohort. If warranted, 
additional follow-up visits may be scheduled.
Total Duration
Approximately 19 weeks


2015N261138_03
CONFIDENTIAL
201570
39
Table 5
Study Duration of Cohorts 3, 4, 5, 6, 7, 8 (Part A)
Screening
All screening assessments to be completed within 28 days prior to the 
first dose. 
Treatment Period
Each subject will take part in one dosing session. During each study 
period subjects will be in-house from the day prior to dosing until Day 8 
post dose when they will be discharged after post dose assessments 
have been completed. All subjects may return to the unit approximately 2
weeks after discharge from the unit as out-patients for any post-dose 
assessments. 
Follow-up
Approximately 7-14 days after discharge from the unit. If warranted, 
additional follow-up visits may be scheduled.
Total Duration
Approximately 7 weeks
5.1.2.
Part B: Multiple Ascending Dose (IV Bolus followed by an IV
Infusion over 7 days) in Males
Prior to initiation of Part B, a review of all available safety, tolerability, PK and PD data 
from Part A will be conducted and potential changes to the dosing paradigm, safety 
observation period and assessments will be communicated in a future amendment to the 
protocol as appropriate.
Part B is a randomized, placebo-controlled, sequential panel, multiple ascending dose (IV
bolus followed by continuous IV infusion over 7 days), double-blind (Sponsor unblinded)
trial to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of
GSK3335065 in healthy male subjects. Subjects will be assigned to one of four Cohorts
(9, 10, 11 or 12), and subjects will only participate in one single cohort. In each cohort
subjects will be randomized to receive an IV bolus on day 1 subsequently followed by a
continuous IV infusion for seven days.aof either the active study drug (n=6) or placebo
(n=2).
Sentinel Dosing: We will stagger each new ascending dose in Part B so that 2 leading 
subjects will be dosed first. One of these subjects will be randomized to receive active 
treatment, and the second will receive placebo. Once these subjects have completed the 
7-day dosing period, the safety and tolerability data will be reviewed. If there are no 
clinically relevant safety or tolerability concerns, the remaining 6 subjects will be dosed.
During the course of the 7 day infusion period the participants will be given two
approximately 30 minute windows on Day 3 and Day 6 after completion of PK and PD
collection in order to perform activities (i.e. shower) without having the canula inserted.
The window may be modified based on emerging safety and PK data.


2015N261138_03
CONFIDENTIAL
201570
40
Table 6
Study Duration of Cohorts 9, 10, 11, 12 (Part B)
Screening
All screening assessments to be completed within 28 days prior to the 
first dose. 
Treatment Period
During each study period subjects will be in-house from the day prior to 
dosing until Day 15 when they will be discharged after post-dose 
assessments have been completed. Subjects will return to the unit as 
out-patients for any post-dose assessments.
Follow-up
Approximately 14 days after discharge following termination of study drug 
administration. If warranted, additional follow-up visits may be scheduled.
Additional Liver Function Tests (51 days after discharge)
Total Duration
Each cohort is approximately 13 weeks
5.1.3.
Part C: IV Bolus followed by an IV Infusion over 7 days in
WONCBP
Prior to initiation of Part C, a review of all available safety, tolerability, PK and PD data 
from Part A will be conducted and potential changes to the dosing paradigm, safety 
observation period and assessments will be communicated in a future amendment to the 
protocol as appropriate.
Part C will be a randomized, placebo-controlled and double-blind trial to evaluate the
safety, tolerability, pharmacokinetics and pharmacodynamics of GSK3335065 conducted
in WONCBP only, and will consist of two cohorts (13 and 14). Cohort 13 will investigate
a single intravenous dose, and Cohort 14 will investigate a multiple dose (continuous IV
infusion over 7 days). In each cohort subjects will be randomized to receive repeat doses
of either active (n=6) or placebo (n=2).Cohort 13 and 14 can commence upon safety,
tolerability and PK data from the equivalent dose group is available from the male cohort.
Cohort 13 will complete prior to cohort 14 initiation.
In cohort 14 participants will be given two 30 minute windows on Day 3 and Day 6 after
completion of PK and PD collection in order to perform activities (i.e. shower) without
having the canula inserted. These windows may be modified based on emerging safety
and PK data.


2015N261138_03
CONFIDENTIAL
201570
41
Table 7
Study Duration of Cohort 13 (Part C)
Screening
All screening assessments to be completed within 28 days prior to the 
first dose. 
Treatment Period
Each subject will take part in a single dosing session. Subjects will be in-
house from the day prior to dosing until Day 8 post dose when they will 
be discharged after post dose assessments have been completed. 
Subjects will return as out-patients for any post-dose assessments. 
Follow-up
Approximately 7-14 days after discharge from the unit. If warranted, 
additional follow-up visits may be scheduled.
Total Duration
Approximately 7 weeks
Table 8
Study Duration of Cohort 14 (Part C)
Screening
All screening assessments to be completed within 28 days prior to the 
first dose. 
Treatment Period
During the study period subjects will be in-house from the day prior to 
dosing until Day 11 when they will be discharged after post-dose 
assessments have been completed. Subjects will return to the unit as 
out-patients for any post-dose assessments.
Follow-up
14 days after discharge following termination of study drug 
administration. If warranted, additional follow-up visits may be scheduled.
Additional Liver Function Tests- 51 days after discharge
Total Duration
Approximately 13 weeks
5.2.
Number of Participants
Sufficient subjects will be randomised to achieve 112 evaluable subjects (Part A: 64 
healthy male subjects, Part B: 32 healthy male subjects, Part C; 16 WONCBP (8 subjects 
for Cohort 13, 8 subjects for Cohort 14). If subjects drop out early or lost to follow up, 
additional subjects may be enrolled as replacement subjects and assigned to the same 
treatment sequence following Sponsor approval, in order to ensure an adequate number 
of subjects are evaluable.. 
5.3.
Participant and Study Completion
A participant is considered to have completed the study if he/she has completed all 
phases of the study including last scheduled procedure shown in the Schedule of 
Activities.
A subject who receives an active dose of study medication and for whom a 
pharmacokinetic specimens have been collected will be considered an evaluable subject 
for assessing the pharmacokinetics.
The end of the study is defined as the date of the last visit of the last participant in the 
study.


2015N261138_03
CONFIDENTIAL
201570
42
5.4.
Dose Justification
5.4.1.
Starting dose for Part A
Inhibition of KMO in pre-clinical species results not only in a decrease in the rate of 
formation of 3HK, but also in an accumulation of KYN. This increase in KYN works to 
oppose the inhibition of KMO by increasing flux through the pathway. In rats, the 
maximal steady state change in KYN observed following KMO inhibition was between 6 
and 10-fold, while in mice deficient in KMO the baseline KYN level was 19 times higher 
than in wild type animals (Mole et al, 2016). The magnitude of increase in KYN that will 
be observed in humans is not known so it is not possible to predict exactly what level of 
3HK reduction will be observed at any given drug level. Instead modelling has been used 
to establish an appropriate dose range to cover a range of potential human scenarios (2 
fold to 20-fold increase in KYN).  
A model was developed to simulate the clinical doses according to the range increase in 
KYN previously mentioned and for different degrees of 3HK inhibition. The model 
utilised the PK preclinical parameters that were scaled to the human counterparts. More 
specifically, the volume of distribution (V) was predicted from the mean of rat and dog 
volumes, giving a value of 0.39 L/kg (27 L). Prediction of human clearance (CL) was 
undertaken using scaling from rat and dog with the method of exponents. Similar values 
were obtained using methods either restricted (2.9 L/hr) or non restricted (1.9 L/hr) by 
plasma protein binding so subsequent dose estimates use the mean of these values 
(2.4 L/hr). Finally, the half-life is predicted to be 7.8 h.


2015N261138_03
CONFIDENTIAL
201570
43
To set the starting dose minimum anticipated biological effect level (MABEL), it was 
first assumed that the magnitude of the maximal KYN change observed in man following 
KMO inhibition will be substantially smaller than in the rat (2 fold compared to 6-10 
fold), thus making the pathway more sensitive to inhibition. Under these circumstances, a 
dose targeting 0.2 times the cellular Ki would decrease 3HK levels by no more than 10-
20 % while having no measurable impact on KYN levels. In contrast, if the magnitude of 
the maximal change in KYN in man is assumed to be substantially higher than in the rat 
(20 fold compared 6-10 fold), then a dose targeting 0.2 times the cellular Ki would be 
predicted to have no measurable effect on either 3HK or KYN levels. This has therefore 
fold over cell Ki
0.1
1
10
100
1000
decrease of 3HK (%)
0
20
40
60
80
100
2 fold max
20 fold max
MABEL
fold over cell Ki
0.1
1
10
100
1000
increase in KYN (fold change)
2
4
6
8
10
12
14
16
18
20
maximal proposed 
concentration
minimum targe 
inhibition


2015N261138_03
CONFIDENTIAL
201570
44
been selected as the MABEL dose. The figure below depicts the predicted PK profile for 
the MABEL dose.
In accordance with FDA guidance, the maximum recommended starting dose (MRSD) is 
1/10th (applying the default safety factor) the NOAEL human equivalent dose (HED) in 
the more sensitive or more relevant preclinical species, correcting for body surface area 
between species. For GSK3335065 the more sensitive species is the rat as in the rat the 
lowest HED can be identified. The safety factor may be adjusted depending on the 
expected pharmacology, toxicology, and preclinical pharmacokinetics of the drug 
candidate, or previous experience with compounds in the same pharmacologic/structural 
class. As this is a novel mechanism a more conservative safety factor of 100 to calculate 
the MRSD was used.
Using the data from the 2 week Good labroratory practices (GLP) toxicity studies in rat, 
the MRSD was estimated to be 16 mg based on the following calculations:
140 mg/kg/day / 6.2 = 22.6 mg/kg / 100 = 0.226 mg/kg; for a 70 kg human the MRSD is 
~ 16mg. Hence, the proposed 0.1 mg MABEL starting dose is approximately 160-fold 
below the MRSD of 16 mg.
The planned doses and predicted exposures compared to the 2 week GLP study in rats are 
shown in Table 9 below. 


2015N261138_03
CONFIDENTIAL
201570
45
Table 9
Part A  Planned doses, predicted exposures, and anticipated 
margins to rat NOAELs
Dose
Predicted Cmax 
(fold Ki)
(µg/ml)
Margin to 
NOAEL 
(Cmax)
Predicted AUC 
(0-24h)
(g.hr.mL-1)
Margin to 
NOAEL 
(AUC 0-24h)
Cohort 1, 
Period 1
0.1 mg IV 
bolus
0.004 (0.2xKi)
39750
0.036
46667
Cohort 2, 
Period 1
0.25 mg IV 
bolus
0.01 (1xKi)
15900
0.091
18462
To facilitate subject recruitment, the study design will be changed to a parallel cohort design (Amendment 
3).
Cohort 3
1.3 mg IV 
bolus
0.05 (5xKi)
3180
0.481
3493
Cohort 4
2.6 mg IV 
bolus
0.1 (10xKi)
1590
0.944
1780
Cohort 5
5.5 mg IV 
bolus
0.2 (20xKi)
795
2.020
832
Cohort 6
12 mg IV 
bolus
0.46 (50xKi)
346
4.398
382
Cohort 7
35 mg IV 
bolus
1.37 (150xKi)
116
12.753
132
Cohort 8
54 mg IV 
bolus
2.0 (220xKi)
80
22.4
75
Dose Escalation Approach in Part A
The decision to proceed to the next dose level will be based on safety and tolerability data 
obtained up to 8 days post dose (at discharge from clinical unit) from at least 6 subjects at 
the prior dose level. The review data set will at a minimum consist of the listings of any 
adverse events, flagged vital signs, flagged findings during the cardiac monitoring 
(telemetry) ECG, flagged findings in 12-lead ECGs and laboratory findings (including 
LFTs, cardiac troponin [cTN], BNP). Available PK data from the prior dose level, 
together with any available PD data will also be reviewed.
Preliminary PK Data
Estimates of the systemic exposure over 24 hours post-dose, from Part A, Cohorts 1 and 
2, were generally consistent with predictions.
However, the apparent half-life was 
significantly longer than the 7.8 hours that had been predicted. Consequently, the PK 
sampling regimen has been extended to capture the longer terminal phase of elimination.
Preliminary PD Data
Preliminary PD data from Part A to measure the effects of KMO enzyme inhibition
showed wide variability in biomarker plasma concentrations both at baseline and during 
treatment, and included the following biomarkers of the tryptophan pathway: Kynurenine 
(Kyn), 3-hydroxykynurenine (3-HK)), tryptophan, kynurenic acid, anthranilic acid, 3-
hydroxyanthranilic acid, quinolic acid and xanthurenic acid. To 
enable a reliable 
assessment of baseline levels and their underlying variability, as well as to ensure all 


2015N261138_03
CONFIDENTIAL
201570
46
subjects are in a similar physiological state upon receiving the dose allowing time for 
any uncontrolled external influences on biomarker levels (food intake, meal time, sleep 
cycle) to dissipate, subjects will be enrolled at least 12 hours prior to dosing, eg. the 
afternoon of the day prior to the dose. Blood samples for the measurement of tryptophan 
pathway biomarkers will be taken regularly. Sleep disruption will be avoided, as it may 
perturb biomarker levels from their natural levels. On the day prior to dosing (day -1), the 
proposed sample times are times are as follows: -16hrs, -14hrs, -12hrs and 10hrs 
followed by -2hrs and approximately 0.5hrs predose on the day of dosing. (day 1). 
Flexibility around these nominal times will be permitted. 
Highest Dose in Part A
The highest dose planned in Part A is a 54 mg dose with an expected exposure margin in 
terms of AUC to the rat NOAEL of 75-fold. Higher doses may be administered if 
exposures are lower than predicted but the maximum exposure will not exceed the 
75-fold exposure margin in terms of AUC to the rat NOAEL.
5.4.2.
Starting dose for Part B
Prior to initiation of Part B a review of all available safety, tolerability, PK and PD data 
from Part A will be conducted and potential changes to the dosing paradigm, safety 
observation period and assessments will be communicated in a future amendment to the 
protocol as appropriate.
In addition to safety/tolerability and PK, the goal of Part B is to characterize the dose-
response relationship on KMO inhibition using 4 ascending doses.
Dosing in Part A will be completed prior to initiation of dosing in Part B. The first dose 
level in Part B will be set to ensure that the highest exposures safely achieved in Part A 
are not expected to be exceeded. The final decision on the starting dose in Part B will be 
made after review of preliminary Part A safety, tolerability, PK and PD data. A potential 
starting dose in Part B could be 0.14 mg IVB + 0.012 mg/h continuous infusion 
(predicted AUC(0-168) 0.9 ug.hr.ml-1 correlating with an anticipated KMO inhibition of 
approximately 25%). Based on current predictions a 5.5 mg single dose (Panel 5) is 
expected to result in an exposure of ~2 ug.hr.ml-1 (AUC 0-24h) providing sufficient PK 
coverage for a 0.14mg IVB + 0.012 mg/h continuous infusion dose over 7 days. 
Dose Escalation Approach in Part B
In Part B, a decision to proceed to the next dose level will be based on data obtained up to 
15 days post dose (discharge from clinical unit) from at least 6 subjects at the prior dose 
level. The review data set will at a minimum consist of the listings of any adverse events, 
flagged vital signs, flagged findings during the neuropsychiatric testing, flagged findings 
during the cardiac monitoring (telemetry) ECG, 12-lead ECGs, laboratory findings 
(including LFTs, cTN, BNP), and available PK and PD (3HK levels as PD BMx) data.
Doses will be selected to ensure as complete a coverage of the range of pharmacological 
effects based on data observed in Part A as is possible based on acceptable safety and 
tolerability. As a guide the doses (i.v. bolus and infusion rates) to achieve the clinical 


2015N261138_03
CONFIDENTIAL
201570
47
concentrations within the minimal and maximal targeted concentrations were estimated to 
be per as Table 10 below.
Anticipated Clinically Efficacious Dose
The PK/PD study conducted in rats suggests that a concentration around 20 times the 
cellular Ki would be required to achieve an 85% decrease in 3HK levels. GSK3335065 
has cellular half maximal potency around 3 nM giving an apparent cellular Ki of 
0.85 nM. It is largely excluded from erythrocytes, giving a blood:plasma ratio in human 
blood of 0.62, and is moderately bound by human plasma proteins, with a free fraction of 
2.0% at 10 μM. Thus the minimal level required to achieve 85% inhibition would be a 
free drug level of 17 nM, requiring total plasma drug level of 850 nM or total blood drug 
levels of 525 nM (0.18 ug/mL).
5.4.3.
Maximum dose/exposure in Part B
The highest dose planned to be explored will target a concentration just over 100 times 
the Ki in PART B. Modelling suggests that the highest anticipated dose  (73.4 mg total 
dose on day 1 followed by 50.4 mg/day on days 2-7) should achieve reductions of 3HK 
in excess of 90% even if the increase in KYN observed is substantially larger than that 
seen in the rat (20 fold compared to 6-10 fold). This value remains below (177-fold for 
Cmax and 75-fold for AUC(0-24h)) the plasma concentration at the NOAEL in the 
toxicity studies in rats and dogs. The highest dose also remains below the threshold for 
increased drug induced liver injury (DILI) risk (100 mg). Higher doses may be 
administered if exposures are lower than predicted but the maximum exposure will not 
exceed the 75-fold exposure margin in terms of AUC to the NOAEL.
This dose is anticipated to reduce 3HK levels by >90%. Preclinical data support that 
lowering 3HK levels through KMO inhibition >90% in humans is anticipated to be safe 
as KMO deficient mice have undetectable levels of 3HK and elevation of metabolites, 
such as kynurenine (KYN), kynurenic acid (KYNA) and anthranilic acid (AA), but 
appear viable and healthy. A robust decrease in 3HK of >90%  was observed in the dog 
7-day dose range finding study. 3HK levels could not be determined in the rat study. 
However the mid dose used in this rat study had previously been shown to reduce 3HK 
levels by ~85% on the first day of dosing in a pharmacology study. Any adverse effects 
of changes in 3HK would have been noted in these studies.


2015N261138_03
CONFIDENTIAL
201570
48
Table 10
Part B planned doses, predicted exposures, and anticipated margins 
to rat NOAEL. 4 ascending doses are planned in Part B.
Dose 
range IVB 
& IV 
infusion
Expected 
(%) KMO 
inhibition
Targeted 
Concentration 
(Cmax)
(ug/ml)
Margin 
to 
NOAEL 
(Cmax)
AUC(0-168h)
(ug.hr.mL-1)
Margin 
to 
NOAEL
(AUC 
0-24h)
Anticipated 
starting dose 
IVB 0.14 
mg + 
IV Inf. 
0.012 mg/h
25%
0.005 (0.6xKi)
31800
0.9
13067
Anticipated 
pharmacologically
active dose
IVB 7.5 mg 
+ 
IV Inf. 0.63 
mg/h
>60%
0.27 (30xKi)
589
47
250
Anticipated 
pharmacologically
active dose
IVB 12 mg 
+ 
IV Inf. 1.1 
mg/h
>85%
0.45  (50xKi)
353
85
138
Highest  
anticipated dose 
IVB 23 mg 
+ 
IV Inf. 2.1 
mg/h
>90%
0.9 (100xKi)
177
156
75
5.4.4.
Part C:
Doses selected for Part C (single or repeated administration) will be based on doses 
shown to be safe and tolerable in Parts A and B respectively and is expected to sit in the 
pharmacologically relevant range.
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1.
Participant must be 18 to 50 years of age inclusive, at the time of signing the 
informed consent. In Part C (WONCBP) participants must be between 18 and 60
years of age.


2015N261138_03
CONFIDENTIAL
201570
49
Type of Participant and Disease Characteristics
2.
Participants who are overtly healthy as determined by medical evaluation including 
medical history, physical examination, laboratory tests, and cardiac monitoring.
3.
A subject with a clinical abnormality or laboratory parameter(s) which is/are not 
specifically listed in the inclusion or exclusion criteria, outside the reference range 
for the population being studied may be included only if the investigator in 
consultation with the Medical Monitor if required agree and document that the 
finding is unlikely to introduce additional risk factors and will not interfere with the 
study procedures. 
Weight
4.
Body weight  >50kg and body mass index (BMI) within the range 18.5 – 32 kg/m2
(inclusive).
Sex
5.
Abstinence/contraceptives: Length of time required for abstinence or use of 
contraceptives should take into account the reproductive toxicity profile including 
genotoxicity and teratogenicity, the size of the molecule, and the number of doses. 
a.
Male participants:
A male participant must agree to use contraception as detailed in Appendix 5 of this 
protocol during the treatment period and for at least 2 days after the last dose of 
study treatment and refrain from donating sperm during this period.
b.
Female participants: 
Only female participants of non childbearing potential (WONCBP) as defined in 
Appendix 5: Contraceptive Guidance and Collection of Pregnancy Information are 
eligible to participate. 
Informed Consent
6.
Capable of giving signed informed consent as described in Appendix 3 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
Alanine transaminase (ALT) and bilirubin >1.5xULN (isolated bilirubin >1.5xULN 
is acceptable if bilirubin is fractionated and direct bilirubin <35%). 
2.
Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones)


2015N261138_03
CONFIDENTIAL
201570
50
3.
QTcF >450 msec from a mean of triplicate readings taken no more than 2 minutes 
apart
4.
Clinically significant abnormal echocardiogram
5.
The participant has a history or current evidence of depression, bipolar disorder, 
suicidal ideation and behaviour, or a lifetime history of suicide attempt.
6.
cTn or BNP >ULN
Prior/Concomitant Therapy
7.
Use of prohibited medication (Section 7.7 & Section 7.8)
Prior/Concurrent Clinical Study Experience
8.
The subject has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day in the current 
study: 30 days, 5 half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer). 
9.
Exposure to more than four new chemical entities within 12 months prior to the first 
dosing day
Diagnostic assessments
10. 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. For 
potent immunosuppressive agents, subjects with presence of hepatitis B core 
antibody (HBcAb) should also be excluded. 
11. A positive pre-study drug/alcohol screen.
12. A positive test for human immunodeficiency virus (HIV) antibody.
13. Where participation in the study would result in donation of blood or blood products 
in excess of 500 mL within 84 days.
Other Exclusions
14. Poor or unsuitable venous access
15. History of regular alcohol consumption within 6 months of the study defined as: 
An average weekly intake of >14 units.  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.
16. History of sensitivity to any of the study medications, or components thereof or a 
history of drug or other allergy that, in the opinion of the investigator or Medical 
Monitor, contraindicates their participation.
17. History of smoking within 6 months of the study.


2015N261138_03
CONFIDENTIAL
201570
51
6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions

Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit 
juice, and/or pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices from 
7 days before the start of study treatment until after collection of the final PK or PD 
sample.
6.3.2.
Caffeine, Alcohol, and Tobacco

During each dosing session, participants will abstain from ingesting caffeine- or 
xanthine-containing products (eg, coffee, tea, cola drinks, and chocolate) for at least 
24 hours before the start of dosing until after collection of the final pharmacokinetic 
(PK) and/or pharmacodynamic sample.

During each dosing session, participants will abstain from alcohol for 72 hours 
before the start of dosing until after collection of the final PK and/or 
pharmacodynamic sample. Participants will also abstain from alcohol 72 hours 
before the 14 ±2 days follow up procedures have been completed, and 72 hours 
before the 32 ±2 days follow-up procedure as well as the 62 ± 2 days LFT follow up 
procedures have been completed.

Use of tobacco products will not be allowed from screening until after the final 
follow-up visit.
6.3.3.
Activity

Participants will abstain from strenuous exercise for 48 hours before each blood 
collection for clinical laboratory tests. Participants may participate in light 
recreational activities during studies (eg, watching television, reading).
6.3.4.
Exposure to UV
Initial photochemical data suggest that a potential photoreactive risk may exist. As a 
precaution, until this risk is further assessed via experimental evaluation, patients 
receiving GSK3335065 should avoid being in strong direct sunlight and/or UV exposure 
or use protective clothing, sunscreen and sun glasses from dosing till the follow-up visit.
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized in the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse 
events (SAEs).


2015N261138_03
CONFIDENTIAL
201570
52
Individuals who do not meet the criteria for participation in this study (screen failure) are 
allowed to be rescreened once after consultation with the Sponsor.
7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.
7.1.
Treatments Administered
Study Treatment Name:
GSK3335065
Placebo
Dosage formulation:
GSK3335065 Solution for 
injection
Placebo to match 
GSK3335065 Solution for 
injection
Unit dose strength(s)/Dosage 
level(s):
Unit dose strength : 5 mg/mL 
stock that may be diluted
Dosage levels : variable
N/A
Route of Administration 
Intravenous injection and 
infusion
Intravenous injection and 
infusion
Dosing instructions:
Study medication may be 
diluted in 0.9% w/v Sodium 
Chloride and will be 
administered by intravenous 
infusion by study personnel 
following specified regimens
Study medication will be 
administered by intravenous 
infusion by study personnel 
following specified regimens
Packaging and Labeling
Study Treatment will be 
provided in a carton 
containing 1x GSK3335065 
5mg/ml, 5mL vial. Each carton
will be labeled as required per 
country requirement.
Study Treatment will be 
provided in a carton containing 
1x Placebo to match 
GSK3335065, 5mL Vial. Each 
carton and vial will be labeled 
as required per country 
requirement.
Manufacturer
GlaxoSmithKline 
Manufacturing SpA,  Parma
GlaxoSmithKline 
Manufacturing SpA,  Parma


2015N261138_03
CONFIDENTIAL
201570
53
7.2.
Dose Modification
In case a dose reduction is necessary, the study treatment will be administered as follows: 

This protocol allows some alteration from the currently outlined dosing schedule, 
but the maximum predicted exposures will not exceed the 75-fold exposure 
margin in terms of AUC to the rat NOAEL as defined in the 14-day preclinical 
GLP tox studies.

The decision to proceed to the next dose level of GSK3335065, will be made by 
the GSK Study Team based on safety, tolerability and available pharmacokinetic 
and/or pharmacodynamic data obtained in at least 6 subjects on GSK3335065 at 
the prior dose level.  The actual doses to be administered may be adjusted based 
on safety, tolerability and preliminary pharmacokinetic and/or pharmacodynamic 
data at previous dose levels; these dose adjustments may involve either an 
increase or a decrease in the planned dose.

The dosing schedule may also be adjusted to expand a dosing cohort to further 
evaluate safety, tolerability, pharmacokinetic and/or pharmacodynamic findings at 
a given dose level, or to add cohorts to evaluate additional dose levels.  The study 
procedures for these additional subject(s) or cohort(s) will be the same as that 
described for other study subjects.

If the same Serious Adverse Event (SAE) occurs in more than one subject, the 
dose escalation will be temporarily halted and no further subject will be dosed 
until a full safety review of the data has taken place. Relevant reporting and 
discussion with the Medical Monitor, relevant GSK personnel, and with the Ethics 
Committee will then take place prior to any resumption of dosing.

The above criteria will apply even if measured pharmacokinetic parameters are 
below the above mentioned PK stopping criteria, and every effort will be made to 
take a blood sample at the time of the event for pharmacokinetic analysis in the 
presence of any of the above events.
7.3.
Method of Treatment Assignment
Subjects will be randomized to either active or placebo at the start of each cohort in 
accordance with the randomization schedule generated by Clinical Statistics, prior to the 
start of the study, using validated internal software.  
A description of each regimen in Part A, Part B and Part C is provided respectively in 
Table 11, Table 12 , Table 13, Table 14 below.


2015N261138_03
CONFIDENTIAL
201570
54
Table 11
Part A Single Ascending Dose (IV Bolus) in Males:
Cohort 1-8
Subject
Period 1 
(sentinels)
Period 1 
(remainder)
X
Placebo
X
Dose 1
X
Dose 1
X
Dose 1
X
Dose 1
X
Dose 1
X
Dose 1
X
Placebo
Table 12
Part B Multiple Ascending Dose (i.v. bolus followed by an i.v.
infusion) in Males:
Cohort
No. of
Subjects
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Cohort 9
(sentinel)
Cohort 9
(remaining)
Cohort 10
(sentinel)
Cohort 10
(remaining)
Cohort 11
(sentinel)
Cohort 11
(remaining)
Cohort 12
(sentinel)
Cohort 12
(remaining)
1
1
5
1
1
1
5
1
1
1
5
1
1
1
5
1
Dose 1
Placebo
Dose 1
Placebo
Dose 2
Placebo
Dose 2
Placebo
Dose 3
Placebo
Dose 3
Placebo
Dose 4
Placebo
Dose 4
Placebo
Dose 1
Placebo
Dose 1
Placebo
Dose 2
Placebo
Dose 2
Placebo
Dose 3
Placebo
Dose 3
Placebo
Dose 4
Placebo
Dose 4
Placebo
Dose 1
Placebo
Dose 1
Placebo
Dose 2
Placebo
Dose 2
Placebo
Dose 3
Placebo
Dose 3
Placebo
Dose 4
Placebo
Dose 4
Placebo
Dose 1
Placebo
Dose 1
Placebo
Dose 2
Placebo
Dose 2
Placebo
Dose 3
Placebo
Dose 3
Placebo
Dose 4
Placebo
Dose 4
Placebo
Dose 1
Placebo
Dose 1
Placebo
Dose 2
Placebo
Dose 2
Placebo
Dose 3
Placebo
Dose 3
Placebo
Dose 4
Placebo
Dose 4
Placebo
Dose 1
Placebo
Dose 1
Placebo
Dose 2
Placebo
Dose 2
Placebo
Dose 3
Placebo
Dose 3
Placebo
Dose 4
Placebo
Dose 4
Placebo
Dose 1
Placebo
Dose 1
Placebo
Dose 2
Placebo
Dose 2
Placebo
Dose 3
Placebo
Dose 3
Placebo
Dose 4
Placebo
Dose 4
Placebo
Part C: Single (i.v. bolus) or Multiple Dose (i.v. bolus followed by an i.v. infusion) in
WONCBP:


2015N261138_03
CONFIDENTIAL
201570
55
Table 13
Cohort 13: Single (i.v. bolus) Dose
Subject
Period 1 (remainder)
X
Placebo
X
Dose 1
X
Dose 1
X
Dose 1
X
Dose 1
X
Dose 1
X
Dose 1
X
Placebo
Table 14
Cohort 14: Multiple Dose (i.v. bolus followed by an i.v. infusion)
Cohort
No. of
Subjects
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Cohort 14
6
2
Dose 1
Placebo
Dose 1
Placebo
Dose 1
Placebo
Dose 1
Placebo
Dose 1
Placebo
Dose 1
Placebo
Dose 1
Placebo
7.4.
Blinding
This will be a double-blind (Sponsor unblinded) study in which the subjects and site staff 
(Pharmacist unblinded to prepare study drug) will be blinded for the duration of the 
study, and the following will apply. 

The investigator or treating physician may unblind a subject’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 subject as judged by the 
investigator. 

Investigators have direct access to the subject’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 subject’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 subject, unless that information is 
important for the safety of subjects currently in the study. 

The date and reason for the unblinding must be fully documented in the case 
report form (CRF)
A subject may continue in the study if that subject’s treatment assignment is unblinded.


2015N261138_03
CONFIDENTIAL
201570
56
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any participant with an SAE. If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of the 
report, identifying the participant’s treatment assignment, may be sent to investigators in 
accordance with local regulations and/or GSK policy.
7.5.
Preparation/Handling/Storage/Accountability
A description of the methods and materials required for the preparation of GSK3335065 
solution for injection will be detailed in a Study Specific Technical Agreement/Memo 
(SSTA) or Pharmacy Manual which will be accompanied by a Quality Agreement.
No special preparation of study treatment is required.

Only subjects 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 labelled 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 final disposition of unused study treatment 
are provided in the SRM. 

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case 
of unintentional occupational exposure notify the monitor, Medical Monitor 
and/or GSK study contact.

A Material Safety Data Sheet (MSDS)/equivalent document describing 
occupational hazards and recommended handling precautions either will be 
provided to the investigator, where this is required by local laws, or is available 
upon request from GSK.
Precaution will be taken to avoid direct contact with the study treatment.  A Material 
Safety Data Sheet (MSDS) describing occupational hazards and recommended handling 
precautions will be provided to the investigator. In the case of unintentional occupational 
exposure notify the monitor, Medical Monitor and/or GSK study contact.
7.6.
Treatment Compliance

When the individual dose for a participant is prepared from a bulk supply, the 
preparation of the dose will be confirmed by a second member of the study site staff. 

When participants are dosed at the site, they will receive study treatment directly 
from the investigator or designee, under medical supervision.  The date and time of 
each dose administered in the clinic will be recorded in the source documents.  The 


2015N261138_03
CONFIDENTIAL
201570
57
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.  

GSK3335065 will be intravenously administered to subjects at the site.  
Administration will be documented in the source documents and reported in the 
CRF. The date and time of each bolus dose administered in the clinic, and the start / 
stop date and time of each infusion will be recorded in the source documents.  The 
dose of study treatment and study subject 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.  
7.7.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrolment or receives during the study must be recorded along with:

reason for use

dates of administration including start and end dates

dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
Ibuprofen, at doses of 800 mg/day, is permitted for use any time during the study. Other 
concomitant medication may be considered on a case-by-case basis by the Medical 
Monitor.
7.8.
Prohibited Medications and Non-Drug Therapies
Subjects must abstain from taking prescription or non-prescription 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) prior to the first dose of 
study medication until completion of the follow-up visit, unless in the opinion of the 
Investigator and sponsor the medication will not interfere with the study.
The use of paracetamol is not allowed in his study.
7.9.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because only healthy volunteers are eligible for study participation.


2015N261138_03
CONFIDENTIAL
201570
58
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
Discontinuation from treatment is “permanent”. Once a subject is discontinued, she/he 
shall not be allowed to restart treatment.
8.1.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology. 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. 
8.1.2.
QTc Stopping Criteria

The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study.  This formula may not 
be changed or substituted once the participant has been enrolled.

For example, if a participant is eligible for the protocol based on QTcB, then
QTcB must be used for discontinuation of this individual participant as well.

Once the QT correction formula has been chosen for a participant’s eligibility, 
the same formula must continue to be used for that participant for all QTc data 
being collected for data analysis. Safety ECGs and other non-protocol specified 
ECGs are an exception.  

The QTc should be based on single or averaged QTc values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period.  
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.
In addition a healthy volunteer that meets either bulleted criterion below will be 
withdrawn from the study:

QTc >500 msec,

Change from baseline: QTcF >60 msec
8.1.3.
Rechallenge
8.1.3.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed.


2015N261138_03
CONFIDENTIAL
201570
59
8.1.4.
Additional Stopping Criteria
This section provides vital sign (blood pressure, heart rate), respiratory, oral temperature, 
and neuropsychiatric criteria for discontinuation of GSK 3335065 infusion. If criteria 
specified for action here are met, actions must be followed. Study investigators may also 
decide to discontinue dosing based on their clinical judgement for observations that are 
not specifically meet these thresholds, if they feel this is appropriate for best ensuring the 
safety of study subjects.
Blood Pressure:

Resting semi-recumbent systolic blood pressure (SBP) of ≤80 mmHg that is 
confirmed (median of 3 measurements, and at least 20% decrease from baseline) 
and sustained for  ≥20min with or without symptoms of hypotension. Sustained is 
defined as persistent (threshold is met or exceeded on all rechecks over a 20 min 
period; minimum of 3 consecutive measurements over a 20 min interval)

Resting semi-recumbent SBP ≥80 mmHg but ≤100 mHg that is confirmed 
(median of 3 measurements) and sustained if associated with symptoms of 
hypotension ( e.g. fainting, lightheadedness, dizziness, anxiety)

Hypotension requiring intervention such as Trendelenburg position w/wo fluid 
rescucitation

Resting semi-recumbent SBP ≥180 mmHg that is confirmed (median of 
3 measurements, and at least 20% increase from baseline with or without 
symptoms of hypertension (e.g. headaches, lightheadedness, anxiety)
Heart Rate:

Tachycardia (resting semi-recumbent heart rate >100bpm) of any duration 
associated with symptoms that the study investigator considers potentially 
associated with cardiac ischemia and/or hemodynamic compromise. Concerning 
symptoms might include chest pain, shortness of breath or lightheadedness.

Resting semi-recumbent heart rate of ≥130 bpm that is confirmed (median of 
3 measurements) and sustained. Sustained is defined as persistent (threshold is 
met or exceeded on all rechecks over a 20 min period; minimum of 3 consecutive 
measurements over a 10 min interval).

Increase in resting semin-recumbent heart rate ≥60 bpm from the predose baseline 
(median of 3 measurements and sustained).
If a vital sign threshold is exceeded which may result in discontinuation as defined above, 
the vital sign should immediately be repeated  twice (i.e 3 measurements within 
approximately 5 minutes) and the median value will be used at that time point. If the 
median value exceeds the threshold, it will be considered confirmed that the value 
exceeded the potential discontinuation threshold and the subject must be discontinued.
Cardiac Troponin/ B-type Natriuretic Peptide (BNP):


2015N261138_03
CONFIDENTIAL
201570
60
If the local cardiac troponin (cTn) is >ULN or B-type Natriuretic Peptide (BNP) is 
>2x ULN for the assay, that subject will undergo repeat cTN or BNP testing and urgent 
evaluation if symptoms suggestive of cardiac ischemia or heart failure are present, and a 
transthoracic echocardiogram will be performed.
Asymptomatic volunteers:  If the repeat value is within the normal range, the subject may 
continue in the study with close follow-up of symptoms. If the repeat value for cTn 
is >ULN or BNP is >2x ULN the subject must be discontinued from the study.
Symptomatic volunteers: Cardiology consultation will be obtained immediately for any 
subject with new signs or symptoms suggestive of cardiac ischemia or heart failure and 
the subject must be discontinued from the study. Concerning symptoms may include:

chest pain, 

increased shortness of breath

rapid or irregular heartbeat

diaphoresis

anxiety

fatigue, tiredness

confusion
Tympanic Temperature:

Confirmed (median of 3 measurements) ≥38.5ºC at any time point between 
bolus/infusion initiation and 1 hour after completion of the dosing.
Respiratory Issues:

In case the subject complains of dyspnea or shortness of breath, or if there is 
objective evidence of bronchospams or other respiratory difficulty, the subject 
will be immediately evaluated and if confirmed the subject must be discontinued 
from the study.
Neuropsychiatric Issues:
Suicidal Ideation and Behaviour:
If Columbia Suicide Severity Rating Scale (C-SSRS) and/or PSRAE assessments indicate 
a clinically relevant increase in suicidal ideation or behavior or a subject shows new signs 
or symptoms during the infusion period suggestive of an increase in suicidal ideation and 
behavior psychiatric consultation will be obtained and the Sponsor’s Medical Monitor 
should be contacted. Discontinuation is mandated in case the patient scores “yes” on item 
four or item five of the Suicidal Ideation Section of the Columbia Suicide Severity Rating 
Scale (C-SSRS) or “yes” on any item of the Suicidal Behaviour Section. In addition, 
study investigators may also decide to discontinue dosing based on their clinical 
judgment for observations that do not specifically meet these thresholds, if they feel this 
is appropriate for best ensuring the safety of study subjects.
Cognitive Safety:
–
If cognitive test results (i.e. fingertapping test [FTT], 6-item cognitive impairment 
test [6-CIT], Neuropsychiatric Inventory [NPI]) indicate a clinically significant 


2015N261138_03
CONFIDENTIAL
201570
61
effect of GSK3335065 on cognitive safety or the subject shows new signs or 
symptoms during the infusion period suggestive of an effect on cognitive safety, 
psychiatric consultation should be obtained and the Sponsor’s Medical Monitor 
should be contacted. If the increased risk can be confirmed the subject must be 
discontinued from the study.
In case there is objective evidence that a subject is in psychological distress, the subject 
will be immediately evaluated and the subject must be discontinued from the study if the 
investigators based on their clinical evaluation feel this is appropriate for best ensuring 
the safety of study subjects. Concerning symptoms might include:

Nervousness, 

Anxiety, irritability

Sudden worsening of mood

Sudden outbursts of anger (“anger attacks”)

Sudden panic or anxiety attacks

Agitation

Feeling unreal or detached

Confusion or trouble concentrating

Forgetfulness or problems with memory

Mood swings

Trouble sleeping, insomnia

Fatigue, tiredness
8.2.
Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, 
or may be withdrawn at any time at the discretion of the investigator for safety, 
behavioral, compliance or administrative reasons.

If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent.

If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records.

Refer to the Schedule of Activities ((SOA) Section 2) for data to be collected at 
the time of study discontinuation and follow-up and for any further evaluations 
that need to be completed.
8.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 


2015N261138_03
CONFIDENTIAL
201570
62
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 
3 telephone calls and, if necessary, a certified letter to the participant’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 
9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA. 

Protocol waivers or exemptions are not allowed 

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the time frame defined in the 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.

If assessments are scheduled for the same nominal time, THEN the assessments 
should occur in the following order:
1. 12-lead ECG
2. vital signs
3. blood draws (PK then PD)
Note: The timing of the assessments should allow the blood draw to occur at the 
exact nominal time.


2015N261138_03
CONFIDENTIAL
201570
63

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.
9.1.
Efficacy Assessments
There is no efficacy assessment in this study.
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study, 
or that caused the participant to discontinue the study treatment (refer to Section 8). 
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from admissions at the time points specified in the 
SoA (Section 2).

All AEs will be collected from admission until the follow-up visit at the time 
points specified in the SoA (Section 2).

Medical occurrences that begin before the start of study treatment but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the case report form (CRF) not the AE section.

All SAEs will be recorded and reported to the sponsor or designee within 
24 hours, as indicated in Appendix 4. The investigator will submit any updated 
SAE data to the sponsor within 24 hours of it being available.

Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study 
participation, the investigator must promptly notify the sponsor.

The method of recording, evaluating, and assessing causality of AEs and SAEs
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 4.
9.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about
AE occurrence. 


2015N261138_03
CONFIDENTIAL
201570
64
9.2.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and non serious AEs of special 
interest (as defined in Section 12.4 will be followed until the event is resolved, stabilized, 
otherwise explained, or the participant is lost to follow-up (as defined in Section 8.3). 
Further information on follow-up procedures is given in Appendix 4.
9.2.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are 
met. 

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study treatment 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or 
other specific safety information (eg, summary or listing of SAE) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.
9.3.
Treatment of Overdose
For this study, any dose of GSK3335065 greater than the agreed dose for a particular 
cohort, dosing session or study part will be considered as an overdose.
GSK does not recommend specific treatment for an overdose
In the event of an overdose the investigator or treating physician should:
1. Contact the Medical Monitor immediately
2. Closely monitor the subject for adverse events (AEs)/serious adverse events 
(SAEs) and laboratory abnormalities until GSK3335065 can no longer be detected 
systemically (at least 8 days which is equivalent to 5 times the observed 
preliminary half life of ~35 hours for GSK3335065).
3. Obtain a plasma sample for pharmacokinetic (PK) analysis within 1 days from the 
date of the last dose of study treatment if requested by the Medical Monitor 
(determined on a case-by-case basis)


2015N261138_03
CONFIDENTIAL
201570
65
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 subject.
9.4.
Safety Assessments
Planned time points for all safety assessments are provided in the Schedule of Activities 
((SOA) Section 2).
9.4.1.
Physical Examinations

A complete physical examination will include, at a minimum, assessments of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Height 
and weight will also be measured and recorded.

A brief physical examination will include, at a minimum, assessments of the 
lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous
serious illnesses.
9.4.2.
Vital Signs

Tympanic temperature, pulse rate, respiratory rate, and blood pressure will be 
assessed.

Blood pressure and pulse measurements will be assessed in semi-recumbent 
with a completely automated device. Manual techniques will be used only if an 
automated device is not available.

Blood pressure and pulse measurements should be preceded by at least 
5 minutes of rest for the participant in a quiet setting without distractions (eg, 
television, cell phones).

Vital signs (to be taken before blood collection for laboratory tests) will consist 
of 3 pulse and 3 blood pressure measurements (3 consecutive blood pressure 
readings will be recorded at intervals of at least 1 minute) at screening and pre-
dose. The average of the 3 blood pressure readings will be recorded on the CRF.
9.4.3.
Electrocardiograms

Triplicate 12-lead ECG will be obtained as outlined in the SoA (Section 2.2
and Section 2.1) using an ECG machine that automatically calculates the heart 
rate and measures PR, QRS, QT, and [QTc] intervals. Refer to Section 8.1.2 for 
[QTc] withdrawal criteria and additional [QTc] readings that may be necessary.

At each time point at which triplicate ECG are required, 3 individual ECG 
tracings should be obtained as closely as possible in succession, but no more 
than 2 minutes apart. The full set of triplicates should be completed in less than 
4 minutes.


2015N261138_03
CONFIDENTIAL
201570
66

ECG measurement should be preceded by at least 5 minutes rest semi-
recumbent
9.4.4.
Continuous ECG monitoring

Continuous ECG monitoring (using telemetry or a bedside ECG monitor) 
will be performed as described in the Schedule of Activities. Any abnormal 
findings on continuous ECG monitoring should be confirmed by a 12-lead 
ECG.
9.4.5.
Echocardiogram

A transthoracic echocardiogram will be performed as specified in the Time 
and Events table. Images will be obtained in standard views, the time to 
acquire images should not exceed approximately 45 min.
9.4.6.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency. 

The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study 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.

If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in participant 
management or are considered clinically significant by the investigator (eg, SAE 
or AE or dose modification), then the results must be recorded in the CRF.
9.4.7.
Suicidal Risk and Cognitive Safety Monitoring
GSK3335065 is essentially excluded from the CNS but several of the metabolites in the 
KYN pathway cross the blood brain barrier and therefore peripheral inhibition of KMO 
would be expected to alter central levels. Indeed, at a dose that generated systemic 
concentrations equivalent to a high dose used in rat exploratory dose escalation studies 


2015N261138_03
CONFIDENTIAL
201570
67
(10x cellular Ki), kynurenic acid (KYNA) levels increased >10-fold above baseline in 
rats. No observations indicative of an effect on behaviour have been seen in the rat or dog 
following repeat dosing with GSK3335065. An Irwin study has been conducted as part of 
the standard safety pharmacology package to support FTIH, and there were no effects on 
peripheral or central nervous system activity, body temperature or locomotor activity. 
However, KYNA is known to be neurologically active with increased levels leading to a 
decrease in excitatory neurotransmitters such as glutamate, dopamine and acetylcholine 
in humans, and KYNA is increased in cerebrospinal fluid (CSF) of patients with 
schizophrenia or bipolar disorder type 1 with psychotic features.
9.4.7.1.
Columbia Suicide Severity Rating Scale (C-SSRS)
There has been some concern that elevated central KYNA levels may be associated with 
an increased risk of suicidal thinking or behaviour when given to human subjects. GSK 
considers it important to monitor for such events before or during clinical studies with 
compounds such as this. Subjects being treated with GSK3335065 should be assessed 
and monitored appropriately for suicidality and unusual changes in behaviour. 
Baseline assessment of suicidal ideation and behaviour and treatment emergent suicidal 
ideation and behaviour will be assessed during this study using the Columbia Suicide 
Severity Rating Scale (C-SSRS). C-SSRS is a brief questionnaire designed to assess 
severity and change in suicidality by integrating both behaviour and ideation. The C-
SSRS was designed to address the need for a summary measure to track changes in the 
severity/intensity of suicidality across both clinical settings and treatment trials. It 
assesses intensity of ideation (a potentially important marker of severity), specifically 
asking about frequency, duration, intrusiveness, controllability and deterrents. In 
addition, both the modal and most severe forms of ideation are captured. This procedure 
should be performed in subjects receiving continuous infusion of GSK3335065 over 
7 days (Part B and Part C cohort 8) at times outlined in the Schedule of Activities 
(Section 2.2). The questionnaires should be completed, by a health professional trained in 
this procedure following discussions with the subject at each visit. If additional 
information is provided by a caregiver, relative, friend etc then this information should 
also be taken into account when completing the questionnaire. Any suicide attempts or 
Investigator concerns about issues raised during the completion of this questionnaire 
should be discussed immediately (with 24 h) with the GlaxoSmithKline Medical Monitor.
Families and caregivers of participants being treated with GSK3335065 should be alerted 
about the need to monitor participants for the emergence of unusual changes in 
behaviour, as well as the emergence of suicidal ideation and behaviour and to report such 
symptoms immediately to the study investigator.
9.4.7.2.
Possible Suicide Related Adverse Event(s) (PSRAE)
The possibly suicide related adverse event(s) (PSRAE) eCRF page should be completed
if there is an occurrence of an AE which in the Investigators judgment is possibly suicide
related. This may occur but is not limited to an event that involved suicidal ideation, a
preparatory act towards imminent suicidal behavior a suicide attempt, or a completed
suicide. Events identified via the C-SSRS should be reported in the PSRAE eCRF page. 
The Investigator will record information on the eCRF PSRAE form (and AE or SAE 


2015N261138_03
CONFIDENTIAL
201570
68
form as appropriate) and submit to the Sponsor as soon as possible after learning of an 
event.
9.4.7.3.
Neuropsychiatric Inventory (NPI)
As described above, tryptophan metabolites can act as neurotransmitters that potentially 
could also lead to impairment in cognitive function. However this effect is likely to be 
limited to the duration of treatment and, even if observed, this is not seen as a major 
liability in the target patient population. 
The NPI is an assessment of the frequency and severity of behavioral disturbances. The 
inventory comprises 10 dimensions: delusions, hallucinations, dysphoria, apathy, 
euphoria, disinhibition, aggressiveness and agitation, irritability, anxiety, aberrant motor 
activity (Cummings et al, 1994). Each dimension has a screening question with between 
7 and 9 follow-up questions relating to symptoms, asked if the answer to the screening 
question is 'yes'. The NPI takes approximately 10 minutes for the investigator to 
administer by talking to the caregiver.
9.4.7.4.
Six-Item Cognitive Impairment Test (6-CIT)
The 6-CIT is a brief neuropsychological screening test for cognitive impairment taking 
less than 5 minutes (three orientation items, count backwards from 20, months of the year 
in reverse order, and learn an address).
9.4.7.5.
Finger Tapping Test (FTT)
The FTT is a quick neuropsychological test that examines motor functioning, 
specifically, motor speed and lateralized coordination are assessed through this test
9.4.8.
Assessment at infusion site
The infusion site will be assessed at various times up to 36 hours post-dose using a 0–3 
scale as follows: Grade 0=none; Grade 1=pain or itching or erythema; Grade 2=pain or 
swelling, with inflammation or phlebitis; Grade 3=ulceration or necrosis.
9.5.
Pharmacokinetics
9.5.1.
Blood Sample Collection
Blood samples for pharmacokinetic (PK) analysis of GSK3335065 in plasma will be 
collected at the time points indicated below. The actual date and time of each blood 
sample collection will be recorded. The timing of PK samples may be altered and/or PK 
samples may be obtained at additional time points to ensure thorough PK monitoring. 
Processing, storage and shipping procedures are provided in the Study Reference Manual 
(SRM). 
Part A (cohort 1 &2) and Part C (cohort 7): 


2015N261138_03
CONFIDENTIAL
201570
69
1 mL of blood will be collected into Ethylenediaminetetraacetic acid (EDTA) tubes and 
processed to plasma for pharmacokinetic analysis, at the following time-points:
1 hr pre-dose, then 6 mins, 12 mins, 15 mins, 20 mins, 30 mins 1 hr, 2 hr, 3 hr, 6 hr, 9 hr, 
12 hr, 15 hr, 18 hr, 24 hr, 30 hr, 36 hr, 42 hr, 48 hr, 60 hr and 72 hr post-dose.
Part A (cohort 3 - 8) and Part C (cohort 13): 
1 mL of blood will be collected into EDTA tubes and processed to plasma for 
pharmacokinetic analysis, at the following time-points:
1 hr pre-dose, then 6 mins, 12 mins, 15 mins, 20 mins, 30 mins 1 hr, 2 hr, 3 hr, 6 hr, 9 hr, 
12 hr, 15 hr, 18 hr, 24 hr, 30 hr, 36 hr, 42 hr, 48 hr, 60 hr,72 hr, 84 hr, 96 hr, 108 hr, 120 
hr, 132 hr, 144 hr, 156 hr, 168 hr post-dose.
Blood samples for PK analysis may also be taken  during the follow up visit: 
approximately 7 to 14 days after subjects have left the unit. 
Part B (cohort 9-12) & C (cohort 14):
2 mL of blood will be collected into EDTA tubes and processed to plasma for 
pharmacokinetic analysis, at all time-points specified below, except the ones in bold. 
These time-points will collects 4 mL in EDTA tubes.
Study Day
PK sampling timepoint(s)
1
-1 hr, -30 mins, 6 mins, 15 mins, 30 mins, 1 hr, 2 hr,  3 hr, 4.5
hr, 6 hr, 9 hr, 12 hr, 18 hr.
2
Morning sample (around 08:00am) taken before first meal of 
the day
3-7
Morning sample (around 08:00am) taken before first meal of 
the day
8
Immediately after end of infusion, 6 hrs and 12 hrs following 
infusion termination
9
18 hrs, 24 hrs and 36 hrs following infusion termination
10
42 hrs, 48 hrs and 60 hrs following infusion termination
11
72 hrs, 84 hrs following infusion termination
12
96 hrs, 108 hrs following infusion termination
13
120 hrs, 132 hrs following infusion termination
14
144 hrs, 156 hrs following infusion termination
15
168hrs following infusion termination
Details of PK blood sample processing, storage and shipping procedures are provided in 
the Study Reference Manual (SRM). 


2015N261138_03
CONFIDENTIAL
201570
70
9.5.2.
Urine Sample Collection
In this study, urine samples for analysis of GSK3335065 and its metabolites will be 
collected at the time points listed below.  The timing of urine samples may be altered 
and/or samples may be obtained at additional time points to ensure thorough PK 
monitoring.
Immediately prior to dosing on Day 1, each subject will be instructed to void their 
bladder; this first void will be discarded. Urine in this void samples can be used as the 
‘pre-dose sample’
Study Part
Sample Required
Collection Details
A
Pre-dose, 20 mL
Collected at anytime between D-1 and D1 (prior to 
dosing)
A
400 mL
Urine collection for all time points listed in the Time 
and Events Tables will begin immediately following 
dose administration for each dosing session. The 
total volume and collection duration will be recorded 
for each subject.  
Samples within the time period 0-24 hours post dose 
will be pooled per subject and a 400 mL aliquot taken 
from the bulk collection once the total volume of the 
0-24 hr collection has been recorded.
B
Pre-Dose, 20 mL
Collected at anytime between D-1 and D1 (prior to 
dosing)
B 
400 mL
Urine collection for all time points listed in the Time 
and Events Tables will begin immediately following 
dose administration. The volume and time will be 
recorded for each urine sample collected and for 
each subject.  
Samples within the time period 48-72 hours will be 
pooled and a 400 mL aliquot taken.
Details of  urine sample processing, storage and shipping procedures are provided in the 
Study Reference Manual (SRM). 


2015N261138_03
CONFIDENTIAL
201570
71
9.6.
Enterotest – Bile Sample Collection
Bile samples will be collected on Day 3 for the analysis of GSK3335065 and any 
metabolites for volunteers in the cohort expected to receive the highest dose level 
(predicted to be cohort 12 [dose level 4]) of Part B only.  
Bile fluid is recovered on a highly absorbent nylon line which is contained within a 
weighted gelatin capsule. The 140 cm line unwinds after capsule swallowing, the capsule 
dissolves in the stomach and the line then passes into the duodenum.  During withdrawal, 
the weighted section of the capsule separates from the line and passes in the stool. 
Additional details of bile Entero-test sample collection, processing, storage, and shipping 
procedures will be provided in the SRM.
9.6.1.
Sample Analysis
Plasma PK analysis will be performed under the control of PTS-Bioanalysis, 
Immunogenicity & Biomarkers (BIB), GlaxoSmithKline, the details of which will be 
included in the Study Reference Manual (SRM). Concentrations of GSK3335065 will be 
determined in plasma samples using the currently approved bioanalytical methodology.
Once the plasma has been analyzed for GSK3335065 any remaining plasma may be 
analyzed for other compound-related metabolites under a separate PTS, GSK protocol.  
Urine and bile samples will similarly be analysed under a separate PTS-GSK protocol.  
The results of these analyses will be reported separately.
9.7.
Biomarker(s)/Pharmacodynamics Markers
Blood samples for pharmacodynamic (PD) analysis will be collected at the time points 
indicated below.  The actual date and time of each blood sample collection will be 
recorded.  The timing of PD samples may be altered and/or PD samples may be obtained 
at additional time points to ensure thorough PD monitoring.
2 mL of blood will be collected into EDTA tubes and processed to plasma for 
pharmacodynamic analysis.
Part A
Day -1, biomarker sampling on the day  before dosing: , which correspond approximately
to -16 hr, -14 hr, -12 hr and -10 hr prior to dosing.
Day 1, biomarker sampling on the day of dosing:  which correspond approximately to -2 
hr and within 30 minutes of dosing.
Day 1, biomarker sampling post dose: 6 mins, 15 mins, 30 mins, 1 hr, 1.5 hr, 2 hr, 3 hr, 
4.5 hr, 6 hr, 9 hr, 12 hr, 15 hr, 18 hr, 24 hr, 30 hr, 36 hr, 42 hr, 48 hr, 60 hr,72 hr, 84 hr, 
96 hr, 108 hr, 120 hr, 132 hr, 144 hr, 156 hr, 168 hr post-dose.
Blood samples for PD analysis may also be taken  during the follow up visit: 
approximately 7 to 14 days after subjects have left the unit. 


2015N261138_03
CONFIDENTIAL
201570
72
Part B & C
Study Day
PD sampling timepoint(s)
1
-1 hr, - 30 mins, 6 mins, 15 mins, 30 mins, 1 hr, 2 hr,  3 hr, 4.5 hr, 6
hr, 9 hr, 12 hr, 18 hr. 
2-7
Morning sample (08:00am) prior provision of meal
8
6 hrs and 12 hrs following infusion termination
9
18 hrs, 24 hrs and 36 hrs following infusion termination
10
42 hrs, 48 hrs and 60 hrs following infusion termination
11
72 hrs, 84hrs following infusion termination
12
96 hrs, 108 hrs following infusion termination
13
120 hrs, 132 hrs following infusion termination
14
144 hrs, 156 hrs following infusion termination
15
168hrs, 180 hrs following infusion termination
Additional 3HK samples may be withdrawn based on emerging data.
9.7.1.
Sample Analysis
Plasma analysis for biomarker concentrations will be performed under the control of 
PTS-BIB GlaxoSmithKline, the details of which will be included in the Study Reference 
Manual (SRM). Blood samples will be collected to measure KMO enzyme inhibition by 
looking at levels of the biomarkers Kynurenine (Kyn) and 3-hydroxykynurenine (3-HK) 
as secondary endpoints.
In addition, plasma concentrations of the other tryptophan pathway biomarkers may also 
be determined which may include (but not be limited to): tryptophan, kynurenic acid, 
anthranilic acid, 3- hydroxyanthranilic acid, quinolic acid and xanthurenic acid. Raw 
data will be archived at the bioanalytical site (detailed in the SRM).
Once the plasma has been analyzed for some or all of the tryptophan pathway 
metabolites/biomarkers as listed above, any remaining plasma may be analyzed for other 
relevant analytes and the results reported under a separate GlaxoSmithKline protocol.
9.8.
Genetics
A 6 mL sample for DNA isolation will be collected from participants who have 
consented to participate in the genetics analysis component of the study. Participation is 
optional. Participants who do not wish to participate in the genetic research may still 
participate in the study.
In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent.
See Appendix 6 for Information regarding genetic research. Details on processes for 
collection and shipment and destruction of these samples can be found in the Study 
Reference Manual.


2015N261138_03
CONFIDENTIAL
201570
73
9.9.
Health Economics OR Medical Resource Utilization and 
Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study.
10.
STATISTICAL CONSIDERATIONS
10.1.
Hypotheses
The main purpose of this study is to assess the safety and tolerability of single and 
repeated intravenous doses of GSK3335065 in healthy volunteers. No formal hypotheses 
are being tested and no statistical testing will be performed on the safety data.
10.2.
Sample Size Considerations
10.2.1.
Sample Size Assumptions
Sufficient subjects will be randomised to achieve a total of 112 evaluable subjects (Part 
A: 64 subjects, part B: 32 subjects and part C: 16 subjects). Part A began comprised of 2 
cohorts each with 8 healthy male subjects (6 active, 2 placebo) in a single ascending dose 
escalation cross-over design. Following preliminary PK data, Part A will  be in a parallel 
design with 6 additional cohorts and 8 healthy male subjects in each cohort (6 active, 2 
placebo). Part B will comprise of 4 cohorts each with 8 healthy male subjects (6 active, 2 
placebo) in a multiple ascending dose escalation. Part C will be comprised of 2 cohorts 
each with 8 subjects that are WONCBP (6 active, 2 placebo) in a single dose and multiple 
dose. Additional subjects or cohorts may be enrolled to allow for evaluation of additional 
dose levels.
If a subject prematurely discontinues the study in Part B or Part C Cohort 8 of the study, 
additional replacement subjects may be randomised and assigned to the same treatment 
sequence at the discretion of the Sponsor in order to achieve 112 evaluable subjects.  
No statistical techniques were used to determine the sample size. The sample size is 
based upon practical considerations for an FTIH study. 
10.2.2.
Sample Size Sensitivity
No sample size sensitivity was performed.
10.2.3.
Sample Size Re-estimation or Adjustment
A sample size re-estimation is not planned.


2015N261138_03
CONFIDENTIAL
201570
74
10.3.
Data Analysis Considerations
10.3.1.
Analysis Populations
The ‘All Subjects’ population will be defined as all subjects randomised to treatment who 
receive at least one dose of study treatment. This population will be used for all tables, 
figures, listings and analyses unless otherwise stated. 
The ‘PK Concentration’ population will be defined as all subjects for whom a 
pharmacokinetic sample was obtained and analysed. This population will be used for all 
summaries of PK concentration data. 
The ‘PK Parameter’ population will be defined as all subjects in the ‘PK Concentration’ 
population who provide pharmacokinetic parameters. This population will be used for all 
summaries and analyses of pharmacokinetic parameters. 
All analyses will be based on the actual treatment each subject received. Any departures 
from the planned treatment according to the randomization schedule will be documented 
in the CSR.
10.3.2.
Treatment Comparisons
10.3.2.1.
Primary Comparisons of Interest
There will be no direct comparisons between treatment groups for the safety data.
10.3.2.2.
Other Comparisons of Interest
To assess the effect of GSK3335065 on the pharmacodynamic biomarkers and 
exploratory biomarkers, all active treatment groups will be compared to placebo.
10.3.3.
Interim Analysis
Informal data review will be performed between dose escalation of each cohort in part A 
and between dose escalation in part B (multiple dose ascending phase) to support (i) 
whether the dose should be escalated and (ii) the next dose level.  PK and safety data 
(including any available PD data) will be reviewed.   The GSK pharmacokineticist will 
extract PK data (including treatment information) from SMS2000 via PKHARP. 
Standard concentration-time graphs will be derived for each subject by the GSK 
pharmacokineticist. These parameters will be summarised by each dose level and will be 
overlaid with initial model’s predictions for a comparison. The safety data will be listed 
and presented for each individual subject by treatment group. 
A formal interim analysis are also planned to occur after the completion of Part A. All 
available data including PK, safety and, if available, selected PD data will be included in 
this interim analysis. Interim analysis will allow a preliminary assessment of all available 
data. As this study is double-blind (Sponsor unblinded), the review team will be 
unblinded with respect to the treatment each subject received.  Final data base lock and 
final analysis will occur when all data are cleaned and entered to database. 


2015N261138_03
CONFIDENTIAL
201570
75
10.3.4.
Key Elements of Analysis Plan
Final analysis will be performed after the completion of the study and final database lock.   
Data will be listed and summarized according to GlaxoSmithKline reporting standards, 
where applicable. 
Unless stated otherwise, descriptive summaries will include n, mean, standard deviation 
(SD), coefficient of variation (%CV), median, minimum, and maximum, 95% confidence 
interval (CI) for non-transformed data with continuous variables.  For log-transformed 
data this will be geometric means with associated 95% confidence interval (CI), and the 
between-subject CV (%CVb) for continuous variables, whereas n and percent will be 
used as summary statistics for categorical variables.
Complete details of the planned statistical analysis will be given in the Reporting and
Analysis Plan (RAP). Any deviation from the planned analysis will be documented in the 
final study report. 
Placebo data from all doses will be pooled by Part for the summary tables. 
10.3.5.
Safety Analyses
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively according to GSK’s Integrated Data Standards Library (IDSL) standards.  
No formal statistical analysis of the safety data will be conducted.
10.3.5.1.
Extent of Exposure
The dates and times, the infusion rate, infusion volume of treatment dosing will be listed 
to indicate exposure to study drug.
10.3.5.2.
Adverse Events
Adverse events will be coded using the MedDRA coding dictionary, to give a preferred 
term and a system organ class, which will then be used when summarising the data. The 
verbatim term will be used in the listings.
The incidence of all adverse events (regardless of causality) will be summarised for each 
treatment group and sorted by system organ class and then by descending total incidence 
(i.e. across all treatment groups). System organ classes will not be presented when the 
overall incidence for any adverse event within the particular system is zero. If the total 
incidence for any two or more adverse events is equal, the events will be presented in 
alphabetical order. In addition, adverse events considered possibly drug-related by the 
investigator will be summarised separately.
Separate summaries of serious adverse events and adverse events leading to permanent 
discontinuation of study treatment or withdrawal from the study will be produced. 


2015N261138_03
CONFIDENTIAL
201570
76
10.3.5.3.
Clinical Laboratory Evaluation
All haematology, urinalysis and clinical chemistry laboratory values will be flagged high 
or low relative to their reported normal ranges.  Separate listings describing subjects with 
haematology and clinical chemistry laboratory values with values of potential clinical 
concern will be produced. 
10.3.5.4.
Other Safety Measures
The ECG interval data (PR, QRS, QT, QTc and ventricular rate) and vital signs data 
(systolic blood pressure, diastolic blood pressure and heart rate) will be listed and
summarised by treatment group and planned relative time. ECG findings will also be
listed. Any vital signs with values of potential clinical concern will be listed.
10.3.6.
Pharmacokinetic Analyses
Individual, mean and median plasma GSK3335065 concentration-time profiles will be 
plotted by treatment (linear and semi-linear profiles). Blood sampling times will be 
related to the start of the infusion procedure. Actual sampling times will be used to 
calculate all of the non-compartmental pharmacokinetic parameters. Individual 
concentrations of GSK3335065 in plasma will be listed and summarised by treatment and 
nominal time.  
Where data permit, the following pharmacokinetic parameters will be determined from 
the plasma concentration-time data for GSK3335065. 
Part A and Cohort 7 (Part C):
•
Area under the plasma concentration-time curve from time 0 to last quantifiable 
concentration (AUC0 – t) and extrapolated to infinity (AUC0 – ∞) 
•
Time to last observation (tlast).
•
First observed peak concentrations (Cmax)
•
Time to Cmax (tmax).
•
Clearance (CL).
•
Volume of distribution (V).
•
The associated apparent terminal elimination half life (t½) will be calculated 
Part B and Cohort 8 (Part C):
•
Area under the plasma concentration-time curve from time 0 to last quantifiable 
concentration (AUC0 – t) and extrapolated to infinity (AUC0 – ∞) 
•
Time to last observation (tlast).
•
Average concentration (Cavg)  
•
Clearance (CL).
•
Volume of distribution (V).


2015N261138_03
CONFIDENTIAL
201570
77
The number of data points used to determine the terminal phase will also be listed. 
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to standard operating procedure SOP-CPK-001 v01 and using WinNonlin v6.3 
by Clinical Pharmacokinetics M&S, Qsci. All derived parameters described above will be 
listed and summarised according to SOP-BMD-4002 (Standard Statistical Methods for 
the analysis of Pharmacokinetic Data). 
10.3.7.
Pharmacodynamic Analyses
The planned PD biomarkers (3HK and KYN) and other secondary/exploratory such as 
generic inflammatory biomarkers and various metabolites such as: tryptophan, Kynurenic 
acid, anthranilic acid, 3- hydroxyanthranilic acid, quinolic acid and xanthurenic acid will 
be listed and summarised by treatment group and planned relative time. An exploratory 
statistical analysis may be performed on the biomarker data if deemed appropriate. More 
details will be given in the RAP. 
10.3.8.
Pharmacokinetics/Pharmacodynamics Analyses
PK/PD analysis of the biomarkers will be conducted between PD biomarkers and PK, 
other exploratory PK/PD analysis of the biomarkers may be conducted should changes in 
biomarkers be detected. More details will be provided in the RAP.
10.3.9.
Exploratory Analyses
Details of exploratory analysis will be discussed in Report and Analysis Plan (RAP).


2015N261138_03
CONFIDENTIAL
201570
78
11.
REFERENCES
Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The 
Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. 
Neurology. 1994 Dec;44(12):2308-14.
GlaxoSmithKline Document Number 2016N273923_01, GSK3335065 Investigators 
Brochure, Version 01, Effective date 1 June 2017 
Guiney WJ, Beaumont C, Thomas SR, Robertson DC, McHugh SM, Koch A, Richards 
D.  Use of Entero-Test, a simple approach for non-invasive clinical evaluation of the 
biliary disposition of drugs. Br J Clin Pharmacol. 2011;72:133–142
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.
Liddle J , Beaufils B, Binnie M, Bouillot A, Denis AA, Hann MM, The Discovery of 
Potent and Selective Kynurenine 3-Monooxygenase Inhibitors for the Treatment of Acute 
Pancreatitis, Bioorg Med Chem Lett 27 (9), 2023-2028. 2017 Mar 09
Mole DJ, Webster SP, Uings I, Zheng X, Binnie M et al, Kynurenine–3–monooxygenase 
inhibition prevents multiple organ failure in rodent models of acute pancreatitis.Nature 
Medicine. 2016; 22: 202–209 
Skouras C, Zheng X, Binnie M, Homer NZM,. Murray TBJ, Robertson D, et al , 
Increased levels of 3-hydroxykynurenine parallel disease severity in human acute 
pancreatitis Scientific Reports 6:2016; 33951 


2015N261138_03
CONFIDENTIAL
201570
79
12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
3-HK
3-hydroxykynurenine
WONCBP
women of non child bearing potential
SAD
Single Ascending Dose
POC
Proof of concept
PK
pharmacokinetics
PD
pharmacodynamics
TRP
Tryptophan 
KYN
kynurenine
IDO
indole dioxygenases
KMO
kynurenine-3-monooxygenase
KYNA
kynurenic acid
AA
anthranillic acid
CNS
central nervous system
CV
Cardiovascular
cTnI
cardiac troponin I
BNP
brain natriuretic peptide
ULN
Upper Limit Normal
ECG
Electrocardiogram
BP
Blood Pressure
HR
Heart rate
NOAEL
No Observed Adverse effect level
FTIH
first time in human
Mg
milligram
LFT
Liver Function test
Kg
Kilogram
L
Liter
Hr
Hour
MRSD
maximum recommended starting dose
FDA
Food & Drug Administration
HED
human equivalent dose
MABEL
Minimum Anticipated Biological Effect Level
GLP
Good Laboratory Practice
µg
Microgram
Cmax
Maximum observed plasma concentration
AUC (0-24)
Area under concentration time curve from zero to time 24 h
cTN
Cardiac troponin
nM
Nanomolar
µM
Micromolar
DILI
Drug induced liver injury
BMI
Body Mass Index
ICF
informed consent form
ALT
Alanine transaminase


2015N261138_03
CONFIDENTIAL
201570
80
HBsAg
hepatitis B surface antigen
HBcAb
hepatitis B core antibody
HIV
human immunodeficiency virus
CRF
Case report form
GCSP
Global Clinical Safety and Pharmacovigilance
SSTA
Study Specific Technical Agreement
SRM
Study Reference Manual
MSDS
Material Safety Data Sheet
SBP
systolic blood pressure
mmHg
Millimetres of mercury
C-SSRS
Columbia Suicide Severity Rating Scale
PSRAE
Possibly suicide related Adverse event
FTT
fingertapping test
6-CIT
6-item cognitive impairment tes
NPI
Neuropsychiatric Inventory
IRB
Institutional Review Boards
IEC
Independent Ethics Committees
SUSAR
suspected unexpected serious adverse reactions
CSF
cerebrospinal fluid
SRM
Study Reference Manual
BIB
Bioanalysis, Immunogenicity & Biomarkers
IDSL
Integrated Data Standards Library
MAD
multiple ascending dose
CI
confidence interval
SD
standard deviation
CV
coefficient of variation
RAP
Reporting and Analysis Plan
IDSL
Integrated Data Standards Library
MedRA
Medical Dictionary of Regulatory activities
AUC0 – ∞
Area under the plasma concentration-time curve from time 0 to 
extrapolated to infinity
Tlast
Time to last observation
T max
Time to Cmax
CL
Clearance
V
Volume of distribution
T 1/2
terminal elimination half life
Cavg
Average concentration
mg
Milligrams
EDTA
Ethylenediaminetetraacetic acid


2015N261138_03
CONFIDENTIAL
201570
81
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
MedRA
WinNonlin


2015N261138_03
CONFIDENTIAL
201570
82
12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 15 will be performed by the Doctors Laboratory

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 15
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
MCV
MCH
WBC count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Reticulocytes
Clinical Chemistry1
BUN
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-Oxaloacetic 
Transaminase (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase (SGPT)
Total Protein
Glucose fasting2
Calcium
Alkaline phosphatase
Albumin
cTnI  
BNP
Routine Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other Screening 
Tests

HIV

Hepatitis B (HBsAg)

Hepatitis C (Hep C antibody)

FSH and estradiol (as needed in women of non-child bearing potential only)3

Alcohol and drug screen (to include at minimum: amphetamines, barbiturates, cocaine, 
opiates, cannabinoids and benzodiazepines)
The results of each test must be entered into the CRF.
NOTES :
1.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 8.1 and Appendix 7 and Study Treatment Rechallenge Guidelines  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.
Glucose fasting at screening and admission. 
3.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC.


2015N261138_03
CONFIDENTIAL
201570
83
12.3.
Appendix 3: Study Governance Considerations
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (eg, advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study. 


2015N261138_03
CONFIDENTIAL
201570
84

Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative. 

Participants who are rescreened are required to sign a new ICF.
The ICF may contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research in accordance with SOP-GSKF-410. The 
investigator or authorized designee will explain to each participant the objectives of the 
exploratory research. Participants will be told that they are free to refuse to participate 
and may withdraw their consent at any time and for any reason during the storage period. 
A separate signature will be required to document a participant's agreement to allow any 
remaining specimens to be used for exploratory research. Participants who decline to 
participate will not provide this separate signature.]
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.


2015N261138_03
CONFIDENTIAL
201570
85

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
Where required by applicable regulatory requirements, an investigator signatory will be
identified for the approval of the clinical study report. The investigator will be provided
reasonable access to statistical tables, figures, and relevant reports and will have the
opportunity to review the complete study results at a GSK site or other mutually
agreeable location. GSK will also provide the investigator with the full summary of the 
study results. The investigator is encouraged to share the summary results with the study 
subjects, as appropriate. 
GSK will provide the investigator with the randomization codes for their site only after 
completion of the full statistical analysis. 
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.
A manuscript will be progressed for publication in the scientific literature if the results 
provide important scientific or medical knowledge.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (eg, laboratory 
data). The investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 


2015N261138_03
CONFIDENTIAL
201570
86

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 eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available.

Definition of what constitutes source data can be found in the site’s Source 
Document Identification Form or equivalent form.
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
Committees Structure
Dose Escalation Committee
The decision to proceed to the next dose level within the study part will be made by a 
Dose Escalation Committee (DEC) consisting of the Principal Investigator (or 
appropriate 
designee), 
Medical 
Monitor, 
GSK 
Study 
Team 
Leader, 
GSK 
Pharmacokineticist, a GSK GCSP representative and GSK Statistician. All GSK 


2015N261138_03
CONFIDENTIAL
201570
87
personnel including the GSK Statistician and the GSK Pharmacokineticist will remain 
unblinded throughout the course of the study. The decision to progress to Part B and Part 
C will also be made by the DEC.
Dose escalation criteria for Part A
In Part A, the decision to proceed to the next dose level will be based on safety and 
tolerability data obtained up to 8 days post dose (discharge from clinical unit) from at 
least 6 subjects at the prior dose level. The review data set will at a minimum consist of 
the listings of any adverse events, flagged vital signs, flagged findings during the cardiac 
monitoring (telemetry) ECG, flagged findings in 12-lead ECGs and laboratory findings 
(including LFTs, cTN, BNP). Available PK data from the prior dose level, together with
any available PD data will also be reviewed. The highest dose planned in Part A is a 54 
mg dose with an expected exposure margin in terms of AUC to the rat NOAEL of 75-
fold. Higher doses may be administered if exposures are lower than predicted but the 
maximum exposure will not exceed the 75-fold exposure margin in terms of AUC to the 
NOAEL.
Decision to proceed to Part B
Prior to initiation of Part B a review of all available safety, tolerability, PK and PD data 
from Part A will be conducted and potential changes to the dosing paradigm, safety 
observation period and assessments will be communicated in a future amendment to the 
protocol as appropriate.
The first dose level in Part B will be set to ensure that the highest exposures safely 
achieved in Part A are not expected to be exceeded. The review data set will at a 
minimum consist of the listings of any adverse events, flagged vital signs, flagged 
findings during the cardiac monitoring (telemetry) ECG, flagged findings in 12-lead 
ECGs and laboratory findings (including LFTs, cTN, BNP).
Dose escalation criteria for Part B
In Part B, the decision to proceed to the next dose level will be based on data obtained up 
to 15 days post dose (discharge from clinical unit) from at least 6 subjects at the prior 
dose level. The review data set will at a minimum consist of the listings of any adverse 
events, flagged vital signs, flagged findings during the neuropsychiatric testing, flagged 
findings during the cardiac monitoring (telemetry) ECG, 12-lead ECGs, laboratory 
findings (including LFTs, cTN, BNP), available PK, and PD (3HK levels as PD BMx) 
data. Higher doses may be administered if exposures are lower than predicted but the 
maximum exposure will not exceed the 75-fold exposure margin in terms of AUC to the 
NOAEL.
In Part C, doses that have been demonstrated to be safe and well tolearated in Part A and 
B, respectively will be dosed.
Dose escalation stopping rules
Dose escalation stopping criteria will include the following:


2015N261138_03
CONFIDENTIAL
201570
88

a serious adverse event (SAE) occurs in one or more subjects receiving 
GSK3335065 that is considered at least possibly related to the study drug;

Severe non-serious AEs in two or more subjects in the same cohort receiving 
GSK3335065 that are considered at least possibly related to the study drug
If any of the above dose escalation stopping rules are met the dose escalation will be 
temporarily halted and no further subject will be dosed until a full safety review of the 
data has taken place. Relevant reporting and discussion with the Medical Monitor, 
relevant GSK personnel, with the Ethics Committee and approval of a substantial 
amendment will then take place prior to any resumption of dosing.
The trial may be paused during review of newly available preclinical/clinical safety, PK 
or PD data or other items of interest at any time during trial conduct and no further 
subject will be dosed until a full safety review of the data has taken place. Relevant 
reporting and discussion with the Medical Monitor, relevant GSK personnel, with the 
Ethics Committee, and approval of a substantial amendment will then take place prior to 
any resumption of dosing.


2015N261138_03
CONFIDENTIAL
201570
89
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study treatment, whether or not considered related to the 
study treatment.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.

Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 


2015N261138_03
CONFIDENTIAL
201570
90
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 


2015N261138_03
CONFIDENTIAL
201570
91
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.


2015N261138_03
CONFIDENTIAL
201570
92
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.


2015N261138_03
CONFIDENTIAL
201570
93
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 or the SAE coordinator.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in Study Reference Manual.


2015N261138_03
CONFIDENTIAL
201570
94
12.5.
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)
Women in the following categories are not considered WOCBP
1.
Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy

Documented tubal ligation
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
2.
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 not be allowed in 
the study. 
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 duration of the study
and for at least 2 days from last dose: 

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 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 


2015N261138_03
CONFIDENTIAL
201570
95
penile penetration during the duration of the study and for at least 2 days from
last dose.

Refrain from donating sperm for duration of study and for at least 2 days from 
last dose
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. 


2015N261138_03
CONFIDENTIAL
201570
96
12.6.
Appendix 6: Genetics
USE/ANALYSIS OF DNA

Genetic variation may impact a participant’s response to therapy, susceptibility, 
severity and progression of disease. Variable response to therapy may be due to 
genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular 
subtype of the disease being treated. Therefore, where local regulations and IRB/IEC 
allow, a blood sample will be collected for DNA analysis

DNA samples will be used for research related to acute pancreatitis and related 
diseases. They may also be used to develop tests/assays including diagnostic tests) 
related to acute pancreatitis. Genetic research may consist of the analysis of one or 
more candidate genes or the analysis of genetic markers throughout the genome [or 
analysis of the entire genome] (as appropriate)

DNA samples will be analyzed if it is hypothesized that this may help further 
understand the clinical data. 

The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to acute pancreatitis or study treatments of this class. The
results of genetic analyses may be reported in the clinical study report or in a 
separate study summary.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained while research on acute pancreatitis (or study 
treatments of this class) continues but no longer than 15 years after the last subject 
last visit or other period as per local requirements.


2015N261138_03
CONFIDENTIAL
201570
97
12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments 
Phase I Liver chemistry stopping criteria have been designed to assure subject safety and 
to evaluate liver event etiology (in alignment with the FDA premarketing clinical liver 
safety guidance).
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Phase I liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria – Liver Stopping Event
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 following Liver Stopping Event
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 

Viral hepatitis serology3

Blood sample for pharmacokinetic (PK) 
analysis, obtained according to PK 
sampling schedule  

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 


2015N261138_03
CONFIDENTIAL
201570
98
Liver Chemistry Stopping Criteria – Liver Stopping Event
recommended
If ALT≥3xULN AND bilirubin < 2xULN  and 
INR ≤1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24-
72 hrs

Monitor subjects weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
INR >1.5:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG or gamma 
globulins).

Serum acetaminophen adduct HPLC assay 
(quantifies potential acetaminophen 
contribution to liver injury in subjects with 
definite or likely acetaminophen use in the 
preceding week [James, 2009]. 

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF 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.
Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C RNA; 
Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 


2015N261138_03
CONFIDENTIAL
201570
99
12.8.
Appendix 8: Cognitive Assessments
12.8.1.
Columbia Severity Suicide Rating scale
Please refer to Study Reference Manual.
12.8.2.
Neuropsychiatric Inventory (NPI)
Please refer to Study Reference Manual
12.8.3.
Six-item Cognitive Impairment Test (6-CIT)
Please refer to Study Reference Manual
12.8.4.
Finger Tapping Test (FTT
Please refer to Study Reference Manual.


2015N261138_03
CONFIDENTIAL
201570
100
12.9.
Appendix 9: Telemetry Assessments


2015N261138_03
CONFIDENTIAL
201570
101
12.10.
Appendix 10: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).
DOCUMENT HISTORY
Document
Date
Amendment 03
DD-MMM-YYYY
Amendment 02
21-August 2017
Amendment 01
11-July-2017
Original Protocol
14 June 2017
Amendment 01 11-July-2017
Overall Rationale for the Amendment: Correction of Inconsistency in text between 
Appendix 5 and protocol body
Section # 
and Name
Description of Change
Brief Rationale
Section 12.5 
Appendix 5 
Edits to male contraception and 
sperm donation restriction timelines 
to align with the protocol body from 
3 months in the appendix to 2 days 
as in the protocol body
Edits requested by MHRA following review 
of the protocol


2015N261138_03
CONFIDENTIAL
201570
102
Amendment 02 21-August-2017
Overall Rationale for the Amendment: Change in washout period window in Part A 
and minor administrative changes.
Section # and 
Name
Description of Change
Brief Rationale
2.1 Schedule of 
Assessments
Day 1 LFT needs to be performed
LFT on Day 1 originally not ticked in 
error.
2.2 Schedule of 
Assessments

Urine Drug/Alcohol 
Breath Test

Clarifcation of 12-Lead 
ECG timepoints between 
Day 3 and Day 11.

Superscript reference incorrect.

Need to specify what timepoints 
ECGs are collected 
5.1.1 Part A: Single 
Ascending Dose 
(IV Bolus) in males 
(Table 3)
Projected washout period: 
between approximately 10 to 21 
days between doses
Washout period between doses in Part 
A (SAD) projected to be approximately 
10-21 days, which is supported by the 
predicted half life of GSK3335065 
(approximately 8 hours) and preclinical 
safety data. While the washout period 
between single ascending doses may 
exceed 21 days it must not fall below 5x 
predicted half life of the parent 
(5x8hours = 40hours; half life will be 
updated based on newly generated PK 
data). These changes are not expected 
to affect the safety of the study 
participants.
Until actual t1/2 data from humans is 
available, in order to be conservative, 
the washout period will be at least 10 
days, which is approximately 30X 
predicted t1/2.
6.2 Exlusion 
Criteria 3 & Section 
9.4.3 
Electrocardiograms
The two sections are not in 
alignment as to correct procedure 
for triplicate ECGs at screening
Triplicate ECGs at screening will be 
taken no more than 2 mins apart, within 
4 minutes
9.5.1 (PK) Blood 
Sample Collection 
Part B
Clarification as to which samples 
need to have 4 or 2 ml collected.
Omitted from protocol in error
9.5.2 Urine Sample 
Collection
Removed urine collections for 
Part C
Urinary metabolism data needs only to 
be generated for Part A & B.

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
201570
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for Study 201570: Randomized, 
Double-blind, Placebo Controlled Dose Escalation Study to 
Evaluate Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamics of Single Doses (Intravenous bolus) and 
constant intravenous infusion over 7 Days of GSK3335065 in 
Healthy Adult Subjects.
Compound Number 
:
GSK3335065
Effective Date 
:
22-Oct-2018
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 201570

This RAP is intended to describe the safety, tolerability, pharmacokinetic and 
pharmacodynamic analyses required for the study. 

This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) for the end of study final reporting deliverable.
RAP Author(s):
Approver
Date
Approval Method
10-Oct-2018
CARS eSignature
Associate Statistician (FPD, Clinical Statistics)
10-Oct-2018
CARS eSignature
Statistician (FPD, Clinical Statistics)
11-Oct-2018
CARS eSignature
Manager (FPD, Clinical Pharmacology
Modelling & Simulation)
Manager (FPD, Clinical Pharmacology
Modelling & Simulation)
10-Oct-2018
CARS eSignature
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD
PPD
PPD


CONFIDENTIAL
201570
2
RAP Team Approvals:
Approver
Date
Approval Method
Medical Monitor
10-Oct-2018
CARS eSignature
Director, Clinical Development (FPD)
Clinical Investigations Lead/Operational Study 
Lead
10-Oct-2018
CARS eSignature
Clinical Research Scientist (FPD, GCSD)
Data Quality Lead
10-Oct-2018
CARS eSignature
Principal Clinical Data Manager (FPD, GCDO)
Global Clinical Safety & Pharmacovigilance
11-Oct-2018
CARS eSignature
SERM Director (SMG Pharma Safety)
11-Oct-2018
CARS eSignature
Manager (FPD, Clinical Pharmacology
Modelling & Simulation)
10-Oct-2018
CARS eSignature
Manager (FPD, Clinical Pharmacology
Modelling & Simulation)
Lead Programmer
17-Oct-2018
CARS eSignature
Principal Programmer/Analyst (FPD, Clinical 
Statistics)
Clinical Statistics and Clinical Programming Line Approvals:
Approver
Date
Approval Method
(eSignature approval name: 
22-Oct-2018
CARS eSignature
Statistics Director (FPD, Clinical Statistics)
On behalf of 
 (Line Manager, 
FPD, Clinical Statistics)
17-Oct-2018
CARS eSignature
Programming Manager (FPD, Clinical 
Programming)
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL
201570
3
TABLE OF CONTENTS
Page
1.
INTRODUCTION......................................................................................................5
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................6
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................6
2.2.
Study Objective(s) and Endpoint(s)...............................................................6
2.3.
Study Design ................................................................................................8
2.4.
Statistical Hypotheses.................................................................................12
3.
PLANNED ANALYSES ..........................................................................................13
3.1.
Interim Analyses .........................................................................................13
3.2.
Final Analyses ............................................................................................13
3.3.
Changes to the Protocol Defined Statistical Analysis Plan..........................13
4.
ANALYSIS POPULATIONS ...................................................................................14
4.1.
Protocol Deviations.....................................................................................15
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................16
5.1.
Study Treatment & Sub-group Display Descriptors.....................................16
5.2.
Baseline Definitions ....................................................................................17
5.2.1.
Derivations and Handling of Missing Baseline Data.....................18
5.3.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................18
6.
STUDY POPULATION ANALYSES .......................................................................19
6.1.
Overview of Planned Study Population Analyses........................................19
7.
SAFETY ANALYSES .............................................................................................20
7.1.
Adverse Events Analyses ...........................................................................20
7.2.
Clinical Laboratory Analyses.......................................................................21
7.3.
Other Safety Analyses ................................................................................22
8.
PHARMACOKINETIC ANALYSES.........................................................................23
8.1.
Primary Pharmacokinetic Analyses.............................................................23
8.1.1.
Endpoint / Variables.....................................................................23
8.1.1.1.
Drug Concentration Measures....................................23
8.1.1.2.
Derived Pharmacokinetic Parameters.........................23
8.1.2.
Summary Measure ......................................................................24
8.1.3.
Population of Interest...................................................................24
8.1.4.
Strategy for Intercurrent (Post-Randomization) Events ................24
8.1.5.
Statistical Analyses / Methods .....................................................24
9.
PHARMACODYNAMIC BIOMARKER ANALYSES ................................................25
9.1.
Primary and Exploratory Pharmacodynamic Analyses................................25
9.1.1.
Endpoint / Variables.....................................................................25
9.1.2.
Summary Measure ......................................................................25
9.1.3.
Population of Interest...................................................................25
9.1.4.
Strategy for Intercurrent (Post-Randomization) Events ................25
9.1.5.
Other details ................................................................................25


CONFIDENTIAL
201570
4
10. REFERENCES.......................................................................................................26
11. APPENDICES........................................................................................................27
11.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................27
11.2.
Appendix 2: Schedule of Activities ..............................................................30
11.2.1.
Protocol Defined Schedule of Events...........................................30
11.3.
Appendix 3: Assessment Windows .............................................................31
11.3.1.
Definitions of Assessment Windows for Analyses........................31
11.4.
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................32
11.4.1.
Study Phases ..............................................................................32
11.4.1.1.
Study Phases for Concomitant Medication .................32
11.4.2.
Treatment Emergent Flag for Adverse Events .............................32
11.5.
Appendix 5: Data Display Standards & Handling Conventions....................33
11.5.1.
Reporting Process .......................................................................33
11.5.2.
Reporting Standards....................................................................33
11.5.3.
Reporting Standards for Pharmacokinetic....................................35
11.6.
Appendix 6: Derived and Transformed Data ...............................................36
11.6.1.
General........................................................................................36
11.6.2.
Study Population..........................................................................36
11.6.3.
Safety ..........................................................................................37
11.6.4.
Pharmacokinetic ..........................................................................37
11.6.5.
Pharmacodynamic.......................................................................37
11.7.
Appendix 7: Reporting Standards for Missing Data.....................................38
11.7.1.
Premature Withdrawals................................................................38
11.7.2.
Handling of Missing Data.............................................................38
11.7.2.1.
Handling of Missing and Partial Dates ........................38
11.7.2.2.
Handling of Partial Dates............................................39
11.7.2.3.
Handling of Missing Data for Statistical 
Analysis......................................................................39
11.8.
Appendix 8: Values of Potential Clinical Importance ...................................40
11.8.1.
Laboratory Values........................................................................40
11.8.2.
ECG.............................................................................................41
11.8.3.
Vital Signs....................................................................................41
11.9.
Appendix 9: Abbreviations & Trade Marks ..................................................42
11.9.1.
Abbreviations...............................................................................42
11.9.2.
Trademarks .................................................................................43
11.10. Appendix 10: List of Data Displays..............................................................44
11.10.1. Data Display Numbering..............................................................44
11.10.2. Mock Example Shell Referencing ................................................44
11.10.3. Deliverables.................................................................................44
11.10.4. Study Population Tables..............................................................45
11.10.5. Safety Tables...............................................................................46
11.10.6. Pharmacokinetic Tables...............................................................50
11.10.7. Pharmacokinetic Figures .............................................................51
11.10.8. Pharmacodynamic Tables ...........................................................52
11.10.9. Pharmacodynamic Figures ..........................................................53
11.10.10.ICH Listings .................................................................................54
11.10.11.Non-ICH Listings..........................................................................57
11.11. Appendix 11: Example Mock Shells for Data Displays ................................59


CONFIDENTIAL
201570
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 201570 (Amendment 3):
Revision Chronology:
2015N261138_00
14-JUN-2017
Original
2015N261138_01
11-JUL-2017
Correction of Inconsistency in text between 
Appendix 5 and protocol body. For further details, 
please see the protocol.
2015N261138_02
21-AUG-2017
Change in washout period window in Part A and 
minor administrative changes. For further details, 
please see the protocol.
2015N261138_03
29-Nov-2017
Change in post dose safety observation period,
PK and PD assessment time points based on 
emerging PK data.
For further details, please see the protocol.
Following safety review after sentinel dosing of Part A Cohort 3 (08-Feb-2018), the study 
was terminated because a relationship between GSK3335065 and ventricular tachycardia 
in a subject could not be excluded. The development of ventricular tachycardia in this 
subject significantly changed the risk: benefit profile.
Please note that although the RAP will use the terminology “participants”, all displays 
(Tables, Figures & Listings) will use the term 'Subjects'.


CONFIDENTIAL
201570
6
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Changes from the originally planned statistical analysis specified in the protocol are 
outlined in Table 1.
Table 1
Changes to Protocol Defined Analysis Plan
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes

To determine the safety and 
tolerability 
of 
GSK3335065 
administered as a single IV 
bolus (Part A and C), and as a 
constant IV infusion over 7 days 
(Part B and C) in healthy 
volunteers

To determine the safety and 
tolerability of GSK3335065 
administered as a single IV 
bolus (Part A) in healthy 
volunteers

As the study is terminated 
following the safety review 
in Part A Cohort 3 Sentinel 
dosing, only available Part 
A data will be reported

To 
determine 
the 
pharmacokinetic characteristics 
of GSK3335065 administered as 
a single IV bolus (Part A and C), 
and as a constant IV infusion 
over 7 days (Part B and C) in 
healthy volunteers

To 
determine 
the 
pharmacokinetic 
characteristics 
of 
GSK3335065 administered 
as a single IV bolus (Part A) 
in healthy volunteers

Determine 
dose/exposure 
effects of GSK3335065 on KMO 
inhibition 
(pharmacodynamics) 
in healthy volunteers (Part A)

Determine 
dose/exposure 
effects of GSK3335065 on 
KMO 
inhibition 
(pharmacodynamics) 
in 
healthy volunteers (Part A)
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To determine the safety and tolerability 
of GSK3335065 administered as a 
single IV bolus (Part A and C), and as a 
constant IV infusion over 7 days (Part B 
and C) in healthy volunteers

Adverse event / Serious Adverse event 
monitoring

Laboratory parameters (hematology, clinical 
chemistry, urinalysis)

12-lead ECG parameters (PR, QRS, QT, QTcF, 
etc.)

Vital signs (systolic and diastolic blood 
pressure, heart rate)
Secondary Objectives
Secondary Endpoints

To determine the pharmacokinetic 
characteristics of GSK3335065 
administered as a single IV bolus (Part 

Pharmacokinetic Parameters: AUC(0 – t), 
AUC(0 – ∞), tlast, Cmax, Cavg, tmax, CL, V, t½


CONFIDENTIAL
201570
7
Objectives
Endpoints
A and C), and as a constant IV infusion 
over 7 days (Part B and C) in healthy 
volunteers

Determine dose/exposure effect of 
GSK3335065 on KMO inhibition 
(pharmacodynamics) in healthy 
volunteers (All Parts)

Evaluate changes in levels of TRP metabolites 
(3HK and KYN)
Exploratory Objectives
Exploratory Endpoints

Determine the effect of KMO inhibition 
on other components of the KYN 
pathway of TRP metabolism (All Parts)

To investigate the plasma, urinary 
(Parts B & C) and biliary (Part B) 
metabolic pathways of GSK3335065 in 
healthy subjects

Evaluate changes in TRP, KYNA, 3-HAT, XA, 
QA and other pathway components.

GSK335065-related material in plasma, urine 
and bile


CONFIDENTIAL
201570
8
2.3.
Study Design
In Protocol Amendment 3 the design of Part A changed. As such the RAP will refer to 
the most recent protocol. Please refer to Protocol Amendment 2 for details of the original 
design.
Overview of Study Design and Key Features
Part A:
Revised Part A Schematic:


CONFIDENTIAL
201570
9
Overview of Study Design and Key Features
Part B:
Part C:


CONFIDENTIAL
201570
10
Overview of Study Design and Key Features
Design Features

Three part, randomized, placebo-controlled double blind 
(Sponsor unblind) dose escalation study 

Adaptive design to combine Single Ascending Dose (SAD) by 
IV bolus (Part A) with Ascending Doses by IV constant 
infusion dosing for 7 days (Part B) in healthy volunteers. 

Part A Cohorts 1– 8 are in a parallel group design in male 
participants.

Part B Cohorts are in a parallel group design in male 
participants

Part C will recruit WONCBP only, and a single dose by IV 
bolus will be investigated prior to multiple dose (7 day) being 
investigated, with both cohorts in a parallel group design
Dosing
Part A:

The first 2 subjects in each cohort will act as sentinels. 

One of these subjects will be randomized to active treatment, 
and the other will receive placebo. At least 24 hours will 
elapse (relative to the start of dosing) before administration of 
GSK3335065 to the subsequent subjects at the same dose 
level to allow for assessment of potential adverse 
experiences. 

If there are no clinically relevant safety or tolerability concerns, 
the remaining 6 subjects will receive the dose. 

In each cohort subjects are randomized to placebo or active
dose in a parallel design

Doses are administered through IV bolus


CONFIDENTIAL
201570
11
Overview of Study Design and Key Features
Part B: (as the study is terminated this is now not applicable)

Constant infusion dosing in Part B will be initiated after 
completion of dosing in Part A using an initial dose level that is 
considered safe and well tolerated and expected not to 
exceed the highest exposures safely achieved in Part A.

In all cohorts, each dose level will consist of an IV bolus
subsequently followed by a continuous IV infusion for seven
days.

There will be 2 sentinel subjects such that each new 
ascending dose will be staggered in Part B. One subject will 
be randomized to receive active treatment, and the other 
placebo. 

Once these subjects have completed the 7 day dosing, the 
safety and tolerability data will be reviewed. If there are no 
clinically relevant safety or tolerability concerns, the remaining 
6 subjects will be dosed. 
Part C: (as the study is terminated this is now not applicable)

Cohort 13 will investigate a single intravenous dose, and
Cohort 14 will investigate a multiple dose (continuous IV
infusion over 7 days) both in WONCBP only.  

Cohort 13 and 14 can commence once safety, tolerability and
PK data from the equivalent dose group is available from the
healthy male cohort.

Cohort 13 will complete prior to cohort 14 initiation.
Time & Events

Refer to Appendix 2: Schedule of Activities
Treatment Assignment

Subjects will be randomized to achieve a total of 112
evaluable participants

Part A will consist of 64 healthy male participants over eight
cohorts.

Part B will consist of 32 healthy male participants over four
cohorts

Part C will consist of 16 participants that are WONCBP over
two cohorts.

Each cohort will consist of 8 participants, with 6 randomized to
GSK3335065 and 2 randomized to placebo in accordance
with the randomization schedule generated by Clinical
Statistics, prior to the start of the study, using validated
internal software.  


CONFIDENTIAL
201570
12
Overview of Study Design and Key Features

For further details refer protocol for the study.
Interim Analysis

Informal data review will be performed between dose
escalation of each cohort in part A and between dose
escalation in part B (multiple dose ascending phase) to
support (i) whether the dose should be escalated and (ii) the
next dose level.  

A formal interim analysis will also occur after the completion of
Part A

After the study was terminated – the interim analysis will no
longer go ahead
Final Analysis

Final analysis is planned for participants who were screened
for the study prior to its termination. All data available prior to
termination of the study will be reported.
2.4.
Statistical Hypotheses
The main purpose of this study is to assess the safety and tolerability of single and 
repeated intravenous doses of GSK3335065 in healthy volunteers. No formal hypotheses 
are being tested and no statistical testing will be performed on the safety data.


CONFIDENTIAL
201570
13
3.
PLANNED ANALYSES
3.1.
Interim Analyses
Informal data review was performed between dose escalation of cohort 1 - 8 in part A and 
was due to be performed between dose escalation in part B (multiple dose ascending 
phase) to support (i) whether the dose should be escalated and (ii) the next dose level.  
PK and safety data (including any available PD data) was/will be reviewed. The GSK 
pharmacokineticist extracts PK data (including treatment information) from SMS2000 
via PKHARP. Standard concentration-time graphs were/will be derived for each 
participant by the GSK pharmacokineticist. These parameters were/will be summarised 
by each dose level and will be overlaid with initial model’s predictions for a comparison. 
The safety data was/will be listed and presented for each individual participant by 
treatment group. 
A formal interim analysis was also planned to occur after the completion of Part A. 
However, a safety review was performed for cohort 3 sentinel dosing and the decision 
was taken to terminate the study due to the occurrence of a Suspected Unexpected 
Serious Adverse Reaction (SUSAR). It was clear that the risk: benefit profile for 
GSK3335065 in healthy volunteers had significantly altered. All data available for Part A 
will now be used in the final reporting.
3.2.
Final Analyses
The final planned analyses will be performed after the completion of the following 
sequential steps:
1.
All participants screened for the study prior to its termination will be part of the final 
analysis.
2.
All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management.
3.
All criteria for unblinding the randomisation codes have been met. 
4.
Randomisation codes have been distributed according to RandAll NG procedures.
3.3.
Changes to the Protocol Defined Statistical Analysis Plan
Table 2 details the changes and deviations to the originally planned statistical analysis 
specified in the protocol [(Dated: 29-Nov-2017)].
Table 2
Changes to Protocol Defined Statistical Analysis Plan
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes

An 
exploratory 
statistical 
analysis may be performed on 
the biomarker data if deemed 
appropriate.

Biomarker data will be 
summarized

Lack of data following study 
termination


CONFIDENTIAL
201570
14
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes

PK/PD 
analysis 
of 
the 
biomarkers will be conducted 
between PD biomarkers and PK, 
other 
exploratory 
PK/PD 
analysis of the biomarkers may 
be conducted should changes in 
biomarkers be detected

PK/PD analysis will not be 
conducted
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Enrolled 
Population

Defined as all subjects who were enrolled for 
the trial irrespective of whether they were 
randomized or not and for whom a record 
exists on the study database.

Study Population
Screened 
Subjects

Screened Subjects population will be defined 
as all subjects who were screened regardless 
of whether they were successful 

Screen failures 
All Subjects

All Subjects population will be defined as all 
subjects randomised to treatment who receive 
at least one dose of study treatment. 

Subjects will be reported based on the 
treatment they actually received

Study Population

Safety

PD
PK Concentration

PK Concentration population will be defined as 
all subjects for whom a pharmacokinetic 
sample was obtained and analysed. 

PK

PK/PD
PK Parameter

PK Parameter population will be defined as all 
subjects in the ‘PK Concentration’ population 
who provide pharmacokinetic parameters. 

PK
NOTES:

Please refer to 11.10: List of Data Displays which details the population to be used 
for each display being generated.

Additional populations (to those described in the protocol) have been created for 
the purpose of required displays


CONFIDENTIAL
201570
15
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 1 dated: 2nd August
2017.

Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations and deviations which may lead to exclusion from the 
analysis are captured and categorised on the protocol deviations dataset. 

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 PIMS.


CONFIDENTIAL
201570
16
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Details Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description
Description[1]
Order[2]
Part A
A1
Part A. Cohort 1 GSK3335065 (IV) 
Active Dose 1 
GSK3335065 0.1 mg
2
A2
Part A. Cohort 2 GSK3335065 (IV) 
Active Dose 2
GSK3335065 0.25 mg
3
AA3
Part A. Cohort 3 GSK3335065 (IV) 
Active Dose 3
GSK3335065 1.3 mg
4
AA4
Part A. Cohort 4 GSK3335065 (IV) 
Active Dose 4
GSK3335065 Dose 4
5
AA5
Part A. Cohort 5 GSK3335065 (IV) 
Active Dose 5
GSK3335065 Dose 5
6
AA6
Part A. Cohort 6 GSK3335065 (IV) 
Active Dose 6
GSK3335065 Dose 6
7
AA7
Part A. Cohort 7 GSK3335065 (IV) 
Active Dose 7
GSK3335065 Dose 7
8
AA8
Part A. Cohort 8 GSK3335065 (IV) 
Active Dose 8
GSK3335065 Dose 8
9
PA1/
PA2/
PA3/
PA4/
PA5/
PA6/
PA7/
PA8[3]
Part A. Placebo Cohort 1/
Part A. Placebo Cohort 2/
Part A. Placebo Cohort 3/
Part A. Placebo Cohort 4/
Part A. Placebo Cohort 5/
Part A. Placebo Cohort 6/ 
Part A. Placebo Cohort 7/ 
Part A. Placebo Cohort 8
Placebo
1
Part B
B9
Part B. Cohort 9 GSK3335065 (IV) 
Active Dose 9
GSK3335065 Dose 9
2
B10
Part B. Cohort 10 GSK3335065 
(IV) Active Dose 10
GSK3335065 Dose 10 
3


CONFIDENTIAL
201570
17
Treatment Details Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description
Description[1]
Order[2]
B11
Part B. Cohort 11 GSK3335065 
(IV) Active Dose 11
GSK3335065 Dose 11
4
B12
Part B. Cohort 12 GSK3335065 
(IV) Active Dose 12
GSK3335065 Dose 12
5
PB9/
PB10/
PB11/
PB12
Part B. Placebo Cohort 9 /
Part B. Placebo Cohort 10/ 
Part B. Placebo Cohort 11/
Part B. Placebo Cohort 12
Placebo
1
Part C
C13
Part C. Cohort 13 GSK3335065 
(IV) Active Dose 13
GSK3335065 Dose 13
2
C14
Part C. Cohort 14 GSK3335065 
(IV) Active Dose 14
GSK3335065 Dose 14
3
PC13/
PC14
Part C. Placebo Cohort 13/
Part C. Placebo Cohort 14
Placebo
1
NOTES:
[1] As the study was terminated during Part A Cohort 3 the remaining doses are not completed
[2] Order represents treatments being presented in TFL, as appropriate.
[3] Placebo is pooled by part for all analysis except the pharmacodynamic analysis
Treatment comparisons will be displayed as follows using the descriptors as specified:
1.
GSK3335065 X.X mg vs Placebo
2.
GSK3335065 Y.Y mg vs Placebo etc.
5.2.
Baseline Definitions
For all endpoints apart from the PD biomarkers, the baseline value will be the latest pre-
dose assessment. For the PD data, the baseline will be the average of all pre-dose 
measurements (incl. Day -1). Unless otherwise stated in the schedule of activities, the 
mean of replicate assessments at any given time point will be used as the value for that 
time point (e.g. for ECGs).
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing.


CONFIDENTIAL
201570
18
5.2.1.
Derivations and Handling of Missing Baseline Data
Definition
Reporting Details
Change from Baseline
= Post-Dose Visit Value – Baseline
% Change from Baseline
= 100 x [(Post-Dose Visit Value – Baseline) / Baseline]
Maximum Change from Baseline
= Calculate the change from baseline at each given timepoint and 
determine the maximum change
NOTES :

Unless otherwise specified, the baseline definitions specified in Section 5.2 Baseline Definitions will be used for 
derivations for endpoints / parameters and indicated on summaries and listings.

Unless otherwise stated, if baseline data is missing no derivation will be performed and will be set to missing.

The baseline definition will be footnoted on all change from baseline displays.
5.3.
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


CONFIDENTIAL
201570
19
6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the “Screened”, “Enrolled” and “All
Subjects” 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 and 
Table 3 provides an overview of the analysis required during interim and final reporting.
Table 3
Overview of Planned Study Population Analyses
Endpoint / Parameter / Display Type
Data Displays Generated
Table
Figure
Listing
Subject Disposition
Subject Status and Reason for Study Withdrawal
Y
Reasons for Subject Withdrawal
Y
Screening Status and Reasons for Screen Failure
Y
Y
Subjects for Whom the Treatment Blind was Broken
Y
Randomized and Actual Treatments
Y
Protocol Deviations
Important Protocol Deviations
Y
Y
Subjects with Inclusion/Exclusion Criteria Deviations
Y
Populations Analysed
Study Populations
Y
Participants Excluded from any population
Y
Demographic and Baseline Characteristics
Demographic Characteristics
Y
Y
Age Ranges
Y
Race and Racial Combinations
Y
Y [1]
Prior and Concomitant Medications
Current Medical Conditions
Y
Past Medical Conditions
Y
Concomitant Medications
Y
Y
Exposure and Treatment Compliance
Exposure to Study Treatment
Y
Y
NOTES:

Y = Yes display generated at end of study only
[1] Listing of race.


CONFIDENTIAL
201570
20
7.
SAFETY ANALYSES
The safety analyses will be based on the “All Subjects” 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. Table 4 provides an 
overview of the planned analyses.
Table 4
Overview of Planned Adverse Event Analyses
Endpoint / Parameter/ Display Type
Absolute
Summary
Individual
T
F
L
Adverse Events (AEs)
All AEs by Maximum Intensity and SOC and PT
Y
Y
Common AEs (2 or more subjects) by Overall Frequency
Y
Common Non-serious AEs (2 or more subjects) by SOC and PT (Number of 
Participants and Occurrences)
Y
Drug-Related AEs by SOC and PT and Maximum Intensity
Y
Subject Numbers for Individual AEs
Y
Relationship Between AE SOCs, PT and Verbatim Text
Y
Assessment at Infusion site
Y
Serious and Other Significant AEs
All SAEs
Y
Y
All SAEs by SOC and PT (Number of Participants and Occurrences)
Y
Fatal Serious AEs
Y
Drug-Related Serious AEs 
Y
Drug-Related Fatal Serious AEs
Y
Reasons for Considering as a Serious AE
Y
AEs Leading to Withdrawal from Study / Permanent Discontinuation of Study 
Treatment by SOC and PT
Y
Y


CONFIDENTIAL
201570
21
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.
Table 5
Overview of Planned Clinical Laboratory Analyses
Endpoint / Parameter/ Display Type
Absolute
Change from BL
Summary
Individual
Summary
Individual
T
F
L
T
F
L
Chemistry
Chemistry Changes from Baseline 
Y
Worst Case Chemistry Results Relative to Normal 
Range Post-Baseline Relative to Baseline
Y
Chemistry Results by PCI
Y
Hematology
Hematology Changes From Baseline
Y
Worst Case Hematology Results Relative to Normal 
Range Post-Baseline Relative to Baseline
Y
Hematology Results by PCI
Y
Urinalysis
Urine Concentration Changes from Baseline
Y
Worst Case Urinalysis Results Relative to Normal 
Range Post-Baseline Relative to Baseline
Y
Urinalysis Results by PCI
Y
Hepatobiliary (Liver)
Liver Monitoring/Stopping Event Reporting
Y
Hepatobiliary Laboratory Abnormalities
Y
All Laboratory
All Laboratory Data for Subjects with any Value of PCI
Y
Laboratory Values of PCI
Y
Laboratory Data with Character Results [1]
Y
Urinalysis Data for Participants with Any Value of PCI
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated at end of study only, YI = Yes display 
generated at end of study and at interim, PCI = Potential Clinical Importance

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.

[1] Urine dipstick results


CONFIDENTIAL
201570
22
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.
Table 6
Overview of Planned Other Safety Analyses
Endpoint / Parameter/ Display Type
Absolute
Change from BL
Summary
Individual
Summary
Individual
T
F
L
T
F
L
ECG
ECG Findings 
Y
Maximum QTc Values Post-Baseline Relative to 
Baseline by Category
Y
ECG Values by Visit [1]
Y
Y
Y
Y
Summary of Maximum Increase in QTc Values Post-
Baseline Relative to Baseline by Category 
Y
All ECG Values for Subjects with any Value of PCI
Y
ECG Values of PCI
Y
All ECG Findings for Participants with an Abnormal 
ECG Finding
Y
Abnormal ECG Findings
Y
Echocardiogram and Continuous ECG monitoring
Echocardiogram Findings
Y
ECG monitoring and Telemetry Findings
Y
Vital Signs
Vital Signs by Visit
Y
Y
Y
Y
Worst Case Vital Signs Results Relative to Normal 
Range Post-Baseline Relative to Baseline
Y
All Vital Signs for Subjects with any Value of PCI
Y
Y
Vital Signs of PCI
Y
Y
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated at the end of the study, PCI = Potential Clinical 
Importance

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
[1] Includes continuous cardiac monitoring results


CONFIDENTIAL
201570
23
8.
PHARMACOKINETIC ANALYSES
8.1.
Primary Pharmacokinetic Analyses
8.1.1.
Endpoint / Variables
The pharmacokinetic (PK) parameters of interest are: AUC(0 – t), AUC(0 – ∞), tlast, Cmax, 
Cavg, tmax, CL, V, and t½.
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
The analysis will be performed by, or be under the direct auspices of, Clinical 
Pharmacology Modelling and Simulation (CPMS), GlaxoSmithKline. PK parameters will 
be calculated by standard non-compartmental analysis in WinNonLin, using 
concentration-time data based on actual sample times, as described in the standard 
operating procedure SOP-314000. All derived PK parameters will be listed and 
summarized according to SOP-BMD-4002 (Standard Statistical Methods for the analysis 
of Pharmacokinetic Data).
Table 7
Derived Pharmacokinetic Parameters
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-∞)
Area under the concentration-time curve extrapolated to infinity will be calculated as: 
AUC = AUC(0-t) + C(t) / lambda_z
%AUCex
The percentage of AUC (0-∞) obtained by extrapolation (%AUCex) will be calculated as:
[AUC(0-inf) – AUC(0-t)] / AUC(0-inf) x 100
Cmax
Maximum observed concentration, determined directly from the concentration-time data.
tmax
Time to reach Cmax, determined directly from the concentration-time data.
t½
Apparent terminal half-life will be calculated as: 
t½ = ln2 / lambda_z
Clearance 
(CL)
CL = Dose / AUC (0-inf)
Volume of 
Distribution 
at Steady 
State 
(Vdss)
Vdss = CL x MRTiv 
where MRTiv is Mean Residence Time and Mean Absorption Time and is given by 
MRTiv = (AUMC(0-inf)/AUC(0-inf)) – T/2 where T is the infusion duration


CONFIDENTIAL
201570
24
Parameter
Parameter Description
tlast
Time of the last measurable concentration, determined directly from the concentration-
time data.
NOTES:

Additional parameters may be included as required.

Lambda_z is the terminal phase rate constant.
8.1.2.
Summary Measure
Unless otherwise specified, endpoints / variables defined in Section 8.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
Individual plasma GSK3335065 concentration-time profiles will be plotted by treatment 
(linear and semi-linear profiles). Blood sampling times will be related to the start of the 
infusion procedure. Actual sampling times will be used to calculate all the non-
compartmental pharmacokinetic parameters. Individual concentrations of GSK3335065 
in plasma will be listed and summarised by treatment and nominal time.  
8.1.3.
Population of Interest
The pharmacokinetic (PK) analyses will be based on the “PK Concentration” and “PK 
Parameter” population, unless otherwise specified.
8.1.4.
Strategy for Intercurrent (Post-Randomization) Events
No statistical analysis will be completed for the pharmacokinetic endpoints, only 
summary statistics. Only the single dose data is available for analysis so this section is 
irrelevant to the PK analysis.
8.1.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK IDSL Data Standards and statistical principles.
For each of the parameters mentioned above the following summary statistics will be 
calculated and tabulated by dose group for Part A:

Untransformed Data: N, n, arithmetic mean, 95% confidence interval (CI) for 
the arithmetic mean, SD, median, minimum, maximum.

Loge-transformed Data: Geometric mean, 95% CI for the geometric mean, SD 
of loge-transformed data and %CVb.
For tmax, tlast and t½ the summary statistics specified for untransformed data above will 
be generated.


CONFIDENTIAL
201570
25
9.
PHARMACODYNAMIC BIOMARKER ANALYSES
9.1.
Primary and Exploratory Pharmacodynamic Analyses
9.1.1.
Endpoint / Variables
For KMO inhibition, the key endpoint of interest are the TRP metabolites (i.e. 3HK and 
KYN). As part of the exploratory analysis other metabolites such as TRP, KYNA, 3-
HAT, XA, QA and other pathway components are of interest.
To investigate the metabolic pathway of GSK335065 in healthy participants, 
GSK335065-related material in plasma, urine and bile will be considered.
9.1.2.
Summary Measure
Unless otherwise specified, endpoints / variables defined in Section 9.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed by treatment group and planned relative time.
9.1.3.
Population of Interest
The pharmacodynamic analyses and biomarker will be based on the “All Subjects” 
population, unless otherwise specified.
9.1.4.
Strategy for Intercurrent (Post-Randomization) Events
No statistical analysis will be completed for the pharmacokinetic endpoints, only 
summary statistics. Only the single dose data is available for analysis so this section is 
irrelevant to the PD analysis.
9.1.5.
Other details
Due a procedural issue in analysing cohort 3 pharmacodynamic samples, cohort 3 
pharmacodynamic levels cannot be compared against cohort 1 and cohort 2. 
For the pharmacodynamic related displays only: participants in cohort 3 (placebo or 
active) will be presented separately from cohorts 1 and 2 (i.e. placebo will not be pooled 
across cohorts). In cohorts 1 and 2, placebo PD samples were not collected.
Please note that the Anthranilic acid (AA) and quinolinic acid (QA) metabolites were not 
measured and as such they will not be reported.


CONFIDENTIAL
201570
26
10.
REFERENCES
 GlaxoSmithKline, Greenford UK, Statistics and Pharmacokinetics in 
Clinical Pharmacology Studies PhUSE 2006 Paper ST03
GlaxoSmithKline Document Number 2015N261138_03 201570, Randomized, Double-
blind, Placebo Controlled Dose Escalation Study to Evaluate Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of Single Doses (Intravenous bolus) and 
constant intravenous infusion over 7 Days of GSK3335065 in Healthy Adult Subjects 
(Amendment 3 – 29-Nov-2017)
GUI_137354, Information for Authors: Reporting and Analysis Plan (RAP), Global
GUI_51487, Non-Compartmental Analysis of Pharmacokinetic Data, CPMS Global
SOP_314000, Non-Compartmental Analysis of Clinical Pharmacokinetic Data
SOP_54838, Development, Review & Approval of Reporting & Analysis Plan (RAP),
Global
PPD


CONFIDENTIAL
201570
27
11.
APPENDICES
11.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
Inclusion Criteria
Number
Inclusion Description
1
Participant must be 18 to 50 years of age inclusive, at the time of signing the 
informed consent. In Part C (WONCBP) participants must be between 18 and 60 
years of age.
2
Participants who are overtly healthy as determined by medical evaluation including 
medical history, physical examination, laboratory tests, and cardiac monitoring.
3
A subject with a clinical abnormality or laboratory parameter(s) which is/are not 
specifically listed in the inclusion or exclusion criteria, outside the reference range for 
the population being studied may be included only if the investigator in consultation 
with the Medical Monitor if required agree and document that the finding is unlikely to 
introduce additional risk factors and will not interfere with the study procedures.
4
Body weight >50kg and body mass index (BMI) within the range 18.5 – 32 kg/m2 
(inclusive).
5
Abstinence/contraceptives: Length of time required for abstinence or use of
contraceptives should take into account the reproductive toxicity profile including 
genotoxicity and teratogenicity, the size of the molecule, and the number of doses.
Male participants:
A male participant must agree to use contraception as detailed in Appendix 5 of the
protocol during the treatment period and for at least 2 days after the last dose of 
study treatment and refrain from donating sperm during this period.
Female participants:
Only female participants of non childbearing potential (WONCBP) as defined in the 
protocol Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information are eligible to participate.
6
Capable of giving signed informed consent as described in Appendix 3 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.


CONFIDENTIAL
201570
28
Exclusion Criteria
Number
Inclusion Description
1
Alanine transaminase (ALT) and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is 
acceptable if bilirubin is fractionated and direct bilirubin <35%).
2
Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones)
3
QTcF >450 msec from a mean of triplicate readings taken no more than 2 minutes 
apart
4
Clinically significant abnormal echocardiogram
5
The participant has a history or current evidence of depression, bipolar disorder, 
suicidal ideation and behaviour, or a lifetime history of suicide attempt.
6
cTn or BNP >ULN
7
Use of prohibited medication (Section 7.7 & Section 7.8) of protocol
8
The subject has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day in the current 
study: 30 days, 5 half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer).
9
Exposure to more than four new chemical entities within 12 months prior to the first 
dosing day
10
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. For
potent immunosuppressive agents, subjects with presence of hepatitis B core 
antibody (HBcAb) should also be excluded.
11
A positive pre-study drug/alcohol screen.
12
A positive test for human immunodeficiency virus (HIV) antibody.
13
Where participation in the study would result in donation of blood or blood products 
in excess of 500 mL within 84 days.
14
Poor or unsuitable venous access
15
History of regular alcohol consumption within 6 months of the study defined as: An 
average weekly intake of >14 units. One unit is equivalent to 8 g of alcohol: a half-
pint


CONFIDENTIAL
201570
29
Number
Inclusion Description
16
History of sensitivity to any of the study medications, or components thereof or a
history of drug or other allergy that, in the opinion of the investigator or Medical
Monitor, contraindicates their participation.
17
History of smoking within 6 months of the study.


CONFIDENTIAL
201570
30
11.2.
Appendix 2: Schedule of Activities
11.2.1.
Protocol Defined Schedule of Events
Please refer to Protocol Amendment 3 Section 2 for full details of the Schedule of 
Activities.


CONFIDENTIAL
201570
31
11.3.
Appendix 3: Assessment Windows
11.3.1.
Definitions of Assessment Windows for Analyses
Nominal time will be used for all analysis except PK analysis where planned and actual 
time will be used.


CONFIDENTIAL
201570
32
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 
start and/or stop date and time of the study treatment
Study Phase
Definition
Pre-Treatment 
Date ≤ Study Treatment Start Date
On-Treatment
Study Treatment Start Date < Date ≤ Study Treatment Stop Date
Post-Treatment
Date > Study Treatment Stop Date 
11.4.1.1.
Study Phases for Concomitant Medication
Study Phase
Definition
Prior
If medication end date is not missing and is before enrolment
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.
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. (plus, washout or protocol-specified time limit (e.g. half-life of 
drug, certain number of days, etc.).

Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment Stop Date 
[+ 5 x half-life].
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.


CONFIDENTIAL
201570
33
11.5.
Appendix 5: Data Display Standards & Handling 
Conventions
11.5.1.
Reporting Process
Reporting Process
Software

The currently supported versions of SAS software 9.4 will be used.
Reporting Area
HARP Server
UK1SALX00175
HARP Area
arenv/arprod/GSK3335065/mid201570/final_01
QC Spreadsheet
arenv/arprod/GSK3335065/mid201570/final_01/documents
Analysis Datasets 

Analysis datasets will be created according to Legacy GSK A&R dataset standards
Generation of RTF Files

RTF files will be generated for the end of study SAC
11.5.2.
Reporting Standards
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated:

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 
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.

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 participant’s listings. 


CONFIDENTIAL
201570
34
Reporting Standards

Visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) will be 
included in listings but omitted from figures, summaries and statistical analyses.
Unscheduled Visits

Unscheduled visits will not be included in summary tables.

Unscheduled visits will not be included in 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, %
Reporting of Pharmacokinetic Concentration Data
Descriptive Summary 
Statistics
Refer to IDSL Statistical Principle 6.06.1
Assign zero to NQ values (Refer to GUI_51487 for further details)
Reporting of Pharmacokinetic Parameters
Descriptive Summary 
Statistics (Log 
Transformed)
N, n, geometric mean, 95% CI of geometric mean, standard deviation (SD) of 
logged data and [between and or within] geometric coefficient of variation (CVb/w 
(%)) will be reported.
[1] CVb (%) = √ (exp(SD2) - 1) * 100
(SD = SD of log transformed data) 
(MSE = mean square error from mixed effect model of loge-transformed data).
Parameters Not 
Being Log 
Transformed
Tmax, t1/2, tlast
Summary Tables
Cmax, tmax, AUC(0-t), AUC (0-∞), CL, V, t1/2, and tlast as data permit
Listings
All parameters collected in the dataset will be listed
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.


CONFIDENTIAL
201570
35
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 the 
[PKOne standards]
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 SOP_3140000
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.


CONFIDENTIAL
201570
36
11.6.
Appendix 6: Derived and Transformed Data
11.6.1.
General
Multiple Measurements at One 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 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 with both High and Low values for Normal Ranges at any post-baseline visits 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 randomisation date:

Ref Date = Missing                       → Study Day = Missing 

Ref Date < Randomisation Date   → Study Day = Ref Date – Randomisation Date    

Ref Data ≥ Randomisation Date   → Study Day = Ref Date – (Randomisation 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)

Frequency is 2 for BID and 1 for QD. Treatment compliance could be greater than 100% if there are 
events of overdose. Cumulative compliance (since Day 1) at each visit will be calculated.

Planned Treatment Duration is defined as the number of days planned on study treatment. As Part A is 
single dose this would be one day.
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 randomized but did not report a treatment start date will be categorised as 
having zero days of exposure. 
Demographics
Age

GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed as 
follows:
o
Any participant with a missing day will have this imputed as day ‘15’. 
o
Any participant with a missing date and month will have this imputed as ‘30th June’.

Birth date will be presented in listings as ‘YYYY’.
Body Mass Index (BMI)

Calculated as Weight (kg) / [Height (m)2


CONFIDENTIAL
201570
37
11.6.3.
Safety
ECG Parameters
RR Interval

IF RR interval (msec) is not provided directly, then RR can be derived as :
[1] If QTcB is machine read & QTcF is not provided, then :
[2] If QTcF is machine read and QTcB is not provided, then: 

If ECGs are manually read, the RR value preceding the measurement QT interval should be a 
collected value THEN do not derive.
Corrected QT Intervals

When not entered directly in the eCRF, corrected QT intervals by Bazett’s (QTcB) and 
Fredericia’s (QTcF) formulas will be calculated, in msec, depending on the availability of other 
measurements.

IF RR interval (msec) is provided then missing QTcB and/or 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 indicated as less than x in the comment field) is present, 
the corresponding numeric value will be imputed as 0.5 * x
11.6.4.
Pharmacokinetic
PK Parameters

Please see Table 7 for derived Pharmacokinetic parameters
11.6.5.
Pharmacodynamic
PD Parameters

The concentrations and change from baseline values (with baseline defined as the average of 
all pre-dose measurements (incl. Day -1)) will be summarized by planned time points.


CONFIDENTIAL
201570
38
11.7.
Appendix 7: Reporting Standards for Missing Data
11.7.1.
Premature Withdrawals
Element
Reporting Detail
General

All participants who withdraw prematurely from the study/study drug will be 
documented and the reason for their withdrawal recorded in the final Clinical 
Pharmacology Study Report (CPSR).  

Withdrawn participants may be replaced in the study except in Part A Cohorts 
(3-8).

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.
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 using a “blank” in participant listing displays. 
Unless all data for a specific visit are missing in which case the data is 
excluded from the table. 
o Answers such as “Not applicable” and “Not evaluable” are not considered to 
be missing data and should be displayed as such.
Outliers

Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
11.7.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General
Partial dates will be displayed as captured in participant listing displays.
Adverse 
Events

The eCRF allows for the possibility of partial dates (i.e., only month and year) to 
be recorded for AE start and end dates; that is, the day of the month may be 
missing. In such a case, the following conventions will be applied for calculating 
the time to onset and the duration of the event:
o
Missing Start Day: First of the month will be used unless this is before the 
start date of study treatment; in this case the study treatment start date will 
be used and hence the event is considered On-treatment as per Appendix 
4: Treatment States and Phases.
o
Missing Stop Day: Last day of the month will be used, unless this is after the 
stop date of study treatment; in this case the study treatment stop date will 
be used.

Completely missing start or end dates will remain missing, with no imputation 
applied. Consequently, time to onset and duration of such events will be 


CONFIDENTIAL
201570
39
Element
Reporting Detail
missing.

AE time will be collected and if it is missing the following imputation will be 
applied:
o
If AE start time is missing then time is imputed as 00:00 unless the AE 
occurs on the first day of dosing in which case it has been imputed as the 
time of first dose. 
o
If AE end time is missing then time is imputed as 23:59.

Start or end dates which are completely missing (i.e. no year specified) will 
remain missing, with no imputation applied.
11.7.2.2.
Handling of Partial Dates
Element
Reporting Detail
Concomitant 
Medications

Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will 
be used for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month.

The recorded partial date will be displayed in listings.
Adverse 
Events

Any partial dates for adverse events will be raised to data management. If the 
full date cannot be ascertained, the following assumptions will be made:
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
However, if these results in a date prior to Week 1 Day 1 and the event 
could possibly have occurred during treatment from the partial information, 
then the Week 1 Day 1 date will be assumed to be the start date. 
o
The AE will then be considered to start on-treatment (worst case).
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.
11.7.2.3.
Handling of Missing Data for Statistical Analysis
Element
Reporting Detail
Imputation

There will be no imputation in any statistical analysis


CONFIDENTIAL
201570
40
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
Hemoglobin 
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 
mmol/L
30
Calcium
mmol/L
2
2.75
Creatinine
mmol/L
∆from BL
↑ 44.2
Glucose
mmol/L
3
9
Magnesium
mmol/L
0.5
1.23
Phosphorus
mmol/L
0.8
1.6
Potassium
mmol/L
3
5.5
Sodium
mmol/L
130
150
Total CO2
mmol/L
18
32
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
Please review the IDSL standards for the Urinalysis PCI criteria.


CONFIDENTIAL
201570
41
11.8.2.
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
Absolute QTc Interval
msec
> 450 [1]
> 450 [2]
≤ 479 [2]
≥ 480 [2]
≤ 499 [2]
≥ 500 [2]
Absolute PR Interval
msec
< 110 [1]
> 220 [1]
Absolute QRS Interval
msec
< 75 [1]
> 110 [1]
Change from Baseline
Increase from Baseline QTc
msec
> 60 [1]
msec
> 30 [2]
≤ 59 [2]
msec
≥ 60 [2]
NOTES: 
1.
To be used to flag ECG values of PCI for tables not split by category
2.
To be used to flag ECG values of PCI for tables which are split by category
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
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


CONFIDENTIAL
201570
42
11.9.
Appendix 9: Abbreviations & Trade Marks
11.9.1.
Abbreviations
Abbreviation
Description
3-HAA (3-HAT)
3-hydroxyanthranilic acid
μg
Microgram
ADaM
Analysis Data Model
AE
Adverse Event
AIC
Akaike's Information Criteria
A&R
Analysis and Reporting 
AUC 
AUC Area under concentration-time curve
AUC(0-inf) 
Area under the concentration-time curve from time zero (pre-dose) extrapolated 
to infinite time
AUC(0-t) 
Area under the concentration-time curve from time zero (pre-dose) to last time 
of quantifiable concentration within a participant across all treatments
AUC(0-tau)
Area under the concentration-time curve from time zero (pre-dose) during a 
dosage interval
AUC (Ro)
Observed Accumulation Ratio for AUC observed accumulation ratio for AUC
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CL 
Clearance
Cmax
Maximum observed concentration
CPMS
Clinical Pharmacology Modelling & Simulation
CS
Clinical Statistics
CSR
Clinical Study Report
C-SSRS
Columbia Suicide Severity Rating Scale
(Cτ)
Trough concentration (Cτ)
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
GSB
Global Safety Board
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


CONFIDENTIAL
201570
43
Abbreviation
Description
ITT
Intent-To-Treat
KYNA
kynurenic acid
MMRM
Mixed Model Repeated Measures
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PKCNC
Pharmacokinetic concentration
PP
PK Parameter
PopPK
Population PK
QA
quinolinic acid
QC
Quality Control
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RAMOS
Randomization & Medication Ordering System 
SAC
Statistical Analysis Complete
SDSP
Study Data Standardization Plan
SDTM
Study Data Tabulation Model
SOP
Standard Operation Procedure
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
TRP
Tryptophan
XA
xanthurenic acid
11.9.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
NONE
NONMEM
SAS
WinNonlin


CONFIDENTIAL
201570
44
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
N/A
Safety
2.1 to 2.28
N/A
Pharmacokinetic
3.1 to 3.3
3.1
Pharmacodynamic 
4.1 to 4.2
4.1 to 4.4
Section
Listings
ICH Listings
1 to 34
Other Listings
35 to 41
11.10.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 11: Example Mock Shells for Data Displays
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
Pharmacokinetic
PK_Fn
PK_Tn
PK_Ln
Pharmacodynamic 
PD_Fn
PD_Tn
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
DR
Dry Run
SAC
Statistical Analysis Complete


CONFIDENTIAL
201750
45
11.10.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
All Subjects
ES8
Summary of Subject Status and Reason for Study 
Withdrawal (Part A)
ICH E3, FDAAA, EudraCT
DR, SAC
1.2.
Screened
ES6
Summary of Screening Status and Reasons for Screen 
Failure (Part A)
Journal Requirements
DR, SAC
Demographic and Baseline Characteristics
1.3.
All Subjects
DM1
Summary of Demographic Characteristics (Part A)
ICH E3, FDAAA, EudraCT
DR, SAC
1.4.
Enrolled
DM11
Summary of Age Ranges (Part A)
EudraCT
DR, SAC
1.5.
All Subjects
DM5
Summary of Race and Racial Combinations (Part A)
ICH E3, FDA, FDAAA, EudraCT
DR, SAC
Protocol Deviations
1.6.
All Subjects
DV1
Summary of Important Protocol Deviations (Part A)
ICH E3
DR, SAC
Populations Analysed
1.7.
Screened
SP1
Summary of Study Populations (Part A)
IDSL
DR, SAC
Prior and Concomitant Medications
1.8.
All Subjects
MH1
Summary of Current Medical Conditions (Part A)
ICH E3
SAC
1.9.
All Subjects
MH1
Summary of Past Medical Conditions (Part A)
ICH E3 
SAC
1.10.
All Subjects
CM1
Summary of Concomitant Medications (Part A)
ICH E3
SAC
Exposure and Treatment Compliance
1.11.
All Subjects
EX5
Summary of Exposure to Study Treatment (Part A)
ICH E3
DR, SAC


CONFIDENTIAL
201750
46
11.10.5.
Safety Tables
Safety: Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
2.1.
All Subjects
AE5A
Summary of All Adverse Events by Maximum Intensity and 
System Organ Class and Preferred Term (Part A)
ICH E3
DR, SAC
2.2.
All Subjects
AE5A
Summary of All Drug-Related Adverse Events by System 
Organ Class and Preferred Term and Maximum Intensity 
(Part A)
ICH E3
SAC
2.3.
All Subjects
AE3
Summary of Common (2 or more subjects) Adverse Events
by Overall Frequency (Part A)
ICH E3
SAC
2.4.
All Subjects
AE15
Summary of Common (More than 2 occurrences) 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
2.5.
All Subjects
CP_AE1p
Summary of All Serious Adverse Events (Part A)
Sort Adverse Event Displays by SOC
DR, SAC
2.6.
All Subjects
CP_AE1p
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from 
Study by System Organ Class and Preferred Term (Part A)
IDSL
SAC
2.7.
All Subjects
CP_AE1p
Summary of all Drug Related Serious Adverse Events (Part 
A)
ICH E3
Sort Adverse Event Displays by 
SOC
SAC


CONFIDENTIAL
201750
47
Safety: Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.8.
All Subjects
AE16
Summary of Serious Adverse Events by System Organ 
Class and Preferred Term (Number of Participants and 
Occurrences)
FDAAA, EudraCT
SAC
Laboratory: Chemistry 
2.9.
All Subjects
LB1
Summary of Chemistry Changes from Baseline (Part A)
ICH E3
Includes Baseline values.
Includes pre-specified 
parameters repeated in 
conventional units.
SAC
2.10.
All Subjects
LB3
Summary of Chemistry Results by PCI (Part A)
Include Baseline planned 
timepoint and category instead 
of change category
SAC
2.11.
All Subjects
LB15
Summary of Worst Case Chemistry Results Relative to 
Normal Range Post-Baseline Relative to Baseline (Part A)
ICH E3
SAC
Laboratory: Hematology
2.12.
All 
Subjects
LB1
Summary of Hematology Changes from Baseline (Part A)
ICH E3
Includes baseline values.
SAC
2.13.
All Subjects
LB15
Summary of Worst Case Hematology Results Relative to 
Normal Range Post-Baseline Relative to Baseline (Part A)
ICH E3
SAC
2.14.
All Subjects
LB3
Summary of Hematology Results by PCI (Part A)
As per 2.10
SAC


CONFIDENTIAL
201750
48
Safety: Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Laboratory: Urinalysis
2.15.
All Subjects
LB1
Summary of Urine Concentration Changes from Baseline 
(Part A)
ICH E3
Includes Baseline values.
SAC
2.16.
All Subjects
UR1
Summary of Worst Case Urinalysis Results (Discrete or 
Character Values) Post-Baseline Relative to Baseline (Part 
A)
ICH E3
Define change categories 
according to actual values 
expected from lab dataset
SAC
2.17.
All Subjects
LB3
Summary of Urinalysis Results by PCI (Part A)
As per 2.10
SAC
Laboratory: Hepatobiliary (Liver)
2.18.
All Subjects
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting 
(Part A)
IDSL
SAC
2.19.
All Subjects
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities (Part 
A)
IDSL
SAC
ECG
2.20.
All Subjects
EG1
Summary of ECG Findings (Part A)
IDSL
SAC
2.21.
All Subjects
EG10
Summary of Maximum QTc Values Post-Baseline Relative 
to Baseline by Category (Part A)
IDSL
DR, SAC
2.22.
All Subjects
EG2
Summary of ECG Values by Visit (Part A)
IDSL
Includes continuous cardiac 
monitoring results
SAC


CONFIDENTIAL
201750
49
Safety: Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.23.
All Subjects
EG2
Summary of Change from Baseline in ECG Values by Visit 
(Part A)
IDSL
Includes Baseline values.
Includes continuous cardiac 
monitoring results
SAC
2.24.
All Subjects
EG11
Summary of Maximum Increase in QTc Values Post-
Baseline Relative to Baseline by Category (Part A)
IDSL
SAC
Vital Signs
2.25.
All Subjects
VS1
Summary of Vital Signs by Visit (Part A)
ICH E3
Includes Baseline values.
SAC
2.26.
All Subjects
VS1
Summary of Change from Baseline in Vital Signs by Visit 
(Part A)
Includes Baseline values.
SAC
2.27.
All Subjects
VS3
Summary of Worst Case Vital Signs Results Relative to 
Normal Range Post-Baseline Relative to Baseline (Part A)
IDSL
SAC
2.28.
All Subjects
VS8
Summary of Change from Baseline Vital Signs by PCI 
(Part A)
Include Baseline planned 
timepoint and category instead 
of change category
SAC


CONFIDENTIAL
201750
50
11.10.6.
Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Pharmacokinetic Concentration/Parameters
3.1.
PKCNC
PK01
Summary of Plasma GSK3335065 Pharmacokinetic 
Concentration-Time Data (Part A)
SAC
3.2.
PP
PK03
Summary of Derived Plasma GSK3335065 
Pharmacokinetic Parameters (Part A)
SAC
3.3.
PP
PK05
Summary of Log-Transformed Derived Plasma 
GSK3335065 Pharmacokinetic Parameters (Part A)
SAC


CONFIDENTIAL
201750
51
11.10.7.
Pharmacokinetic Figures
Pharmacokinetic: Figures
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Pharmacokinetic Concentration/Parameters
3.1.
PKCNC
PK16a
Individual Plasma GSK3335065 Concentration-Time Plots 
(Linear and Semi-log)
SAC


CONFIDENTIAL
201750
52
11.10.8.
Pharmacodynamic Tables
Pharmacodynamic Figures
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
KMO inhibition
4.1.
All Subjects
PD1
Summary of primary TRP Metabolite Data by Treatment 
Group and Time (Part A)
3HK and KYN
SAC
4.2.
All Subjects
PD3
Summary of change from baseline in primary TRP 
Metabolite Data by Treatment Group and Time (Part A)
3HK and KYN
SAC


CONFIDENTIAL
201750
53
11.10.9. Pharmacodynamic Figures
Pharmacodynamic Figures
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
KMO inhibition
4.1.
All Subjects
PK16a
Individual primary TRP Metabolite Plots by Time (Part A)
3HK and KYN
Programming Notes: Only use 
the linear scale, replace 
concentration units as 
appropriate and create plots for 
each metabolite on a new page
SAC
4.2.
All Subjects
PK16a
Individual change from baseline in primary TRP Metabolite 
Plots by Time (Part A)
3HK and KYN
Programming Notes: As per 
Figure 4.1
SAC
4.3.
All Subjects
PK16a
Individual exploratory TRP Metabolite Plot by Time (Part A)
TRP, KYNA, AA, 3-HAT, XA, QA
and any other pathway 
components
Programming Notes: As per 
Figure 4.1
SAC
4.4.
All Subjects
PK16a
Individual change from baseline in exploratory TRP 
Metabolite Plots by Time (Part A)
TRP, KYNA, AA, 3-HAT, XA, QA
and any other pathway 
components
Programming Notes: As per 
Figure 4.1
SAC


CONFIDENTIAL
201750
54
11.10.10. ICH Listings
ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.
All Subjects
ES2
Listing of Reasons for Study Withdrawal
ICH E3
DR, SAC
2.
Screened 
Subjects
ES7
Listing of Reasons for Screen Failure
Journal Guidelines
SAC
3.
All Subjects
BL1
Listing of Subjects for Whom the Treatment Blind was 
Broken
ICH E3
DR, SAC
4.
All Subjects
TA1
Listing of Randomised and Actual Treatments
IDSL
DR, SAC
Protocol Deviations
5.
All Subjects
DV2
Listings of Important Protocol Deviations
ICH E3
DR, SAC
6.
All Subjects
IE3
Listing of Subjects with Inclusion/Exclusion Criteria 
Deviations
ICH E3
DR, SAC
Demographic and Baseline Characteristics
7.
All Subjects
DM2
Listing of Demographic Characteristics
ICH E3
SAC
8.
All Subjects
DM9
Listing of Race
ICH E3
SAC
Populations Analysed
9.
Screened
SP3
Listing of Participants Excluded from Any Population
ICH E3
SAC
Prior and Concomitant Medications
10.
All Subjects
CP_CM3
Listing of Concomitant Medications
IDSL
SAC


CONFIDENTIAL
201750
55
ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Exposure and Treatment Compliance
11.
All Subjects
EX3
Listing of Exposure Data
ICH E3
SAC
Adverse Events
12.
All Subjects
AE8CP
Listing of All Adverse Events
ICH E3
DR, SAC
13.
All Subjects
AE2
Listing of Relationship Between Adverse Event System 
Organ Classes, Preferred Terms, and Verbatim Text
IDSL
SAC
14.
All Subjects
AE7
Listing of Subject Numbers for Individual Adverse Events
ICH E3
SAC
Serious and Other Significant Adverse Events
15.
All Subjects
AE8CPa
Listing of Serious Adverse Events
ICH E3
DR, SAC
16.
All Subjects
AE8CPa
Listing of Fatal Serious Adverse Events
ICH E3
SAC
17.
All Subjects
AE8CP
Listing of Adverse Events Leading to Withdrawal from 
Study / Permanent Discontinuation of Study Treatment
ICH E3
DR, SAC
18.
All Subjects
AE14
Listing of Reasons for Considering as a Serious Adverse 
Event
SAC
19.
All Subjects
AE8CP
Listing of All Drug-Related Fatal Serious Adverse Events
SAC
All Laboratory
20.
All Subjects
LB5
Listing of All Laboratory Data for Participants with Any 
Value of Potential Clinical Importance 
ICH E3
Display ALL labs for a subject 
who experienced a value of 
potential clinical importance.
Include time with date
SAC


CONFIDENTIAL
201750
56
ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
21.
All Subjects
LB5
Listing of Laboratory Values of Potential Clinical 
Importance 
Include time with date
SAC
22.
All Subjects
LB14
Listing of Laboratory Data with Character Results 
ICH E3
Dipstick results
SAC
23.
All Subjects
UR2A
Listing of Urinalysis Data for Participants with Any Value of 
Potential Clinical Importance
ICH E3
Display ALL data for a subject 
who experienced a value of 
potential clinical importance.
SAC
ECG
24.
All Subjects
EG3
Listing of All ECG Values for Participants with Any Value of 
Potential Clinical Importance
IDSL
Display ALL ECGs for a subject 
who experienced a value of 
potential clinical importance.
SAC
25.
All Subjects
EG3
Listing of ECG Values of Potential Clinical Importance 
IDSL
SAC
26.
All Subjects
EG5
Listing of All ECG Findings for Participants with an 
Abnormal ECG Finding
IDSL
SAC
27.
All Subjects
EG5
Listing of Abnormal ECG Findings
IDSL
SAC
28.
All Subjects
EG3
Listing of All ECG Values 
SAC
29.
All Subjects
EG3
Listing of All Change from Baseline ECG Values 
SAC


CONFIDENTIAL
201750
57
ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Vital Signs
30.
All Subjects
VS4
Listing of All Vital Signs Data for Participants with Any 
Value of Potential Clinical Importance
IDSL
Display ALL Vital Signs for a 
subject who experienced a value 
of potential clinical importance.
Include participants flagged with 
change from baseline vital sign 
values of PCI
SAC
31.
All Subjects
VS4
Listing of Vital Signs of Potential Clinical Importance 
IDSL
SAC
32.
All Subjects
VS4
Listing of Change from Baseline in Vital Signs of Potential 
Clinical Importance 
IDSL
SAC
33.
All Subjects
VS4
Listing of All Vital Signs Values 
SAC
34.
All Subjects
VS4
Listing of All Change from Baseline Vital Signs Values 
SAC
11.10.11. Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Other Adverse Events Listings
35.
All Subjects
SAFE_L1
Listing of Assessment at Infusion Site
SAC


CONFIDENTIAL
201750
58
Other ECG Listings
36.
All Subjects
SAFE_L2
Listing of Echocardiogram Findings
SAC
37.
All Subjects
SAFE_L2
Listing of ECG monitoring and Telemetry Findings
SAC
Pharmacokinetic Concentration/Parameters
38.
PKCNC
PK07
Listing of Plasma GSK3335065 Pharmacokinetic 
Concentration-Time Data 
SAC
39.
PP
PK13
Listing of Derived Plasma GSK3335065 Pharmacokinetic 
Parameters 
SAC
Pharmacodynamic analysis
40.
All Subjects
PK07
Listing of primary TRP Metabolite Data by Treatment 
Group and Time
3HK and KYN
Include change from baseline 
as well as concentration
SAC
41.
All Subjects
PK07
Listing of exploratory TRP Metabolite Data by Treatment 
Group and Time
TRP, KYNA, AA, 3-HAT, XA, 
QA and any other pathway 
components
Include change from baseline 
as well as concentration
SAC


CONFIDENTIAL
201570
59
11.11.
Appendix 11: Example Mock Shells for Data Displays
Data Display Specification will be made available on Request