Clinical trial NCT02742766
Conditions: Healthy Volunteers
Keywords: Dose escalation study Safety Pharmacodynamics Pharmacokinetics GSK3008356 Tolerability
Sponsor: GlaxoSmithKline
Start date: 2016-03-14; Completion date: 2017-06-16
Enrollment: 104 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a phase I, randomized, placebo-controlled, double-blind (sponsor unblind), three part study. The primary objective of the study is to characterize the safety, and tolerability of GSK3008356 single dose, 14 daily repeat doses in healthy subjects and 28 daily repeat doses in obese subjects. The study has three parts. Part 1, will be a single and multiple-dose, dose-rising study in healthy subjects. Part 2, will be a 14-day, repeat-dose, dose-rising study in healthy subjects, and part 3 will be a 28-day, repeat-dose study in obese subjects. For Parts 1 and 2, data from prior doses cohorts will be available prior to escalation decisions. Data from Parts 1 and 2 will be available prior to initiation of the three parallel cohorts in Part 3. A dose escalation meeting will be held to review these data and document the decision to proceed as planned or make any alterations in dosing, if indicated. Part 1, Part 2 and Part 3 study will have approximately 88, 24 and 30 subjects, respectively.

Detailed description:

Arms: arm 1: Healthy subjects will receive GSK3008356 in morning as single dose or multiple doses of 5 milligrams (mg), 10 mg, 30 mg,45 mg, 75 mg, 90 mg, 125, 180 mg, 200 mg, 250 mg total daily dose or matching placebo in eleven sequential cohorts while receiving a standard fat meal. The initial dosing for the first cohort will be staggered so that 2 subjects will be dosed as sentinel subjects. Provided there are no safety concerns, the remainder of the subjects scheduled for the cohort may be dosed. Eight subjects will be enrolled in each cohort. arm 2: Healthy subjects will receive GSK3008356 or matching placebo, as 14 daily doses in the three sequential cohorts. Subjects in cohort 1 will receive their daily dose in morning, while subjects in cohort 2 and cohort 3 will receive their daily dose in evening. In all the three cohorts, Day 1 and day 14 dosing will occur while receiving a standard fat meal in morning. Eight subjects will be enrolled in each cohort. arm 3: Obese subjects will receive GSK3008356 or matching placebo, as 28 daily doses in the three parallel cohorts. Cohort 1 will evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as morning doses. Cohorts 2 and 3 will evaluate 2 dose strengths (1 per cohort) of GSK3008356 (or matching placebo) administered in the evening. Ten subjects will be enrolled in each cohort.
Interventions: intervention 1: GSK3008356 intervention 2: Placebo
Intervention descriptions: intervention 1: This intervention is available as 0.5, 1, 5, and 25 mg white oral tablet. The formulation will be used to administer dose of 5 mg, 10 mg, 30 mg, 45 mg, 75 mg, 90 mg, 125 mg, 180 mg, 200 mg, and 250 mg total daily dose during the study. intervention 2: This intervention is available as white oral tablet. The formulation will be used as a matching placebo for GSK3008356 during the study.

Protocol documents:
Prot_000.pdf: 
2015N242776_02
CONFIDENTIAL
GlaxoSmithKline group of companies
204856
1
TITLE PAGE
Division:  Worldwide Development
Information Type: Clinical Protocol
Title:
A Phase I, Randomized, Placebo-Controlled, Double-Blind 
(sponsor unblind), Three Part Study to Evaluate the Safety, 
Tolerability, Preliminary PK and PD of Single and Repeat Oral 
Doses of GSK3008356 in Healthy Subjects and Obese Subjects
Compound Number:
GSK3008356
Development Phase
I
Effective Date:
07-FEB-2017
Protocol Amendment Number: 02
Author(s):
Revision Chronology
GlaxoSmithKline 
Document Number
Date
Version
2015N242776_00
2016-MAR-02
Original
2015N242776_01
2016-JUL-22
Amendment No. 1
Amendment No.1: Adds additional Part 1 cohorts which dose the compound in a way that 
provides a more appropriate exposure profile.  This is to obtain better PK/PD data to 
inform progression into Part 2 of the study.  Several administrative changes were also 
made.
2015N242776_02
2017-JAN-22
Amendment No. 2
Amendment No.2: Clarifies dosing regimens for Part 2, adds skin biopsy assessment for 
drug level and activity, and adds information to the Benefit:Risk table based on 13 week 
dog and 13 week rat toxicity study findings and the addition of skin biopsy to procedures.  
Several administrative changes were also made.
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information:
Role
Name
Day Time Phone 
Number and 
Email Address
After-hours 
Phone/Cell/ 
Pager Number
Fax Number
GSK Address
Primary 
Medical 
Monitor
 
 MD, PhD
709 Swedeland Road 
UW2230,
King of Prussia, PA
19406-2711
United States
Secondar
y Medical 
Monitor
MD
709 Swedeland Road 
UW2230,
King of Prussia, PA
19406-2711
United States
Tertiary 
Medical 
Monitor
 MD
709 Swedeland Road 
UW2230,
King of Prussia, PA
19406-2711
United States
SAE fax 
number 
and email
Email:
SAE fax 
number 
and email
Email:
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.   
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number: 204856

I confirm agreement to conduct the study in compliance with the protocol.

I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.

I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study.

Investigator Name:  ______________________________
Investigator Signature
Date


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TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................9
1.1.
Study Rationale ............................................................................................9
2.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................10
3.
STUDY DESIGN ....................................................................................................11
3.1.
Overall Design ............................................................................................11
3.1.1.
Additional Cohorts for Part 1........................................................13
3.1.2.
Revised Dosing Regimens for Part 2 ...........................................13
3.2.
Type and Number of Subjects.....................................................................14
3.3.
Design Justification.....................................................................................15
3.4.
Dose Justification........................................................................................15
3.4.1.
Prediction of human Clearance (CL) and Volume of 
Distribution (Vss) .........................................................................16
3.4.2.
Prediction of Human Efficacious Dose.........................................16
3.4.3.
Planned Doses and Safety Coverage ..........................................18
3.4.3.1.
Starting Dose..............................................................19
3.5.
Benefit:Risk Assessment ............................................................................21
3.5.1.
Risk Assessment .........................................................................22
3.5.2.
Benefit Assessment.....................................................................28
3.5.3.
Overall Benefit:Risk Conclusion...................................................28
4.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............28
4.1.
Inclusion Criteria.........................................................................................28
4.2.
Exclusion Criteria........................................................................................30
4.3.
Inclusion and Exclusion Criteria Notes........................................................31
4.4.
Screening/Baseline/Run-in Failures............................................................32
4.5.
Withdrawal/Stopping Criteria.......................................................................32
4.5.1.
Liver Chemistry Stopping Criteria ................................................32
4.5.1.1.
Study Treatment Restart or Rechallenge....................33
4.5.2.
QTc Stopping Criteria ..................................................................33
4.6.
Subject and Study Completion....................................................................34
5.
STUDY TREATMENT ............................................................................................34
5.1.
Investigational Product and Other Study Treatment....................................34
5.2.
Treatment Assignment................................................................................34
5.3.
Planned Dose Adjustments.........................................................................35
5.4.
Blinding.......................................................................................................36
5.5.
Packaging and Labeling..............................................................................36
5.6.
Preparation/Handling/Storage/Accountability..............................................37
5.7.
Compliance with Study Treatment Administration.......................................37
5.8.
Treatment of Study Treatment Overdose....................................................37
5.9.
Treatment after the End of the Study ..........................................................38
5.10.
Lifestyle and/or Dietary Restrictions............................................................38
5.10.1.
Meals and Dietary Restrictions ....................................................38
5.10.2.
Caffeine, Alcohol, and Tobacco ...................................................38
5.10.3.
Activity .........................................................................................38
5.11.
Concomitant Medications and Non-Drug Therapies....................................39


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5.11.1.
Permitted Medications and Non-Drug Therapies..........................39
5.11.2.
Prohibited Medications and Non-Drug Therapies.........................39
6.
STUDY ASSESSMENTS AND PROCEDURES .....................................................39
6.1.
Time and Events Tables .............................................................................41
6.1.1.
Part 1 – Single Dose....................................................................42
6.1.1.1.
Part 1, Single Dose, Fat Meal Challenge and 
Triglyceride Assessment Relative to Dose and 
PK Sampling...............................................................43
6.1.2.
Part 2 – Repeat Dose, Morning Dose Administration, 
Screening, Day -1, Day 1.............................................................44
6.1.3.
Part 2 – Repeat Dose, Morning Dose Administration, Days 
2-13 .............................................................................................46
6.1.4.
Part 2 – Repeat Dose, Morning Dose Administration, Days 
14-17, Follow-up..........................................................................47
6.1.5.
Part 2 – Repeat Dose, Evening Dose Administration, 
Screening, Day -1, Day 1 and Day 2............................................48
6.1.6.
Part 2 – Repeat Dose, Evening Dose Administration, Days 
3-13 .............................................................................................49
6.1.7.
Part 2 – Repeat Dose, Evening Dose Administration, Day 
14-17, Follow-up..........................................................................50
6.1.8.
Part 2 – Repeat Dose, Fat Meal Challenge and 
Triglyceride Assessment Relative to Dose and PK 
Sampling......................................................................................51
6.1.8.1.
Morning Dose Administration, Day -1, Day 1, 
and Day 14.................................................................51
6.1.8.2.
Evening Dose Administration, Day 1, Day 2, 
and Day 14.................................................................51
6.1.9.
Part 3 – Repeat Dose, Morning Dose Administration, 
Screening, Day -1, Day 1, Day 2..................................................52
6.1.10.
Part 3 – Repeat Dose, Morning Dose Administration, Days 
7, 14, and 21* ..............................................................................53
6.1.11.
Part 3 – – Repeat Dose, Morning Dose Administration, 
Day 27-31 and Follow-up.............................................................54
6.1.12.
Part 3 – Repeat Dose, Evening Dose Administration, 
Screening, Day 1 and Day 2 ........................................................55
6.1.13.
Part 3 – Repeat Dose, Evening Dose Administration, Days 
7, 14, and 21* ..............................................................................56
6.1.14.
Part 3 – Repeat Dose, Evening Dose Administration, Day 
27-31 and Follow-up ....................................................................57
6.1.15.
Part 3 – Repeat Dose, Fat Meal Challenge and 
Triglyceride Assessment Relative to Dose and PK 
Sampling......................................................................................58
6.1.15.1.
Morning Dose Administration, Day -1, Day 1, 
and Day 28.................................................................58
6.1.15.2.
Evening Dose Administration, Day 1, Day 2, 
and Day 28.................................................................58
6.2.
Screening and Critical Baseline Assessments ............................................59
6.3.
Safety .........................................................................................................59
6.3.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........59
6.3.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................59


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6.3.1.2.
Method of Detecting AEs and SAEs ...........................60
6.3.1.3.
Follow-up of AEs and SAEs........................................60
6.3.1.4.
Regulatory Reporting Requirements for SAEs............60
6.3.2.
Pregnancy ...................................................................................61
6.3.3.
Physical Exams ...........................................................................61
6.3.4.
Vital Signs....................................................................................61
6.3.5.
Electrocardiogram (ECG).............................................................61
6.3.6.
Clinical Safety Laboratory Assessments ......................................62
6.4.
Pharmacokinetics .......................................................................................63
6.4.1.
Blood Sample Collection..............................................................64
6.4.2.
Urine Sample Collection ..............................................................65
6.4.3.
Sample Analysis ..........................................................................65
6.4.4.
Statistical Analysis of Pharmacokinetic Data................................65
6.4.5.
Skin Biopsy Sample Collection and Analysis ...............................65
6.5.
Biomarker(s)/Pharmacodynamic Markers ...................................................66
6.5.1.
Postprandial Triglyceride Assessment .........................................66
6.5.2.
Bristol Stool Form Scale ..............................................................67
6.5.3.
Exploratory PD Markers...............................................................67
7.
DATA MANAGEMENT ...........................................................................................67
8.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................68
8.1.
Hypotheses.................................................................................................68
8.2.
Sample Size Considerations.......................................................................68
8.2.1.
Sample Size Sensitivity................................................................68
8.2.2.
Sample Size Re-estimation or Adjustment...................................68
8.3.
Data Analysis Considerations .....................................................................68
8.3.1.
Analysis Populations....................................................................68
8.3.2.
Interim Analysis ...........................................................................68
8.4.
Key Elements of Analysis Plan ...................................................................69
8.4.1.
Primary Analyses.........................................................................69
8.4.2.
Secondary Analyses ....................................................................69
8.4.3.
Other Analyses ............................................................................69
9.
STUDY GOVERNANCE CONSIDERATIONS........................................................69
9.1.
Posting of Information on Publicly Available Clinical Trial Registers............69
9.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................69
9.3.
Quality Control (Study Monitoring) ..............................................................70
9.4.
Quality Assurance.......................................................................................70
9.5.
Study and Site Closure ...............................................................................70
9.6.
Records Retention......................................................................................71
9.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................72
9.8.
Review Committees....................................................................................72
9.8.1.
Dose Escalation Committee.........................................................72
10. REFERENCES.......................................................................................................73
11. APPENDICES........................................................................................................75
11.1.
Appendix 1 – Abbreviations and Trademarks..............................................75


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11.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................79
11.3.
Appendix 3: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................81
11.3.1.
Definition of Adverse Events........................................................81
11.3.2.
Definition of Serious Adverse Events...........................................82
11.3.3.
Definition of Cardiovascular Events .............................................83
11.3.4.
Recording of AEs and SAEs ........................................................84
11.3.5.
Evaluating AEs and SAEs............................................................84
11.3.6.
Reporting of SAEs to GSK...........................................................86
11.4.
Appendix 4: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in FRP and Collection of Pregnancy Information.......................87
11.4.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) ..............87
11.5.
Appendix 5: Bristol Stool Form Scale..........................................................89
11.6.
Appendix 6: Protocol Amendment Changes................................................90


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1.
INTRODUCTION
Nonalcoholic fatty liver disease (NAFLD) represents a continuum of liver disease 
centered on fat accumulation.  NAFLD prevalence is on the rise in parallel with the rise 
of obesity worldwide (Satapathy 2015).  Steatosis (nonalcoholic fatty liver; NAFL), 
nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC) 
represent increased pathology from mild to severe disease.  NAFLD etiology is 
multifactorial and progression is not predictable at this time, though risk factors are being 
identified (Satapathy 2015).
NASH starts with liver fat (triglyceride) accumulation followed by inflammation and 
fibrosis.  Liver biopsy is the gold standard for diagnosing and staging NASH as defined 
by the presence of steatosis, inflammation and hepatocyte ballooning with or without 
fibrosis (Chalasani 2012).  An intervention for the treatment or prevention of NASH 
would have to modulate one or more of these findings.
The two diacylglycerol acyltransferase (DGAT) enzymes, DGAT1 and DGAT2, catalyze 
the final step of triacylglycerol (triglyceride; TG) biosynthesis (Yen 2008).  DGAT is 
expressed in all tissues evaluated including liver, skeletal muscle and adipose tissue with 
the highest expression levels in the small intestine (Cases 1998) and is upregulated in 
NAFLD (Kohjima 2007).  Decreased DGAT1 activity can reduce circulating TG, reduce 
liver TG and is implicated in preventing activation of hepatic stellate cells (HSC) and the 
resultant production of liver fibrosis (Yamaguchi 2008; Yuen 2015).  Inhibiting DGAT1 
could have the potential to treat NASH.
1.1.
Study Rationale
GSK3008356 is a potent and selective DGAT1 inhibitor and is primarily intended for the 
treatment of NASH.  In nonclinical studies, GSK3008356 has efficacy in blocking 
postprandial hypertriglyceridemia in a mouse lipid challenge model.  A significant 
reduction in liver TG and lipid accumulation, body weight and food intake was observed 
in the mouse diet-induced obesity model (DIO).  Please refer to the GSK3008356 
Investigator’s Brochure (IB) [GlaxoSmithKline Document Number 2015N255332_00] 
for details.
DGAT1 inhibitors have been evaluated in healthy and obese subjects (Denison 2014; 
Meyers 2015).  Activity was elicited via a high fat challenge meal measuring inhibition 
of postprandial TG excursion.  Gastrointestinal (GI) intolerability with repeat daily 
dosing was the main issue with compound progression (Denison 2014; Meyers 2015).  
The symptoms were postulated to be due to DGAT1 inhibition resulting in increased free 
fatty acids in the intestine and resultant inflammation and diarrhea (Denison 2014). One 
compound continuing in development (pradigastat/LCQ908) has show efficacy in 
decreasing liver fat in NAFLD subjects when dosed for 6 months despite dose limiting 
diarrhea (Moffet 2015).
This study will be the first to evaluate the safety, tolerability, pharmacokinetics (PK), and 
pharmacodynamics (PD) of single and repeat doses of GSK3008356 administered 
subjects.  Since the main objective is understanding tolerability, the population planned is 


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healthy and healthy obese subjects.  NAFLD and NASH patients will be evaluated in 
subsequent studies once tolerated and active doses are identified.  Since DGAT1 activity 
in the liver may be of more importance than effects in the intestine, tolerability will be 
evaluated through evening (versus morning) repeat dosing to minimize exposure during 
daytime meals.  
The activity of GSK3008356 on DGAT1 inhibition will be assessed through 
measurement of postprandial TG elevation after a standardized fat challenge meal as 
previously published (Denison 2014; Meyers 2015).  
2.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary
Part 1 Single Dose
To characterize the safety, and tolerability of single 
doses of GSK3008356 in healthy subjects.
Part 2 14d Repeat Dose
To characterize the safety, and tolerability of 14 daily 
repeat doses of GSK3008356 in healthy subjects.
Part 3 28d Repeat Dose
To characterize the safety, and tolerability of 28 daily 
repeat doses of GSK3008356 in obese subjects.
Part 1 Single Dose 
Safety parameters including physical examination 
findings, vital signs, 12-lead ECGs, continuous lead II 
cardiac monitoring, clinical laboratory tests and clinical 
monitoring/observation for adverse events.
Part 2 14d Repeat Dose
Safety parameters including physical examination 
findings, vital signs, 12-lead ECGs, continuous lead II 
cardiac monitoring, clinical laboratory tests and clinical 
monitoring/observation for adverse events.
Part 3 28d Repeat Dose
Safety parameters including physical examination 
findings, vital signs, 12-lead ECGs, continuous lead II 
cardiac monitoring, clinical laboratory tests and clinical 
monitoring/observation for adverse events.
Secondary
Part 1 Single Dose
To determine the pharmacokinetics of GSK3008356 
after a single dose in healthy subjects
To assess dose proportionality of GSK3008356 after a 
single dose in healthy subjects
To evaluate the preliminary pharmacodynamics after a 
single dose of GSK3008356 in healthy subjects.
Part 2 14d Repeat Dose
To determine the pharmacokinetics of GSK3008356 
after 14 daily doses in healthy subjects.
To assess dose proportionality of GSK3008356 after 
14 daily doses in healthy subjects.
To examine the extent of accumulation and 
achievement of steady-state following 14 daily doses of 
GSK3008356 in healthy subjects.
Part 1 Single Dose 
PK endpoints include the AUC(0-t), AUC(0-24), Cmax, 
tmax, AUC(0-∞), t½, Ae, and CLr  of GSK3008356 as 
data permit.
AUC(0- t), AUC(0-∞), and Cmax for the assessment of 
dose proportionality as data permit.
Fat challenge meal postprandial triglyceride levels.
Part 2 14d Repeat Dose
PK endpoints include the AUC(0-τ) Cmax, and tmax on 
Day 1 and 14, and t½, Ae, and CLR on Day 14 of 
GSK3008356 as data permit. 
AUC(0- τ) and Cmax on Day 1 and 14 for the 
assessment of dose proportionality as data permit.
Observed accumulation ratio based on AUC(0- τ), (Ro), 
and Cmax (RCmax) on Day 14 versus Day 1 as data 
permit. Trough plasma concentrations (Ctrough) to 


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Objectives
Endpoints
To evaluate the preliminary pharmacodynamics after 
14 daily repeat doses of GSK3008356 in healthy 
subjects.
Part 3 28d Repeat Dose 
To determine the pharmacokinetics of GSK3008356 
after 28 daily doses in obese subjects.
To assess dose proportionality of GSK3008356 after 
28 daily doses in obese subjects.
To examine the extent of accumulation and 
achievement of steady-state following 28 daily doses of 
GSK3008356 in obese subjects.
To evaluate the preliminary pharmacodynamics of 
28 daily doses of GSK3008356 in obese subjects.
assess steady state after repeat dosing, as data 
permit.
Fat challenge meal postprandial triglyceride levels.
Part 3 28d Repeat Dose
PK endpoints include the AUC(0- τ) Cmax, and tmax
on Day 1 and 28, and t½, Ae, and CLr  on Day 28 of 
GSK3008356 as data permit. 
AUC(0- τ) and Cmax on Day 1 and 28 for the 
assessment of dose proportionality as data permit.
Observed accumulation ratio based on AUC(0-τ), (Ro), 
and Cmax (RCmax) on Day 28 versus Day 1 as data 
permit. Trough plasma concentrations (Ctrough) to 
assess steady state after repeat dosing, as data 
permit.
Fat challenge meal postprandial triglyceride levels.
Exploratory 
Part 2 14d Repeat Dose
Part 3 28d Repeat Dose
To evaluate the change in serum lipid levels and 
weight after 14 daily repeat doses of GSK3008356 in 
healthy subjects and 28 daily repeat GSK3008356 
doses in obese subjects.
To evaluate the impact of evening dosing on 
tolerability.
To evaluate partitioning of GSK3008356 into skin in 
Part 2 only.
Part 2 14d Repeat Dose
Part 3 28d Repeat Dose
Serum lipid panel, weight.
Clinical monitoring/observation for adverse events with 
a focus on gastrointestinal findings and a stool scale.
Skin biopsy for drug concentration and activity.
3.
STUDY DESIGN
3.1.
Overall Design
Study 204856 will be a randomized, double-blind (sponsor unblind), placebo controlled 
trial in three Parts.  
1. Part 1, will be a single-dose (SD), dose-rising study in healthy subjects.  Subjects 
will receive GSK3008356 (or matching placebo), as a single dose in each of five 
sequential cohorts while receiving a standard 30% fat meal.  The initial dosing for 
the first cohort will be staggered so that 2 subjects will be dosed as sentinel 
subjects. Provided there are no safety concerns, the remainder of the subjects 
scheduled for the cohort may be dosed.


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2. Part 2, will be a 14-day, repeat-dose (RD), dose-rising study in healthy subjects.  
Subjects will receive GSK3008356 (or matching placebo), as 14 daily doses in 
each of three sequential cohorts.  Day 1 and day 14 dosing for the first cohort will 
occur while receiving a standard 30% fat meal.  The final two cohorts will receive 
the same morning 30% fat meals, but will explore daily dosing in the evening
rather than in the morning.
3. Part 3, will be a 28-day, repeat-dose study in obese subjects.  Subjects will receive 
GSK3008356 (or matching placebo), as 28 daily doses in each of three parallel 
cohorts.  Cohort 1 will evaluate 1 dose strength of GSK3008356 (or matching 
placebo) administered as morning doses.  Cohorts 2 and 3 will evaluate 2 dose 
strengths (1 per cohort) of GSK3008356 (or matching placebo) administered in 
the evening.
Please refer to Figure 1 for details.
Figure 1
Study Part Schematic


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3.1.1.
Additional Cohorts for Part 1
Based on emerging PK data, the original planned Part 1 doses were adjusted, per 
protocol, to 5, 10, 30, 75 and 200 mg (Section 5.3, Figure 1).  This was due to a much 
shorter observed half-life compared to the predicted half-life (1.5-3h observed versus 
14.1h predicted).  
While the adjusted doses did allow observation of a PD response in Cohort 5, the overall 
single dose data were limited and could not adequately inform a PK/PD model or support 
informed progression into Part 2 of the study.  It was determined to further explore the 
PK/PD through additional Part 1 cohorts.  The purpose of the additional cohorts is to 
explore dose administration in a manner that should provide a more acceptable PK profile 
than that observed to date.  This includes divided doses to achieve time above the target 
exposure with varying levels of Cmax and doses directly related to regimens that may be 
used in Part 2 of the study. There will be no changes to the current challenge meal or 
assessments.
3.1.2.
Revised Dosing Regimens for Part 2
Based on preliminary PK data from Part 1, the doses and regimens are now better 
clarified for Part 2.  Part 2 Cohorts 1, 2 and 3 will be administered in the AM as divided 
doses to achieve a daily time above the target exposure with varying levels of Cmax.  
Specifically, Cohort 1 will have a regimen of 2 doses separated by 16 hours similar to 
Part 1 Cohort 8.  The purpose is to explore a BID PK profile.  Cohorts 2 and 3 will have a 
regimen of nine hourly doses similar to Part 1 Cohorts 10 and 11.  The purpose is to 
explore PK profiles that approximate a sustained release formulation to guide further 
dosage development.    There will be no changes to the current challenge meal or 
assessments except for the addition of a skin biopsy outlined in Section 6.4.5.
The regimens are as follows:
Part 2, Cohort 1 would evaluate 10 mg administered twice at time 0h and 16h for a total 
dose of 20 mg.
Part 2, Cohort 2 would evaluate 27 mg daily administered as 9 doses of 3 mg hourly 
from time 0 to time 8h daily for 14 days.  
Part 2, Cohort 3 would evaluate either 9 mg daily administered as 9 doses of 1 mg 
hourly from time 0 to time 8h or 45 mg daily as 9 doses of 5 mg hourly from time 0 to 
time 8h.
Neither the predicted human Cmax, nor the predicted daily human AUC of evaluated 
doses is expected to exceed the dog NOAEL exposure of Cmax (7.73 µg/mL) and 
AUC(0-t) (111 µg.h/mL).  
However, data from a 13-week oral toxicity study in dogs indicate that the NOAEL for 
dosing duration >28 days will likely be lower than the current NOAEL.  While these dog 
data do not impact the risk for this protocol as they do not change the NOAEL (Section 
3.5.1), these data will impact the future viability of certain dose regimens.  


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The regimens selected for Part 2 as outlined above are regimens have future development 
viability based on human exposure below the oral 13-week repeat dose dog testicular 
observation NOAEL exposure of Cmax (0.642 µg/mL) and AUC(0-t) (5.49 µg.h/mL).  
The highest dose regimen planned for Part 3 (45 mg daily as 9 doses of 5 mg hourly from 
time 0 to time 8h) is expected to result in the highest Part 2 Cmax (0.203 µg/mL) and 
AUC (1.261 µg.h/mL) exposure, based on Part 1 data.  
These predicted exposures are still 3.2-fold and 4.4-fold below the oral 13-week repeat 
dose dog testicular observation NOAEL Cmax and AUC exposure, respectively.  The 
predicted exposures are 38.1-fold and 88.1-fold below the current NOAEL Cmax and 
AUC exposure, respectively.
3.2.
Type and Number of Subjects
Part 1, Single Dose, Healthy Subjects:
Approximately 40 subjects will be enrolled, 8 in each cohort, such that approximately 6-8 
subjects complete dosing and critical assessments in each Part 1 Cohort. Additional 
subjects/cohorts may be enrolled to allow for evaluation of additional dose levels. The six
additional cohorts will enrol approximately 48 subjects.
Part 2, 14d Repeat Dose, Healthy Subjects:
Approximately 24 subjects will be enrolled, 8 in each cohort, such that approximately 6-8 
subjects complete dosing and critical assessments in each Part 2 Cohort. Additional 
subjects/cohorts may be enrolled to allow for evaluation of additional dose levels. 
Part 3, 28d Repeat Dose, Obese Subjects:
Approximately 30 subjects will be enrolled, 10 in each cohort, such that approximately 6-
10 subjects complete dosing and critical assessments in each Part 3 Cohort. Additional 
subjects/cohorts may be enrolled to allow for evaluation of additional dose levels. 
If subjects prematurely discontinue the study, additional replacement subjects may be 
randomised and assigned to the same treatment sequence at the discretion of the Sponsor 
in consultation with the investigator.
For Parts 1 and 2, data from prior doses cohorts will be available prior to escalation 
decisions.  Data from Parts 1 and 2 will be available prior to initiation of the three parallel 
cohorts in Part 3.  A dose escalation meeting will be held to review these data and 
document the decision to proceed as planned or make any alterations in dosing, if 
indicated (Section 9.8.1).
Subjects in Parts 1 and 2 will be randomized such that 6 subjects receive GSK3008356 
and 2 subjects receive matching placebo in each cohort of 8 subjects.  Subjects in Part 3 
will be randomized such that 8 subjects receive GSK3008356 and 2 subjects receive 
matching placebo in each cohort of 10 subjects.


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3.3.
Design Justification
Parts 1 and 2 designs are based on well established and published methods to evaluate the 
first single and repeat dose administration of experimental drugs, including the use of 
sentinel dosing for Part 1, Cohort 1.  Part 3 design is based on established and published 
methods to evaluate both inpatient and outpatient dosing in subjects.  The use of a fat 
meal challenge and postprandial TG as a PD measure for DGAT1 inhibition is based on 
published clinical trial design.
Part 1 is not expected to have significant gastrointestinal tolerability issues, so will only 
use daytime dosing and TG evaluation to identify the active dose range to progress into 
Part 2.
Part 2 will evaluate daytime dosing for the first cohort, but will switch to evening dosing 
based on prior published DGAT1 inhibitor clinical trial data where daytime dosing 
resulted in GI intolerability.  Postprandial TG will be used to measure PD response.  The 
Bristol Stool Form Scale (BSFS) will be used in this part to assist in evaluating GI 
tolerability.  The purpose is to identify an active dose which is also tolerated to progress 
into Part 3.
Part 3 will evaluate daytime and evening dosing in obese subjects under both controlled 
(inpatient) and less controlled (outpatient/home dosing) conditions of drug administration 
and diet.  The obese subject population is at the beginning of the “healthy-obese-
NAFLD-NASH-cirrhotic” continuum.  Postprandial TG measure and BSFS will be 
utilized to evaluate DGAT1 inhibition PD and GI tolerability, respectively.
As noted, GI intolerability is a liability with other DGAT1 inhibitors and may be a 
liability with GSK3008356.  This may be due to accumulation of free fatty acids in the 
intestine, associated with meals, causing inflammation and diarrhea (Denison 2014).  The 
GSK3008356 concentration at 12 hour post-dose is estimated to be ~42% of maximum 
observed plasma concentration (Cmax).  This indicates that, if the drug is given in the 
evening, by the time a subject is consuming daytime meals (~12 h post-dose the next 
morning), the plasma concentration would be significantly lower.  Based on the DGAT1 
inhibition mechanism of action, a lower exposure during daytime meals may improve GI 
tolerability.  
3.4.
Dose Justification
GSK3008356 dose selection in this study is based on the no-observed adverse event level 
(NOAEL) and respective exposures in 4-week dog study, and takes into consideration the 
predicted human PK and the target systemic exposure predicted for efficacy, as well as 
the minimum anticipated biological effect level (MABEL), and US Food and Drug 
Administration (FDA) guidance.


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3.4.1.
Prediction of human Clearance (CL) and Volume of Distribution 
(Vss)
Human blood clearance (CL) of GSK3008356 is predicted to be low (Table 1) based on 
the various methods employed and assuming that the blood to plasma ratio is 1 for all 
species.
Table 1
Summary of Predicted Human Pharmacokinetic Parameters1
Prediction Method
Human CL
(mL/min)
Human CL/F
(mL/min)
Human Blood 
Vss (L)
Human Blood 
Vss/F (L)
Method 1: allometric scaling of apparent 
clearance CL/F
-
58
-
-
Method 2: allometric scaling of clearance CL
82.3
82.32
92
922
Method 3: IVIVC (Well Stirred model)
76
762
-
-
1Assuming human body weight of 70 kg; 2assuming bioavailability of 100%
The preclinical and in vitro data used for the above prediction are listed in Table 2 and 
Table 3.
Table 2
Plasma clearance in preclinical species
Plasma Clearance (in vivo) in preclinical species
CL
(mL/min/kg)
Body Weight 
(kg)
Fup
(%)
Mean 
Std Dev 
Mean 
Mean 
Mouse
1.39
0.10
0.025
29.1 
Rat 
6.65
1.60
0.25
15.4 
Dog 
2.60
0.23
11.00
66.2 
Table 3
Intrinsic clearance in vitro in human hepatocytes
Intrinsic clearance in vitro in human hepatocytes
CL
(mL/min/g)
Liver Scaling Factor
(g/kg)
Human Fup
(%)
Human
0.120
24.5
37.1
3.4.2.
Prediction of Human Efficacious Dose
Overall, the CL/F (82.3 mL/min) and Vss/F (92 L) with the assumption of 100% 
bioavailability based on Method 2 is considered the most appropriate for simulations to 
estimate the human efficacious dose. Of the three preclinical species, dog exhibited a 2-
compartmental PK profile following intravenous (IV) infusion. Fitting the dog data with 


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a 2-compartmental model showed a Vc/Vp ratio of 1.31 and a Q/CL ratio of 2.5. In 
humans it is very likely the PK will also exhibit 2-compartmental behaviour. Assuming 
same Vc/Vp and Q/CL ratio in humans, the intra-compartmental clearance (Q/F) would 
be 205 mL/min, and Vc and Vp would be 52.4 L and 40 L, respectively, with a sum of 92 
L as predicted by allometric scaling. These parameters will translate to a ke of 0.094 h-1, a 
k12 of 0.235 h-1, and a k21 of 0.307 h-1, which can then be used in simulations to obtain 
the Cmax, C4, C24 and AUC(0-) at a specific dose, assuming tmax of 1.5 h (ka of 1.4 
h-1).
The human efficacious dose was calculated based on doses required to maintain trough 
levels from the (A) animal efficacy models and (B and C) a published PK/PD model.  
A. The human efficacious dose was calculated based on the doses required to 
maintain trough levels as seen in the mouse DIO studies at 3mg/kg BID. The 
mean trough level from three mouse DIO studies was 169.8 ng/mL. After 
correcting for potency differences between mouse and human in vitro cell-based 
assay (human keratinocyte IC50 = 74 nM; mouse C2C12 IC50 = 100.8 nM) this 
translates to a prediced human Ctrough of 124.7 ng/mL. The human dose required 
to achieve the total target concentration was simulated (C24, i.e., Ctrough
>124.7 ng/mL). By this method the projected efficacious human oral dose for a 70 
kg human is 43 mg once daily. Since the mouse DIO studies did not explore doses
lower than 1mg/kg BID, 1 mg/kg BID and its associated mean trough level (81.66 
ng/mL) were considered the MABEL in mouse. This translates to a human Ctrough
of 60 ng/mL and human MABEL of ~21 mg. The MABEL is the dose/exposure 
that results in 10-20% of the maximum pharmacologic effect of receptor 
blockade.  If the human keratinocyte IC20 (15 nM) rather than the IC50 (74 nM) is 
used, the human MABEL dose will be ~8.7 mg. 
B. Denison published a PK/PD model of the DGAT1 inhibitor AZD7687 based on a
single-dose study (Denison 2014).  In the study, postprandial increases in TG 
were measured (AUCincr ) under untreated conditions (baseline AUCincr ) versus 
AZD7687 treated conditions (TG AUCincr).  Using an inhibitory effect sigmoid 
Emax model (E = E0 − [E0 − Emax] ∗[Cτ / (Cτ + EC50
τ)]), he described a steep 
concentration–effect relationship between the postprandial TG AUCincr decrease 
compared to the baseline AUCincr versus plasma concentration of AZD7687 at 
start of the meal (C4). The maximal reduction (Emax) in TG AUCincr versus 
baseline AUCincr that could be achieved was −84±9%. Half of the Emax was 
observed at a concentration of 0.44±0.07 μmol/L (EC50). The percent change in 
TG AUCincr versus baseline AUCincr at an AZD7687 concentration of 0 (E0) was 
estimated to be 15±6% and the shape factor (τ) was estimated to be 4±2. 
AZD7687 had a plasma protein binding of 94.5% (fu of 5.5%) and an IC50 of 
0.014 μM in a human duodenal cell line (HuTu80) based on TG synthesis 
measurement. 
Assuming GSK3008356 also exert same effect on postprandial serum TG 
concentrations, and accounting for plasma protein binding difference (62.9% for 
GSK3008356) and IC50 difference (74 nM for GSK3008356), the total plasma 
concentration to exert half of the maximal reduction in TG (EC50) will be 
0.345 μmol/L. The projected efficacious dose is 18 mg using this approach (~75% 


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reduction in TG AUCincr versus baseline AUCincr). Similarly, the calculated 
MABEL dose is 9.6 mg (~20% reduction in TG AUCincr versus baseline AUCincr).
C. Denison did not model the exposure-effect relationship between the decrease in 
TG AUCincr compared to baseline AUCincr versus plasma AZD7687 AUC(0-). 
However, we estimated the AZD7687 AUC(0-) based on their published plasma 
concentration versus time curves, and model it using the inhibitory effect sigmoid 
Emax model: E = E0 − [E0 − Emax] ∗[AUCτ / (AUCτ + EAUC50
τ)]. According 
to the model the maximal reduction (Emax) in TG AUCincr versus baseline 
AUCincr was −81%. Half of the maximal reduction was observed at an AUC of 
6.21 μmol.h/L (EAUC50). The percent change in TG AUCincr versus baseline
AUCincr at an AZD7687 AUC of 0 (E0) was estimated to be 13% and the shape 
factor (τ) was estimated to be 6. Assuming GSK3008356 follows same PK/PD 
relationship, and accounting for plasma protein binding difference and IC50
difference, the final estimated EAUC50 for GSK3008356 would be 4.87 μmol.h/L. 
The projected efficacious dose would therefore be 12 mg with ~75% reduction in 
TG AUCincr versus baseline AUCincr. The calculated MABEL dose would be 7 mg 
with ~20% reduction in TG AUCincr versus baseline AUCincr.
Overall, based on models A, B, and C, the efficacious human oral dose is projected to be 
12-43 mg, and the MABEL dose is projected as 7-21 mg. Simulated PK parameters are 
shown in Table 4 and predicted PK parameters for the planned study doses are shown in 
Table 5.  Note the 25 mg dose was selected as the target efficacious dose based on the 
models and used to set the planned dose range with a starting dose at or lower than 
MABEL dose of 7 mg (Table 5).
Table 4
Simulated PK parameters at a particular dose for GSK3008356
Dose (mg)
Cmax (ng/mL)
C24 (ng/mL)
AUC(0-)
(ng.h/mL)
Tmax 
(h)
T1/2 (h)
7
88.55
20.37
1421
1.5
14.1
12
151.8
34.92
2436
1.5
14.1
25
316.25
72.75
5075
1.5
14.1
43
543.95
125.13
8729
1.5
14.1
3.4.3.
Planned Doses and Safety Coverage
Five (5) dose levels are planned for the study: 5 mg, 10 mg, 25 mg, 50 mg, and 75 mg.  


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3.4.3.1.
Starting Dose
The starting dose of 5 mg is justified based the maximum recommended safe starting 
dose (MRSD) method as outline by the FDA.
The FDA guidance suggests calculating a human equivalent dose (HED), based on the
NOAEL in the most sensitive or most relevant preclinical species, using scaling factors 
that are based on differences in body surface area between species.  The HED is
converted to an MRSD in humans by dividing by a safety factor.  The safety factor may 
be adjusted depending on the pharmacology, toxicology, and preclinical 
pharmacokinetics of the drug, or previous experience with compounds in the same 
pharmacologic/structural class.  Using the 4-week dog study safety information (NOAEL 
at 50 mg/kg), the HED was estimated to be 28 mg/kg.  Using a safety factor of 100, the 
estimated MRSD in humans would be 17 mg for a 60 kg human.
The planned doses and the predicted exposure compared to the 4-week dog study 
NOAEL (Cmax = 7.73 µg/mL, AUC 111 μg.h/mL at 50 mg/kg) are presented in Table 5.  
The estimated human dose that would result in an AUC exposure equivalent to the 4-
week dog study NOAEL exposure is 547 mg. Using a safety factor of 100, the starting
dose would be ~5.5 mg. As stated above, the MABEL dose may be 7-21 mg. To be 
conservative, a dose of 5 mg was chosen as the starting dose.
The GSK3008356 starting dose of 5 mg in humans is 0.083 mg/kg based on a 60 kg body 
weight.  This is ~600-fold lower than the dog NOAEL dose (50 mg/kg).  The predicted 
human exposure after a single 5 mg dose is ~122-fold below the Cmax and ~109-fold 
below the AUC at the dog NOAEL (Table 5).
Planned Doses and Safety Cover 
Plasma GSK3008356 concentrations will be determined after each dose cohort and the 
AUC and Cmax will be estimated.  The dose for the next cohort will be determined by 
estimating the predicted exposure based on the observed exposure in the preceding 
cohort(s).  Dose escalation will not exceed the NOAEL exposure in the 4-week dog
study.  


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Table 5
Predicted, Human Cmax, C12, C24, and AUC(0-∞)Observed and 
Additional Predicted Human Exposures Following Single Oral 
Administration of GSK3008356
Proposed dose
Predicted 
Cmax
Fold-cover 
for Cmax
Predicted 
C12
Predicted 
C24
Predicted 
AUC(0-∞)
Fold-cover 
for AUC
(mg)
(mg/kg)1
(ng/mL)
Dog2
(ng/mL)
(ng/mL)
(ng.h/mL)
Dog2
5
0.083
63.25
122
26.35
14.55
1015
109
10
0.167
126.5
61
52.70
29.1
2030
55
25
0.417
316.25
24
131.75
72.75
5075
22
50
0.833
632.5
12
263.50
145.5
10150
11
75
1.250
948.75
8
395.25
218.25
15225
7
Actual dose
Cmax
Fold-cover 
for Cmax
Observed 
AUC(0-∞)
Fold-cover 
for AUC
(mg)
(mg/kg)1
(ng/mL)
Dog2
(ng.h/mL)
Dog2
5
0.083
92
84
191
581
10
0.167
191
40
314
353
30
0.500
458.5
17
841
132
75
1.250
890.9
9
1963
57
200
3.333
1865.3
4
5488
20
Additional Predicted 
doses
Predicted 
Cmax
Fold-cover 
for Cmax
Predicted 
AUC(0-∞)
Fold-cover 
for AUC
(mg)
(mg/kg)1
(ng/mL)
Dog2
(ng.h/mL)
Dog2
125
2.08
1290
6.0
3620
30.7
250
125q4 x2
4.17
1500
5.2
7236
15.3
250
125q16 x2
4.17
1300
5.9
7115
15.6
200
evening
3.33
2070
3.7
5797
19.1
90
10q1h x 9
1.50
300
25.8
2601
42.7
45
5q1h x 9
0.75
150
51.5
1297
85.6
180
20q1h x 9
3.00
600
12.9
5201
21.3
1.
Based on 60 kg human body weight
2.
Based on the 4-week dog study, 50 mg/kg/day dose, week 4 average Cmax (7.73 µg/mL) and AUC(0-t) 
(111 µg.h/mL)


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Observed Doses, Additional Planned Doses, and Safety Cover 
The actual doses administered and observed exposures relative to the dog NOAEL are 
found in Table 5.  The highest dose administered (200 mg) had a 4-fold and 20-fold 
safety coverage to the dog NOAEL Cmax and AUC, respectively.  
The expected exposures for the additional Part 1 cohorts will be at or below those 
observed in the Part 1 cohorts dosed to date (Table 5).
The proposed doses of GSK3008356 may be adjusted, as appropriate, based on the 
safety, tolerability, and pharmacokinetic data obtained in preceding cohorts.
3.5.
Benefit:Risk Assessment
Summaries of findings from non-clinical studies conducted with GSK3008356 can be 
found in the IB.  The current study, 204856, represents the first administration of 
GSK3008356 to healthy subjects.  Considerations for safety monitoring are derived 
primarily from non-clinical data. The following section (Section 3.5.1) outlines the risk 
assessment and mitigation strategy for this protocol.


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3.5.1.
Risk Assessment
Potential Risk of Clinical Significance and 
Summary of Data/Rationale for Risk
Impact on eligibility criteria
Mitigation Strategy
Investigational Product (IP) [e.g., GSK3008256]
Hepatic Effects
Oral 7d repeat dose dog study:  Minimal to mild, focal 
hepatocellular degeneration/necrosis was observed 
(minimal in one female given 50 mg/kg/day; minimal to 
mild in the male and female given 200 mg/kg/day).  
Minimal mixed inflammatory cell infiltrates within liver 
sinusoids noted for the female given 200 mg/kg/day.  
Clinical pathology findings included increases in alanine 
aminotransferase (ALT) (up to 1.96X baseline), increases 
in aspartate aminotransferase (AST) (up to 1.76X 
baseline), increased glutamate dehydrogenase (GLDH) (to 
3.8X baseline) at all dose levels. Increased total bile acid 
concentrations (to 3.2X baseline) and decreased plasma 
albumin and total protein concentrations (to 0.90X 
baseline) were noted at various testing intervals for dogs 
given 50 or 200 mg/kg/day.  These changes may be 
related to hepatocellular injury and/or associated with 
reduced food consumption.
Oral 28d and 13 week repeat dose dog studies:  Increases 
ALT were noted for males and females given 2, 5 and 50 
mg/kg/day at Week 1 (ranging from1.88X to 2.5X 
baseline).  By Week 4, increases were 1.72X to 2.2X 
baseline values.   The ALT increases were not progressive 
with continued dosing. There were no correlative liver 
histopathology findings. Similar increases in ALT (up to 
2.71X baseline) and AST (up to 1.57X) were observed in 
the 13 week study (evaluating doses up to 60 mg/kg/day) 
and were reversible following a 4-week off-treatment 
period.
Exclusion criterion #1:
ALT and bilirubin > 1.5xULN (isolated bilirubin >1.5xULN is 
acceptable if bilirubin is fractionated and direct bilirubin 
<35%).
Exclusion criterion #2:
Current or chronic history of liver disease, or known 
hepatic or biliary abnormalities (with the exception of 
Gilbert's syndrome or asymptomatic gallstones).
Exclusion criterion #6
History of regular alcohol consumption within 6 months of 
the study.
Exclusion criterion #10:
A positive pre-study Hepatitis B surface antigen or positive 
Hepatitis C antibody result within 3 months of screening.
Sentinel dosing – staggered dosing in 2 subjects in Part 1 
Cohort 1 prior to enrolment of the remainder of Cohort 1.
LFT evaluation planned at baseline, day 2, day 4, day 7, 
day 14, day 21, day 28, and also as indicated.
Exclusion criteria as noted in column 2.
Stopping criterion of ALT ≥3xULN with no rechallenge of 
drug product.


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Potential Risk of Clinical Significance and 
Summary of Data/Rationale for Risk
Impact on eligibility criteria
Mitigation Strategy
Oral 7d and 28 repeat dose rat study:  No hepatic related 
findings. 
Oral 13 week repeat dose rat study: Increased liver 
weights (to 1.2X mean control) were observed in female 
rats given 1000 mg/kg/day with no clinical pathology or 
microscopic correlates.
HepatoTaq:  No significant findings.
Gastrointestinal Tolerability
Oral 7d, 28d, and 13 week repeat dose dog studies: In the 
28d study, excessive salivation was observed for males 
given ≥2 mg/kg/day. Dose-related effects on body weight 
(decreased body weight gain or body weight loss) and/or 
reduced food consumption were observed in all studies.  
Increased frequency of fecal abnormalities (unformed/ 
stool/mucous and/or watery) were observed in the 13 week 
study.
Oral 7d, 28d, and 13 week repeat dose rat studies: Non-
dose related decreases in mean body weight gain for rats 
were observed in the 7day study.  No effects on body 
weight were noted in the 28 day and 13-week rat studies.
Scientific Literature:  Clinical DGAT1 inhibition may result 
in dose limiting nausea, vomiting and, watery (non-
malabsorption) diarrhea which stopped upon 
discontinuation of dosing. (Denison 2014; Meyers 2015).
Exclusion criterion #4:
Current or chronic history of gastrointestinal illness or 
conditions interfering with normal gastrointestinal anatomy 
or motility. Examples include gastrointestinal bypass 
surgery, cholecystectomy, partial or total gastrectomy, 
small bowel resection, vagotomy, malabsorption, Crohn’s 
disease, ulcerative colitis, IBS, or celiac sprue.
Diarrhea scale (Bristol Stool Form Scale) and frequency of 
stool (Section 6.5.2).
Subject may be withdrawn at any time at the discretion of 
the investigator for safety.


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Potential Risk of Clinical Significance and 
Summary of Data/Rationale for Risk
Impact on eligibility criteria
Mitigation Strategy
Dermal Effects
Oral 7d, 28d, and 13 week repeat dose dog studies: Dose-
related, minimal to mild atrophy of the sebaceous glands 
was observed and was considered to be related to 
pharmacology.  Finding was reversible in the 13 week 
study following a 4-week off-dose period.
Oral 7d, 28d, and 13 week repeat dose rat studies:  No 
dermal-related findings.
Scientific Literature:  DGAT1 inhibition may result in 
sebaceous gland atrophy and alopecia as observed in 
animal studies (Floettmann 2015), but similar effects have 
not been reported in clinical trials to date.
None
Subject may be withdrawn at any time at the discretion of 
the investigator for safety.


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Potential Risk of Clinical Significance and 
Summary of Data/Rationale for Risk
Impact on eligibility criteria
Mitigation Strategy
Testicular Effects
Oral 7d and 28d repeat dose dog study: No effects in 
testes or epididymides observed at doses up to 200 
mg/kg/day for 7d and up to 50 mg/kg/day for 28d.
Oral 7d, 28d and 13w repeat dose rat study:  No effects in 
testes or epididymides observed at doses up to 300 
mg/kg/day for 7d and 28d and up to1000 mg/kg/day for 
13w.
Oral 13w repeat dose dog study: Minimal to mild 
degeneration of the testicular seminiferous tubule 
epithelium with secondary changes within the epididymides 
(luminal germ cell debris and/or reduced sperm) was 
observed in terminal dogs given ≥30 mg/kg/day. 
Following the end of the 4-week off-dose period, testicular 
degeneration was still present in dogs given 60 mg/kg/day 
and is not unexpected given the long spermatogenic cycle 
in dogs (typically 90 days).
None
While there is no impact on the study NOAEL, dose 
regimen selection will be based regimens which will result 
in human exposure below the oral 13w repeat dose dog 
testicular observation NOAEL exposure of Cmax 
(0.642 µg/mL) and AUC(0-t) (5.49 µg.h/mL).
Subject may be withdrawn at any time at the discretion of 
the investigator for safety.


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Potential Risk of Clinical Significance and 
Summary of Data/Rationale for Risk
Impact on eligibility criteria
Mitigation Strategy
Cardiovascular Effects
Single dose cardiovascular rat and dog studies:   In rats, 
transient increases in heart rate (17%) and blood pressure 
(18%) were observed at 100 mg/kg but not as 30 and 
300 mg/kg.  The increases in both heart rate and blood 
pressure produced a transient increase in rate-pressure-
product (RPP; an index of cardiac workload; 37%), 
Because similar changes were not observed at the highest 
evaluated dose of 300 mg/kg, a clear relationship to 
GSK3008356 administration was not established. No
acute effects on cardiovascular function were noted in 
dogs.
Oral 28d and 13 week dog studies: No cardiovascular-
related findings (ECG assessments).
Rabbit left ventricular wedge assay: No effects on QT 
interval, transmural dispersion of repolarization, 
QRS duration or contractility (concentrations of up to 
10 M). 
hERG: IC25 value was estimated to be 85.7 µM 
(31.49 µg/mL).  Insufficient inhibition of hERG occurred to 
allow for the reliable estimation of an IC50 value.The 
estimated IC25 value is >150X greater than the estimated 
free Cmax in humans at the maximum predicted clinical 
efficacious dose of 43 mg.  
Based on the low magnitude and transient nature of the 
heart rate and blood pressure increases noted in rats and 
the low risk for QT prolongation (based on in vitro findings), 
the risk for CV effects in humans is considered low.
Exclusion criterion #3:
QTcF < 450 msec.
Monitoring via telemetry (day 1), 12-lead ECG, and vital 
signs monitoring.
Stopping Criteria (Section 4.5.2):
QTcF > 500 msec
QTc change from baseline > 60 msec.


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Potential Risk of Clinical Significance and 
Summary of Data/Rationale for Risk
Impact on eligibility criteria
Mitigation Strategy
Study Procedures
Skin Biopsy
Complications of punch skin biopsy are uncommon but 
may include bleeding, infection, and scarring.
Bleeding and infection risk are very uncommon with 
underlying disease conditions (hemophilia, diabetes, older 
age, and immunosuppression) slightly increasing the risk.
Scarring risk is increased in individuals with a history of 
scarring.
Exclusion criterion #5:
History of risk for or actual experience of complications 
from skin biopsy including excess bleeding, infection, or 
scarring/keloid formation.
Observation of the subject while in the clinical unit and at 
follow-up after discharge from the unit. 
Subject may be withdrawn at any time at the discretion of 
the investigator for safety.


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3.5.2.
Benefit Assessment
As the subjects of this study are healthy subjects they are not expected to receive any 
direct benefits from the investigation product.  The subject may benefit from the general 
medical data collected through study assessments such as clinical laboratory tests and 
ECGs.  Participation in the study may provide societal benefit through advancing 
development of new treatments in an area of unmet need.
3.5.3.
Overall Benefit:Risk Conclusion
Conducting this clinical trial is reasonable based on the measures taken to minimize risk 
to subjects participating, balanced against the potential risks identified in associated with 
GSK3008356 and the potential general benefits outlined above. 
4.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the Investigator’s Brochure 
(IB).
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
4.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
1. Between 18 and 65 years of age inclusive, at the time of signing the informed 
consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. For Part 1 and Part 2: Healthy as determined by the investigator or medically 
qualified designee based on a medical evaluation including medical history, physical 
examination, laboratory tests and cardiac monitoring.
3. For Part 3: Obese subjects may have chronic disease not specifically excluded and not 
requiring chronic medication for treatment and are otherwise healthy as determined 
by the investigator or medically qualified designee based on a medical evaluation 
including medical history, physical examination, laboratory tests and cardiac 
monitoring.
A subject with a clinical abnormality or laboratory parameter(s) which is/are not 


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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 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 50 kg 
5. For Part 1 and Part 2 body mass index (BMI) 19 – 25 kg/m2 (inclusive)
6. For Part 3 BMI ≥30 kg/m2
SEX
7. Males or Females of non-childbearing potential as follows:
Males:
Male subjects with female partners of child bearing potential must comply with the 
following contraception requirements (Section 4.3) from the time of first dose of study 
medication until at least five half-lives of study medication after the last dose of study 
medication.
a.
Vasectomy with documentation of azoospermia.  
b.
Male condom plus partner use of one of the contraceptive options below:

Contraceptive subdermal implant 

Intrauterine device or intrauterine system 

Oral Contraceptive, either combined or progestogen alone [Hatcher 2007] 
Injectable progestogen [Hatcher 2007]

Contraceptive vaginal ring [Hatcher 2007]

Percutaneous contraceptive patches [Hatcher 2007]
Females: 
A female subject is eligible to participate if she is not pregnant (as confirmed by a 
negative serum human chorionic gonadotrophin (hCG) test), not lactating, and the 
following conditions applies:
a.
Non-reproductive potential defined as:
Pre-menopausal females with one of the following:
Documented tubal ligation
Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion 
Hysterectomy


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Documented Bilateral Oophorectomy
Postmenopausal defined as 12 months of spontaneous amenorrhea in 
questionable cases a blood sample with simultaneous follicle stimulating 
hormone (FSH) > 40 MlU/ml and estradiol < 40 pg/ml (<147 pmol/L) is 
confirmatory. Females on hormone replacement therapy (HRT) and whose 
menopausal status is in doubt will not be allowed.
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
INFORMED CONSENT
8. Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the consent form and in this protocol.
4.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
1. 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 (Section 4.3)
4. Current or chronic history of gastrointestinal illness or conditions interfering with 
normal gastrointestinal anatomy or motility. Examples include gastrointestinal bypass 
surgery, cholecystectomy, partial or total gastrectomy, small bowel resection, 
vagotomy, malabsorption, Crohn’s disease, ulcerative colitis, IBS, or celiac sprue. 
5. History of risk for or actual experience of complications from skin biopsy including 
excess bleeding, infection, or scarring/keloid formation (Part 2 only).
CONCOMITANT MEDICATIONS
6. Use of prescription or non-prescription drugs, including vitamins, herbal and dietary 
supplements (including St John’s Wort) within 7 days (or 14 days if the drug is a 
potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose 
of study drug, unless in the opinion of the Investigator and GSK Medical Monitor the 
medication will not interfere with the study procedures or compromise subject safety. 
By exception, subject may take acetaminophen (≤ 2 grams/day) up to 48 hours prior 
to the first dose of study drug.


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RELEVANT HABITS
7. Subjects should refrain from consumption of red wine, Seville oranges, grapefruit or 
grapefruit juice and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices 
from 7 days prior to the first dose of study medication until after the final dose.
8. History of regular alcohol consumption within 6 months of the study defined as an 
average weekly intake of >14 standard drinks.  One standard drink is equivalent to 10
g of alcohol: 285 ml of beer, 100 ml of wine or 30 ml of 40% alcohol by volume 
distilled spirits.
9. For Part 1 and Part 2, urinary cotinine levels indicative of smoking or history or 
regular use of tobacco- or nicotine-containing products within 3 months prior to 
screening.
CONTRAINDICATIONS 
10. 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.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
11. 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.
12. A positive pre-study drug/alcohol screen.  
13. A positive test for HIV antibody.
14. Where participation in the study would result in donation of blood or blood products 
in excess of 750 mL within 90 day period.
15. 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).
16. Exposure to more than four new chemical entities within 12 months prior to the first 
dosing day.
4.3.
Inclusion and Exclusion Criteria Notes
For contraception requirements, the list provided is an all-inclusive list of those methods 
that meet the following GSK definition of highly effective: having a failure rate of less 
than 1% per year when used consistently and correctly and, when applicable, in 
accordance with the product label. For non-product methods (e.g., male sterility), the 
investigator determines what is consistent and correct use. The GSK definition is based 
on the definition provided by the International Conference on Harmonization (ICH)
[ICH, M3 (R2) 2009].”


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4.4.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and Serious Adverse Events (SAE) (see Section 6.3.1.4).
4.5.
Withdrawal/Stopping Criteria
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as 
soon as possible. 

The site must counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or should 
continue in the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and if necessary a certified letter to the subject’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be considered 
to have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records. 
The reason(s) for not completing the study will be recorded in the case report form 
(CRF), and the investigator must document, if applicable, the reason (if specified by the 
subject) for withdrawal of consent.  A withdrawn subject may be replaced with another 
subject who will be assigned to the same treatment randomization.
4.5.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and 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


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Study treatment will be discontinued for a subject if liver chemistry stopping criteria are 
met:
Figure 2
Phase I Liver Chemistry Stopping Criteria – Liver Stopping Event 
Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments  section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 2 (Section 11.2).
4.5.1.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed.
4.5.2.
QTc Stopping Criteria
A subject that meets either bulleted criterion below will be withdrawn from the study.  

QTcF > 500 msec,

Change from baseline: QTc >60 msec
For trial eligibility the same QT correction formula (QTcF) will be used.   The same QT 
correction formula (QTcF) will be used for all QTc data being collected for data analysis.  
Discontinuation decisions would ideally use the same QT correction formula will be 
used.  The exception would be safety ECGs or other non-protocol specified ECGs outside 
the control of the clinical unit.
Withdrawal of subjects is to be based on an average QTc value of triplicate ECGs.  If an 
ECG demonstrates a prolonged QT interval, then obtain 2 more ECGs over a brief (e.g., 


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5-10 minute) recording period and then use the averaged QTc values of the 3 ECGs to 
determine whether the subject should be discontinued from the study.  
4.6.
Subject and Study Completion
A completed subject is one who has completed all phases of the study including the 
follow-up visit.
The end of the study is defined as the last subject’s last visit.
5.
STUDY TREATMENT
5.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments (Table 6).
Table 6
Study Treatment
Study Treatment
Product name:
GSK3008356
Placebo
Formulation description /
Dosage form:
Tablet
Tablet
Unit dose strengths/Dosage levels:
0.5, 1, 5, and 25 mg
Route of Administration
Administered orally
Administered orally
Dosing instructions:
Daily for up to 28 days
Daily for up to 28 days
Physical description:
White Tablet
White Tablet
Manufacturer
GlaxoSmithKline
GlaxoSmithKline
5.2.
Treatment Assignment
Subjects will be assigned to treatments in accordance with the randomization schedule 
generated by Clinical Statistics, prior to the start of the study, using validated software.
A description of each regimen is provided in the table below (Table 7):


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Table 7
Regimen Description
Regimen 
Code
Study Medication
Regimen 
Code
Study Medication
AA
5 mg GSK3008356, morning dosing
AP
5 mg GSK3008356, evening dosing
BA
10 mg GSK3008356, morning dosing
BP
10 mg GSK3008356, evening dosing
CA
25 mg GSK3008356, morning dosing
CP
25 mg GSK3008356, evening dosing
DA
50 mg GSK3008356, morning dosing
DP
50  mg GSK3008356, evening dosing
EA
75 mg GSK3008356, morning dosing
EP
75 mg GSK3008356, evening dosing
FA
Matched placebo, morning dosing
FP
Matched placebo, evening dosing
GA
125 mg GSK3008356, morning dosing
LA
5 mg GSK3008356 q1h x 9 doses, 
morning dosing
HA
125 mg GSK3008356 q4h x 2 doses, 
morning dosing
MA
20 mg GSK3008356 q1h x 9 doses, 
morning dosing
IA
125 mg GSK3008356 q16h x 2 doses, 
morning dosing
NA
10 mg GSK3008356 q16h x 2 doses, 
morning dosing
JA
200  mg GSK3008356,
evening dosing
OA
3 mg GSK3008356 q1h x 9 doses, 
morning dosing
KA
10 mg GSK3008356 q1h x 9 doses, 
morning dosing
PA
1 mg GSK3008356 q1h x 9 doses, 
morning dosing
5.3.
Planned Dose Adjustments

This protocol allows some alteration from the currently outlined dosing schedule, 
but the maximum predicted daily exposure will not exceed Cmax = 7.73 µg/mL or 
AUC 111 μg.h/mL.

The decision to proceed to the next dose level will be made by the GSK Study 
Team, in conjunction with the investigator based on safety, tolerability and 
preliminary pharmacokinetic and/or pharmacodynamic data obtained in at least 4
subjects at the prior dose level in Parts 1 and 2 (dose escalation Parts).  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, 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.  Any cohort expansion or addition will be 


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contingent on approval of an amended protocol by the Human Research Ethics 
Committee (HREC).

If the same Serious Adverse Event 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.
5.4.
Blinding
This will be a double blind (sponsor unblind) 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  CRF
A subject will be withdrawn if the subject’s treatment code is unblinded by the 
investigator or treating physician. The primary reason for discontinuation (the event or 
condition which led to the unblinding) will be recorded in the CRF.

GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind 
the treatment assignment for any subject 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 subject’s treatment assignment, may be sent to 
investigators in accordance with local regulations and/or GSK policy.
5.5.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.


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5.6.
Preparation/Handling/Storage/Accountability
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 Study reference Manual (SRM).

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff

A Material Safety Data Sheet (MSDS)/equivalent document describing 
occupational hazards and recommended handling precautions either will be 
provided to the investigator, where this is required by local laws, or is available 
upon request from GSK.
5.7.
Compliance with Study Treatment Administration
When the individual dose for a subject is prepared from a bulk supply, the preparation of 
the dose will be confirmed by a second member of the study site staff. 
When subjects are dosed at the site, they will receive study treatment directly from the 
investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents.  The dose of study 
treatment and study 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.  
Study site personnel will examine each subject’s mouth to ensure that the study treatment 
was ingested.
When subjects self-administer study treatment(s) at home, compliance with study drug
will be assessed through querying the subject during the site visits and documented in the 
source documents and CRF.  A record of the number of study drug tablets dispensed to 
and taken by each subject must be maintained and reconciled with study treatment and 
compliance records.  Treatment start and stop dates, including dates for treatment delays 
and/or dose reductions will also be recorded in the CRF.
5.8.
Treatment of Study Treatment Overdose
GSK does not recommend specific treatment for an overdose.  The investigator or 
physician in charge of the subject at the time will use clinical judgment to treat any 
overdose.


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5.9.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because only healthy subjects or healthy obese subjects are eligible for study 
participation.
5.10.
Lifestyle and/or Dietary Restrictions
5.10.1.
Meals and Dietary Restrictions
Subjects should refrain from consumption of red wine, Seville oranges, grapefruit or 
grapefruit juice and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices 
from 7 days prior to the first dose of study medication until after the final dose.
Subjects in Part 3, evening dosing, should refrain from any meals after the evening dose 
until breakfast the next morning.
5.10.2.
Caffeine, Alcohol, and Tobacco

For Part 1 and Part 2, subjects will abstain from ingesting caffeine- or xanthine-
containing products (e.g., coffee, tea, cola drinks and chocolate) for 24 hours prior to 
the start of dosing until collection of the final pharmacokinetic and or 
pharmacodynamic sample during each cohort. 

For Part 3, during each inpatient visit, subjects will abstain from ingesting caffeine-
or xanthine-containing products (e.g., coffee, tea, cola drinks and chocolate) for 24 
hours prior to the start of dosing until collection of the final pharmacokinetic and or 
pharmacodynamic sample during the inpatient stay.

During each dosing session, subjects will abstain from alcohol for 24 hours prior to 
the start of dosing until collection of the final pharmacokinetic and or 
pharmacodynamic sample during each session. 

For Part 1 and Part 2, use of tobacco products is not allowed from inpatient check-in 
and the start of dosing until after the final follow-up visit.

For Part 3 inpatient sessions, use of tobacco products is not allowed from inpatient 
check-in until after discharge from the unit.

For Part 3, outpatient Subjects who use tobacco products will be instructed that use 
of nicotine-containing products (including nicotine patches) will not be permitted 
while they are in the Clinical Unit.  
5.10.3.
Activity
Subjects will abstain from strenuous exercise for 1 hour prior to each blood collection for 
clinical laboratory tests.  Subjects may participate in light recreational activities during 
studies (e.g., watch television, read).


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5.11.
Concomitant Medications and Non-Drug Therapies
Based on the in vitro data generated to date, it is unlikely for GSK3008356 to affect the 
pharmacokinetics of co-administered CYP, OATP1B1/1B3, P-gp or BCRP substrates.  
Please refer to the IB [GlaxoSmithKline Document Number 2015N255332_00] for 
details.
5.11.1.
Permitted Medications and Non-Drug Therapies
Paracetamol, at doses of 1 grams/day is permitted for use any time during the study. 
Other concomitant medication may be considered on a case by case basis by the
investigator in consultation with the Medical Monitor if required.
5.11.2.
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.
6.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table Section 6.1
The following points must be noted: 

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
4. skin biopsy.
Note: The timing of the assessments should allow the blood draw to occur at the 
exact nominal time.

The timing and number of planned study assessments, including safety, 
pharmacokinetic, pharmacodynamic/biomarker or others 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. 


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
The nominal dosing time for evening dose cohorts (20:00 local) in the respective 
Time and Events Tables is for illustrative purposes only.  The nominal evening 
dose time selected for use will be documented for each evening dose cohort. The
actual dose time will be recorded as well.

The change in timing or addition of time points for any planned study 
assessments must be documented in a Note to File which is approved by the 
relevant GSK study team member and then archived in the study sponsor and 
site study files, but this will not constitute a protocol amendment. 

The HREC and investigators will be informed of any safety issues that require 
alteration of the safety monitoring scheme or amendment of the Informed 
Consent Form. 

No more than 650 mL of blood will be collected over the duration of the study, 
including any extra assessments that may be required.


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6.1.
Time and Events Tables
Please refer to Figure 3 below to understand the how the multiple Time and Events Tables relate to the study Parts.
Figure 3
Study Part and Related Time and Events Tables
Part 1 SD Daytime Dosing
Screen to Follow Up
6.1.1
Meal, TG, PK detail
6.1.1.1
Part 2 14d RD: Daytime Dosing
Screen to Day 1
6.1.2
Meal, TG, PK detail
6.1.8.1
Day 2 to 13
6.1.3
Day 14 to Follow up
6.1.4
Part 2 14d RD: Evening Dosing
Screen to Day 2
6.1.5
Meal, TG, PK detail
6.1.8.2
Day 3 to 13
6.1.6
Day 14 to Follow up
6.1.7
Part 3 28d RD: Daytime Dosing
Screen to Day 2
6.1.9
Meal, TG, PK detail
6.1.15.1
Day 3 to 27
6.1.10
Day 27 to Follow up
6.1.11
Part 3 28d RD: Evening Dosing
Screen to Day 2
6.1.12
Meal, TG, PK detail
6.1.15.2
Day 3 to 27
6.1.13
Day 27 to Follow up
6.1.14


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6.1.1.
Part 1 – Single Dose
Screening
(within 
28d)
Day -2, 
Day -1 9
Day 1
Day 2 Day 3 Day 4
Follow Up
(Day 6-8)
Pre-
dose
0h
0.25h
0.5h
1h
1.5h
2h
4h
6h
8h
12h
18h 24h
36h
48h
72h
Informed Consent
X
Medical/medication/drug/alcohol 
history
X
X
X
Complete Physical Exam, Weight
X
X1
X1
X
HIV, Hep B, Hep C
X
Pregnancy Test2
X
X
X
Estradiol/FSH3
X
Urine Drug, Cotinine & Alcohol Screen4
X
X
Fat Meal5
X
X
Triglyceride Assessment5

X
============
Study Drug Dose10
X10
Vital Signs (BP, HR, pulse, Temp)6
X
X
X
X
X
X
X
X
X
X
12-Lead ECG
X
X
X
X
X
X
X
Telemetry
============================
Hematology, Chemistry
X
X
X
X
X
X
X
UA
X
X
X
X
X
Exploratory PD Labs
X
X
X
X
X
Plasma PK and Metabolite 
Sampling5, 7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine PK and Metabolite Sampling7

==================================

Adverse Event Review
===========================================================================
BSFS8
=====================================================================
Concomitant Medication Review
===========================================================================
Outpatient Visits
X
X
Inpatient Check-in
X
Inpatient Check-out
X


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1.
Brief physical exam, weight.
2.
Serum hCG at screening and follow up, urine hCG pre-dose on Day -1 – all females.
3.
If indicated.
4.
An alcohol breath test is acceptable.
5.
Detailed Fat Meal and Triglyceride Assessment relative to Dose and Plasma PK Sampling can be found in Section 6.1.1.1.
6.
Temperature Screening and Day -1 only.
7.
Plasma analysis for circulating metabolite profile; Urine analysis to aid structural identification.  Urine samples for parent and metabolite structure will be collected pre-dose and 
over the post-dose intervals 0-12 hours and 12-24 hours. Plasma and urine samples for metabolites will be analyzed from only the highest dose cohort.
8.
The number of BSFS stool types will be collected in real time for each 24h period (Section 11.5).
9.
Based on logistics, check-in and all Day -1 assessments may occur on Day -2 with the exception of the Fat Meal and TG Assessment, both of which must be done on Day -1.
10. For cohorts where multiple doses are to be administered either q1h, q4h or q16h, Time 0 is the first dose and subsequent doses are per regimen (q1h, q4h or q16) and the 
subsequent doses are not noted on the T&E Table. For the single evening cohort, the dose will be at hour 16 and not noted on the T&E Table.
6.1.1.1.
Part 1, Single Dose, Fat Meal Challenge and Triglyceride Assessment Relative to Dose and PK Sampling
Day -1, Day 1
Pre-
dose
0h
0.25h
0.5h
1h
1.5h
2h
3h
4h
5h
6h
7h
8h
9h
12h
18h
Study Drug Dose1, 3
X3
Fat Meal
X
Triglyceride Assessment
X
X
X
X
X
X
X
X
X
X
Plasma Pharmacokinetic Sampling1, 2
X
X
X
X
X
X
X
X
X
X
X
1.
Day 1 only 
2.
PK Samples included in table to provide relative time to dosing, fat meal and triglyceride assessment.  
The full PK time points are found in Section 6.1.1
3.
For cohorts where multiple doses are to be administered either q1h, q4h or q16h, Time 0 is the first dose and subsequent doses are per regimen 
(q1h, q4h or q16) and the subsequent doses are not noted on the T&E Table. For the single evening cohort, the dose will be at hour 16 and not 
noted on the T&E Table


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6.1.2.
Part 2 – Repeat Dose, Morning Dose Administration, Screening, Day -1, Day 1
Screening
(within 28d)
Day -2, 
Day -1 9
Day 1
Pre-
dose
0h
0.25h
0.5h
1h
1.5h
2h
4h
6h
8h
12h
18h 24h
Informed Consent
X
Medical/medication/drug/alcohol history
X
X
Complete Physical Exam, Weight
X
X1
HIV, Hep B, Hep C
X
Pregnancy Test2
X
X
Estradiol/FSH3
X
Urine Drug, Cotinine & Alcohol Screen4
X
X
Fat Meal5
X
X
Triglyceride Assessment5

X
============
Study Drug Dose10
X10
Vital Signs (BP, HR, pulse, Temp)6
X
X
X
X
X
X
X
12-Lead ECG
X
X
X
X
X
X
Telemetry
=============================
Hematology, Chemistry
X
X
X
X
UA
X
X
X
Exploratory PD Labs
X
X
X
Plasma PK and Metabolite Sampling5, 7
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Event Review
====================================================
BSFS8
==============================================
Concomitant Medication Review
====================================================
Outpatient Visits
X
Inpatient Check-in
X


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1.
Brief physical exam, weight.
2.
Serum hCG at screening and follow up, urine hCG pre-dose on Day -1 – all females.
3.
If indicated.
4.
An alcohol breath test is acceptable.
5.
Detailed Fat Meal and Triglyceride Assessment relative to Dose and Plasma PK Sampling can be found in Section 6.1.8.1.
6.
Temperature Screening and Day -1 only.
7.
Plasma analysis for circulating metabolite profile; Plasma samples for metabolites will be analyzed from only the highest dose cohort.
8.
The number of BSFS stool types will be collected in real time for each 24h period (Section 11.5).
9.
Based on logistics, check-in and all Day -1 assessments may occur on Day -2 with the exception of the Fat Meal and TG Assessment, both of which 
must be done on Day -1.
10. For cohorts where multiple doses are to be administered either q1h or q16h, Time 0 is the first dose and subsequent doses are per regimen (q1h or 
q16) and the subsequent doses are not noted on the T&E Table.


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6.1.3.
Part 2 – Repeat Dose, Morning Dose Administration, Days 2-13
Days 2-13
Pre-dose
0h
Study Drug Dose6
X6
Vital Signs (BP, HR, pulse)
X
12-Lead ECG1
X
Hematology, Chemistry2
X
UA3
X
Exploratory PD Labs3
X
Plasma PK and Metabolite Sampling4
X
Adverse Event Review
==================
BSFS5
==================
Concomitant Medication Review
==================
1.
Day 2 (equal to Day 1 24h time point), 7, 12, and 13 only.
2.
Day 2 (equal to Day 1 24h time point ), 4, and Day 7 only
3.
Day 2 (equal to Day 1 24h time point) and Day 7 only
4.
Day 2 (equal to Day 1 24h time point), 4, 5, 6, 12, and 13 only 
5.
The number of BSFS stool types will be collected in real time for each 24h 
period (Section 11.5).
6.
For cohorts where multiple doses are to be administered either q1h or 
q16h, Time 0 is the first dose and subsequent doses are per regimen (q1h 
or q16) and the subsequent doses are not noted on the T&E Table.


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6.1.4.
Part 2 – Repeat Dose, Morning Dose Administration, Days 14-17, Follow-up
Day 14
Day 15 Day 16 Day 17
Follow Up
(Day 20-22)
Pre-
dose
0h
0.25h
0.5h
1h
1.5h
2h
4h
6h
8h
12h
18h 24h
36h
48h
72h
Medical/medication/drug/alcohol history
X
Complete Physical Exam, Weight
X1
X
Pregnancy Test2
X
Fat Meal3
X
Triglyceride Assessment3
X
============
Study Drug Dose6
X6
Vital Signs (BP, HR, pulse)
X
X
X
X
X
X
X
X
12-Lead ECG
X
X
X
X
X
X
Hematology, Chemistry
X
X
X
X
X
X
UA
X
X
X
X
Exploratory PD Labs
X
X
X
X
Plasma PK and Metabolite Sampling3, 4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Skin Biopsy7
X7
X7
X7
Adverse Event Review
======================================================================
BSFS5
======================================================================
Concomitant Medication Review
======================================================================
Outpatient Visits
X
Inpatient Check-out
X
1.
Brief physical exam and weight Day 17 only 
2.
Serum hCG at follow up, all females.
3.
Detailed Fat Meal, Triglyceride Assessment, Plasma PK Sampling and Plasma Metabolite Sampling can be found in Section 6.1.8.1
4.
Plasma analysis for circulating metabolite profile; Plasma samples for metabolites will be analyzed from only the highest dose cohort.
5.
The number of BSFS stool types will be collected in real time for each 24h period (Section 11.5).
6.
For cohorts where multiple doses are to be administered either q1h or q16h, Time 0 is the first dose and subsequent doses are per regimen (q1h or q16) and the 
subsequent doses are not noted on the T&E Table.
7.
Cohort 1 (10mg q16) collect only at 1h and 24h Day 14; Cohorts 2 & 3 (3mg, 1mg or 5mg q1h) collect only at 6h and 24h Day 14


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6.1.5.
Part 2 – Repeat Dose, Evening Dose Administration, Screening, Day -1, Day 1 and Day 2
Screening
(within 28d)
Day -1 
Day 1 (6)
Day 2 (6)
PM
12h Pre-
dose
Pre-
dose
0h
0.25h 0.5h
1h
1.5h
2h
4h
6h
12h 14h
18h 24h
Informed Consent
X
Medical/medication/drug/alcohol history
X
X
Complete Physical Exam, Weight
X
X1
HIV, Hep B, Hep C
X
Pregnancy Test2
X
X
Estradiol/FSH3
X
Urine Drug, Cotinine & Alcohol Screen4
X
X
Fat Meal5
X
X
Triglyceride Assessment5

=======
Study Drug Dose6
X
Vital Signs (BP, HR, pulse, Temp)7
X
X
X
X
X
X
X
12-Lead ECG
X
X
X
X
X
X
Telemetry
==========================
Hematology, Chemistry
X
X
X
X
UA
X
X
X
Exploratory PD Labs
X
X
X
Plasma PK and Metabolite Sampling5, 8
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Event Review
==========================================================
BSFS9
==================================================
Concomitant Medication Review
==========================================================
Outpatient Visits
X
Inpatient Check-in
X
1.
Brief physical exam, weight.
2.
Serum hCG at screening, urine hCG pre-dose on Day -1 – all females.
3.
If indicated
4.
An alcohol breath test is acceptable.
5.
Detailed Fat Meal, Triglyceride Assessment, Plasma PK Sampling and Plasma Metabolite Sampling can be found in Section 6.1.8.2


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6.
0hr is relative to Study Dose administered and will be approximately at 18:00 hrs, making 12h Pre-dose approximately 06:00, 6h post-dose approximately 
00:00 Day 2 and 12h post-dose approximately 06:00 Day 2.  The actual nominal dose time will be the same for each subject within Part 2.
7.
Temperature at Screening and Day -1 only.
8.
The 24h time point is Day 2 pre-dose.  Plasma analysis for circulating metabolite profile; Plasma samples for metabolites will be analyzed from only the highest 
dose cohort.
9.
The number of BSFS stool types will be collected in real time for each 24h period (Section 11.5)
6.1.6.
Part 2 – Repeat Dose, Evening Dose Administration, Days 3-13
Days 3-13   (1)
12h Pre-dose
Pre-dose
0h
Study Drug Dose1
X
Vital Signs (BP, HR, pulse)
X2
12-Lead ECG
X2
Hematology, Chemistry
X3
UA
X4
Exploratory PD Labs
X5
Plasma PK and Metabolite Sampling
X6
Adverse Event Review
===========================
BSFS8
===========================
Concomitant Medication Review
===========================
1.
0hr is relative to Study Dose administered and will be approximately at 18:00 hrs, making 
12h Pre-dose approximately 06:00. The actual nominal dose time will be the same for each 
subject within Part 2.
2.
Day 7, 12, and 13.
3.
Day  4, and 7 only
4.
Day 7 only
5.
Day 7 12h Pre-dose only
6.
Day 4, 5, 6, 12, and 13
7.
The number of BSFS stool types will be collected each 24h period (Section 11.5)


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6.1.7.
Part 2 – Repeat Dose, Evening Dose Administration, Day 14-17, Follow-up
Day 14
Day 15
Day 16
Day 17
Follow Up
(Day 20-22)
12h 
Pre-
dose
0h
0.25h 0.5h
1h
1.5h
2h
4h
6h
12h 14h
18h 24h
36h
48h
72h
Medical/medication/drug/alcohol history
X
Complete Physical Exam, Weight
X1
X
Pregnancy Test2
X
Fat Meal3
X
Triglyceride Assessment3

Study Drug Dose4
X
Vital Signs (BP, HR, pulse)
X
X
X
X
X
X
X
12-Lead ECG
X
X
X
X
X
Hematology, Chemistry
X
X
X
X
X
UA
X
X
X
Exploratory PD Labs
X
X
X
Plasma PK and Metabolite Sampling3,5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Event Review
=================================================================
BSFS6
=================================================================
Concomitant Medication Review
=================================================================
Outpatient Visits
X
Inpatient Check-out
X
1.
Brief physical exam and weight Day 17 only  
2.
Serum hCG at follow up, all females.
3.
Detailed Fat Meal, Triglyceride Assessment, Plasma PK Sampling and Plasma Metabolite Sampling can be found in Section 6.1.8.2
4.
0hr is relative to Study Dose administered and will be approximately at 18:00 hrs, making 12h Pre-dose approximately 06:00 and 6h post-dose approximately 
00:00 Day 15. The actual nominal dose time will be the same for each subject within Part 2.
5.
Plasma analysis for circulating metabolite profile; Plasma samples for metabolites will be analyzed from only the highest dose cohort.
6.
The number of BSFS stool types will be collected in real time for each 24h period (Section 11.5)


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6.1.8.
Part 2 – Repeat Dose, Fat Meal Challenge and Triglyceride Assessment Relative to Dose and PK Sampling
6.1.8.1.
Morning Dose Administration, Day -1, Day 1, and Day 14
Day -1, Day 1, Day 14
Pre-
dose
0h
0.25h
0.5h
1h
1.5h
2h
3h
4h
5h
6h
7h
8h
9h
12h
18h
Study Drug Dose1
X
Fat Meal
X
Triglyceride Assessment
X
X
X
X
X
X
X
X
X
X
Plasma Pharmacokinetic Sampling1, 2
X
X
X
X
X
X
X
X
X
X
X
1.
Day 1 and 14 only.  For cohorts where multiple doses are to be administered either q1h or q16h, Time 0 is the first dose and subsequent doses are 
per regimen (q1h or q16) and the subsequent doses are not noted on the T&E Table.
2.
PK Samples included in table to provide relative time to dosing, fat meal and triglyceride assessment.  
The full PK time points are found in Section 6.1.2, Section 6.1.3, and Section 6.1.4.
6.1.8.2.
Evening Dose Administration, Day 1, Day 2, and Day 14
Day 1, Day 2 and Day 14
Pre-dose (h)
0h
Post-dose (h)
11h
10h
9h
8h
7h
6h
5h
4h
3h
< 0.5h pre-dose
0.25h
0.5h
Study Drug Dose1
X1,3
Fat Meal
X
Triglyceride Assessment
X
X
X
X
X
X
X
X
X
X
Plasma Pharmacokinetic Sampling2
X
X
X
1.
Day 1 and 14 only
2.
PK Samples included in table to provide relative time to dosing, fat meal and triglyceride assessment.  
The full PK time points are found in Section 6.1.5, Section 6.1.6, and Section 6.1.7.  
3.
0hr is relative to Study Dose administered and will be approximately at 18:00 hrs, making 12h Pre-dose approximately 06:00 and Making Day 2 Fat Meal 
14h Post-Day 1 Dose (10h Pre-Day 2 Dose). The actual nominal dose time will be the same for each subject within Part 2.


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6.1.9.
Part 3 – Repeat Dose, Morning Dose Administration, Screening, Day -1, Day 1, Day 2
Screening
(within 28d)
Day -2, 
Day -1 8
Day 1
Day 2
Pre-
dose
0h
0.25h
0.5h
1h
1.5h
2h
4h
6h
8h
12h
18h 24h
0h
1h
Informed Consent
X
Medical/medication/drug/alcohol history
X
X
Complete Physical Exam, Weight
X
X1
HIV, Hep B, Hep C
X
Pregnancy Test2
X
X
Estradiol/FSH3
X
Urine Drug, Cotinine & Alcohol Screen4
X
X
Fat Meal5
X
X
Triglyceride Assessment5

X
============
Study Drug Dose
X
X
Vital Signs (BP, HR, pulse, Temp)6
X
X
X
X
X
X
X
12-Lead ECG
X
X
X
X
X
X
Telemetry
=============================
Hematology, Chemistry
X
X
X
X
UA
X
X
X
Exploratory PD Labs
X
X
X
Plasma PK Sampling5,
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Event Review
==========================================================
BSFS7
====================================================
Concomitant Medication Review
==========================================================
Outpatient Visits
X
Inpatient Check-in
X
Inpatient Check-out
X
1.
Brief physical exam, weight.
2.
Serum hCG at screening and follow up, urine hCG pre-dose on Day -1 – all females.
3.
If indicated.
4.
An alcohol breath test is acceptable.


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5.
Detailed Fat Meal and Triglyceride Assessment relative to Dose and Plasma PK Sampling can be found in Section 6.1.15.1.
6.
Temperature Screening and Day -1 only.
7.
The number of BSFS stool types will be collected in real time for each 24h period (Section 11.5).
8.
Based on logistics, check-in and all Day -1 assessments may occur on Day -2 with the exception of the Fat Meal and TG Assessment, both of which must be done 
on Day -1.
6.1.10.
Part 3 – Repeat Dose, Morning Dose Administration, Days 7, 14, and 21*
Days 7, 14, and 21
Pre-dose
0h
Medical/medication/drug/alcohol history
X
Brief Physical Exam, Weight
X
Study Drug Dose
X
Vital Signs (BP, HR, pulse)
X
12-Lead ECG
X
Hematology, Chemistry
X
UA
X
Exploratory PD Labs
X
Plasma PK Sampling
X
Adverse Event Review
====================
BSFS1
====================
Concomitant Medication Review
====================
Outpatient Visits
X
1.
The number of BSFS stool types will be collected in real time for each 24h period 
while at home (Section 11.5).  BSFS Diary Cards to be bought to the unit and 
reviewed/data entered during the visit.
*NOTE for Days 3-6, 8-13, 15-20, and 22-27: Subjects will dose at home and maintain BSFS Diary cards as directed.


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6.1.11.
Part 3 – – Repeat Dose, Morning Dose Administration, Day 27-31 and Follow-up
Day 27
Day 28
Day 29 Day 30 Day 31
Follow Up
(Day 34-36)
PM
Pre-
dose
0h
0.25h
0.5h
1h
1.5h
2h
4h
6h
8h
12h
18h 24h
36h
48h
72h
Medical/medication/drug/alcohol history
X
X
Complete Physical Exam, Weight
X1
X1
X
Pregnancy Test2
X
Fat Meal3
X
Triglyceride Assessment3
X
============
Study Drug Dose
X
Vital Signs (BP, HR, pulse)
X
X
X
X
X
X
X
X
X
12-Lead ECG
X
X
X
X
X
X
Hematology, Chemistry
X
X
X
X
X
X
UA
X
X
X
X
Exploratory PD Labs
X
X
X
X
Plasma PK Sampling3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Event Review
==========================================================================
BSFS4
==========================================================================
Concomitant Medication Review
==========================================================================
Outpatient Visits
X
Inpatient Check-in
X
Inpatient Check-out
X
1.
Brief physical exam and weight Day 27 and 31
2.
Serum hCG at follow up, all females.
3.
Detailed Fat Meal, Triglyceride Assessment and Plasma PK Sampling can be found in Section 6.1.15.1
4.
The number of BSFS stool types will be collected in real time for each 24h period (Section 11.5). BSFS Diary Cards to be bought to the unit and reviewed/data entered during 
the visit.


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6.1.12.
Part 3 – Repeat Dose, Evening Dose Administration, Screening, Day 1 and Day 2
Screening
(within 28d)
Day -1 
Day 1 (6)
Day 2 (6)
PM
12h Pre-
dose
Pre-
dose
0h
0.25h 0.5h
1h
1.5h
2h
4h
6h
12h 14h
18h 24h
0h
1h
Informed Consent
X
Medical/medication/drug/alcohol history
X
X
Complete Physical Exam, Weight
X
X1
HIV, Hep B, Hep C
X
Pregnancy Test2
X
X
Estradiol/FSH3
X
Urine Drug, Cotinine & Alcohol Screen4
X
X
Fat Meal5
X
X
Triglyceride Assessment5

=========
Study Drug Dose6
X
X
Vital Signs (BP, HR, pulse, Temp)7
X
X
X
X
X
X
12-Lead ECG
X
X
X
X
X
Telemetry
=========================
Hematology, Chemistry
X
X
X
X
UA
X
X
X
Exploratory PD Labs
X
X
X
Plasma PK Sampling5, 8
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Event Review
================================================================
BSFS9
=========================================================
Concomitant Medication Review
================================================================
Outpatient Visits
X
Inpatient Check-in
X
Inpatient Check-out
X
1.
Brief physical exam, weight.
2.
Serum hCG at screening, urine hCG pre-dose on Day -1 – all females.
3.
If indicated
4.
An alcohol breath test is acceptable.


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5.
Detailed Fat Meal, Triglyceride Assessment, Plasma PK Sampling and Plasma Sampling can be found in Section 6.1.15.2
6.
0hr is relative to Study Dose administered and will be approximately at 18:00 hrs, making 12h Pre-dose approximately 06:00, 6h post-dose approximately 00:00 Day 2 and 
12h post-dose approximately 06:00 Day 2.  The actual nominal dose time will be the same for each subject within Part 3.
7.
Temperature at Screening and Day -1 only.
8.
The 24h time point is Day 2 pre-dose.  
9.
The number of BSFS stool types will be collected in real time for each 24h period (Section 11.5)
6.1.13.
Part 3 – Repeat Dose, Evening Dose Administration, Days 7, 14, and 21*
Days 7, 14, and 21   (2)
Pre-dose
0h
Medical/medication/drug/alcohol history
X
Brief Physical Exam, Weight
X
Study Drug Dose
X
Vital Signs (BP, HR, pulse)
X
12-Lead ECG
X
Hematology, Chemistry
X
UA
X
Exploratory PD Labs
X
Plasma PK Sampling
X
Adverse Event Review
=================
BSFS1
=================
Concomitant Medication Review
=================
Outpatient Visits
X
1.
The number of BSFS stool types will be collected in real time for each 24h period 
while at home (Section 11.5).  BSFS Diary Cards to be bought to the unit and 
reviewed/data entered during the visit.
2.
0hr is relative to Study Dose administered and will be approximately at 18:00 hrs.  
The actual nominal dose time will be the same for each subject within Part 3.
*NOTE for Days 3-6, 8-13, 15-20, and 22-27: Subjects will dose at home and maintain BSFS Diary cards as directed.  If subjects are 
checking into the unit prior to dosing on Day 27, the dose may be administered in the unit rather than at home


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6.1.14.
Part 3 – Repeat Dose, Evening Dose Administration, Day 27-31 and Follow-up
Day 27
Day 28
Day 29
Day 30
Day 31
Follow Up
(Day 34-36)
PM
12h 
Pre-
dose
0h
0.25h 0.5h
1h
1.5h
2h
4h
6h
12h 14h
18h 24h
36h
48h
72h
Medical/medication/drug/alcohol history
X
X
Complete Physical Exam, Weight
X1
X1
X
Pregnancy Test2
X
Fat Meal3
X
X
Triglyceride Assessment3

Study Drug Dose4
X
X
Vital Signs (BP, HR, pulse)
X
X
X
X
X
X
X
X
12-Lead ECG
X
X
X
X
X
Hematology, Chemistry
X
X
X
X
X
UA
X
X
X
Exploratory PD Labs
X
X
X
Plasma PK Sampling3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Event Review
=======================================================================
BSFS5
=======================================================================
Concomitant Medication Review
=======================================================================
Outpatient Visits
X
Inpatient Check-out
X
Inpatient Check-out
X
1.
Brief physical exam and weight Day 17 only  
2.
Serum hCG at follow up, all females.
3.
Detailed Fat Meal, Triglyceride Assessment and Plasma PK Sampling can be found in Section 6.1.15.2
4.
0hr is relative to Study Dose administered and will be approximately at 18:00 hrs, making 12h Pre-dose approximately 06:00 and 6h post-dose approximately 00:00 
Day 29.  Day 27 dose may be administered in the unit rather than at home if the subject has checked in prior to Day 27 dose. The actual nominal dose time will be the 
same for each subject within Part 3.
5.
The number of BSFS stool types will be collected in real time for each 24h period (Section 11.5). BSFS Diary Cards to be bought to the unit and reviewed/data entered 
during the visit.


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6.1.15.
Part 3 – Repeat Dose, Fat Meal Challenge and Triglyceride Assessment Relative to Dose and PK Sampling
6.1.15.1.
Morning Dose Administration, Day -1, Day 1, and Day 28
Day -1, Day 1, Day 28
Pre-
dose
0h
0.25h
0.5h
1h
1.5h
2h
3h
4h
5h
6h
7h
8h
9h
12h
18h
Study Drug Dose1
X
Fat Meal
X
Triglyceride Assessment
X
X
X
X
X
X
X
X
X
X
Plasma Pharmacokinetic Sampling1, 2
X
X
X
X
X
X
X
X
X
X
X
1.
Day 1 and 28 only 
2.
PK Samples included in table to provide relative time to dosing, fat meal and triglyceride assessment.  
The full PK time points are found in Section 6.1.9, Section 6.1.10, and Section 6.1.11.
6.1.15.2.
Evening Dose Administration, Day 1, Day 2, and Day 28
Day 1, Day 2 and Day 28
Pre-dose (h)
0h
Post-dose (h)
11h
10h
9h
8h
7h
6h
5h
4h
3h
< 0.5h pre-dose
0.25h
0.5h
Study Drug Dose1
X3
Fat Meal
X
Triglyceride Assessment
X
X
X
X
X
X
X
X
X
X
Plasma Pharmacokinetic Sampling1, 2
X
X
X
1.
Day 1, Day 2, and 28 only
2.
PK Samples included in table to provide relative time to dosing, fat meal and triglyceride assessment.  
The full PK time points are found in Section 6.1.12, Section 6.1.13, and Section 6.1.14.
3.
0hr is relative to Study Dose administered and will be approximately at 18:00 hrs, making 12h Pre-dose approximately 06:00 and Making Day 2 Fat Meal 
14h Post-Day 1 Dose (10h Pre-Day 2 Dose).  The actual nominal dose time will be the same for each subject within Part 3.


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6.2.
Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed at 
screening.
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.
Medical/medication/family history will be assessed at screening as related to the
inclusion/exclusion criteria listed in Section 4.  All subsequent assessments will be 
updates.
6.3.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 6.1).  Additional time points for safety tests (such as vital signs, physical exams 
and laboratory safety tests) may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring.
6.3.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 3 (Section 11.3)
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
6.3.1.1.
Time period and Frequency for collecting AE and SAE information

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded from the time a subject consents to participate in the 
study up to and including any follow-up contact. 

AEs will be collected from the start of Study Treatment until the follow-up 
contact (see Section 6.3.1.3), at the time points specified in the Time and Events 
Table (Section 6.1).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in
Section 11.3.

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the 
investigator must promptly notify GSK.


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NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in
Section 11.3.
6.3.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?”

“Have you had any (other) medical problems since your last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?” 
6.3.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, and non-serious AEs of special interest 
(as defined in Section 3.5.1) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 4.5). Further information on follow-up procedures is given in 
Section 11.3.
6.3.1.4.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs related to study treatment (even 
for non- interventional post-marketing studies) is essential so that legal obligations and 
ethical responsibilities towards the safety of subjects and the safety of a product under 
clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, HREC and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the HREC, if appropriate according to local requirements.


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6.3.2.
Pregnancy

Details of all pregnancies in female subjects and female partners of male subjects 
will be collected after the start of dosing and until after the follow-up visit.

If a pregnancy is reported then the investigator should inform GSK within 2 
weeks of learning of the pregnancy and should follow the procedures outlined in
Section 11.4 (Appendix 4).
6.3.3.
Physical Exams

A complete physical examination will include, at a minimum, assessment of the 
Cardiovascular, Respiratory, Gastrointestinal, Dermatologic and Neurological 
systems, height, and weight. Height will be measured and recorded only at 
screening.

A brief physical examination will include, at a minimum assessments of the skin,
lungs, cardiovascular system, and abdomen (liver and spleen).  Weight will be 
recorded with the brief physical exam as per the Time and Events Tables, but is 
not part of the brief physical exam.

Investigators should pay special attention to clinical signs related to previous 
serious illnesses
6.3.4.
Vital Signs

Vital signs include systolic and diastolic blood pressure and pulse and will be 
measured in semi-supine position after 5 minutes rest.

Temperature will also be measured as a vital sign but will not require positioning 
or rest prior to measuring.
6.3.5.
Electrocardiogram (ECG)

Triplicate 12-lead ECGs will be obtained for trial eligibility

Single 12-lead ECGs will be obtained at each timepoint during the study using an 
ECG machine that automatically calculates the heart rate and measures PR, QRS, 
QT, and QTcF intervals.  Refer to Section 4.5.2 for QTc withdrawal criteria.

Withdrawal of subjects is to be based on an average QTc value of triplicate ECGs.  
If an ECG demonstrates a prolonged QT interval, then obtain 2 more ECGs over a 
brief period of time and then use the averaged QTc values of the 3 ECGs to 
determine whether the subject should be discontinued from the study

Continuous cardiac telemetry will be performed.  Full disclosures will be 
reviewed in detail and the review maintained as part of the subject’s source 
documents


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6.3.6.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 8, must be conducted in 
accordance with the Laboratory Manual, and Protocol Time and Events Schedule.
Laboratory requisition forms must be completed and samples must be clearly labelled 
with the subject number, protocol number, site/centre number, and visit date. Details for 
the preparation and shipment of samples will be provided by the laboratory and are 
detailed in the SRM or the laboratory manual. Reference ranges for all safety parameters 
will be provided to the site by the laboratory responsible for the assessments.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the CRF.
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
Hematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 8.


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Table 8
Protocol Required Safety Laboratory Assessments
Hematology
Platelet Count
RBC Indices:
Automated WBC Differential:
RBC Count
MCV
Neutrophils
WBC Count (absolute) 
MCH
Lymphocytes
Reticulocyte Count
MCHC
Monocytes
Hemoglobin
Eosinophils
Hematocrit
Basophils
Clinical Chemistry (Chemsitry)
BUN
Potassium
AST (SGOT)
Total and direct bilirubin
Creatinine
Chloride
ALT (SGPT)
Uric Acid
Glucose, fasting/non-fasting*
bicarbonate
GGT
Albumin
Sodium
Calcium
Alkaline phosphatase
Total Protein
Bile Acids
*Glucose will be fasting for all screening, day 1 pre-dose, and follow-up assessments.  Glucose will be non-fasting 
for all other time points.
NOTE: Details of Liver Chemistry Stopping Criteria and Follow-Up Procedures are given in Section 4.5.1 and
Section 11.2 (Appendix 3)
Routine Urinalysis (UA)
Specific gravity
pH, glucose, protein, blood and ketones by dipstick
Microscopic examination (within 120 minutes of collection)
Triglyceride Assessment (Postprandial response)
Triglycerides
Exploratory Pharmacodynamics (Exploratory PD Labs)
Cholesterol
Triglycerides
HDL
LDL
VLDL-Triglycerides (if feasible)
Other screening tests
HIV
Hepatitis B (HBsAg)
Hepatitis C (Hep C antibody -- if second generation Hepatitis C antibody positive, a hepatitis C antibody Chiron 
RIBA immunoblot assay (or other third generation immunoassay) or Hepatitis C Virus RNA test (either quantitative 
or qualitative) should be reflexively performed on the same sample to confirm the result) 
FSH and estradiol (as needed in women of non-child bearing potential only)
Serum  and urine hCG Pregnancy test (as needed for women of child bearing potential)
Urine cotinine levels
Alcohol and drug screen (to include at minimum: amphetamines, barbiturates, cocaine, opiates, cannabinoids and 
benzodiazepines).
6.4.
Pharmacokinetics
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacology 
Modeling and Simulation Department, GlaxoSmithKline. Plasma GSK3008356 
concentration-time data will be analyzed by non-compartmental methods with 
WinNonlin [Version 5.2 or higher].  Calculations will be based on the actual sampling 
times recorded during the study.  Full details will be provided in the reporting and 


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analysis plan (RAP).  The following plasma pharmacokinetic parameters will be 
determined for each treatment, as data permit:
Table 9
GSK3008356 Pharmacokinetic Parameters to be Estimated
Part/Day
Plasma GSK3008356 PK Parameters Calculated (as data permit)
Part 1 Single Dose 
AUC(0-), AUC(0-t), AUC(0-24), Cmax, tmax, t1/2
Part 2 Day 1
AUC(0-τ), Cmax, tmax
Part 2 Day 14
AUC(0-τ), Cmax, tmax, t1/2
Part 3 Day 1
AUC(0-τ), Cmax, tmax
Part 3 Day 28
AUC(0-τ), Cmax, tmax, t1/2
Additional GSK3008356 PK Parameters to be Calculated:
Dose proportionality of GSK3008356 PK parameters will be assessed following single 
dose administration (AUC0-t), AUC(0-∞), Cmax) and repeat dose administration 
(AUC(0-τ), Cmax).
Accumulation ratio will be determined by comparing AUC(0-τ) on Days 14 (Part 2) and 
28 (Part 3) to AUC(0-τ) obtained on Day 1:
Part 2: Ro= [AUC(0-τ),day 14]/ [AUC(0-τ), Day 1]
Part 3: Ro= [AUC(0-τ),day 28]/ [AUC(0-τ), Day 1]
Achievement of steady-state will be determined by evaluating trough plasma 
concentrations (Ctrough) following repeat oral doses, as data permit
Part 2: Plasma GSK3008356 pre-dose concentration will be determined on Days 
2, 4, 5, 6, 12, 13, 14 and the 24 h post dose on Day 14 of Part 2, 
Part 3: Plasma GSK3008356 pre-dose concentration will be determined on Days
2, 7, 14, 21, 28 and the 24 h post dose on Day 28 of Part 3
From the GSK3008356 urine data, the total amount excreted (Ae) will be determined 
following single dose in Part 1 and on Day 14 (Part 2) and Day 28 (Part 3).
Additional PK parameters may be calculated and details will be provided in the RAP.  
Actual elapsed times from dosing will be used in the PK analysis.  Individual PK 
parameter values will be listed and a descriptive summary by treatment will be provided.  
Additional comparative plots of the PK parameters for other comparisons of interest may 
also be generated.
6.4.1.
Blood Sample Collection
Blood samples for PK analysis of GSK3008356 and for circulating metabolite analysis
will be collected at the time points indicated in the Time and Events Tables (Section 6.1). 
The actual date and time of each 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.


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Details of the blood sample collection, including volume to be collected, processing, 
storage and shipping procedures are provided in the Study Reference Manual.
6.4.2.
Urine Sample Collection
Urine samples for PK analysis of GSK3008356 and for metabolite analysis will be 
collected at the time points indicated in the Time and Events Tables (Section 6.1).  The 
timing of urine samples may be altered and/or samples may be obtained at additional time 
points to ensure thorough monitoring.
Details of urine sample collection, including volume to be collected, processing, storage 
and shipping procedures are provided in the SRM.
6.4.3.
Sample Analysis
Plasma and urine (if feasible) analysis will be performed under the management of 
Platform Technology and Sciences, Drug Metabolism and Pharmacokinetics (PTS-
DMPK), GlaxoSmithKline.  Concentrations of GSK3008356 will be determined in 
plasma and urine (if feasible) samples using the currently approved analytical 
methodology.  Raw data will be archived at the bioanalytical site (detailed in the SRM).
Once the plasma has been analyzed for GSK3008356 any remaining plasma may be 
analyzed qualitatively for other compound-related metabolites and the results reported 
under a separate PTS-DMPK protocol. The urine samples will also be analyzed for 
compound-related metabolites and the results reported under a separate PTS-DMPK 
protocol.
6.4.4.
Statistical Analysis of Pharmacokinetic Data
Details of the statistical analyses of PK data, including dose proportionality, 
accumulation ratio, steady-state assessment, and pharmacokinetic/pharmacodynamic 
analysis will be provided in the RAP.
6.4.5.
Skin Biopsy Sample Collection and Analysis
Skin biopsy for PK analysis and activity of GSK3008356 will be collected at the time 
points indicated in the Time and Events Tables (Section 6.1).  The actual date and time of 
each sample collection will be recorded.  
Details of the skin biopsy sample collection, including collection procedures, sample 
preparation, sample storage, and shipping procedures are provided in the Study Reference 
Manual. 
Drug concentration analysis of the skin samples will be performed under the management 
of PTS-DMPK.  Concentrations of GSK3008356 may be determined through standard 
Liquid Chromatography Tandem Mass Spectrometry (LC MS/MS) in homogenate and/or 
using Matrix Assisted Laser Desorption/Ionization (MALDI) analysis through approved 
analytical methodology.  Analysis of pharmacology (if feasible) may also be performed 
potentially including lipodomics/metabolomics for lipid levels, including TG, in the skin.  


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Additional target engagement studies may also be performed (if feasible) including 
thermal shift assay and/or human skin lipogenesis (SLiP) assay.  Raw data will be 
archived at the bioanalytical site (detailed in the SRM).  All skin biopsy analysis results 
will be reported under a separate PTS-DMPK protocol.
6.5.
Biomarker(s)/Pharmacodynamic Markers
6.5.1.
Postprandial Triglyceride Assessment
DGAT1 inhibition has been observed to cause a decrease in postprandial TG levels after 
subjects are dosed with a high-fat meal (Meyers 2015; Denison 2014).
Fat content of 40% to 60% by calories in a 1000kcal meal were used in the clinical trials 
(Meyers 2015; Denison 2014).  In one study, the fat content was decreased to 20% and 
30% due to intolerability at higher percentages (Denison 2014).  
The meals were administered either without prior DGAT1 inhibitor dosing or 1-2h after 
DGAT inhibitor dosing and were consumed within 15 minutes.  They were prepared as a 
standardized mixed fat meal (Karpe 1997).
TG levels were obtained across 7-11h post meal (9-12h post-dose).  The TG AUC 
increase at baseline was compared to the post-dose TG AUC increase and evaluated for 
evidence of DGAT1 inhibition PD activity.
For the present study, the fat meal will be set at 30% fat by calories and will be consumed 
within 15 minutes (15 minutes ± 10 minutes).  The 30% fat meal provided adequate 
postprandial excursion allowing TG AUC measurement at baseline (Meyers 2015).  
The baseline meal for morning dose subjects will be administered on Day -1, 2h after the 
nominal “dose” time (Figure 4a).  The test meals will be administered 2h post-
GSK3008356 dose for subjects receiving morning doses (Figure 4b).  This will be days 1 
and 14 or 28, depending on the study Part. 
The baseline meal for evening dose subjects will be administered 10h pre-GSK3008356 
dose on Day 1 (Figure 4b).  This is 10h prior to the very first dose.   The evening dose 
test meals will be administered 10h prior to the evening dose on Day 2 (14h after the first 
dose on Day 1; Figure 4b).  The evening dose test meals will also be administered 10h 
prior to the evening dose on Day 14 or 28 (14h after the first dose on Day 13 or 27), 
depending on the study Part.
The TG measurement will be collected from 1h prior to meal through 10h after meal.  
This is from 1h post GSK3008356 dose through 12h post-GSK3008356 dose for subjects 
receiving morning doses.  It is from 11h pre-GSK3008356 dose (13h post-dose) to just 
prior to next dose (12h post-previous dose) for subjects receiving evening dose.  Please 
refer to the Time and Events Tables for details (Section 6.1.8.1 and Section 6.1.8.2 for 
examples).


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The TG collection time will result in a pre-meal “baseline” and continue to where the 
levels return to pre-meal baseline after postprandial excursion (Meyers 2015; Denison
2014).  
Figure 4
Postprandial Triglyceride Assessment Schematic
6.5.2.
Bristol Stool Form Scale
The Bristol Stool Form Scale (Lewis 1997) which describes 7 types of stool, will be used 
by the subjects and verified by the staff in real time in all parts of the study.  Please refer 
to Section 11.5 for scale details.  The number of each type of stool will be collected 
across the 24h calendar day.
6.5.3.
Exploratory PD Markers
Cholesterol, high density lipoproteins (HDL), low density lipoproteins (LDL), very-low 
density lipoprotein triglycerides (VLDL-TG) and spot TG labs will be collected.  Spot 
TG are defined as not collected as part of the fat meal challenge postprandial TG 
assessment.
7.
DATA MANAGEMENT

For this study subject data will be entered into CRO eCRFs (approved by GSK), 
transmitted electronically to GSK or designee and combined with data provided 
from other sources in a validated data system.  

Management of clinical data will be performed in accordance with applicable 
GSK standards and data cleaning procedures to ensure the integrity of the data, 
e.g., removing errors and inconsistencies in the data.


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
Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and a validated medication 
dictionary, (internal GSKDrug or external WHODrug).  

CRFs (including queries and audit trails) will be retained by GSK, and copies will 
be sent to the investigator to maintain as the investigator copy.  Subject initials 
will not be collected or transmitted to GSK according to GSK policy.
8.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
8.1.
Hypotheses
There are no formal hypotheses being tested. An estimation approach will be taken to 
provide a plausible range of values. For the pharmacokinetic endpoints, where 
appropriate, point estimates and 90% confidence intervals will be provided.
8.2.
Sample Size Considerations
Sample sizes are based on feasibility. No formal power calculations were performed.
8.2.1.
Sample Size Sensitivity
No statistical sample size sensitivity calculations were performed.
8.2.2.
Sample Size Re-estimation or Adjustment
Sample size re-estimation will not be conducted.
8.3.
Data Analysis Considerations
8.3.1.
Analysis Populations
PK Concentration Population: Subjects for whom a pharmacokinetic sample was 
obtained and analyzed.
PK Parameter Population: All subjects in the PK Concentration Population who receive 
at least one active dose of GSK3008356 and provide pharmacokinetic parameters.
Safety Population: All subjects who received at least one dose of study medication.
8.3.2.
Interim Analysis
No interim analysis is planned.


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8.4.
Key Elements of Analysis Plan
8.4.1.
Primary Analyses
All data listings and summaries will be presented. Listings will be sorted by subject and 
time. Summaries will be presented by regimen, and nominal time. Unless stated 
otherwise, descriptive summaries will include n (number of subjects), mean, standard 
deviation (SD), coefficient of variation (CV), median, minimum, and maximum for 
continuous variables, n and percent for categorical variables. In addition, the geometric 
mean, with associated 95 % confidence interval and between-subject CVs (CVb), based 
on the geometric mean, will be included for the log-transformed PK parameters.
8.4.2.
Secondary Analyses
Please refer to Section 6.4.4.
8.4.3.
Other Analyses
Please refer to Section 6.4.4 and Section 6.4.5.
9.
STUDY GOVERNANCE CONSIDERATIONS
9.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
9.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of the site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:

HREC review and favorable opinion/approval of the study protocol and 
amendments as applicable

Obtaining signed informed consent

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to the HREC)


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
GSK will provide full details of the above procedures, either verbally, in writing, 
or both.

Signed informed consent must be obtained for each subject prior to participation 
in the study
9.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the CRF will 
serve as the source document.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
9.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and 
the regulatory agencies may conduct a regulatory inspection at any time during or 
after completion of the study. 

In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss 
the conduct of the study, any findings/relevant issues and to implement any 
corrective and/or preventative actions to address any findings/issues identified.
9.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard 
Operating Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this 
study at any time for reasons including, but not limited to, safety or ethical issues 
or severe non-compliance. For multicenter studies, this can occur at one or more 
or at all sites.  


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
If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable).  When feasible, GSK will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK will
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature
discontinuation of the study and the reason(s) for the action.  

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the HREC promptly and provide the 
reason for the suspension or premature discontinuation.
9.6.
Records Retention

Following closure of the study, the investigator or the head of the medical 
institution (where applicable) must maintain all site study records (except for 
those required by local regulations to be maintained elsewhere), in a safe and 
secure location.  

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review 
in conjunction with assessment of the facility, supporting systems, and relevant 
site staff.  

Where permitted by local laws/regulations or institutional policy, some or all of 
these records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.  

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, 
including re-generating a hard copy, if required.  Furthermore, the investigator 
must ensure there is an acceptable back-up of these reproductions and that an 
acceptable quality control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by 
any institutional requirements or local laws or regulations, GSK 
standards/procedures, and/or institutional requirements. 

The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of 
ownership of the records in the event the investigator is no longer associated with
the site.


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9.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
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.
9.8.
Review Committees
9.8.1.
Dose Escalation Committee
For Part 1 and Part 2, 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. The GSK Medical 
Monitor and the GSK Pharmacokineticist will remain unblinded throughout the course of 
the study.  The decision to progress from Part 1 to Part 2 and from Part 2 to Part 3 will 
also be made by the DEC.
Dose escalation decisions will be based on data obtained from 4 or more subjects 
receiving GSK3008356 at the prior dose level. The review data set will at minimum 
consist of AE listings, liver function test results, PK results derived from 24 hour plasma 
profiles, and PD (TG) data.  Flagged vital signs, cardiac monitoring (telemetry), ECG and 
laboratory findings will also be reviewed.


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10.
REFERENCES
Cases, S. et al. “Identification of a gene encoding an acyl CoA:diacylglycerol 
acyltransferase, a key enzyme in triacylglycerol synthesis.” Proceedings of the National 
Academy of Science, USA, 1998, 95(22): 13018-13023.
Chalasani, N, et al. “Liver Disease: Practice Guideline by the American Association for 
the Study of Liver Diseases, American College of Gastroenterology, and the American 
Gastroenterological Association.” Hepatology, 2012, 55(6): 2005-2023.
Denison, H, et al. “Diacylglycerol acyltransferase 1 inhibition with AZD7687 alters lipid 
handling and hormone secretion in the gut with intolerable side effects: a randomized 
clinical trial.” Diabetes, Obesity and Metabolism, 2014, 16(4): 334-343.
Floettmann, E, et al. “Pharmacological Inhibition of DGAT1 Induces Sebaceous Gland 
Atrophy in Mouse and Dog Skin While Overt Alopecia Is Restricted to the Mouse.” 
Toxicologic Pathology, 2015, 43:376-383.
GSK3008356 Investigator’s Brochure (IB).  GSK Document Number 2015N255332_00. 
Effective Date 19 January 2016.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, editors. 
Contraceptive Technology. 19th edition. New York: Ardent Media, 2007: 24. Table 3-2.
James LP, et al. “Pharmacokinetics of Acetaminophen-Adduct in Adults with 
Acetaminophen Overdose and Acute Liver Failure.” Drug Metabolism and Disposition 
2009; 37:1779-1784.
Karpe, F. “Effects of diet on postprandial lipaemia: a suggestion for methodological 
standardization.” Nutrition Metabolism and Cardiovascular Diseases, 1997, 7:44-55.
Kohjima, M. et al. “Re-evaluation of fatty acid metabolism-related gene expression in 
nonalcoholic fatty liver disease.” International Journal of Molecular Medicine, 2007, 
20(3): 351-358.
Lewis SJ and Heaton KW. “Stool form as a useful guide to intestinal transit time.” 
Scandinavian Journal of Gastroenterology, 1997, 32(9): 920-924.
Meyers, CD, “Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of 
Pradigastat, a Novel Diacylglycerol Acyltransferase 1 Inhibitor in Overweight or Obese, 
but Otherwise Healthy Human Subjects.” The Journal of Clinical Pharmocology, 2015, 
55(9): 1031-1041.
Moffet, S, “CLCQ908A2216 Clinical Trial Results.” Novartis Clinical Trial Results 
Website, 01 April 2015, Last Accessed 22 December 2015, 
<https://www.novctrd.com/CtrdWeb/displaypdf.nov?trialresultid=14104>
Satapathy, SK and Sanyal, AJ, “Epidemiology and Natural History of Nonalcoholic Fatty 
Liver Disease.” Seminars in Liver Disease, 2015, 35:221-235.


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Yamaguchi, K, et al. “Diacylglycerol Acyltranferase 1 Anti-Sense Oligonucleotides 
Reduce Hepatic Fibrosis in Mice With Nonalcoholic Steatohepatitis.” Hepatology, 2008, 
47:625-635.
Yen, C-LE, et al. “DGAT enzymes and triacylglycerol biosynthesis.” Journal of Lipid 
Research, 2008, 49: 2283–2301.
Yuen, JJ, et al. “DGAT1-deficiency affects the cellular distribution of hepatic retinoid 
and attenuates the progression of CCl4-induced liver fibrosis.” HepatoBiliary Surgery and 
Nutrition, 2015; 4(3):184-196


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11.
APPENDICES
11.1.
Appendix 1 – Abbreviations and Trademarks
Abbreviations
Ae
cumulative amount of unchanged drug excreted into the urine
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the curve
AUC(0-τ)
area under the concentration-time curve from time zero (pre-dose) to the 
end of dosing interval
AUC(0-t)
area under the plasma concentration-time curve from time zero to time t
AUC(0-∞)
the area under the curve from time 0 extrapolated to infinite time
AUC (0-24)
the area under the curve from time 0 to 24 hour
AUCincr
postprandial increase in triglyceride area under the curve
BCRP
breast cancer resistance protein
BID
twice a day
BMI
body mass index
BP
blood pressure
BSFS
Bristol Stool Form Scale
BUN
blood urea nitrogen
C12
concentration at 12 hours
C24
concentration at 24 hours
CL
apparent total body clearance of drug from plasma
CLR
renal clearance of drug from plasma
Cmax
maximum observed plasma concentration
CONSORT
consolidated standards of reporting trials
CPK
creatine phosphokinase
CRF
case report form
CRO
contract research organization
Ctrough
trough plasma concentrations
CV
cardiovascular
CV
coefficient of variation
CVb
between-subject coefficient of variation
CYP
cytochrome P450
DEC
Dose Escalation Committee
DGAT
diacylglycerol acyltransferase
DGAT1
diacylglycerol acyltransferase 1
DGAT2
diacylglycerol acyltransferase 2
DIO
diet-induced obesity
DMPK
Drug Metabolism and Pharmacokinetics
eCRF
electronic case report form
e.g.
exempli gratia (for example)
E
effect


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E(0)
effect at baseline
EAUC50
AUC in which 50% of Emax is achieved
EC50
concentration in which 50% of Emax is achieved
ECG
electrocardiogram
Emax
maximum drug-induced effect
FDA
(US) Food and Drug Administration
FRP
females of reproductive potential
FSH
follicle stimulating hormone
g
grams
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GGT
gamma glutamyl transferase
GI
gastrointestinal
GLDH
glutamate dehydrogenase
GSK
GlaxoSmithKline
HBsAg
hepatitis B surface antigen
HBcAb
hepatitis B core antibody
HCC
hepatocellular carcinoma
hCG
human chorionic gonadotropin
HDL
high-density lipoprotein
HED
human equivalent dose
hERG
human Ether-à-go-go-Related Gene
HIV
human immunodeficiency virus
HR
heart rate
HREC
Human Research Ethics Committee
HRT
hormone replacement therapy
HSC
hepatic stellate cells
IB
investigator’s brochure
IBS
irritable bowel syndrome
IC50
half maximal inhibitory concentration
ICH
International Conference on Harmonisation
INR
international normalized ratio
IV
intravenous
ka
absorption rate constant
ke
elimination rate constant from the central compartment
kg
kilogram
L
liter
LC MS/MS
liquid chromatography tandem mass spectrometry
LDH
lactate dehydrogenase
LDL
low-density lipoprotein
LFT
liver function test
m2
square meter
MABEL
minimum anticipated biological effect level
MALDI
matrix assisted laser desorption/ionization
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration


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MCV
mean corpuscular volume
MedDRA
medical dictionary for regulatory activities
mg
milligram
mIU/ml
milli-international units per milliliter
mL
milliliter
MRSD
maximum recommended safe starting dose
MSDS
material safety data sheet
msec
millisecond
NAFL
nonalcoholic fatty liver
NAFLD
nonalcoholic fatty liver disease
NASH
nonalcoholic steatohepatitis
ng
nanogram
ng/mL
nanogram per millilitre
nM
nanometer
NOAEL
no observed adverse effect level
NSAIDS
nonsteroidal anti-inflammatory drugs
OATP
organic anion-transporting polypeptide
PD
pharmacodynamics
P-gp
P-Glycoprotein 
PK
pharmacokinetics
PTS-DMPK
Platform Technology and Sciences, Drug Metabolism and 
Pharmacokinetics
QTc
corrected QT interval
QTcF
corrected QT interval to Fridericia’s formula 
RAP
report and analysis plan
RBC
red blood cell
RCmax
accumulation ratio calculated from Cmax,ss and Cmax
RD
repeat-dose
RNA
ribonucleic acid
Ro
observed accumulation based on AUC(0-τ)
RPP
rate-pressure-product
SAE
serious adverse event
SD
single-dose
SD
standard deviation
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SLiP
skin lipogenesis (assay)
SRM
study reference manual
τ
shape factor
t1/2
elimination half-life
TG
triglyceride
Tmax
time to maximum observed plasma concentration
UA
urinalysis
ULN
upper limit of normal
µg/mL
microgram per milliliter
μg.h/mL
Microgram per hour per milliliter


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μM
micrometer
μmol.h/L
micromole-hour per liter
Vc
volume of central compartment
Vp
volume of peripheral compartment
Vss
volume of distribution at steady state
Vss/F
volume of distribution at steady state after non-IV administration
VLDL
very-low density lipoprotein
VLDL-TG
very-low density lipoprotein triglycerides
WBC
white blood cell
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Chiron RIBA
HepatoTaq
WinNonlin


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11.2.
Appendix 2: 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 within 7 days of the last 
dose4

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form 
including acetaminophen, herbal remedies, 
other over the counter medications.

Record alcohol use on the liver event 
alcohol intake case report form
If ALT≥3xULN AND bilirubin 2xULN  or 


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


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11.3.
Appendix 3: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
11.3.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

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 medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

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 prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected 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 this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).
Events NOT meeting definition of an AE include:

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 subject’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 subject’s 
condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 


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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.
11.3.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject 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 hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject 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 out-patient setting.  Complications that occur during hospitalization are 
AEs.  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 disability/incapacity
NOTE:

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 (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption


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e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.

Examples of such events are 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
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
11.3.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization


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11.3.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’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 instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.
11.3.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or 


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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 natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of 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 when 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 
prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.

If a subject 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 the designated 
reporting time frames.


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11.3.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the Medical Monitor and the SAE 
coordinator.

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data

If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the Medical 
Monitor and the SAE coordinator by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.


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11.4.
Appendix 4: Modified List of Highly Effective Methods for 
Avoiding Pregnancy in FRP and Collection of Pregnancy 
Information
11.4.1.
Modified List of Highly Effective Methods for Avoiding Pregnancy 
in Females of Reproductive Potential (FRP)
This list does not apply to FRP with same sex partners, when this is their preferred and 
usual lifestyle or for subjects who are and will continue to be abstinent from penile-
vaginal intercourse on a long term and persistent basis.

Contraceptive subdermal implant 

Intrauterine device or intrauterine system 

Oral Contraceptive, either combined or progestogen alone [Hatcher 2007] 

Injectable progestogen [Hatcher 2007]

Contraceptive vaginal ring [Hatcher 2007]

Percutaneous contraceptive patches [Hatcher 2007]

Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2007].  

Male condom plus partner use of one of the contraceptive options below:
o
Contraceptive subdermal implant 
o
Intrauterine device or intrauterine system 
o
Oral Contraceptive, either combined or progestogen alone [Hatcher 2007] 
Injectable progestogen [Hatcher 2007]
o
Contraceptive vaginal ring [Hatcher 2007]
o
Percutaneous contraceptive patches [Hatcher 2007]
This is an all inclusive list of those methods that meet the GSK definition of highly 
effective: having a failure rate of less than 1% per year when used consistently and, 
correctly and, when applicable, in accordance with the product label.  For non-product 
methods (e.g.  male sterility), the investigator determines what is consistent and correct 
use. The GSK definition is based on the definition provided by the ICH [ICH, M3 (R2) 
2009]. 
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.

Investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study.  This 
applies only to subjects who are randomized to receive study medication. 


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
After obtaining the necessary signed informed consent from the female partner 
directly, the investigator will record pregnancy information on the appropriate form 
and submit it to GSK within 2 weeks of learning of the partner’s pregnancy

Partner will also be followed to determine the outcome of the pregnancy.  
Information on the status of the mother and child will be forwarded to GSK. 

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date.  Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure.


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11.5.
Appendix 5: Bristol Stool Form Scale
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third party 
copyright laws and therefore have been excluded.


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11.6.
Appendix 6: Protocol Amendment Changes
AMENDMENT 1
Where the Amendment Applies
This Protocol Amendment 1 applies to all sites participating in the study.
Summary of Amendment Changes with Rationale
This Protocol Amendment 1 is to add additional Part 1 cohorts which dose the compound 
in a way that provides a more appropriate exposure profile.  This is based on preliminary 
pharmacokinetic data indicating a much shorter observed half-life compared to the 
predicted half-life (1.5-3h observed versus 14.1h predicted).  While the adjusted doses in 
the first 5 cohorts did allow observation of a PD response in Cohort 5, the overall single 
dose data to date are limited and could not adequately inform a PK/PD model or support 
informed progression into Part 2 of the study.  The additional cohorts include divided 
doses to achieve time above the target exposure with varying levels of Cmax and doses 
directly related to regimens that may be used in Part 2 of the study.  There will be no 
changes to the current challenge meal or assessments.  Several administrative changes 
were also made.
Detailed Rationale and Planned Additional Cohorts
Part 1, Cohort 6 would evaluate 125 mg as a single dose.  This would provide exposure 
and time above the target threshold between 75 mg and 200 mg.  The objective would be 
to determine if activity is present with potentially lower incidence of GI tolerability 
signals.  This would support potential daily repeat dose cohorts in Part 2.
Part 1, Cohort 7 would evaluate 125 mg administered twice at time 0h and 4h for a total 
dose of 250 mg.  The objective of this cohort is to explore maintenance of time above 
target efficacy threshold with Cmax exposure less than that observed at 200 mg SD and 
enable up to 250 mg/day (given as dived doses) as potential regimens for Part 2 of the 
study.  
Part 1, Cohort 8 would evaluate 125 mg administered twice at time 0h and 16h for a 
total dose of 250 mg.  Like Cohort 7, this cohort would provide further information on 
tolerability and enable the potential regimen of 125 mg BID (daily in the morning and at 
night) for Part 2 of the study.
Part 1, Cohort 9 would evaluate 200 mg administered once at night.  The objective 
would be to determine if the active dose has less GI AEs if administered so that peak 
exposure is not associated with meals.  This cohort would also enable a potential regimen 
of 200 mg once daily at night for Part 2 of the study.
Part 1, Cohort 10 would evaluate 90 mg administered as 9 doses of 10 mg hourly from 
time 0 to time 8h.  The objective would be to administer the compound in a way that 
results in exposures more closely resembling an extended release formulation. 


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Part 1, Cohort 11 would evaluate either 45 mg administered as 9 doses of 5 mg hourly 
from time 0 to time 8h or 180 mg as 9 doses of 20 mg hourly from time 0 to time 8h.  The 
choice of the hourly 5 mg versus 20 mg would depend on whether PD was observed in 
Cohort 7.  The objective would be to administer the compound in a way that results in 
exposures more closely resembling an extended release formulation and to more 
narrowly confirm the target threshold for PD activity. 
The predicted exposures relative to the dog NOAEL for the proposed additional Part 1 
cohorts is found in Table 5.  Neither the predicted human Cmax, nor the predicted human 
AUC is expected to exceed the dog NOAEL. 
List of Specific Changes 
NOTE: for PREVIOUS TEXT, the content is exactly as in the original; for 
REVISED TEXT, text deleted from the original has a dotted underline and text 
added has a solid underline. 
Change 1: Title Page 
PREVIOUS TEXT 
Author(s): 
 
REVISED TEXT 
Author(s): 
 
RATIONALE 
Administrative: Two authors were removed as they have left the project.  Two authors 
were added who are new to the project and contributed to the amendment.  The names 
were re-formatted. 
PPD
PPD


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Change 2: Figure 1 Study Part Schematic
PREVIOUS TEXT


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REVISED TEXT 
RATIONALE
The Figure was modified to reflect the actual doses administered in Part 1, Cohorts 1-5 
and to provide information regarding the additional Part 1, Cohorts 6-11.
Change 3: New Section 3.1.1 Additional Cohorts for Part 1
Based on emerging PK data, the original planned Part 1 doses were adjusted, per 
protocol, to 5, 10, 30, 75 and 200 mg (Section 5.3, Figure 1).  This was due to a much 
shorter observed half-life compared to the predicted half-life (1.5-3h observed versus 
14.1h predicted).  
While the adjusted doses did allow observation of a PD response in Cohort 5, the overall 
single dose data were limited and could not adequately inform a PK/PD model or support 
informed progression into Part 2 of the study.  It was determined to further explore the 
PK/PD further through additional Part 1 cohorts.  The purpose of the additional cohorts is 
to explore dose administration in a manner that should provide a more acceptable PK 
profile than that observed to date.  This includes divided doses to achieve time above the 
target exposure with varying levels of Cmax and doses directly related to regimens that 


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may be used in Part 2 of the study.  There will be no changes to the current challenge 
meal or assessments.
RATIONALE
The section was added to provide background and information regarding the additional
Part 1, Cohorts 6-11.
Change 4: Section 3.2 Type and Number of Subjects 
PREVIOUS TEXT
Part 1, Single Dose, Healthy Subjects:
Approximately 40 subjects will be enrolled, 8 in each cohort, such that approximately 6-8 
subjects complete dosing and critical assessments in each Part 1 Cohort. Additional 
subjects/cohorts may be enrolled to allow for evaluation of additional dose levels
REVISED TEXT 
Part 1, Single Dose, Healthy Subjects:
Approximately 40 subjects will be enrolled, 8 in each cohort, such that approximately 6-8 
subjects complete dosing and critical assessments in each Part 1 Cohort. Additional 
subjects/cohorts may be enrolled to allow for evaluation of additional dose levels. The six 
additional cohorts will enrol approximately 48 subjects.
RATIONALE
The sentence was added to provide the anticipated subject numbers for the additional 
cohorts.


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Change 5: Table 5 in Section 3.4.3.1 Starting Dose
PREVIOUS TEXT
Table 5
Predicted Human Cmax, C12, C24, and AUC(0-∞) Following Single Oral 
Administration of GSK3008356
Proposed dose
Predicted 
Cmax
Fold-cover 
for Cmax
Predicted 
C12
Predicted 
C24
Predicted 
AUC(0-∞)
Fold-cover 
for AUC
(mg)
(mg/kg)1
(ng/mL)
Dog2
(ng/mL)
(ng/mL)
(ng.h/mL)
Dog2
5
0.083
63.25
122
26.35
14.55
1015
109
10
0.167
126.5
61
52.70
29.1
2030
55
25
0.417
316.25
24
131.75
72.75
5075
22
50
0.833
632.5
12
263.50
145.5
10150
11
75
1.250
948.75
8
395.25
218.25
15225
7
1.
Based on 60 kg human body weight
2.
Based on the 4-week dog study, 50 mg/kg/day dose, week 4 average Cmax (7.73 µg/mL) and AUC(0-t) 
(111 µg.h/mL) 


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REVISED TEXT 
Table 5
Predicted, Human Cmax, C12, C24, and AUC(0-∞) Observed and 
Additional Predicted Human Exposures Following Single Oral 
Administration of GSK3008356
Proposed dose
Predicted 
Cmax
Fold-cover 
for Cmax
Predicted 
C12
Predicted 
C24
Predicted 
AUC(0-∞)
Fold-cover 
for AUC
(mg)
(mg/kg)1
(ng/mL)
Dog2
(ng/mL)
(ng/mL)
(ng.h/mL)
Dog2
5
0.083
63.25
122
26.35
14.55
1015
109
10
0.167
126.5
61
52.70
29.1
2030
55
25
0.417
316.25
24
131.75
72.75
5075
22
50
0.833
632.5
12
263.50
145.5
10150
11
75
1.250
948.75
8
395.25
218.25
15225
7
Actual dose
Cmax
Fold-cover 
for Cmax
Observed 
AUC(0-∞)
Fold-cover 
for AUC
(mg)
(mg/kg)1
(ng/mL)
Dog2
(ng.h/mL)
Dog2
5
0.083
92
84
191
581
10
0.167
191
40
314
353
30
0.500
458.5
17
841
132
75
1.250
890.9
9
1963
57
200
3.333
1865.3
4
5488
20
Additional Predicted 
doses
Predicted 
Cmax
Fold-cover 
for Cmax
Predicted 
AUC(0-∞)
Fold-cover 
for AUC
(mg)
(mg/kg)1
(ng/mL)
Dog2
(ng.h/mL)
Dog2
125
2.08
1290
6.0
3620
30.7
250
125q4 x2
4.17
1500
5.2
7236
15.3
250
125q16 x2
4.17
1300
5.9
7115
15.6
200
evening
3.33
2070
3.7
5797
19.1
90
10q1h x 9
1.50
300
25.8
2601
42.7
45
5q1h x 9
0.75
150
51.5
1297
85.6
180
20q1h x 9
3.00
600
12.9
5201
21.3
1.
Based on 60 kg human body weight
2.
Based on the 4-week dog study, 50 mg/kg/day dose, week 4 average Cmax (7.73 µg/mL) and AUC(0-t) 
(111 µg.h/mL) 


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RATIONALE
Actual doses and observed exposures for Part 1, Cohorts 1-5 were added to provide 
context to the pharmacokinetic profile to date and understand the safety coverage related 
to the dog NOAEL exposures.  Predicted exposures for the additional Part 1 cohorts and 
the related safety coverage to the dog NOAEL were also added.
Change 6: New Text in Section 3.4.3.1 Starting Dose
Observed Doses, Additional Planned Doses, and Safety Cover 
The actual doses administered and observed exposures relative to the dog NOAEL are 
found in Table 5.  The highest dose administered (200 mg) had a 4-fold and 20-fold 
safety coverage to the dog NOAEL Cmax and AUC, respectively.  
The expected exposures for the additional Part 1 cohorts will be at or below those 
observed in the Part 1 cohorts dosed to date (Table 5).
The proposed doses of GSK3008356 may be adjusted, as appropriate, based on the 
safety, tolerability, and pharmacokinetic data obtained in preceding cohorts.
RATIONALE
The new text provides a description of the new data added to Table 5.
Change 7: Table 6 in Section 5.1 Investigational Product and Other Study 
Treatment
PREVIOUS TEXT
Table 6
Study Treatment
Study Treatment
Product name:
GSK3008356
Placebo
Formulation description / 
Dosage form:
Tablet
Tablet
Unit dose strengths/Dosage levels:
0.1, 0.5, 1, 5, and 25 mg
Route of Administration
Administered orally
Administered orally
Dosing instructions:
Daily for up to 28 days
Daily for up to 28 days
Physical description:
White Tablet
White Tablet
Manufacturer
GlaxoSmithKline
GlaxoSmithKline


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REVISED TEXT 
Table 6
Study Treatment
Study Treatment
Product name:
GSK3008356
Placebo
Formulation description / 
Dosage form:
Tablet
Tablet
Unit dose strengths/Dosage levels:
0.1, 0.5, 1, 5, and 25 mg
Route of Administration
Administered orally
Administered orally
Dosing instructions:
Daily for up to 28 days
Daily for up to 28 days
Physical description:
White Tablet
White Tablet
Manufacturer
GlaxoSmithKline
GlaxoSmithKline
RATIONALE
Administrative: Dose strength 0.1 mg was not utilized for this study and therefore that 
unit dose strength is removed from the table.
Change 8: Table 7 in Section 5.2. Treatment Assignment
PREVIOUS TEXT
Regimen 
Code
Study Medication
Regimen 
Code
Study Medication
AA
5 mg GSK3008356, morning dosing
AP
5 mg GSK3008356, evening dosing
BA
10 mg GSK3008356, morning dosing
BP
10 mg GSK3008356, evening dosing
CA
25 mg GSK3008356, morning dosing
CP
25 mg GSK3008356, evening dosing
DA
50 mg GSK3008356, morning dosing
DP
50  mg GSK3008356, evening dosing
EA
75 mg GSK3008356, morning dosing
EP
75 mg GSK3008356, evening dosing
FA
Matched placebo, morning dosing
FP
Matched placebo, evening dosing


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REVISED TEXT 
Regimen 
Code
Study Medication
Regimen 
Code
Study Medication
AA
5 mg GSK3008356, morning dosing
AP
5 mg GSK3008356, evening dosing
BA
10 mg GSK3008356, morning dosing
BP
10 mg GSK3008356, evening dosing
CA
25 mg GSK3008356, morning dosing
CP
25 mg GSK3008356, evening dosing
DA
50 mg GSK3008356, morning dosing
DP
50  mg GSK3008356, evening dosing
EA
75 mg GSK3008356, morning dosing
EP
75 mg GSK3008356, evening dosing
FA
Matched placebo, morning dosing
FP
Matched placebo, evening dosing
GA
125 mg GSK3008356, morning dosing
JA
200  mg GSK3008356,
evening dosing
HA
125 mg GSK3008356 q4h x 2 doses, 
morning dosing
KA
10 mg GSK3008356 q1h x 9 doses, 
morning dosing
IA
125 mg GSK3008356 q16h x 2 doses, 
morning dosing
LA
5 mg GSK3008356 q1h x 9 doses, 
morning dosing
MA
20 mg GSK3008356 q1h x 9 doses, 
morning dosing
RATIONALE
The new text provides detail for the additional Part 1 Cohorts.
Change 9: Time and Events Table: Section 6.1.1 Part 1 – Single Dose 
PREVIOUS TEXT
Screening
(within 28d)
Day -2, 
Day -1 9
Day 1
Pre-dose
0h
Study Drug Dose
X
REVISED TEXT
Screening
(within 28d)
Day -2, 
Day -1 9
Day 1
Pre-dose
0h
Study Drug Dose10
X10
10.
For cohorts where multiple doses are to be administered either q1h, q4h or q16h, Time 0 is the first dose and 
subsequent doses are per regimen (q1h, q4h or q16) and the subsequent doses are not noted on the T&E Table. For 
the single evening cohort, the dose will be at hour 16 and not noted on the T&E Table.


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RATIONALE 
The addition of citation 10 and the corresponding footnote text clarifies time 0 for cohorts 
where regimens consisting of multiple doses or evening doses are to be administered. 
Change 10: Time and Events Table: Section 6.1.1.1 Part 1 – Single Dose Fat 
Meal Challenge and Triglyceride Assessment Relative to Dose and PK 
Sampling 
PREVIOUS TEXT 
 
Day -1, Day 1 
Pre-
dose 
0h 
Study Drug Dose1 
 
X 
 
REVISED TEXT 
 
Day -1, Day 1 
Pre-
dose 
0h 
Study Drug Dose1, 3 
 
X3 
3 
For cohorts where multiple doses are to be administered either q1h, q4h or q16h, Time 0 is the 
first dose and subsequent doses are per regimen (q1h, q4h or q16) and the subsequent doses are 
not noted on the T&E Table. For the single evening cohort, the dose will be at hour 16 and not noted 
on the T&E Table. 
 
RATIONALE 
The addition of citation 3 and the corresponding footnote text clarifies time 0 for cohorts 
where regimens consisting of multiple doses or evening doses are to be administered. 
Change 11: Section 11.5 Appendix 5: Bristol Stool Form Scale 
PREVIOUS TEXT 
The Bristol Stool Form Scale was assessed as a method to evaluate change in intestinal 
function, including diarrhea (Lewis 1997).  For this study, the subjects will have the 
number of types of stool tabulated for each 24h period from Day -1 through Follow-up. 
The number of each type and total across types will be recorded. Stool Type will be 
based on the chart below.   
AND 
Example Collection Table: 
 
Day -1 
Day 1 
Day 2 
Day 3 
... 
Day 28 
... 
.Day 36 
 


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REVISED TEXT  
The Bristol Stool Form Scale was assessed as a method to evaluate change in intestinal 
function, including diarrhea (Lewis 1997).  For this study, the subjects will have the 
number of types of stool tabulated for each 24h period from Day 1 through Follow-up. 
The number of each type and total across types will be recorded. Stool Type will be 
based on the chart below.   
AND 
Example Collection Table: 
 
Day 1 
Day 2 
Day 3 
... 
Day 28 
... 
.Day 36 
 
RATIONALE 
It was incorrectly noted that BSFS data collection was to start on Day -1.  Collection of 
data is actually to start on Day 1.  
Change 12: Section 3.5.1 Risk Assessment 
PREVIOUS TEXT 
HepatoTaq®:  No significant findings. 
REVISED TEXT  
HepatoTaq:  No significant findings. 
RATIONALE 
The symbol ® for the trademark “HepatoTaq” was removed as this trademark is not 
owned by GSK.  The change was a required compliance review change.  It was not 
identified by the compliance group with the original protocol compliance review. 
 
 


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AMENDMENT 2
Where the Amendment Applies
This Protocol Amendment 2 applies to all sites participating in the study.
Summary of Amendment Changes with Rationale
This Protocol Amendment 2 is to clarify dosing regimens for Part 2, to add skin biopsy 
assessment for drug level and activity, and add information to the Benefit:Risk table 
based on 13 week dog and 13 week rat toxicity study findings and the addition of skin 
biopsy to procedures.
The regimen clarification and addition of skin biopsy is based on preliminary 
pharmacokinetic data indicating a much shorter observed half-life compared to the 
predicted half-life and the results (1.5-3h observed versus 14.1h predicted).  Data from 
Part 1 of the study have identified the appropriate dosing regimens for Part 2 and that 
evening dosing was no longer indicated.  Addition of skin biopsy will help further define 
if the short observed half-life is in part based on distribution to tissue.  
Pharmacodynamics has been observed in the skin in preclinical studies.  There will be no 
changes to the current challenge meal or assessments beyond the addition of the skin 
biopsy.  Several administrative changes were also made.
Detailed Rationale and Planned Additional Cohorts
Part 2, Cohort 1 would evaluate 10 mg administered twice at time 0h and 16h for a total 
dose of 20 mg.  The objective is to explore a non-extended release BID regimen for 14d.
Part 2, Cohort 2 would evaluate 27 mg daily administered as 9 doses of 3 mg hourly 
from time 0 to time 8h daily for 14 days.  The objective would be to administer the 
compound in a way that results in exposures more closely resembling an extended release 
formulation. 
Part 2, Cohort 3 would evaluate either 9 mg daily administered as 9 doses of 1 mg 
hourly from time 0 to time 8h or 45 mg daily as 9 doses of 5 mg hourly from time 0 to 
time 8h.  The choice of the hourly 1 mg versus 5 mg would depend on whether PD was 
observed in Part 2, Cohort 2.  The objective would be to administer the compound in a 
way that results in exposures more closely resembling an extended release formulation 
and to more narrowly confirm the target threshold for PD activity.
The predicted exposures relative to the dog NOAEL for the proposed additional Part 1 
cohorts is found in Table 5.  Neither the predicted human Cmax, nor the predicted human 
AUC is expected to exceed the dog NOAEL.


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List of Specific Changes
NOTE: for PREVIOUS TEXT, the content is exactly as in the original; for 
REVISED TEXT, text deleted from the original has a dotted underline and text 
added has a solid underline.
Change 1: Title Page
PREVIOUS TEXT
Author(s):
 
REVISED TEXT
Author(s):
 
RATIONALE
Administrative: One author was removed as he has left the project.  One author was 
added who is new to the project and contributed to the amendment.
Change 2: Title Page
PREVIOUS TEXT
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
REVISED TEXT
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
RATIONALE
Copyright date was updated.
PPD
PPD


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Change 3: Section 2 Objective(s) and Endpoint(s)
PREVIOUS TEXT
Objectives
Endpoints
Exploratory 
Part 2 14d Repeat Dose
Part 3 28d Repeat Dose
To evaluate the change in serum lipid levels and 
weight after 14 daily repeat doses of GSK3008356 in 
healthy subjects and 28 daily repeat GSK3008356 
doses in obese subjects.
To evaluate the impact of evening dosing on 
tolerability.
Part 2 14d Repeat Dose
Part 3 28d Repeat Dose
Serum lipid panel, weight.
Clinical monitoring/observation for adverse events with 
a focus on gastrointestinal findings and a stool scale.
REVISED TEXT
Objectives
Endpoints
Exploratory 
Part 2 14d Repeat Dose
Part 3 28d Repeat Dose
To evaluate the change in serum lipid levels and 
weight after 14 daily repeat doses of GSK3008356 in 
healthy subjects and 28 daily repeat GSK3008356 
doses in obese subjects.
To evaluate the impact of evening dosing on 
tolerability.
To evaluate partitioning of GSK3008356 into skin in 
Part 2 only.
Part 2 14d Repeat Dose
Part 3 28d Repeat Dose
Serum lipid panel, weight.
Clinical monitoring/observation for adverse events with 
a focus on gastrointestinal findings and a stool scale.
Skin biopsy for drug concentration and activity.
RATIONALE
New text added to reflect the addition of skin biopsy to Part 2 of the study.  A 
punctuation correction was also made.


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Change 4: Figure 1 Study Part Schematic
PREVIOUS TEXT


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REVISED TEXT 
RATIONALE
The Figure was modified to reflect the actual doses administered and AM regimens in 
Part 2, Cohorts 1-3.
Change 5:  New Section 3.1.2 Revised Dosing Regimens for Part 2
Based on preliminary PK data from Part 1, the doses and regimens are now better 
clarified for Part 2.  Part 2 Cohorts 1, 2 and 3 will be administered in the AM as divided 
doses to achieve a daily time above the target exposure with varying levels of Cmax.  
Specifically, Cohort 1 will have a regimen of 2 doses separated by 16 hours similar to 
Part 1 Cohort 8.  The purpose is to explore a BID PK profile.  Cohorts 2 and 3 will have a 
regimen of nine hourly doses similar to Part 1 Cohorts 10 and 11.  The purpose is to 
explore PK profiles that approximate a sustained release formulation to guide further 
dosage development.    There will be no changes to the current challenge meal or 
assessments except for the addition of a skin biopsy outlined in Section 6.4.5.


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The regimens are as follows:
Part 2, Cohort 1 would evaluate 10 mg administered twice at time 0h and 16h for a total 
dose of 20 mg.
Part 2, Cohort 2 would evaluate 27 mg daily administered as 9 doses of 3 mg hourly 
from time 0 to time 8h daily for 14 days.  
Part 2, Cohort 3 would evaluate either 9 mg daily administered as 9 doses of 1 mg 
hourly from time 0 to time 8h or 45 mg daily as 9 doses of 5 mg hourly from time 0 to 
time 8h.
Neither the predicted human Cmax, nor the predicted daily human AUC of evaluated 
doses is expected to exceed the dog NOAEL exposure of Cmax (7.73 µg/mL) and 
AUC(0-t) (111 µg.h/mL).  
However, data from a 13-week oral toxicity study in dogs indicate that the NOAEL for 
dosing duration >28 days will likely be lower than the current NOAEL.  While these dog 
data do not impact the risk for this protocol as they do not change the NOAEL (Section
3.5.1), these data will impact the future viability of certain dose regimens.  
The regimens selected for Part 2 as outlined above are regimens have future development 
viability based on human exposure below the oral 13-week repeat dose dog testicular 
observation NOAEL exposure of Cmax (0.642 µg/mL) and AUC(0-t) (5.49 µg.h/mL).  
The highest dose regimen planned for Part 3 (45 mg daily as 9 doses of 5 mg hourly from 
time 0 to time 8h) is expected to result in the highest Part 2 Cmax (0.203 µg/mL) and 
AUC (1.261 µg.h/mL) exposure, based on Part 1 data.  
These predicted exposures are still 3.2-fold and 4.4-fold below the oral 13-week repeat 
dose dog testicular observation NOAEL Cmax and AUC exposure, respectively.  The 
predicted exposures are 38.1-fold and 88.1-fold below the current NOAEL Cmax and 
AUC exposure, respectively.
RATIONALE
The section was added to provide clarification, background and information regarding the 
selected regimens for Part 2, Cohorts 1-3.  The section also creates context for the 
expected Part 2 maximal exposure compared to the 13-week dog oral toxicity study 
testicular observation NOAEL.  The context defines dose regimens with future 
development viability.
Change 6: Section 3.2 Type and Number of Subjects
NEW TEXT
Subjects in Parts 1 and 2 will be randomized such that 6 subjects receive GSK3008356 
and 2 subjects receive matching placebo in each cohort of 8 subjects.  Subjects in Part 3 


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will be randomized such that 8 subjects receive GSK3008356 and 2 subjects receive 
matching placebo in each cohort of 10 subjects.
RATIONALE
The new wording was added at the end of Section 3.2 to clarify the allocation of active 
versus placebo in the completed Part 1 cohorts and the upcoming Parts 2 and 3 cohorts.


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Change 7: Section 3.5.1 Risk Assessment
PREVIOUS TEXT
Potential Risk of Clinical 
Significance and Summary 
of Data/Rational for Risk
Impact on eligibility criteria
Mitigation Strategy
Investigational Product (IP) [e.g., GSK3008256]
Hepatic Effects
Oral 7d repeat dose dog study:  
Minimal to mild, focal hepatocellular 
degeneration/necrosis was observed 
(minimal in one female given 50 
mg/kg/day; minimal to mild in the 
male and female given 200 
mg/kg/day).  Minimal mixed 
inflammatory cell infiltrates within 
liver sinusoids noted for the female 
given 200 mg/kg/day.  Clinical 
pathology findings included increases 
in alanine aminotransferase (ALT) 
(up to 1.96X baseline), increases in 
aspartate aminotransferase (AST) 
(up to 1.76X baseline), increased 
glutamate dehydrogenase (GLDH) 
(to 3.8X baseline) at all dose levels. 
Increased total bile acid 
concentrations (to 3.2X baseline) and 
decreased plasma albumin and total 
protein concentrations (to 0.90X 
baseline) were noted at various 
testing intervals for dogs given 50 or 
200 mg/kg/day.  These changes may 
be related to hepatocellular injury 
and/or associated with reduced food 
consumption.
Oral 28d repeat dose dog study:  
Increases ALT were noted for males 
and females given 2, 5 and 50 
mg/kg/day at Week 1 (ranging 
from1.88X to 2.5X baseline).  By 
Week 4, increases were 1.72X to 
2.2X baseline values.   The ALT 
increases were not progressive with 
continued dosing. There were no 
correlative liver histopathology 
findings.
Oral 7d and 28 repeat dose rat study:  
No hepatic related findings.
HepatoTaq:  No significant findings.
Exclusion criterion #1:
ALT and bilirubin > 1.5xULN (isolated 
bilirubin >1.5xULN is acceptable if 
bilirubin is fractionated and direct 
bilirubin <35%).
Exclusion criterion #2:
Current or chronic history of liver 
disease, or known hepatic or biliary 
abnormalities (with the exception of 
Gilbert's syndrome or asymptomatic 
gallstones).
Exclusion criterion #6
History of regular alcohol 
consumption within 6 months of the 
study.
Exclusion criterion #10:
A positive pre-study Hepatitis B 
surface antigen or positive Hepatitis 
C antibody result within 3 months of 
screening.
Sentinel dosing – staggered dosing 
in 2 subjects in Part 1 Cohort 1 prior 
to enrolment of the remainder of 
Cohort 1.
LFT evaluation planned at baseline, 
day 2, day 4, day 7, day 14, day 21, 
day 28, and also as indicated.
Exclusion criteria as noted in column 
2.
Stopping criterion of ALT ≥3xULN 
with no rechallenge of drug product.


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Potential Risk of Clinical 
Significance and Summary 
of Data/Rational for Risk
Impact on eligibility criteria
Mitigation Strategy
Gastrointestinal Tolerability
Oral 7d and 28d repeat dose dog 
study: In the 28d study, excessive 
salivation was observed for males 
given ≥2 mg/kg/day. Dose-related 
effects on body weight (decreased 
body weight gain or body weight loss) 
and/or reduced food consumption 
were observed in both studies.
Oral 7d and 28d repeat dose rat 
study: Non-dose related decreases in 
mean body weight gain for rats were 
observed in the 7day study.  No 
effects on body weight were noted in 
the 28 day rat study.
Scientific Literature:  Clinical DGAT1 
inhibition may result in dose limiting 
nausea, vomiting and, watery (non-
malabsorption) diarrhea which 
stopped upon discontinuation of 
dosing. (Denison 2014; Meyers 
2015).
Exclusion criterion #4:
Current or chronic history of 
gastrointestinal illness or conditions 
interfering with normal 
gastrointestinal anatomy or motility. 
Examples include gastrointestinal 
bypass surgery, cholecystectomy, 
partial or total gastrectomy, small 
bowel resection, vagotomy, 
malabsorption, Crohn’s disease, 
ulcerative colitis, IBS, or celiac sprue.
Diarrhea scale (Bristol Stool Form 
Scale) and frequency of stool 
(Section 6.5.2).
Subject may be withdrawn at any 
time at the discretion of the 
investigator for safety.
Dermal Effects
Oral 7d and 28d repeat dose dog 
study: In the 28 day study, dose-
related, minimal to mild atrophy of the 
sebaceous glands was observed and 
was considered to be related to 
pharmacology.
Oral 7d and 28 repeat dose rat study:  
No dermal-related findings.
Scientific Literature:  DGAT1 
inhibition may result in sebaceous 
gland atrophy and alopecia as 
observed in animal studies 
(Floettmann 2015), but similar effects 
have not been reported in clinical 
trials to date.
None
Subject may be withdrawn at any 
time at the discretion of the 
investigator for safety.


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Potential Risk of Clinical 
Significance and Summary 
of Data/Rational for Risk
Impact on eligibility criteria
Mitigation Strategy
Cardiovascular Effects
Single dose cardiovascular rat and 
dog studies:   In rats, transient 
increases in heart rate (17%) and 
blood pressure (18%) were observed 
at 100 mg/kg but not as 30 and
300 mg/kg.  The increases in both 
heart rate and blood pressure 
produced a transient increase in rate-
pressure-product (RPP; an index of 
cardiac workload; 37%),  Because 
similar changes were not observed at 
the highest evaluated dose of 300 
mg/kg, a clear relationship to 
GSK3008356 administration was not 
established. No acute effects on 
cardiovascular function were noted in 
dogs.
Oral 28d dog study : No 
cardiovascular-related findings (ECG 
assessments performed in the 28 day 
study).
Rabbit left ventricular wedge assay:
No effects on QT interval, transmural 
dispersion of repolarization, 
QRS duration or contractility 
(concentrations of up to 10 M). 
hERG: IC25 value was estimated to 
be 85.7 µM (31.49 µg/mL).  
Insufficient inhibition of hERG 
occurred to allow for the reliable 
estimation of an IC50 value. The 
estimated IC25 value is >150X greater 
than the estimated free Cmax in 
humans at the maximum predicted 
clinical efficacious dose of 43 mg.  
Based on the low magnitude and 
transient nature of the heart rate and 
blood pressure increases noted in 
rats and the low risk for QT 
prolongation (based on in vitro 
findings), the risk for CV effects in 
humans is considered low.
Exclusion criterion #3:
QTcF < 450 msec.
Monitoring via telemetry (day 1), 12-
lead ECG, and vital signs monitoring.
Stopping Criteria (Section 4.5.2):
QTcF > 500 msec
QTc change from baseline > 60 
msec.


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REVISED TEXT
Potential Risk of Clinical 
Significance and Summary 
of Data/Rationale for Risk
Impact on eligibility criteria
Mitigation Strategy
Investigational Product (IP) [e.g., GSK3008256]
Hepatic Effects
Oral 7d repeat dose dog study:  
Minimal to mild, focal hepatocellular 
degeneration/necrosis was observed 
(minimal in one female given 50 
mg/kg/day; minimal to mild in the 
male and female given 200 
mg/kg/day).  Minimal mixed 
inflammatory cell infiltrates within 
liver sinusoids noted for the female 
given 200 mg/kg/day.  Clinical 
pathology findings included increases 
in alanine aminotransferase (ALT) 
(up to 1.96X baseline), increases in 
aspartate aminotransferase (AST) 
(up to 1.76X baseline), increased 
glutamate dehydrogenase (GLDH) 
(to 3.8X baseline) at all dose levels. 
Increased total bile acid 
concentrations (to 3.2X baseline) and 
decreased plasma albumin and total 
protein concentrations (to 0.90X 
baseline) were noted at various 
testing intervals for dogs given 50 or 
200 mg/kg/day.  These changes may 
be related to hepatocellular injury 
and/or associated with reduced food 
consumption.
Oral 28d and 13 week repeat dose 
dog studies:  Increases ALT were 
noted for males and females given 2, 
5 and 50 mg/kg/day at Week 1 
(ranging from1.88X to 2.5X baseline).  
By Week 4, increases were 1.72X to 
2.2X baseline values.   The ALT 
increases were not progressive with 
continued dosing. There were no
correlative liver histopathology 
findings. Similar increases in ALT (up 
to 2.71X baseline) and AST (up to 
1.57X) were observed in the 13 week 
study (evaluating doses up to 60 
mg/kg/day) and were reversible 
following a 4-week off-treatment 
period.
Oral 7d and 28 repeat dose rat study:  
No hepatic related findings. 
Exclusion criterion #1:
ALT and bilirubin > 1.5xULN (isolated 
bilirubin >1.5xULN is acceptable if 
bilirubin is fractionated and direct 
bilirubin <35%).
Exclusion criterion #2:
Current or chronic history of liver 
disease, or known hepatic or biliary 
abnormalities (with the exception of 
Gilbert's syndrome or asymptomatic 
gallstones).
Exclusion criterion #6
History of regular alcohol 
consumption within 6 months of the 
study.
Exclusion criterion #10:
A positive pre-study Hepatitis B 
surface antigen or positive Hepatitis 
C antibody result within 3 months of 
screening.
Sentinel dosing – staggered dosing 
in 2 subjects in Part 1 Cohort 1 prior 
to enrolment of the remainder of 
Cohort 1.
LFT evaluation planned at baseline, 
day 2, day 4, day 7, day 14, day 21, 
day 28, and also as indicated.
Exclusion criteria as noted in column 
2.
Stopping criterion of ALT ≥3xULN 
with no rechallenge of drug product.


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Potential Risk of Clinical 
Significance and Summary 
of Data/Rationale for Risk
Impact on eligibility criteria
Mitigation Strategy
Oral 13 week repeat dose rat study: 
Increased liver weights (to 1.2X 
mean control) were observed in 
female rats given 1000 mg/kg/day 
with no clinical pathology or 
microscopic correlates.
HepatoTaq:  No significant findings.
Gastrointestinal Tolerability
Oral 7d, 28d, and 13 week repeat 
dose dog studies: In the 28d study, 
excessive salivation was observed 
for males given ≥2 mg/kg/day. Dose-
related effects on body weight 
(decreased body weight gain or body 
weight loss) and/or reduced food 
consumption were observed in all
studies.  Increased frequency of fecal 
abnormalities (unformed/ 
stool/mucous and/or watery) were 
observed in the 13 week study.
Oral 7d, 28d, and 13 week repeat 
dose rat studies: Non-dose related 
decreases in mean body weight gain 
for rats were observed in the 7day 
study.  No effects on body weight 
were noted in the 28 day and 13-
week rat studies.
Scientific Literature:  Clinical DGAT1 
inhibition may result in dose limiting 
nausea, vomiting and, watery (non-
malabsorption) diarrhea which 
stopped upon discontinuation of 
dosing. (Denison 2014; Meyers 
2015).
Exclusion criterion #4:
Current or chronic history of 
gastrointestinal illness or conditions 
interfering with normal 
gastrointestinal anatomy or motility. 
Examples include gastrointestinal 
bypass surgery, cholecystectomy, 
partial or total gastrectomy, small 
bowel resection, vagotomy, 
malabsorption, Crohn’s disease, 
ulcerative colitis, IBS, or celiac sprue.
Diarrhea scale (Bristol Stool Form 
Scale) and frequency of stool 
(Section 6.5.2).
Subject may be withdrawn at any 
time at the discretion of the 
investigator for safety.


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Potential Risk of Clinical 
Significance and Summary 
of Data/Rationale for Risk
Impact on eligibility criteria
Mitigation Strategy
Dermal Effects
Oral 7d, 28d, and 13 week repeat 
dose dog studies: Dose-related, 
minimal to moderate atrophy of the 
sebaceous glands was observed and 
was considered to be related to 
pharmacology.  Finding was 
reversible in the 13 week study 
following a 4-week off-dose period.
Oral 7d, 28d, and 13 week repeat 
dose rat studies:  No dermal-related 
findings.
Scientific Literature:  DGAT1 
inhibition may result in sebaceous 
gland atrophy and alopecia as 
observed in animal studies 
(Floettmann 2015), but similar effects 
have not been reported in clinical 
trials to date.
None
Subject may be withdrawn at any 
time at the discretion of the 
investigator for safety.
Testicular Effects
Oral 7d and 28d repeat dose dog 
study: No effects in testes or 
epididymides observed at doses up 
to 200 mg/kg/day for 7d and up to 50 
mg/kg/day for 28d.
Oral 7d, 28d and 13w repeat dose rat 
study:  No effects in testes or 
epididymides observed at doses up 
to 300 mg/kg/day for 7d and 28d and 
up to1000 mg/kg/day for 13w.
Oral 13w repeat dose dog study: 
Minimal to mild degeneration of the 
testicular seminiferous tubule 
epithelium with secondary changes 
within the epididymides (luminal germ 
cell debris and/or reduced sperm) 
was observed in terminal dogs given 
≥ 30 mg/kg/day. 
Following the end of the 4-week off-
dose period, testicular degeneration 
was still present in dogs given 60 
mg/kg/day and is not unexpected 
given the long spermatogenic cycle in 
dogs (typically 90 days).
None
While there is no impact on the study 
NOAEL, dose regimen selection will 
be based regimens which will result 
in human exposure below the oral 
13w repeat dose dog testicular 
observation NOAEL exposure of 
Cmax (0.642 µg/mL) and AUC(0-t) 
(5.49 µg.h/mL).
Subject may be withdrawn at any 
time at the discretion of the 
investigator for safety.


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Potential Risk of Clinical 
Significance and Summary 
of Data/Rationale for Risk
Impact on eligibility criteria
Mitigation Strategy
Cardiovascular Effects
Single dose cardiovascular rat and 
dog studies:   In rats, transient 
increases in heart rate (17%) and 
blood pressure (18%) were observed 
at 100 mg/kg but not as 30 and 
300 mg/kg.  The increases in both 
heart rate and blood pressure 
produced a transient increase in rate-
pressure-product (RPP; an index of 
cardiac workload; 37%),  Because 
similar changes were not observed at 
the highest evaluated dose of 300 
mg/kg, a clear relationship to 
GSK3008356 administration was not 
established. No acute effects on 
cardiovascular function were noted in 
dogs.
Oral 28d and 13 week dog studies:
No cardiovascular-related findings 
(ECG assessments).
Rabbit left ventricular wedge assay:
No effects on QT interval, transmural 
dispersion of repolarization, 
QRS duration or contractility 
(concentrations of up to 10 M). 
hERG: IC25 value was estimated to 
be 85.7 µM (31.49 µg/mL).  
Insufficient inhibition of hERG 
occurred to allow for the reliable 
estimation of an IC50 value. The 
estimated IC25 value is >150X greater 
than the estimated free Cmax in 
humans at the maximum predicted 
clinical efficacious dose of 43 mg.  
Based on the low magnitude and 
transient nature of the heart rate and 
blood pressure increases noted in 
rats and the low risk for QT 
prolongation (based on in vitro 
findings), the risk for CV effects in 
humans is considered low.
Exclusion criterion #3:
QTcF < 450 msec.
Monitoring via telemetry (day 1), 12-
lead ECG, and vital signs monitoring.
Stopping Criteria (Section 4.5.2):
QTcF > 500 msec
QTc change from baseline > 60 
msec.


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Potential Risk of Clinical 
Significance and Summary 
of Data/Rationale for Risk
Impact on eligibility criteria
Mitigation Strategy
Study Procedures
Skin Biopsy
Complications of punch skin biopsy 
are uncommon but may include 
bleeding, infection, and scarring.
Bleeding and infection risk are very 
uncommon with underlying disease 
conditions (hemophilia, diabetes, 
older age, and immunosuppression) 
slightly increasing the risk.
Scarring risk is increased in 
individuals with a history of scarring.
Exclusion criterion #5:
History of risk for or actual 
experience of complications from skin 
biopsy including excess bleeding, 
infection, or scarring/keloid formation.
Observation of the subject while in 
the clinical unit and at follow-up after 
discharge from the unit. 
Subject may be withdrawn at any 
time at the discretion of the 
investigator for safety.
RATIONALE
New section added to the Risk Assessment section to provide detail regarding the 13-
week dog oral toxicity study testicular observation NOAEL.  Details from the 13 week 
dog and 13 week rat oral toxicity studies regarding risk in other organ systems were also 
added.  Detail regarding the risk for Skin biopsy was also added.  A spelling error in the 
column heading was also corrected.
Change 8: Section 4.2 Exclusion Criteria
NEW TEXT
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
5. History of risk for or actual experience of complications from skin biopsy including 
excess bleeding, infection, or scarring/keloid formation (Part 2 only).
RATIONALE
The new exclusion criterion added to mitigate the risk of complications from the skin 
biopsy procedure.  
Note that the exclusion criteria previously numbered 5 through 15 were re-numbered 6 
through 16 to accommodate the new criterion number 5 inserted into the Concurrent 
Conditions/Medical History section.


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Change 9: Table 7 Regimen Description in Section 5.2 Treatment 
Assignment 
PREVIOUS TEXT 
Regimen 
Code 
Study Medication 
Regimen 
Code 
Study Medication 
AA 
5 mg GSK3008356, morning dosing 
AP 
5 mg GSK3008356, evening dosing 
BA 
10 mg GSK3008356, morning dosing 
BP 
10 mg GSK3008356, evening dosing 
CA 
25 mg GSK3008356, morning dosing 
CP 
25 mg GSK3008356, evening dosing 
DA 
50 mg GSK3008356, morning dosing 
DP 
50  mg GSK3008356, evening dosing 
EA 
75 mg GSK3008356, morning dosing 
EP 
75 mg GSK3008356, evening dosing 
FA 
Matched placebo, morning dosing 
FP 
Matched placebo, evening dosing 
GA 
125 mg GSK3008356, morning dosing 
JA 
200  mg GSK3008356, 
evening dosing 
HA 
125 mg GSK3008356 q4h x 2 doses, 
morning dosing 
KA 
10 mg GSK3008356 q1h x 9 doses, 
morning dosing 
IA 
125 mg GSK3008356 q16h x 2 doses, 
morning dosing 
LA 
5 mg GSK3008356 q1h x 9 doses, 
morning dosing 
 
 
MA 
20 mg GSK3008356 q1h x 9 doses, 
morning dosing 
 


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REVISED TEXT 
Regimen 
Code
Study Medication
Regimen 
Code
Study Medication
AA
5 mg GSK3008356, morning dosing
AP
5 mg GSK3008356, evening dosing
BA
10 mg GSK3008356, morning dosing
BP
10 mg GSK3008356, evening dosing
CA
25 mg GSK3008356, morning dosing
CP
25 mg GSK3008356, evening dosing
DA
50 mg GSK3008356, morning dosing
DP
50  mg GSK3008356, evening dosing
EA
75 mg GSK3008356, morning dosing
EP
75 mg GSK3008356, evening dosing
FA
Matched placebo, morning dosing
FP
Matched placebo, evening dosing
GA
125 mg GSK3008356, morning dosing
LA
5 mg GSK3008356 q1h x 9 doses, 
morning dosing
HA
125 mg GSK3008356 q4h x 2 doses, 
morning dosing
MA
20 mg GSK3008356 q1h x 9 doses, 
morning dosing
IA
125 mg GSK3008356 q16h x 2 doses, 
morning dosing
NA
10 mg GSK3008356 q16h x 2 doses, 
morning dosing
JA
200  mg GSK3008356,
evening dosing
OA
3 mg GSK3008356 q1h x 9 doses, 
morning dosing
KA
10 mg GSK3008356 q1h x 9 doses, 
morning dosing
PA
1 mg GSK3008356 q1h x 9 doses, 
morning dosing
RATIONALE
The new text (Regimens NA, OA, and PA) provides detail for the doses planned for the 
Part 2 Cohorts.  Note the previously included Regimen LA is also a planned dose option 
for Part 2.  The table position of previously included Regimens JA, KA, LA, and MA 
were moved for formatting purposes.
Change 10: Section 6 Study Assessments and Procedures
PREVIOUS TEXT

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.  


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REVISED TEXT

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
4. skin biopsy.
RATIONALE
The skin biopsy procedure was added to the procedure order list.
Change 11: Time and Events Table: Section 6.1.2 Part 2 – Repeat Dose, 
Morning Dose Administration, Screening, Day -1, Day 1
NEW TEXT
Citation 10 and Footnote 10 added for Study Drug Dose
10. For cohorts where multiple doses are to be administered either q1h or q16h, Time 0 is the first dose and 
subsequent doses are per regimen (q1h or q16) and the subsequent doses are not noted on the T&E Table.
RATIONALE
The addition of citation 10 and the corresponding footnote text clarifies time 0 for cohorts 
where regimens consisting of multiple doses are to be administered.  
Change 12: Time and Events Table: Section 6.1.3 Part 2 – Repeat Dose, 
Morning Dose Administration, Days 2-13
NEW TEXT
Citation 6 and Footnote 6 added for Study Drug Dose
6.
For cohorts where multiple doses are to be administered either q1h or q16h, Time 0 is the first dose and 
subsequent doses are per regimen (q1h or q16) and the subsequent doses are not noted on the T&E Table.


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RATIONALE
The addition of citation 6 and the corresponding footnote text clarifies time 0 for cohorts 
where regimens consisting of multiple doses are to be administered.  
Change 13: Time and Events Table: Section 6.1.4 Part 2 – Repeat Dose, 
Morning Dose Administration, Days 14-17, Follow-up
NEW TEXT
Citation 6 and Footnote 6 added for Study Drug Dose
6.
For cohorts where multiple doses are to be administered either q1h or q16h, Time 0 is the first dose and 
subsequent doses are per regimen (q1h or q16) and the subsequent doses are not noted on the T&E Table.
Skin biopsy row added
Day 14
Day 15 Day 16 Day 17
Follow Up
(Day 20-22)
Pre-dose 0h
0.25h
0.5h
1h
1.5h
2h
4h
6h
8h
12h
18h
24h
36h
48h
72h
Skin Biopsy7
X7
X7
X7
Citation 7 and Footnote 7 added for Skin biopsy
7.
Cohort 1 (10mg q16) collect only at 1h and 24h Day 14; Cohorts 2 & 3 (3mg, 1mg or 5mg q1h) collect only at 6h 
and 24h Day 14
RATIONALE
The addition of citation 6 and the corresponding footnote text clarifies time 0 for cohorts 
where regimens consisting of multiple doses are to be administered.  The skin biopsy 
procedure was added as an assessment.  Citation 7 and the corresponding footnote clarify 
that only two biopsies are to be collected on Day 14 for each cohort.  Footnote 7 also 
clarifies the collection times in each cohort.
Change 14: Time and Events Table: Section 6.1.8 Part 2 – Repeat Dose, Fat 
Meal Challenge and Triglyceride Assessment Relative to Dose and PK 
Sampling, 6.1.8.1. Morning Dose Administration, Day -1, Day 1, and Day 14
PREVIOUS TEXT
Footnote 1:
1.
Day 1 and 14 only.


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NEW TEXT
Footnote 1:
1.
Day 1 and 14 only.  For cohorts where multiple doses are to be administered either q1h or q16h, Time 0 is the first 
dose and subsequent doses are per regimen (q1h or q16) and the subsequent doses are not noted on the T&E 
Table.
RATIONALE
The addition to footnote 1 clarifies time 0 for cohorts where regimens consisting of 
multiple doses are to be administered.  
Change 15:  New Section 6.4.5 Skin Biopsy Sample Collection and Analysis
Skin biopsy for PK analysis and activity of GSK3008356 will be collected at the time 
points indicated in the Time and Events Tables (Section 6.1).  The actual date and time of 
each sample collection will be recorded.  
Details of the skin biopsy sample collection, including collection procedures, sample 
preparation, sample storage, and shipping procedures are provided in the Study Reference 
Manual. 
Drug concentration analysis of the skin samples will be performed under the management 
of PTS-DMPK.  Concentrations of GSK3008356 may be determined through standard 
Liquid Chromatography Tandem Mass Spectrometry (LC MS/MS) in homogenate and/or 
using Matrix Assisted Laser Desorption/Ionization (MALDI) analysis through approved 
analytical methodology.  Analysis of pharmacology (if feasible) may also be performed 
potentially including lipodomics/metabolomics for lipid levels, including TG, in the skin.  
Additional target engagement studies may also be performed (if feasible) including 
thermal shift assay and/or human skin lipogenesis (SLiP) assay.  Raw data will be 
archived at the bioanalytical site (detailed in the SRM).  All skin biopsy analysis results 
will be reported under a separate PTS-DMPK protocol.
RATIONALE
The new section details skin biopsy collection, analysis and reporting.  


2015N242776_02
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Change 16: Section 8.4.3 Other Analyses
PREVIOUS TEXT
Please refer to Section 6.4.4.
NEW TEXT
Please refer to Section 6.4.4 and Section 6.4.5.
RATIONALE
The addition is to clarify that other analysis will take place for the skin biopsy as 
described in the skin biopsy section (Section 6.4.5).
Change 17: Section 11.1 Appendix 1 – Abbreviations and Trademarks
NEW TEXT
Abbreviations added:
LC MS/MS
liquid chromatography tandem mass spectrometry
MALDI
matrix assisted laser desorption/ionization
SLiP
skin lipogenesis (assay)
RATIONALE
Abbreviations in the amendment text were added to the table.

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
204856
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for
A Phase I, Randomized, Placebo-Controlled, Double-Blind 
(sponsor unblind), Three Part Study to Evaluate the Safety, 
Tolerability, Preliminary PK and PD of Single and Repeat 
Oral Doses of GSK3008356 in Healthy Subjects and Obese 
Subjects
Compound Number 
:
GSK3008356
Effective Date 
:
03-AUG-2017
Description:
The purpose of this RAP is to describe the planned analyses and output to be included in 
the Clinical Study Report for Protocol 204856.
This RAP is intended to describe the Safety, Pharmacokinetic (PK), and 
Pharmacodynamic (PD) 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) deliverable.
Author’s Name and Functional Area: 
01-AUG-2017
Senior Statistician, Accenture
01-AUG-2017
Manager, CPMS, GSK
Approved by: 
02-AUG-2017
Manager of Clinical Statistics, Accenture
03-AUG-2017
Manager, Clinical Statistics, GSK
Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD
PPD
PPD


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TABLE OF CONTENTS
PAGE
1.
REPORTING & ANALYSIS PLAN SYNPOSIS.........................................................6
2.
SUMMARY OF KEY PROTOCOL INFORMATION ................................................10
2.1.
Changes to the Protocol Defined Statistical Analysis Plan..........................10
2.2.
Study disposition: Termination after Part 2..................................................10
2.3.
Study Objective(s) and Endpoint(s).............................................................11
2.4.
Study Design ..............................................................................................13
2.5.
Statistical Hypotheses.................................................................................14
3.
PLANNED ANALYSES ..........................................................................................14
3.1.
Interim Analyses .........................................................................................14
3.2.
Final Analyses ............................................................................................14
4.
ANALYSIS POPULATIONS ...................................................................................15
4.1.
Protocol Deviations.....................................................................................15
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................17
6.
STUDY POPULATION ANALYSES .......................................................................18
6.1.
Overview of Planned Analyses ...................................................................18
6.1.1.
Subject Disposition ......................................................................19
6.1.2.
Demographics and Baseline Characteristics................................19
6.1.3.
Concomitant Medications.............................................................19
6.1.4.
Drug Exposure.............................................................................19
6.1.5.
Medical History ............................................................................20
6.1.6.
Protocol Deviation........................................................................20
7.
PRIMARY STATISTICAL ANALYSES....................................................................21
7.1.
Safety Analyses..........................................................................................21
7.1.1.
Overview of Planned Adverse Events Analyses...........................21
7.1.1.1.
Adverse Events ..........................................................21
7.1.1.2.
Adverse Event Incidence Rates for All Subjects .........22
7.1.1.3.
Severity of Adverse Events.........................................22
7.1.1.4.
Relationship to Study Treatment.................................22
7.1.1.5.
Serious Adverse Events (SAE), Adverse 
Events Leading to Drug Discontinuation, and 
Death .........................................................................23
7.1.2.
Overview of Planned Clinical Laboratory Analysis .......................23
7.1.2.1.
Clinical Laboratory......................................................24
7.1.3.
Overview of Planned Other Safety Analyses................................25
7.1.3.1.
Vital Signs ..................................................................25
7.1.3.2.
ECG ...........................................................................26
7.1.3.3.
Other Exams ..............................................................26
8.
SECONDARY STATISTICAL ANALYSES .............................................................27
8.1.
Pharmacokinetic Analyses..........................................................................27


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8.1.1.
Overview of Planned Pharmacokinetic Analyses .........................27
8.1.2.
Drug Concentration Measures .....................................................28
8.1.3.
Pharmacokinetic Parameters.......................................................28
8.1.3.1.
Deriving Pharmacokinetic Parameters........................28
8.1.3.2.
Statistical Analysis of Pharmacokinetic 
Parameters.................................................................30
8.2.
Biomarker/Pharmacodynamic Markers Analyses........................................34
8.2.1.
Overview of Planned Biomarker/Pharmacodynamic 
Analyses......................................................................................34
8.2.1.1.
Postprandial Triglyceride Evaluation...........................35
8.2.1.2.
Postprandial Triglyceride AUC....................................37
8.2.1.3.
Bristol Stool Form Scale (BSFS).................................37
8.2.2.
Exploratory Pharmacodynamic Markers ......................................37
8.3.
Pharmacokinetic / Pharmacodynamic Analyses..........................................38
8.3.1.
Population Pharmacokinetic / Pharmacodynamic Analyses .........38
9.
OTHER STATISTICAL ANALYSES .......................................................................39
9.1.
Exploratory Analysis ...................................................................................39
9.1.1.
Skin Biopsy in Part 2....................................................................39
10. REFERENCES.......................................................................................................40
11. APPENDICES........................................................................................................41
11.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................42
11.1.1.
Protocol Deviation Definition........................................................42
11.1.2.
Per Protocol Population ...............................................................42
11.2.
Appendix 2: Time & Events.........................................................................43
11.2.1.
Protocol Defined Time & Events ..................................................43
11.2.1.1.
Part 1 – Single Dose...................................................43
11.2.1.2.
Part 1 – Single Dose, Fat Meal Challenge and 
Triglyceride Assessment Relative to Dose and 
PK Sampling...............................................................44
11.2.1.3.
Part 2 – Repeat Dose, Morning Dose 
Administration, Screening, Day -1, Day 1 ...................45
11.2.1.4.
Part 2 – Repeat Dose, Morning Dose 
Administration, Days 2-13...........................................46
11.2.1.5.
Part 2 – Repeat Dose, Morning Dose 
Administration, Days 14-17, Follow-up .......................47
11.2.1.6.
Part 2 – Repeat Dose, Fat Meal Challenge and 
Triglyceride Assessment Relative to Dose and 
PK Sampling--Morning Dose Administration, 
Day -1, Day 1, and Day 14 .........................................48
11.3.
Appendix 3: Assessment Windows .............................................................49
11.3.1.
Definitions of PK Assessment Windows.......................................49
11.3.2.
Definitions of Triglyceride (Postprandial) Assessment 
Windows......................................................................................50
11.3.3.
Definitions of Vital Signs and ECG Assessment Windows ...........50
11.4.
Appendix 4: Treatment States and Phases.................................................52
11.4.1.
Treatment Phases .......................................................................52


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11.4.2.
Treatment States .........................................................................52
11.4.2.1.
Treatment States for AE Data.....................................52
11.5.
Appendix 5: Data Display Standards & Handling Conventions....................53
11.5.1.
Study Treatment & Sub-group Display Descriptors......................53
11.5.2.
Baseline Definition & Derivations .................................................54
11.5.2.1.
Baseline Definitions....................................................54
11.5.2.2.
Derivations and Handling of Missing Baseline 
Data ...........................................................................55
11.5.3.
Reporting Process & Standards...................................................56
11.6.
Appendix 6: Derived and Transformed Data ...............................................59
11.6.1.
General........................................................................................59
11.6.2.
Study Population..........................................................................59
11.6.3.
Safety ..........................................................................................60
11.7.
Appendix 7: Premature Withdrawals & Handling of Missing Data ...............61
11.7.1.
Premature Withdrawals................................................................61
11.7.2.
Handling of Missing Data.............................................................61
11.7.2.1.
Handling of Missing Dates..........................................61
11.7.2.2.
Handling of Partial Dates............................................62
11.7.2.3.
Handling of Missing Data for Statistical 
Analysis......................................................................63
11.8.
Appendix 8: Values of Potential Clinical Importance ...................................64
11.8.1.
Laboratory Values........................................................................64
11.8.2.
ECG.............................................................................................65
11.8.3.
Vital Signs....................................................................................65
11.9.
Appendix 9: Pharmacokinetic / Pharmacodynamic Analyses ......................66
11.9.1.
Overview of Planned Pharmacokientic (PK) / 
Pharamcodynamic (PD) Analyses ...............................................66
11.9.2.
Statistical Analyses of Postprandial Triglyceride ..........................67
11.9.2.1.
Correlation Analysis....................................................67
11.9.2.2.
Exposure – Response Analysis ..................................67
11.10. Appendix 10: Model Checking and Diagnostics for Statistical 
Analyses.....................................................................................................69
11.10.1. Statistical Analysis Assumptions..................................................69
11.11. Appendix 11 – Abbreviations ......................................................................71
11.11.1. Abbreviations...............................................................................71
11.12. Appendix 12: List of Data Displays..............................................................73
11.12.1. General Data Display Numbering ................................................73
11.12.2. Mock Example Shell Referencing ................................................73
11.12.3. Deliverable [Priority].....................................................................73
11.12.4. General Note for Display..............................................................74
11.12.5. Study Population..........................................................................75
11.12.5.1. Study Population Tables.............................................75
11.12.5.2. Safety Tables .............................................................77
11.12.5.3. Safety Figures ............................................................80
11.12.5.4. Pharmacokinetic Tables .............................................80
11.12.5.5. Pharmacokinetic Figures ............................................82
11.12.5.6. Pharmacodynamic (and / or Biomarker) Tables:.........82
11.12.5.7. Pharmacodynamic (and / or Biomarker) 
Figures: ......................................................................84
11.12.5.8. ICH Listings................................................................86


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11.12.5.9. Non-ICH Listings ........................................................90
11.13. Appendix 13: Example Mock Shells for Data Displays ................................93


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1.
REPORTING & ANALYSIS PLAN SYNPOSIS
Overview
Key Elements of the RAP
Purpose
The purpose of this report and analysis plan (RAP) is to describe the analyses to 
be included in the Clinical Pharmacology Study Report (CPSR) for Study 204856
Protocol
This RAP is based on Protocol Amendment 2, dated: 07-Feb-2017 of study 
204856 for GSK204856 and eCRF Version 1.3 (22-May-2017).
Part 1
Primary 
Objective
To characterize the safety, and tolerability of single doses of GSK3008356 in 
healthy subjects.
Primary 
Endpoint
Safety parameters including physical examination findings, vital signs, 12-lead 
ECGs, continuous lead II cardiac monitoring, clinical laboratory tests and clinical 
monitoring/observation for adverse events.
Study 
Design
Single Dose Tolerability and PK: this part was a randomized, placebo-controlled, 
double blind (sponsor unblind), single-dose, dose-rising study in healthy subjects. 
There are 5 cohorts with 8 subjects each (6 are on the active drug and 2 are on a
matching placebo) while receiving a standard 30% fat meal.
Based on emerging PK data, the original planned Part 1 doses were adjusted due 
to a much shorter observed half-life. Further details are shown in Figure 1: 
Schematic of Study Design.  
Analysis 
Populations
Screened: Comprised of all subjects screened which also includes subjects with 
screen failure.
Enrolled: Comprised of all subjects who consented and screened with eligibility 
verified.
Safety (Primary): Comprised of subjects who received at least one dose of study 
medication.
PKC (PK Concentration) (Secondary): Comprised of subjects for whom a 
pharmacokinetic sample was obtained and analysed.
PKP (PK Parameter) (Secondary): Comprised of all subjects in the PKC 
population who receive at least one active dose of GSK3008356 and provide 
pharmacokinetic parameters.
PD: Comprised of subjects in the Safety population for whom at least one a 
postprandial Triglyceride sample was obtained and analysed at baseline and post 
baseline. 
Hypothesis
There are no formal hypotheses being tested. 
Primary 
Analyses
Safety data will be presented either in tabular and/or graphical format and 
summarised descriptively. GSK’s Integrated Data Standards Library (IDSL) 
standards for the displays are being used. 


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Overview
Key Elements of the RAP
Secondary 
Analyses
Pharmacokinetic:

Summary Statistics for AUC0-t, AUC0-∞, AUC0-24, Cmax, Tmax, t1/2, 
Ae, and CLr as data permit;
Dose Proportionality:

Assessment of dose proportionality by AUC0-t, AUC0-∞, and Cmax;
Pharmacodynamic (TG):

Summary statistics for absolute for TG values by treatment and day and 
Time Point

Summary statistics for Corrected TG by treatment day and time point

Summary statistics for AUC [AUC(1-12), AUC(2-5), Corrected AUC(1-12), 
Corrected AUC(2-5)] of TG by treatment and day

Summary statistics for percent (%) change from baseline in AUC AUC 
[AUC(1-12), AUC(2-5), Corrected AUC(1-12), Corrected AUC(2-5)] by 
treatment and day. 
Pharmacodynamic (BSFS):

Summary of number of subjects and number of BSFS by type, day, and  
treatment 

Summary of total number of BSFS by day and treatment
Pharmacokinetic / Pharmacodynamic

PK / PD analyses including correlation and Emax model will not be 
performed but are recorded in Appendix 9 due to the lack of a repeat 
dose regimen that was both active for TG suppression and tolerated from
a GI perspective.
Part 2
Primary 
Objective
To characterize the safety, and tolerability of 14 daily repeat doses of 
GSK3008356 in healthy subjects.
Primary 
Endpoint
Safety parameters including physical examination findings, vital signs, 12-lead 
ECGs, continuous lead II cardiac monitoring, clinical laboratory tests and clinical 
monitoring/observation for adverse events.
Study 
Design
Repeat Dose Tolerability and PK: this part was a randomized, placebo-controlled, 
double blind (sponsor unblind), 14-day, repeat-dose, dose-rising study in healthy 
subjects. There are 3 cohorts with 8 subjects each (6 are on the active drug and 2 
are on a matching placebo) while they received a standard 30% fat meal on day -
1, day 1, and day 14, respectively.
Analysis 
Populations
Screened: Comprised of all subjects who screened which included subjects with 
screen failure.


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Overview
Key Elements of the RAP
Enrolled: Comprised of all subjects who consented and screened with eligibility 
verified.
Safety (Primary): Comprised of subjects who received at least one dose of study 
medication and had at least one safety evaluation.
PKC (PK Concentration) (Secondary): Comprised of subjects who received at 
least one dose of GSK3008356 and for whom at least one sample was obtained 
which yielded a valid concentration value upon bioassay.
PKP (PK Parameter) (Secondary): Comprised of all subjects in the PKC 
population who receive at least one active dose of GSK3008356 and provide 
pharmacokinetic parameters.
PD: Comprised of subjects in the Safety population for whom at least one a 
postprandial Triglyceride sample was obtained and analysed at baseline and post 
baseline.
Hypothesis
There are no formal hypotheses being tested. 
Primary 
Analyses
Safety data will be presented either in tabular and/or graphical format and 
summarised descriptively. GSK’s Integrated Data Standards Library (IDSL) 
standards for the displays are being used 
Secondary 
Analyses
Pharmacokinetic:

Summary Statistics for AUC(0-∞) on Day 1, AUC0-τ, Cmax, Tmax on Day 
1 and Day 14, and t1/2,  Ae, and CLr on Day 14 of GSK3008356 as data 
permit.
Dose Proportionality: 

Assessment of dose proportionality by AUC(0-∞) on Day 1, AUC0-tau and 
Cmax on Day 1 and Day 14;
Accumulation Ratio: 

Assessment of observed accumulation ratio by AUC(0-tau), (Ro), and 
Cmax (Rcmax) on Day 14 vs. Day 1 as data permit.

Assessment of steady-state accumulation ratio (Rs) by AUC(0-tau) on 
Day 14 vs. AUC(0-∞) on Day 1 as data permit. 
Steady State:

Assessment of steady state after repeat dosing by trough plasma 
concentration on Days 2, 4, 5, 6, 12, 13, 14 (pre-dose), 15 (24 h post-
dose on Day 14).
Pharmacodynamic (TG):

Summary statistics for absolute for TG values by treatment and day and 
time point


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Overview
Key Elements of the RAP

Summary statistics for corrected TG by treatment, day and time

Summary statistics for AUC of TG by treatment and day

Summary statistics for percent (%) change from baseline in AUC of TG
Pharmacodynamic (BSFS):

Summary of number of subjects and number of BSFS by type, day, and  
treatment

Summary of total number of BSFS by day and treatment  
Pharmacokinetic / Pharmacodynamic

PK / PD analyses including correction and Emax model will not be 
performed but are in Appendix 9 due to the lack of a repeat dose regimen 
that was both active for TG suppression and tolerated from a GI 
perspective.
Exploratory 
Analyses
Serum Lipid Levels and Weight

Summary Statistics for the change in serum lipid levels and weight after 
14 daily repeat doses of GSK3008356 in healthy subjects
Skin Biopsy:

Assessment of skin biopsy and analyses will be performed under the 
management of PTS IVIVT BIB and details will not be included in this 
RAP.


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2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
There were changes or deviations to the originally planned statistical analysis which are 
specified in protocol amendment 02 (Dated: 07-FEB-2017).  The details of previous 
protocols are as follows:

The original protocol was created on 02 March 2016.

Protocol amendment 01 was created on 22 July 2016. Adds additional Part 1 
cohorts which dose the compound in a way that provides a more appropriate 
exposure profile.  This is to obtain better PK/PD data to inform progression into 
Part 2 of the study.

Protocol amendment 02 was created on 22 January 2017. Clarifies dosing 
regimens for Part 2, adds skin biopsy assessment for drug level and activity, and 
adds information to the Benefit:Risk table based on 13 week dog and 13 week rat 
toxicity study findings and the addition of skin biopsy to procedures. 
Further Rationale for Amendment 1 and Amendment 2:
Amendment 1 was based on preliminary pharmacokinetic data indicating a much shorter 
observed half-life compared to the predicted half-life (1.5-3h observed versus 14.1h 
predicted).  While the adjusted doses in the first 5 cohorts did allow observation of a PD 
response in Cohort 5, the overall single dose data to date are limited and could not 
adequately inform a PK/PD model or support informed progression into Part 2 of the 
study.  
Amendment 2 clarified the Part 2 regimens and added a skin biopsy.  The former change 
provided specific regimens and noted evening dosing was no longer indicated.  Addition 
of skin biopsy was to further define if the short observed half-life is in part based on 
distribution to tissue.  Pharmacodynamics has been observed in the skin in preclinical 
studies. 
2.2.
Study disposition: Termination after Part 2
Dose escalation within a study Part was based on review of data from prior cohorts as 
outlined in Section 9.8.1 of the protocol.  Across cohorts, a combination of tolerability, 
particularly in the GI organ system class, and pharmacodynamic (PD) activity (as 
identified through postprandial TG suppression) would be used to identify doses to 
progress across study Parts (see Section 3.3 in the protocol).
Specifically, Part 1 doses with PD activity would be progressed into Part 2.  GI 
tolerability was not expected to be an issue in Part 1 and not expected to impact 
progression into Part 2.  Part 2 doses with PD activity and which had tolerability from a 
GI AE perspective were to be progressed into Part 3.


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Part 1 data indicated that single doses of 125 mg or greater were tolerated and had 
postprandial TG suppression.  Divided doses of 45 mg GSK3008356 or greater were 
tolerated and had postprandial TG suppression. The dose of 45 mg (5 mg hourly for 9 
hours) had complete suppression.  Divided doses below 45 mg GSK3008356 were not 
evaluated and exploration of lower divided doses was planned for Part 2.
Based on Part 1 data, the short observed GSK3008356 half-life and future NOAEL 
identified from a 13 week repeat dose dog toxicology study, Part 2 initially evaluated 
placebo or 20 mg GSK3008356 as 10 mg at time 0h and 16h.  
Blinded data indicate that 20 mg GSK3008356 divided dosing was not tolerated with 6 of 
8 subjects withdrawn early due to GI issues.  Dosing was stopped for all subjects before 
Day 7 of a planned 14 days: 6 due to the GI issues and 2 as the remaining subjects in the 
cohort were discontinued following discussions between GSK and the Principle 
Investigator.  No PD (postprandial TG suppression) was observed on Day 1; Day 14 
could not be evaluated.
Subsequently, placebo or 2 mg GSK3008356 as 1 mg at time 0h and 16h and placebo or 
6 mg GSK3008356 as 3 mg at time 0h and 16h were evaluated in Cohorts 2 and 3.  All 
subjects except for 1 in the placebo or 6mg cohort completed the 14 days of dosing, 
indicating that the doses were tolerated.  However, no postprandial TG suppression was 
observed in either the 2mg or 6mg GSK3008356 divided dosing cohorts.
Based on these data, Part 2 did not identify a tolerated dose with PD activity and Part 3
was not initiated.
For the purposes of the 204856 RAP, all sections and references pertaining to Part 3 will 
be redacted.  For any information pertaining to Part 3 design, objectives and endpoints, 
please refer to the relevant sections in the protocol. Analysis for Part 3 is therefore not 
included in the RAP.
2.3.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary
Part 1 Single Dose
To characterize the safety, and 
tolerability of single doses of 
GSK3008356 in healthy subjects.
Part 1 Single Dose
Safety parameters including physical examination 
findings, vital signs, 12-lead ECGs, continuous lead II 
cardiac monitoring, clinical laboratory tests and clinical 
monitoring/observation for adverse events.
Part 2 14d Repeat Dose
To characterize the safety, and 
tolerability of 14 daily repeat doses of 
GSK3008356 in healthy subjects.
Part 2 14d Repeat Dose
Safety parameters including physical examination 
findings, vital signs, 12-lead ECGs, continuous lead II 
cardiac monitoring, clinical laboratory tests and clinical 
monitoring/observation for adverse events.


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Objectives
Endpoints
Secondary 
Part 1 Single Dose
To determine the pharmacokinetics 
of GSK3008356 after a single dose in 
healthy subjects;
To assess dose proportionality of 
GSK3008356 after a single dose in 
healthy subjects;
To evaluate the preliminary 
pharmacodynamics after a single 
dose of GSK3008356 in healthy 
subjects.
Part 1 Single Dose
PK endpoints include the AUC(0-t), AUC(0-24), Cmax, 
tmax, AUC(0-∞), t1/2, Ae, and CLr of GSK3008356 as 
data permit;
AUC(0-t), AUC(0-∞), and Cmax for the assessment of 
dose proportionality as data permit;
Fat challenge meal postprandial triglyceride levels.
Part 2 14d Repeat Dose
To determine the pharmacokinetics 
of GSK3008356 after 14 daily doses 
in healthy subjects;
To assess dose proportionality of 
GSK3008356 after 14 daily doses in 
healthy subjects;
To examine the extent of 
accumulation and achievement of 
steady-state following 14 daily doses 
of GSK3008356 in healthy subjects;
To evaluate the preliminary 
pharmacodynamics after 14 daily 
repeat doses of GSK3008356 in 
healthy subjects.
Part 2 14d Repeat Dose
PK endpoints include the AUC(0-∞) on Day 1, AUC(0-
τ), Cmax, and tmax on Day 1 and 14, and t1/2, Ae, and 
CLr on Day 14 of GSK3008356 as data permit;
AUC(0-∞) in Day 1, AUC(0-τ) and Cmax on Day 1 and 
14 for the assessment of dose proportionality as data 
permit;
Observed accumulation ratio based on AUC(0-τ), (Ro), 
and Cmax (RCmax) on Day 14 versus Day 1 as data 
permit. The steady-state accumulation ratio (Rs) by 
AUC(0-tau) on Day 14 vs. AUC(0-∞) on Day 1 as data 
permit.
Trough plasma concentrations (Ctrough) to assess 
steady state after repeat dosing, as data permit;
Fat challenge meal postprandial triglyceride levels.
Exploratory 
Part 2 14d Repeat Dose
To evaluate the change in serum lipid 
levels and weight after 14 daily 
repeat doses of GSK3008356 in 
healthy subjects 
To evaluate the impact of evening 
dosing on tolerability.
To evaluate partitioning of 
GSK3008356 into skin.
Part 2 14d Repeat Dose
Serum Lipid panel, weight;
Clinical monitoring/observation for adverse events with 
a focus on gastrointestinal findings and a stool scale.
Skin biopsy for drug concentration and activity.


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2.4.
Study Design
Figure 1
Schematic of Study Design adapted from Protocol Amendment 2
Design Features

This is a randomized, double-blind (sponsor unblind), placebo 
controlled trial in three Parts, but Part 3 was cancelled. For 
the schematic of the study design for Part 3, please refer to 
the relevant sections in the protocol (see the schematic in 
Figure 1 for further details on Part 1 and Part 2).

Part 1, is a single-dose (SD), dose-rising study in healthy 
subjects.

Part 2, is a 14-day, repeat-dose (RD), dosing-rising study in 
healthy subjects.
Dosing

Part 1, subjects were screened within 28 days before dosing, 
and morning dosing began on day 1. Subjects were only 
dosed on Day 1 in the morning. Doses were adjusted based
on protocol amendment 02. The figure above includes the
planned and actual doses which were used.

Part 2, subjects were screened within 28 days before doing, 
dosed over 14 days in the morning and twice a day. Doses 
were adjusted during the study, to 10 mg BID in Cohort 1, 1 
mg BID in Cohort 2, and 3mg BID in Cohort 3. The figure 
above includes the planned and actual dosing which were 
used.
Treatment Assignment

Part 1, 8 subjects receive GSK3008356 (or matching 
placebo), at a treatment allocation ratio of 6:2 in each of 10 
cohorts. The actual dosing received are 5mg, 10mg, 30mg, 


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75mg, 200mg, 125mg, 200mg divided into 0 hour and 4 hour, 
200mg divided into 0 hour and 16 hour, 90mg divided hourly 
by 9, and 45mg divided hourly by 9, respectively.

Part 2, 8 subjects receive GSK3008356 (or matching 
placebo), at a treatment allocation ratio of 6:2, with repeat 
doses in each of 3 cohorts. The actual doing received are 
10mg BID in cohort 1, 1mg BID in cohort 2, and 3mg BID in 
Cohort 3.
Note: All actual doses start from the morning regardless of the treatment group 
description.
2.5.
Statistical Hypotheses
The primary objectives of this study are to evaluate the safety, tolerability and 
pharmacokinetics of single and repeat doses of GSK300835. No formal hypotheses will 
be tested.  
3.
PLANNED ANALYSES
3.1.
Interim Analyses
No interim analysis was planned for this study.  However, preliminary safety, tolerability, 
and available pharmacokinetic and pharmacodynamic data was reviewed internally at 
GSK prior to dose escalation.
3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All subjects have completed the study as defined in the protocol.
2.
All required database cleaning activities have been completed and final database 
release and database freeze 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.


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4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Screened

Comprised of all subjects who were screened 
including subjects with screen failure.

Study Disposition
Enrolled

Comprised of all subjects who consented and 
were screened with eligibility verified.

Study Population
Safety:

Comprised of all subjects who receive at least 
one dose of study medication.

This population will be based on the 
treatment/dose the subject actually received.

Study Population

Safety

Bristol Stool Form 
Scale

Exploratory PD 
Markers
PKC:
PK Concentration

Comprised of subjects for whom a 
pharmacokinetic sample was obtained and 
analysed.

This population will be based on the 
treatment/dose the subject actually received.

Analysis of PK 
Concentrations
PKP:
PK Parameter

Comprised of all subjects in the PKC 
population who receive at least one active 
dose of GSK3008356 and provide 
pharmacokinetic parameters.

This population will be based on the 
treatment/dose the subject actually received.

Analysis of PK 
Parameters

PK/PD
PD

Comprised of subjects in the Safety population 
for whom at least one postprandial Triglyceride 
sample was obtained and analysed at baseline 
and post baseline.

Postprandial TG
NOTES: 

Please refer to Appendix 12: List of Data Displays which details the population to be used for each display 
generated.
4.1.
Protocol Deviations
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed.
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan.
o
Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations are captured and categorised on the protocol deviations 
dataset.  This includes deviations which may lead to exclusion of data from the
analysis, specifically those which invalidate laboratory measurements/assays.


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o
This dataset will be the basis for the summaries and listings of protocol 
deviations.
A separate listing of all inclusion/exclusion criteria deviations will also be provided. This 
summary will be based on data as recorded on the inclusion/exclusion page of the eCRF.


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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS
Table 1 below lists the appendices which describe various rules, conventions, and 
considerations for data analyses and data handling. 
Table 1
Overview of Appendices
Section
Component
11.1
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population
11.2
Appendix 2: Time & Events
11.3
Appendix 3: Assessment Windows
11.4
Appendix 4: Treatment States & Phases
11.5
Appendix 5 Data Display Standards & Handling Conventions
11.6
Appendix 6: Derived and Transformed Data
11.7
Appendix 7: Premature Withdrawals & Handling of Missing Data
11.8
Appendix 8: Values of Potential Clinical Importance
11.9
Appendix 9: Pharmacokinetic / Pharmacodynamic Analyses
11.10
Appendix 10: Model Checking and Diagnostics for Statistical Analysis
11.11
Appendix 11: Abbreviations
11.12
Appendix 12: List of Data Displays
11.13
Appendix 13: Example Mock Shells for Data Displays


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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Analyses
The study population analyses will be based on the “Safety” population, unless otherwise 
specified.
In general, summary tables will be presented in sets, with separate tables for Part 1 and 
Part 2 of the study. Listings will include all subjects, showing part /dosing regimen. For 
placebo group, pooling of placebo subjects within each part is considered a general report 
rule, unless otherwise specified. Exceptions to pooling may occur when meals might 
impact assessment, like PD (see Section 8.2). Table 2 provides an overview of the 
planned study population analyses, with full details of data displays being presented in 
Appendix 12: List of Data Displays: List of Data Displays.
Table 2
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
Treatment Status and Reasons for Discontinuation of Study 
Treatment [2]
Y
Y
Screening Status and Reasons for Screen Failure
Y
Y
Subjects for Whom the Treatment Blind was Broken
Y
Planned and Actual Treatments
Y
Protocol Deviations
Important Protocol Deviations
Y
Y
Subjects with Inclusion/Exclusion Criteria Deviations
Y
Populations Analysed
Study Populations [1]
Y
Demographic and Baseline Characteristics
Demographic Characteristics
Y
Y
Race and Racial Combinations
Y
Y [3]
Prior and Concomitant Medications
Current Medical Conditions
Y
Past Medical Conditions
Y
Concomitant Medications
Y
Exposure and Treatment Compliance
Exposure to Study Treatment
Y
Y
NOTES:

Y = Yes display generated.
[1] For Part 1, Including the differently pooled placebo: first, pooling of placebo in all cohorts; secondarily, pooling of all 


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placebo except for cohort 8.
[2] Part 2 Only
[3] Listing of Race
6.1.1.
Subject Disposition
Subject disposition will summarize all subjects.  
The number of subjects screened, failed screening, randomized, in each population 
(Safety, PKC, PKP, and PD), completing and withdrawing from the study (along with 
reasons for withdrawal) will be summarized and listed.
The details can be found at Appendix 12: List of Data Displays as well as at the file of 
the mock shell.
6.1.2.
Demographics and Baseline Characteristics
Subject age, gender, race, ethnicity, and baseline weight/height/BMI will be summarized 
and listed.
The details can be found at Appendix 12: List of Data Displays as well as in the file of 
the mock shell.
6.1.3.
Concomitant Medications
Concomitant medications are defined as all non-study medications, excluding those 
known to be discontinued prior to study enrolment. 
The GSKDrug dictionary will be used to code all verbatim medication terms.  
Concomitant medications will be listed and summarized by class.
The details can be found at Appendix 12: List of Data Displays as well as at the file of 
the mock shell.
6.1.4.
Drug Exposure
Exposure will be assessed for Part 1 and Part 2 separately.
For Part 1, the dose received by each subject will be summarized descriptively by cohort 
of the active treatment.
In Part 2, for each subject, the number of doses, total dose, and the duration (in days) of 
dosing with the study drug (GSK3008356) will be calculated.  These will be listed by 
subject and summarized descriptively by the cohort active treatment.


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The details can be found at Appendix 12: List of Data Displays as well as at the file of 
the mock shell.
6.1.5.
Medical History
Medical history will be listed by subject.
The details can be found at Appendix 12: List of Data Displays as well as at the file of 
the mock shell.
6.1.6.
Protocol Deviation
All important protocol deviations will be summarised and listed.
The details can be found at Appendix 2: Time & Events as well as at the file of the mock 
shell.


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7.
PRIMARY STATISTICAL ANALYSES
7.1.
Safety Analyses
The primary analyses will be based on the “Safety” population, unless otherwise 
specified. For placebo group, pooling of placebo subjects within each part is considered a 
general report rule, unless otherwise specified. All summary tables and figures are for 
each part separately and all listings are for both parts combined into one, unless otherwise 
specified.
7.1.1.
Overview of Planned Adverse Events Analyses
The safety analyses will be based on the Safety population unless otherwise specified.
Table 3 provides an overview of the planned analyses, with full details of data displays 
being presented in Appendix 12: List of Data Displays.
Table 3
Overview of Planned Safety Analyses
Endpoint / Parameter/ Display Type
Absolute
Summary
Individual
T
F
L
Adverse Events  (AEs)
All AEs by SOC and PT
Y
Y
AEs by GI SOC and PT
Y
Most Frequent Adverse Events by Overall Frequency
Y
Drug-Related AEs by SOC and PT
Y
Subject Numbers for Individual AEs
Y
Relationship Between AE SOCs, PT and Verbatim Text
Y
Serious and Other Significant Events
All SAEs
Y
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
Pregnancy
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated, SOC = System Organ Class, PT = Preferred 
Term.

Summary = Represents TF related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
7.1.1.1.
Adverse Events
Adverse events will be assessed for Part 1 and Part 2 separately. Adverse events will be 
summarized by the cohort of active treatments and pooling of placebo subjects within 
each part.


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An AE is any untoward medical occurrence in a patient or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.
No distinction will be made between pre-treatment AEs and treatment emergent AEs in 
this study, as AE collection is scheduled to start after first dose of study medication.
AE verbatim text will be coded and classified by system organ class (SOC) (body 
system) and preferred term (PT) using MedDRA (current version 19.0).
AEs will be summarized by number of subjects and percentage of total subjects, by SOC
and PT. Summaries and listings will be provided for all AEs, AEs by severity, drug-
related AEs, serious AEs, and AEs leading to drug withdrawal.
The details can be found at Appendix 12: List of Data Displays as well as at the file of 
the mock shell.
7.1.1.2.
Adverse Event Incidence Rates for All Subjects
The primary presentation of AE data is prepared without regard to causality or 
relationship to study medication. Subjects will be counted only once at each level of 
summarization, by SOC and by PT.
7.1.1.3.
Severity of Adverse Events
The investigator makes assessment of intensity for each AE reported during the study and 
assigns it to one of the following categories:
Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.
Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities.
Severe:  An event that prevents normal everyday activities.
AEs will be summarized by severity. If a subject has multiple occurrences of the same 
SOC or PT, then it will be counted as the maximum severity among them. 
7.1.1.4.
Relationship to Study Treatment
For each AE, the investigator will assess the relationship between study treatment and the 
AE occurrence, using clinical judgment.  The investigator will provide a YES / NO 
answer to the question “Is there a reasonable possibility that the AE may have been 
caused by the study treatment?  Use best judgment at initial entry.  May be amended 
when additional information becomes available.”


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The subset of AEs which are classified as “related” (answer = YES) will be summarized 
in the same way as all AEs (Section 7.1.1).
The details can be found at Appendix 12: List of Data Displays as well as at the file of 
the mock shell.
7.1.1.5.
Serious Adverse Events (SAE), Adverse Events Leading to Drug 
Discontinuation, and Death
The subset of AEs which are serious (SAEs) and/or lead to discontinuation of study drug, 
withdrawal from the study, or death will be summarized in the same way as all AEs 
(Section 7.1.1.2). These AEs will be listed, indicating “serious” and/or the outcome.
The results of pregnancy testing will be listed. The details can be found at Appendix 12-
List of Data Display as well as the file of the mock shell.
7.1.2.
Overview of Planned Clinical Laboratory Analysis
The safety analyses will be based on the Safety population, unless otherwise specified.
Table 4 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 12: List of Data Displays.
Table 4
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
Hematology
Hematology Changes from Baseline
Y
Urinalysis
Urine Concentration Changes from Baseline
Y
Urinalysis Dipstick Results
Y
Hepatobiliary (Liver)
Liver Monitoring/Stopping Event Reporting
Y
Y
Matrix Display of Maximum LFT (ALT, AST, ALP, and 
Total Bilirubin) Values
Y
Individual LFT (ALT, AST, ALP, and Total Bilirubin) 
Values versus Study Time by Treatment Group and Test
Y
All Laboratory
All Laboratory Data for Subjects with any Value of 
Potential Clinical Concern/PCI
Y


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Endpoint / Parameter/ Display Type
Absolute
Change from BL
Summary
Individual
Summary
Individual
T
F
L
T
F
L
Laboratory Values of PCI
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated, 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.
7.1.2.1.
Clinical Laboratory
Clinical laboratory results will be assessed for Part 1 and Part 2 separately. Laboratory 
evaluations will be summarized by the cohort of active treatments and pooling of placebo 
subjects within each part.
Clinical laboratory evaluations are divided into:
Haematology:  Platelet Count, RBC Count, WBC Count (absolute), Reticulocyte 
Count, Hemoglobin, Hematocrit, MCV, MCH, MCHC, Neutrophils, 
Lymphocytes, Monocytes, Eosinophils, Basophils;
Clinical Chemistry: BUN, Creatinine, Glucose, Sodium, Bile Acids, Potassium, 
Chloride, bicarbonate, Calcium, AST (SGOT), ALT (SGPT), GGT, Alkaline 
phosphatase, Total and direct bilirubin, Uric Acid, Albumin, Total Protein;
Urinalysis:  Specific gravity, pH, glucose, protein, blood, ketones, Microscopic 
examination;
Liver Function Tests (LFTs): total bilirubin, ALT.
Tables with descriptive statistics of change from baseline will be produced for all 
numerical tests for subjects with non-missing assessments. For categorical tests the 
number and percent of subjects for each category will be produced. Prior to analysis, all 
applicable numeric assessments will be converted to standard units.
Listing of all laboratory data for subjects with any value of PCI will be produced.
Listings of laboratory data with any value of PCI will be produced, too.
A listing will be created for subjects with any post baseline Liver Function Test (LFTs)
with other Laboratory parameters, i.e. one of ALT and total bilirubin, classified as PCI..
Special figures, “matrix displays”, will be produced showing pairwise plots of the LFT 
values.  To create these plots, the maximum value (over time) for each subject for each 
LFT will be calculated.  Then for each pair of tests (e.g., total bilirubin vs ALT), each 


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subject will be plotted on the chart according to the maximum value of each.  The subject 
markers (color and symbol) will be coded according to part /treatment.
7.1.3.
Overview of Planned Other Safety Analyses
The safety analyses will be based on the Safety population, unless otherwise specified.
Table 5 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 12: List of Data Displays.
Table 5
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
Change from Baseline in ECG Values by Visit
Y
All ECG Data for Subjects with any Value of PCI
Y
ECG Values of PCI
Y
Abnormal ECG Findings
Y
Vital Signs
Change from Baseline in Vital Signs by Visit
Y
Vital Signs Results by PCI Criteria
Y
All Vital Signs for Subjects with any Value of PCI
Y
Vital Signs of PCI
Y
Other Exams
Physical Exam
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated, 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.
7.1.3.1.
Vital Signs
Vital signs will be assessed for Part 1 and Part 2 separately. The assessment results will 
be summarized by the cohort of active treatments and pooling of placebo subjects within 
each part.
Tables with descriptive statistics of changes from baseline in vital signs (systolic blood 
pressure, diastolic blood pressure, pulse rate, heart rate, etc.) will be produced. Number 
and percent of subjects with any post baseline vital sign results of PCI will be produced.


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A listing of vital signs data will be produced, including flagging for PCI.
7.1.3.2.
ECG
Electrocardiograms (ECGs) will be assessed for Part 1 and Part 2 separately. The 
assessment results will be summarized by the cohort of active treatments and pooling of 
placebo subjects within each part.
Tables with descriptive statistics of changes from baseline will be produced for all 
numerical ECG tests of heart rate, PR interval, QRS interval, QT interval, QT with 
correction (Fridericia’s formula), and number and percent of subjects will be produced 
for all categorical tests (ECG finding). Number and percent of subjects with any post 
baseline ECG results of PCI will be produced.
A listing of ECG data will be produced, including flagging for PCI.
7.1.3.3.
Other Exams
Physical exam data will be listed, showing exam dates and any abnormalities found.


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8.
SECONDARY STATISTICAL ANALYSES
8.1.
Pharmacokinetic Analyses
8.1.1.
Overview of Planned Pharmacokinetic Analyses
The pharmacokinetic (PK) analyses described below will be based on the PKC and PKP 
populations, unless otherwise specified. All summary tables and figures are for each part
separately and all listings are for both parts combined into one, unless otherwise 
specified.
Table 6 below provides an overview of the planned analyses, with full details being 
presented in Appendix 12: Listing of Data Display.
Table 6
Overview of Planned Pharmacokinetic Analyses
Endpoint / Parameter/ 
Display Type
Untransformed
Log-Transformed
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Concentration of GSK3008356
PK Plasma Drug 
Concentration-time 
(Part 1 and Part 2 on 
Days 1 and 14)
Y
Y
Y
Y
Y
Y
PK Trough Plasma 
Concentration-time 
(Part 2)
Y
Y
PK Parameters
Part 1: AUC0-t     
AUC0-24, AUC0-∞,
Cmax
Y
Y*
Y
Part 2: AUC0-∞,on 
Day 1, 
AUC(0-tau), Cmax on 
Days 1 and 2.
Accumulation Ratio
(Ro, Rs and Rcmax), 
Y
Y*
Y
Parts 1 & 2: tmax, t1/2,
Ae, CLr
Y
Y*
Part 1: Dose 
Proportionality 
(AUC0-t, AUC0-∞,
Cmax) 
AUC0-t, AUC0-∞, Cmax: 
Only applied for the 
single dosing.
AUC0-∞: Applied for 
Y
Y**


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Endpoint / Parameter/ 
Display Type
Untransformed
Log-Transformed
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
for all other cohorts 
with multiple dosing.
Part 2: Dose 
Proportionality 
(AUC(0-∞) on Day 1, 
AUC(0-tau), Cmaxon 
Day 1 and Day 14
Y
Y**
Part 2: Accumulation 
Ratio (Ro, Rcmax)
Y
Y**
Part 2: Steady State 
(Ctrough)
Y
Y**
NOTES :

T = Table, F = Figure, L = Listings, Y = Display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

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.    

* Listing of All derived PK parameters will be produced in one listing by part.

** SAS Output of the Statistical Analyses from the statistical model.
8.1.2.
Drug Concentration Measures
Concentrations of plasma GSK3008356 will be listed by Part, Treatment Subject, Day 
and time, and summarised by Part, Treatment, Day and nominal time for the active 
treatment groups. Standard summary statistics will be calculated (i.e. n, mean, standard 
deviation, median, minimum and maximum).
Trough plasma concentration (Ctrough) collected at pre-dose on Days 2, 4, 5, 6, 12, 13, 
14 together with the 24h post-dose on Day 14 from Part 2 will be listed, and summarized 
by Active Treatment and Day.
Individual plasma concentration-time profiles and median/mean profiles by treatment 
group (i.e., by Part, and then Treatment) will be plotted for Part 1 and Part 2 at Day 1 and 
Day 1 and Day 14 respectively. Each of the figures will contain one plot on the 
untransformed scale (i.e. a linear plot) and one plot on the log transformed scale (i.e. semi 
log plot). 
8.1.3.
Pharmacokinetic Parameters
8.1.3.1.
Deriving Pharmacokinetic Parameters
Deriving Pharmacokinetic Parameters:

Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 
11.5.3 Reporting Process & Standards).


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
The pharmacokinetic parameters will be calculated by standard non-compartmental 
analysis according to current working practices and using Phoenix WinNonlin 
Version 6.2.1 or higher.

All calculations of non-compartmental parameters will be based on actual sampling 
times.

Pharmacokinetic parameters described in Table 7 will be determined from the plasma 
concentration-time data, as data permits.
Table 7
Derived Pharmacokinetic Parameters
Parameter
Parameter Description
AUC(0-t)
(Part 1)
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-τ)
(Part 2)
Area under the concentration-time curve from time zero to the time of the end of dosing 
interval (C(T)) will be calculated using the linear trapezoidal rule for each incremental 
trapezoid and the log trapezoidal rule for each decremental trapezoid. 
AUC(0-24)
(Part 1)
Area under the concentration-time curve from time zero to the time of the 24 hour 
concentration (C(24h)) will be calculated using the linear trapezoidal rule for each 
incremental trapezoid and the log trapezoidal rule for each decremental trapezoid. 
AUC0-∞
(Part 1 + 
Part 2 day 
1)
Area under the concentration-time curve extrapolated to infinity will be calculated as: 
AUC(0-inf) = AUC(0-t) + C(t) / lambda_z
This parameter will only be calculated for the single-dose profiles in Part 1 and Day 1 in 
Part 2.
Cmax
Maximum observed concentration, determined directly from the concentration-time data.
Ct
Last quantified 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
Ae
Cumulative amount of drug excreted in urine.
Ae = ∑Cur * Vur
Where Cur is the concentration in urine and Vur is the volume of urine
CLr
Renal Clearance
[1]  Single Dose:     CLr = Ae/AUCinf
[2]  Repeat Dose:   CLr = Ae τ /AUC τ
Where Ae τ is cumulative amount of drug excreted in urine over a dosing interval.
Ctrough
(Part 2)
Observed Concentration at the end of a dosing interval, immediately before next 
administration.
Directly obtained from the observed concentration vs. time curves. They are the pre-dose 
concentration on Days 2, 4, 5, 6, 12, 13, 14 and the 24 h post dose on Day 14.
RO
(Part 2)
Accumulation Ratio, calculated in the multi-dose regimens, as the ratio
[AUC0-τ on the final day (Day 14)]/[ AUC0-τ on Day 1]


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Parameter
Parameter Description
Rcmax
(Part 2)
Accumulation Ratio, calculated in the multi-dose regimens, as the ratio [Cmax on the final 
day (Day 14)]/[Cmax on Day 1]
Rs
(Part 2)
Steady-state Accumulation Ratio, calculated in the multi-dose regimens, as the ratio 
[AUC(0-tau) on final day (Day 14)]/[ AUC0-∞on Day 1]
NOTES:

Additional parameters may be included as required.

Lambda_z is the terminal phase rate constant (also known as the constant of elimination or Kel).  This is 
determined for each concentration*time profile by fitting a log-linear curve through the concentration*time 
points in the terminal phase as data permits.  The determination of which points are included in the terminal 
phase is made according to pre-specified rules.

RO, Rcmax and Rs will be calculated as Day 14 / Day 1 for Part 2 (14-day dosing).
All the derived PK parameters described in the Table 7 will be listed, as data permits. The 
PK parameters will be displayed by dose and then by Day (Day 1 in Part 1, Days 1 and 
14 in Part 2), of each active treatment within each part. For each of these parameters 
except tmax, Ae, and CLr, the following summary statistics will be calculated for the 
active treatment group: median, maximum, minimum, arithmetic mean, standard 
deviation, CVb, geometric mean, 95% confidence interval for the geometric mean and 
standard deviation of logarithmically transformed data. For tmax, Ae, and CLr, median, 
maximum, minimum, arithmetic mean and standard deviation will be calculated.
8.1.3.2.
Statistical Analysis of Pharmacokinetic Parameters
Statistical analysis of the pharmacokinetic parameters data will be the responsibility of 
Accenture with oversight by Clinical Statistics GlaxoSmithKline. Once the plasma has 
been analysed for GSK3008356 any remaining plasma may be analysed qualitatively for 
other compound-related metabolites and the results reported under a separate PTS-DMPK 
protocol. The urine samples will also be analysed for compound-related metabolites and 
the results reported under a separate PTS-DMPK protocol.
The following pharmacokinetic statistical analyses will only be performed, if sufficient 
data is available (i.e. if subjects have well defined plasma profiles).
Dose Proportionality in Part 1 and Part 2
Planned Statistical Analyses
Endpoint(s)

Part 1:
o
AUC(0-t), AUC(0-∞), and Cmax applied to all single dosing active treatments
o
AUC(0-∞) applied to multiple dosing active treatments

Part 2: AUC(0-∞) on Day 1, AUC0-tau and Cmax on Day 1 and Day 14
Model Specification

The Power Model can be described below:
y = α * doseβ
or         y = α * surface areaβ


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Planned Statistical Analyses
where y denotes the PK parameter being analysed (endpoints specified above) and α depends on 
the random error in the single dose and repeat dose parts where subjects take the study drug in a 
parallel-group fashion.
Dose proportionality implies that β=1 and will be assessed by estimating β along with its 90% CI. 
The exponent, β, in the power model will be estimated by regressing the loge-transformed PK 
parameter on loge-transformed dose.
An example of the SAS code that will be used for this analysis:
Part 1:    Proc Mixed;
        model logPKparm = logdose / solution ddfm=kr cl alpha=0.1 outp=pred;
               run;
Note: logPKparm is the log of the following PK parameters: AUC(0-t), AUC(0-∞), and Cmax for all 
single dosing active treatments. AUC(0-∞) for multiple dosing active treatments. We will compare 
the highest dose to the lowest dose for these parameters in single dosing active treatments and 
multiple dosing active treatments, respectively.
Part 2:    Proc Mixed;
                   by day;
       model logPKparm = logdose / solution ddfm=kr cl alpha=0.1 outp=pred
               run;
Note: logPKparm is the log of the following PK parameters: AUC(0-∞) on Day 1, AUC(0-tau) and 
Cmax on Day 1 and Day 14. We will compare the highest dose to the lowest dose for these 
parameters.
Model Checking

Refer to Appendix 10: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

Point estimates of comparison the highest dose to the lowest dose for the mean slopes of PK 
parameters with associated 90% CIs will be presented.


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Accumulation Ratio in Part 2
Planned Statistical Analyses
Endpoint(s)

AUC(0-tau) and Cmax on Day 14 and Day 1 in Part 2; 
Model Specification

The Mixed Model for Ro and Rcmax can be described below:
Endpoint = treatment + day + treatment*day + subject (treatment) + random error
Where endpoint is the loge-transformation of AUC(0-tau) and Cmax.
Fixed effects: treatment, day, and treatment*day interaction
Random effect: subject within treatment.
Treatments will be ordered according to Appendix 5.
For accumulation ratio based on parameters in the endpoint(s) above, following loge-
transformation, endpoints will be analyzed using a mixed model, fitting fixed effect terms and 
random effect as specified above. The accumulation ratio of GSK300836 will be estimated by 
calculating the ratios of AUC(0-tau) and Cmax on Day 14 to Day 1 and the corresponding 90% CI 
for each cohort in Part 2.
An example of the SAS code that will be used for this analysis:
Part 2:    Proc Mixed;
               class treatment day subjid;
               model logPKparm = treatment day treatment*day/ s ddfm=kr cl alpha=0.1  
                                                 outp=pred;
               random subjid (treatment) / type = un;
   run;
  Note: PKparm is PK parameters: AUC(0-tau) and Cmax on Day 1 and Day 14 in Part 2.
Model Checking

Refer to Appendix 10: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

Point estimates of accumulation ratio with associated 90% CIs will be presented.


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Steady State Assessment in Part 2
Planned Statistical Analyses
Endpoint(s)

Ctrough in Part 2
Model Specification

The Mixed Model can be described below:
Endpoint = day + subject + random error
Where endpoint is the loge-transformation of Ctrough which were collected at pre-dose on Days 
2, 4-6, 12-14, 15 (or 24 h post-dose on Day 14) in Part 2. 
Fixed effect: day
Random effect: subject  
Trough plasma concentration (Ctrough) following loge-transformation will be analysed using a mixed 
model, fitting fixed effects and random effects as specified above. Day will be treated as a 
continuous variable in the model. The 90% CI of the slope of the linear regression will be 
calculated for each cohort.
An example of the SAS code that will be used for this analysis:
Part 2:    Proc Mixed;
                class subjid;
                by treatment;
                model logCtrough = day / ddfm=kr cl alpha=0.1 outp=pred;
                 random subjid;
               run;
Model Checking

Refer to Appendix 10: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

Point estimates of slope of the collection day for each active treatment with associated 90% 
CIs will be presented.


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8.2.
Biomarker/Pharmacodynamic Markers Analyses
8.2.1.
Overview of Planned Biomarker/Pharmacodynamic Analyses
The pharmacodynamic analyses for Postprandial Triglyceride will be based on the 
“Pharmacodynamic” population, while exploratory pharmacodynamics lab test and the 
Bristol stool Form Scale will be based on “Safety Population”, unless otherwise 
specified. For placebo group, pooling of placebo subjects within each part is considered a 
general report rule, except for Postprandial Triglyceride (TG) in part 1, where placebo is 
pooled without cohort 8.
All summary tables and figures are for each part separately and all listings are for both 
parts combined into one, unless otherwise specified.
Table 8 below provides an overview of the planned pharmacodynamic analyses with full 
details of data displays being presented in Appendix 12: List of Data Displays.
Table 8
Overview of Planned Pharmacodynamic Analyses
Endpoint / Parameter/ Display Type
Absolute
Summary
Individual
T
F
L
F
Postprandial Triglyceride (TG)
Absolute TG Values by Treatment, Day, and Time 
Point
Y
Y
Y
Y
Corrected TG Post Dose Values by Treatment, Day 
and Time Point
Y
Y
Y
Y
TG AUC (1-12), TG AUC(2-5), Corrected TG 
AUC(1-12), and Corrected TG AUC(2-5) by 
Treatment and Day
Y
Y
Percent (%) Change from Baseline TG AUC by 
Treatment and Day
Y
Y
Bristol Stool Form Scale (BSFS)
BSFS
Y
Y
Y
Exploratory PD Labs (Serum Lipid Levels)
Exploratory PD Labs Data in Serum Lipid (Total 
Cholesterol
HDL
LDL 
VLDL-TG (if feasible)
Spot TG) by Treatment and the Nominal Sampling 
Time Point
Y
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

HDL = High / LDL = Low Density Lipoproteins, VLDL-TG = Very Low Density Lipoprotein Triglycerides

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.

Figures will show both baseline (Day -1) and post-treatment TG levels plotted together over time (from meal).


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8.2.1.1.
Postprandial Triglyceride Evaluation
Each subject will undergo, at pre-dose and post-dose, a fat meal challenge, consisting of 
30% fat by calories, to be consumed within 15 min (±10 min).  Triglyceride (TG) 
measurements will be collected from 1 hour prior to the meal through 10 hours after the 
meal (at meal time and 1, 2, 3, 4, 5, 6, 7, 10 hours post-meal).
The following will be taken into consideration when pooling placebo data.  For all dosing 
with only a single dose administered at 0h, two doses at 0h and 4h, and hourly dosing 
starting 0h x 9 doses, only one meal was provided within the TG assessment period (Part 
1, Cohorts 1, 2, 3, 4, 5, 6, 7, 10, and 11).  For all dosing with two doses administered at 0h 
and 16h, a second meal with 20% fat was provided at 6h post-dose (Part 1, Cohort 8, and 
Part 2, Cohorts 1, 2, and 3). The second meal will impact the TG data beyond 6h and 
these cohorts data should be pooled separately from the single-meal placebo data. For 
only the TG analysis the pooled placebo in Part 1 will not include Cohort 8; placebo data 
in cohort 8 will be displayed separately.
For subjects undergoing a dosing regimen, the post-dose meal will start 2 hours post-dose. 
The first TG measurement will be collected 1 hour post-dose which is 1 hour pre-meal, 
and TG collections will run through 12 hours post-dose.
To serve as a baseline comparator, the same TG profile will be collected prior to dosing, 
also in the morning.  This will be the day prior to morning dosing, for subjects undergoing 
a morning dosing regimen. Please see the following figure for further information on the 
exact dosing:


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Figure 2
Postprandial Triglyceride Assessment Schematic
Tables and Figures will be produced for absolute TG values by Part/Treatment/Day and 
the nominal sampling time points. 
Post dose values of TG will be adjusted so that baseline day and post dose day pre-meal 
values are as close as possible. Post dose values (i.e. Part 1: Day 1; Part 2: Days 1 and 14) 
at each nominal sampling time point will be adjusted by adding the following value:

Part 1 Day 1 Correction:
o
(Day -1 (1hr + 2hr)/2) – (Day 1 (1hr + 2hr)/2)

Part 2:
o
Day 1 Correction:
(Day -1 (1hr + 2hr)/2) – (Day 1 (1hr + 2hr)/2)
o
Day 14 Correction:
(Day -1 (1hr + 2hr)/2) – (Day 14 (1hr + 2hr)/2)
Table and Figure will be also produced for the pre-meal corrected TG post dose values by 
Part/Treatment/Day and the nominal sampling time points. 


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8.2.1.2.
Postprandial Triglyceride AUC
Postprandial triglyceride AUC(1-12) and AUC(2-5) (on day -1 and day 1 in part 1; day -1 
day 1, and day 14 in part 2) will be calculated using trapezoidal rule.
Postprandial triglyceride AUC(1-12) and AUC(2-5) (on day 1 in part 1; day 1 and day 14 
in part 2) will be calculated by adding the correction value in Section 8.2.1.1 to each time 
point after post-dose, but these adjustments/transformations will not apply to TG value at 
baseline day -1. Corrected TG AUC values will be also calculated using the linear 
trapezoidal rule.  
Table and Figure will be produced for TG AUC and corrected TG AUC above of 
postprandial triglyceride by part, treatment, and day.
Table and Figure will be also produced for percent (%) change from baseline (e.g. Part 1: 
(Day 1 and Day -1 difference) /TG AUC on Day -1 ; Part 2: (Day 1 and Day -1 
difference) / TG AUC on Day -1 as well as (Day 14 and Day -1 difference) / TG AUC on 
Day -1) in AUC and correct AUC of postprandial triglyceride by part and treatment.
Listing of individual change from baseline in AUC and Corrected AUC of postprandial 
triglyceride will be produced for both parts combined together.
8.2.1.3.
Bristol Stool Form Scale (BSFS)
The Bristol Stool Form Scale (BSFS) which describes 7 types of stool, will be used by 
the subjects and verified by the staff in real time in all parts of the study.  The number of 
each type of stool will be collected across the 24h calendar day.
The BSFS data will be summarized for Part 1 and Part 2 separately.  
Summary of number of subjects and number of BSFS by type, day, and treatment
Summary of total number of BSFS by day and treatment.
A listing will also be produced showing study day and BSFS score for each entry.
A histogram and a line plot will also be produced by part, treatment and BSFS type.
8.2.2.
Exploratory Pharmacodynamic Markers
Descriptive statistics for serum lipid levels will be tabulated for the time points collected, 
by Part/treatment/Dose. A listing will also be produced. The exploratory PD markers are 
Cholesterol, high density lipoproteins (HDL), low density lipoproteins (LDL), very-low 
density lipoprotein triglycerides (VLDL-TG) and spot TG labs will be collected.  Spot 
TG are defined as not collected as part of the fat meal challenge postprandial TG 
assessment.


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8.3.
Pharmacokinetic / Pharmacodynamic Analyses
The PK/PD analyses in this section will be outside of the scope of this RAP. However, a 
road map of how these analyses can be done are described below.
Based on the lack of a repeat dose regimen that was both active for TG suppression and 
tolerated from a GI perspective, it has been decided not to perform a detailed PK/PD 
model analysis. However, for documentation, the approach we had previously planned 
on taking is in Appendix 9.
8.3.1.
Population Pharmacokinetic / Pharmacodynamic Analyses
A separate RAP will be created for the Population PK/PD analysis for publication 
purpose as data permit that will completed by CPMS, GSK. 
The reporting will be separate from this CSR.


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9.
OTHER STATISTICAL ANALYSES
9.1.
Exploratory Analysis
9.1.1.
Skin Biopsy in Part 2
Details of the skin biopsy sample collection, including collection procedures, sample 
preparation, sample storage, and shipping procedures are provided in the Study Reference 
Manual.
Drug concentration analysis of the skin sample will be performed under the management 
of PTS-DMPK. Concentrations of GSK3008356 may be determined through standard 
Liquid Chromatography Tandem Mass Spectrometry (LC MS/MS) in homogenate and/or 
using Matrix Assisted Laser Desorption/Ionization (MALDI) analysis through approved 
analytical methodology. Analysis of pharmacology (if feasible) may also be performed 
potentially including lipodomics/metabolomics for lipid levels, including TG, in the skin. 
Additional target engagement studies may also be performed (if feasible) including 
thermal shift assay and/or human skin lipogenesis (SLiP) assay. Raw data will be 
archived at the bioanalytical site. All skin biopsy analysis results will be reported under a 
separate PTS-DMPK protocol.


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10.
REFERENCES
GlaxoSmithKline Document Number 2015N242776_02 Study ID Protocol Amendment 
02. A Phase I, Randomized, Placebo-Controlled, Double-Blind(sponsor unblind), Three 
Part Study to Evaluate the Safety, Tolerability, Preliminary PK and PD of Single and 
Repeat Oral Doses of GSK3008356 in healthy Subjects and Obese Subjects’. Report Date 
January 22, 2017. 
Lewis SJ and Heaton KW. “Stool form as a useful guide to intestinal transit time.” 
Scandinavian Journal of Gastroenterology, 1997, 32(9): 920-924.


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11.
APPENDICES
Section
Appendix
11.1
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population
11.2
Appendix 2: Time & Events
11.3
Appendix 3: Assessment Windows
11.4
Appendix 4: Treatment States & Phases
11.5
Appendix 5 Data Display Standards & Handling Conventions
11.6
Appendix 6: Derived and Transformed Data
11.7
Appendix 7: Premature Withdrawals & Handling of Missing Data
11.8
Appendix 8: Values of Potential Clinical Importance
11.9
Appendix 9: Pharmacokinetic / Pharmacodynamic Analyses
11.10
Appendix 10: Model Checking and Diagnostics for Statistical Analysis
11.11
Appendix 11: Abbreviations
11.12
Appendix 12: List of Data Displays
11.13
Appendix 13: Example Mock Shells for Data Displays


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11.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
11.1.1.
Protocol Deviation Definition
Please refer to the exclusion criteria in Section 4.2 of Protocol Amendment02.
11.1.2.
Per Protocol Population
Per Protocol Population will not be applied for this study.


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11.2.
Appendix 2: Time & Events
11.2.1.
Protocol Defined Time & Events
11.2.1.1.
Part 1 – Single Dose
Screening
(within 
28d)
Day -2, 
Day -1 9
Day 1
Day 2 Day 3 Day 4
Follow Up
(Day 6-8)
Pre-
dose
0h
0.25h
0.5h
1h
1.5h
2h
4h
6h
8h
12h
18h 24h
36h
48h
72h
Informed Consent
X
Medical/medication/drug/alcohol 
history
X
X
X
Complete Physical Exam, Weight
X
X1
X1
X
HIV, Hep B, Hep C
X
Pregnancy Test2
X
X
X
Estradiol/FSH3
X
Urine Drug, Cotinine & Alcohol Screen4
X
X
Fat Meal5
X
X
Triglyceride Assessment5

X
============
Study Drug Dose10
X10
Vital Signs (BP, HR, pulse, Temp)6
X
X
X
X
X
X
X
X
X
X
12-Lead ECG
X
X
X
X
X
X
X
Telemetry
============================
Hematology, Chemistry
X
X
X
X
X
X
X
UA
X
X
X
X
X
Exploratory PD Labs
X
X
X
X
X
Plasma PK and Metabolite 
Sampling5, 7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine PK and Metabolite Sampling7

==================================

Adverse Event Review
===========================================================================


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Screening
(within 
28d)
Day -2, 
Day -1 9
Day 1
Day 2 Day 3 Day 4
Follow Up
(Day 6-8)
Pre-
dose
0h
0.25h
0.5h
1h
1.5h
2h
4h
6h
8h
12h
18h 24h
36h
48h
72h
BSFS8
=====================================================================
Concomitant Medication Review
===========================================================================
Outpatient Visits
X
X
Inpatient Check-in
X
Inpatient Check-out
X
1.
Brief physical exam, weight.
2.
Serum hCG at screening and follow up, urine hCG pre-dose on Day -1 – all females.
3.
If indicated.
4.
An alcohol breath test is acceptable.
5.
Detailed Fat Meal and Triglyceride Assessment relative to Dose and Plasma PK Sampling can be found in Section 6.1.1.1 in Protocol Amendment 2.
6.
Temperature Screening and Day -1 only.
7.
Plasma analysis for circulating metabolite profile; Urine analysis to aid structural identification.  Urine samples for parent and metabolite structure will be collected pre-dose and 
over the post-dose intervals 0-12 hours and 12-24 hours. Plasma and urine samples for metabolites will be analyzed from only the highest dose cohort.
8.
The number of BSFS stool types will be collected in real time for each 24h period (Section.11.5 in Protocol Amendment 2).
9.
Based on logistics, check-in and all Day -1 assessments may occur on Day -2 with the exception of the Fat Meal and TG Assessment, both of which must be done on Day -1.
10. For cohorts where multiple doses are to be administered either q1h, q4h or q16h, Time 0 is the first dose and subsequent doses are per regimen (q1h, q4h or q16) and the 
subsequent doses are not noted on the T&E Table. For the single evening cohort, the dose will be at hour 16 and not noted on the T&E Table.
11.2.1.2.
Part 1 – Single Dose, Fat Meal Challenge and Triglyceride Assessment Relative to Dose and PK Sampling
Day -1, Day 1
Pre-
dose
0h
0.25h
0.5h
1h
1.5h
2h
3h
4h
5h
6h
7h
8h
9h
12h
18h
Study Drug Dose1, 3
X3
Fat Meal
X
Triglyceride Assessment
X
X
X
X
X
X
X
X
X
X
Plasma Pharmacokinetic Sampling1, 2
X
X
X
X
X
X
X
X
X
X
X
1.
Day 1 only 
2.
PK Samples included in table to provide relative time to dosing, fat meal and triglyceride assessment.  
The full PK time points are found in Section.6.1.1 in Protocol Amendment 2
3.
For cohorts where multiple doses are to be administered either q1h, q4h or q16h, Time 0 is the first dose and subsequent doses are per regimen 


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(q1h, q4h or q16) and the subsequent doses are not noted on the T&E Table. For the single evening cohort, the dose will be at hour 16 and not 
noted on the T&E Table
11.2.1.3.
Part 2 – Repeat Dose, Morning Dose Administration, Screening, Day -1, Day 1
Screening
(within 28d)
Day -2, 
Day -1 9
Day 1
Pre-
dose
0h
0.25h
0.5h
1h
1.5h
2h
4h
6h
8h
12h
18h
24h
Informed Consent
X
Medical/medication/drug/alcohol history
X
X
Complete Physical Exam, Weight
X
X1
HIV, Hep B, Hep C
X
Pregnancy Test2
X
X
Estradiol/FSH3
X
Urine Drug, Cotinine & Alcohol Screen4
X
X
Fat Meal5
X
X
Triglyceride Assessment5

X
============
Study Drug Dose10
X10
Vital Signs (BP, HR, pulse, Temp)6
X
X
X
X
X
X
X
12-Lead ECG
X
X
X
X
X
X
Telemetry
=============================
Hematology, Chemistry
X
X
X
X
UA
X
X
X
Exploratory PD Labs
X
X
X
Plasma PK and Metabolite Sampling5, 7
X
X
X
X
X
X
X
X
X
X
X
X
Skin biopsy 11
X11
X11
X11
Adverse Event Review
====================================================
BSFS8
==============================================
Concomitant Medication Review
====================================================
Outpatient Visits
X


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Screening
(within 28d)
Day -2, 
Day -1 9
Day 1
Pre-
dose
0h
0.25h
0.5h
1h
1.5h
2h
4h
6h
8h
12h
18h
24h
Inpatient Check-in
X
11.2.1.4.
Part 2 – Repeat Dose, Morning Dose Administration, Days 2-13
Days 2-13
Pre-dose
0h
Study Drug Dose6
X6
Vital Signs (BP, HR, pulse)
X
12-Lead ECG1
X
Hematology, Chemistry2
X
UA3
X
Exploratory PD Labs3
X
Plasma PK and Metabolite Sampling4
X
Skin biopsy7
X
Adverse Event Review
==================
BSFS5
==================
Concomitant Medication Review
==================
1.
Day 2 (equal to Day 1 24h time point), 7, 12, and 13 only.
2.
Day 2 (equal to Day 1 24h time point ), 4, and Day 7 only
3.
Day 2 (equal to Day 1 24h time point) and Day 7 only
4.
Day 2 (equal to Day 1 24h time point), 4, 5, 6, 12, and 13 only 
5.
The number of BSFS stool types will be collected in real time for each 24h 
period (Section11.5. in Protocol Amendment 2).
6.
For cohorts where multiple doses are to be administered either q1h or 
q16h, Time 0 is the first dose and subsequent doses are per regimen (q1h 
or q16) and the subsequent doses are not noted on the T&E Table.
7.
Day 2 (equal to Day 1 24h time point) only


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11.2.1.5.
Part 2 – Repeat Dose, Morning Dose Administration, Days 14-17, Follow-up
Day 14
Day 15 Day 16 Day 17
Follow Up
(Day 20-22)
Pre-
dose
0h
0.25h
0.5h
1h
1.5h
2h
4h
6h
8h
12h
18h 24h
36h
48h
72h
Medical/medication/drug/alcohol history
X
Complete Physical Exam, Weight
X1
X
Pregnancy Test2
X
Fat Meal3
X
Triglyceride Assessment3
X
============
Study Drug Dose6
X6
Vital Signs (BP, HR, pulse)
X
X
X
X
X
X
X
X
12-Lead ECG
X
X
X
X
X
X
Hematology, Chemistry
X
X
X
X
X
X
UA
X
X
X
X
Exploratory PD Labs
X
X
X
X
Plasma PK and Metabolite Sampling3, 4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Skin Biopsy7
X7
X7
X7
Adverse Event Review
======================================================================
BSFS5
======================================================================
Concomitant Medication Review
======================================================================
Outpatient Visits
X
Inpatient Check-out
X
1.
Brief physical exam and weight Day 17 only 
2.
Serum hCG at follow up, all females.
3.
Detailed Fat Meal, Triglyceride Assessment, Plasma PK Sampling and Plasma Metabolite Sampling can be found in Section 6.1.8.1 in Protocol Amendment 2
4.
Plasma analysis for circulating metabolite profile; Plasma samples for metabolites will be analyzed from only the highest dose cohort.
5.
The number of BSFS stool types will be collected in real time for each 24h period (Section 11.5. in Protocol Amendment 2).
6.
For cohorts where multiple doses are to be administered either q1h or q16h, Time 0 is the first dose and subsequent doses are per regimen (q1h or q16) and the 
subsequent doses are not noted on the T&E Table.
7.
Cohort 1 (10mg q16) collect only at 1h and 24h Day 14; Cohorts 2 & 3 (3mg, 1mg or 5mg q1h) collect only at 6h and 24h Day 14


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11.2.1.6.
Part 2 – Repeat Dose, Fat Meal Challenge and Triglyceride Assessment Relative to Dose and PK 
Sampling--Morning Dose Administration, Day -1, Day 1, and Day 14
Day -1, Day 1, Day 14
Pre-
dose
0h
0.25h
0.5h
1h
1.5h
2h
3h
4h
5h
6h
7h
8h
9h
12h
18h
Study Drug Dose1
X
Fat Meal
X
Triglyceride Assessment
X
X
X
X
X
X
X
X
X
X
Plasma Pharmacokinetic Sampling1, 2
X
X
X
X
X
X
X
X
X
X
X
1.
Day 1 and 14 only.  For cohorts where multiple doses are to be administered either q1h or q16h, Time 0 is the first dose and subsequent doses are 
per regimen (q1h or q16) and the subsequent doses are not noted on the T&E Table.
2.
PK Samples included in table to provide relative time to dosing, fat meal and triglyceride assessment.  
The full PK time points are found in Section 11.2.1.3, Section 11.2.1.4, and Section 11.2.1.5. 


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11.3.
Appendix 3: Assessment Windows
11.3.1.
Definitions of PK Assessment Windows
Analysis Set / 
Domain
Target / nominal time
Target Window
Analysis 
Timepoint
Beginning 
Timepoint
Ending 
Timepoint
PK Concentration 
(analyte is 
GSK3008356)
Pre-Dose
within 30 mins of
dosing 
dosing time
0 Hours
0.25 hour
00:13
00:17
Actual draw time
0.5 hour
00:27
00:33
Actual draw time
1 hour 
00:57
01:03
Actual draw time
1.5 hours 
01:27
01:33
Actual draw time
All Subsequent draws 
between 2 hours – 24 
hours* 
Target – 00:10
Target + 00:10
Actual draw time
All Subsequent draws
between 36 hours – 72 
hours*
Target – 00:30
Target + 00:30
Actual draw time
NOTES :

Any actual draws outside of these time windows will be listed as deviations (not necessarily “important”), but will 
still be used in the concentration assay and determination of PK parameters according to the actual draw time.

Any concentrations determined from blood draws inside or outside these windows may still be excluded from PK 
determinations for other reasons, such as sample handling or other protocol deviations.

*  All Subsequent draws after 2 hour will be at hours 4, 6, 8, 12, 18, 24, 36, 48, and 72 in Part 1. 

In Part 2, All Subsequent draws after 2 hour will be at hours 4, 6, 8, 12, and 18 on Day 1; then PK Samples will be 
taken at Pre-Dose on Days 2, 4, 5, 6, 12, and 13 only during period Days 2-13 Morning Dose; and starting on Day 
14, PK Samples will be taken at Pre-dose, hours at 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18, 24, 36, 48, and 72.


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11.3.2.
Definitions of Triglyceride (Postprandial) Assessment Windows
Analysis Set / 
Domain
Target / nominal time
Target Window
Analysis 
Timepoint
Rel to Dosing
Rel to Meal
Beginning 
Timepoint
Ending 
Timepoint
Triglyceride
+01:00
-01:00
Target – 00:15
Target + 00:15
-01:00
+02:00
00:00
Target – 00:15
Target + 00:15
00:00
+03:00
+01:00
Target – 00:15
Target + 00:15
+01:00
+04:00
+02:00
Target – 00:15
Target + 00:15
+02:00
+05:00
+03:00
Target – 00:15
Target + 00:15
+03:00
+06:00
+04:00
Target – 00:15
Target + 00:15
+04:00
All Subsequent assessments
(7, 8, 9, 12 hours post-dose or 
5, 6, 7, 10 hours post-meal)
Target – 00:15
Target + 00:15
Nominal 
Time relative 
to meal
NOTES :

For evening dosing regimens, triglyceride assessments will be at the same times relative to the meal, but the meal 
will be the following morning (not at 2 hours post-dose as with morning dosing).

Any triglyceride assessments outside of these time windows will be listed as deviations (not necessarily 
“important”), but will still be used in the analysis.  However, any evaluation which is closer to an adjacent 
(nominal) time than to its own nominal sampling will not be used.

Any triglyceride assessments inside or outside these windows may still be excluded for other reasons, such as 
sample handling or other protocol deviations.

Part 1: The assessment will be on Day -1 and Day 1; Part 2: The assessment will be on Day -1, Day 1 and Day 
14. On Day -1, Target/nominal time is only relative to fat meal.
11.3.3.
Definitions of Vital Signs and ECG Assessment Windows
Analysis Set / 
Domain
Target / nominal time
Target Window
Analysis 
Timepoint
Beginning 
Timepoint
Ending 
Timepoint
Vital Signs (BP, 
HR, pulse, Temp.)* 
and 12-Lead ECG
Screening
Within 28 day  
Day -1
Screening
Checking in
Day -1
Day -1
Day -1
Pre-Dose
Within 12 hours
before dosing 
dosing time
00:00
1 Hour Post-Dose
Target – 00:15
Target + 00:15
+01:00
4 Hours Post-Dose
Target – 00:15
Target + 00:15
+04:00
12 Hours Post-Dose
Target – 00:15
Target + 00:15
+12:00
NOTES :

There are also 24-hour assessments of these shown in the protocol.  In cases of repeat dose (Part 2), these 
serve as the pre-dose assessment on the next day.  In other cases, they (and 48 and 72 hours) are follow-up 
assessments on subsequent days, in which case, the target window will be 6 hours, but the assessments will 
be used if they occur on that day.

*: Temperature Screening and Day -1 only.


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
ECG: Assessment windows are same as those of Vital Signs excluding time points at Checking in (Day -1), 48 
hours, and follow-up (Days 6-8) for Part 1

Any assessments outside of these time windows will be listed as deviations (not necessarily “important”), but 
will still be used in the analysis.  However, any evaluation which is closer to an adjacent (nominal) time than to 
its own nominal sampling will not be used


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11.4.
Appendix 4: Treatment States and Phases
11.4.1.
Treatment Phases
Assessments and events will be classified according to the time of occurrence relative to 
start and/or stop date of the study treatment in double-blind phase I study.
Treatment 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 
11.4.2.
Treatment States
Assessments and events will be classified according to time of occurrence relative to the 
start and/or stop date of the study treatment.
11.4.2.1.
Treatment States for AE Data
Treatment State
Definition
Pre-Treatment
AE Start Date < Study Treatment Start Date
On-Treatment
If AE onset date is on or after treatment start date & on or before treatment stop date.
Study Treatment Start Date  ≤ AE Start Date ≤ Study Treatment Stop Date 
Post-Treatment
If AE onset date is after the treatment stop date.
AE Start Date > Study Treatment Stop Date 
Onset Time  
Since 1st Dose 
(Days)
If Treatment Start Date ˃  AE Onset Date = AE Onset Date - Treatment Start Date
If Treatment Start Date ≤ AE Onset Date = AE Onset Date - Treatment Start Date +1
Missing otherwise.
Duration (Days) 
AE Resolution Date – AE Onset Date + 1
Drug-related
If relationship is marked ‘YES’ on eCRF.
NOTES: 

If the study treatment stop date is missing then the AE will be considered to be On-Treatment.


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11.5.
Appendix 5: Data Display Standards & Handling 
Conventions
11.5.1.
Study Treatment & Sub-group Display Descriptors
Part 1: All treatments are dosed in the morning; some regimens are single morning dosing 
while other regimens are multiple dosing.
Part 2:   All treatments are dosed in the morning repeated over 14 days. All doses are 
BID.
Consistent with the treatment group code shown in the randomization schedules, parts, 
cohorts, actual doses, and treatment regimens will appear as follows in data displays 
produced:
Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description
Description
Order [1]
Part 1
A1
SD Cohort 1 GSK3008356 Active
5mg
2
A2
SD Cohort 2 GSK3008356 Active
10mg
3
A3
SD Cohort 3 GSK3008356 Active
30mg
4
A4
SD Cohort 4 GSK3008356 Active
75mg
5
A5
SD Cohort 5 GSK3008356 Active
200mg
6
A6
SD Cohort 6 GSK3008356 Active
125mg
7
A7
MD Cohort 7 GSK3008356 Active
100mg t0, t4
8
A8
MD Cohort 8 GSK3008356 Active 
100mg t0, t16
9
A9
SD Cohort 9 GSK3008356 Active
cancelled
n/a
A10
MD Cohort 10 GSK3008356 Active
10mg q1h x 9
10
A11
MD Cohort 11 GSK3008356 Active
5mg q1h x 9
11
P1
Placebo
Placebo
1
Part 2
B1
RD Cohort 1 GSK3008356 Active 
(AM) 14 days dosing
10mg BID 
2
B2
RD Cohort 2 GSK3008356 Active 
(PM) 14 days dosing
1mg BID
3


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Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description
Description
Order [1]
B3
RD Cohort 3 GSK3008356 Active 
(PM) 14 days dosing
3mg BID
4
P2 
RD Placebo 14 days dosing
Placebo
1
NOTES:
1.
General order (left-right or top-down) of treatments being presented in TFLs, as appropriate.  Since displays will be 
separate for the 2 parts of the study, outputs will contain only those doses/regimens used in that part.
11.5.2.
Baseline Definition & Derivations
11.5.2.1.
Baseline Definitions
Parameter
Baseline Used in 
Data Display
Screening 
(within 28 
days)
Day -2,
Day -1 [1]
Day 1 (Pre-Dose)
Part 1 – Single Dose
Vital Signs (BP, HR, 
pulse)
X
X
X
Day 1 (Pre-Dose)
Hematology, 
Chemistry
X
X
Day -2, Day -1
UA
X
X
Day -2, Day -1
12-Lead ECG
X
X
Day 1 (Pre-Dose)
Exploratory PD Labs
(Serum Lipid Levels)
X
X
Day 1 (Pre-Dose)
Part 2 – Repeat Dose
Vital Signs (BP, HR, 
pulse)
X
X
X
Day 1 (Pre-Dose)
Hematology, 
Chemistry
X
X
Day -2, Day -1
UA
X
X
Day -2, Day -1
12-Lead ECG
X
X
Day 1 (Pre-Dose)
Exploratory PD Labs
(Serum Lipid Levels)
X
X
Day 1 (Pre-Dose)
NOTES :

Unless otherwise stated, the mean of replicate assessments at any given time point will be used as the value for 
that time point.

[1]: Based on logistics, Day -1 assessments may occur on Day -2.


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All TG collection is relative to nominal or actual dose time 0h.  For postprandial TG 
assessments, Day -1 is the Baseline TG Excursion since no study drug was administered.  
Day 1 and Day 14 are Post-Dose TG Excursion responses.  Within these TG Excursions, 
times 1h and 2h are pre-meal.  The challenge meal is administered at 2h (after lab 
collection).  Times 3h onward are post-meal (postprandial) TG Excursion.  See the 
Tables in Section 11.2.1.2 and Section 11.2.1.6.
Keep in mind that the 3h (post dose) TG collection is 1h post-meal (postprandial) 
whether on Baseline Day or Post-Dose Day.  However, the labelling of the data point 
should remain relative to dosing (3h) and not changed to be relative to meal.
As noted in Section 8.2, one Part 1 and all three Part 2 cohorts had a second (20% fat) 
meal provided at 6h post-dose.
11.5.2.2.
Derivations and Handling of Missing Baseline Data
Derivation
How Derived
Handling of Missing Data
Change from 
Baseline
= Post-Dose Visit Value – Baseline
Missing if either baseline or 
post is missing
%Change from 
Baseline
= (Post-Dose Visit Value – Baseline)/Baseline
Missing if either baseline or 
post is missing
Log 
Transformation
= [natural] log (PK Parameter)
Missing if PK parameter is 
missing
Back-
Transformation
= EXP(estimate or confidence limit)
Missing if estimate or CL is 
missing
Maximum LFT
= maximum of that LFT (e.g., ALT) value for that 
subject over time
Missing only if all values of that 
LFT are missing for that 
subject
%AUCex
= [AUC(0-inf) – AUC(0-t)] /
AUC(0-inf) x 100
Missing if AUC(0-inf) is missing
Accumulation 
Ratio (Ro)
=[AUC0-τ on the final day (steady state)]/[ AUC0-τ on 
Day 1]
Missing if AUC0-tau is missing 
for either Day 1 or final day
Accumulation 
Ratio (Rs)
=[AUC0-τ on the final day (steady state)]/[ AUC0-inf on 
Day 1]
Missing if either AUC0-tau on 
final day or AUC(0-inf) on Day 
1 is missing. 
Corrected by 
adding the 
adjusting value 
to post dose TG 
values

Part 1 Day 1 Correction:
o
(Day -1 (1hr + 2hr)/2) – (Day 1 (1hr 
+ 2hr)/2)

Part 2:
o
Day 1 Correction:
(Day -1 (1hr + 2hr)/2) –
Missing if any TG value is 
missing for either post dose or 
pre-dose at any time point


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Derivation
How Derived
Handling of Missing Data
(Day 1 (1hr + 2hr)/2)
o
Day 14 Correction:
(Day -1 (1hr + 2hr)/2) –
(Day 14 (1hr + 2hr)/2)
NOTES :

Unless otherwise specified, the baseline definitions specified in Section 11.5.2.1. 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.
11.5.3.
Reporting Process & Standards
Reporting Process
Software

Version 6.2.1 (or higher) of WinNonlin will be used to determine PK parameters.

Version 9.4 of SAS software will be used to create output displays (TLFs).
Analysis Dataset

Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.1 or 
higher & AdaM IG Version 1.1.)

For creation of ADaM datasets (ADCM/ADAE), the same version of dictionary datasets will 
be implemented for conversion from SI to SDTM.
Generation of RTF Files

RTF files will be generated for outputs (TLFs).
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated:
o
4.03 to 4.23: General Principles
o
5.01 to 5.08: Principles Related to Data Listings
o
6.01 to 6.11: Principles Related to Summary Tables
o
7.01 to 7.13: Principles Related to Graphics

For placebo group, pooling of placebo subjects with each part is considered a general report 
rule, unless otherwise specified. All summary tables are for each part and all listings are for 
both parts combined into one, unless otherwise specified.
Formats

All data will be reported according to the actual treatment the subject received unless 
otherwise stated.

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for 


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Reporting Standards
reporting of data based on the raw data collected.

Numeric data will be reported at the precision collected on the eCRF and laboratory reports.
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 of 
concentration and lab data unless otherwise stated.

Actual time relative to dosing will be used to determine PK parameters, unless otherwise 
stated.

The impact of any major deviation from the planned assessment times and/or scheduled 
visit days on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to 
IDSL Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 

Visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) will 
be included in listings but may be omitted from figures, summaries and statistical analyses
if the deviation is great enough, according to Section 11.1.
Unscheduled Visits

Unscheduled visits will not be included in summary tables or figures.

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Reporting of Pharmacokinetic Concentration Data
Descriptive 
Summary Statistics
Refer to IDSL Statistical Principle 6.06.1
Assign zero to NQ (BLQ) 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, based on one-sample analysis:
[1]    CVb (%) = √(exp(SD2) - 1) * 100
(SD = SD of log transformed data)
[2]    CVw (%) = √(exp(MSE) - 1) * 100
       (MSE = mean square error from mixed effect model of loge-
       transformed data).
Parameters Not 
Log Transformed
Parameters tmax, Ae, and CLr will not be transformed.
Summary Tables
All derived PK parameters which were listed in Table 7 in Section 8.1.3
above. 
Listings
Will include, for each subject PK profile, the first point and number of points 


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Reporting Standards
used in the determination of lambda_z.
Figures

Will include Plasma PK Concentration-Time Plots (Linear and Semi-log)
o
Individual (PK16a)
o
Mean (PK17)
o
Median (PK18)

Box plot of PK parameters vs. Treatment


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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.

Subjects having 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
Demographics
Age

GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed 
as follows:
o
Any subject with a missing day will have this imputed as day ‘15’. 
o
Any subject 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
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

Subjects who were randomized but did not report a treatment start date will be categorised as 
having zero days of exposure. 

The cumulative dose will be based on the formula:
Cumulative Dose = Sum of (Number of Days x Total Daily Dose)

If there are any treatment breaks during the study, exposure data will be adjusted accordingly.


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11.6.3.
Safety
ECG Parameters
RR Interval

IF RR interval (msec) is not provided directly, then RR can be derived as:
[1] If QTcF is machine read and QTcF 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: 
Adverse Events

GI AEs/SAEs as specified under SOC as Gastrointestinal (GI)
Laboratory Parameters

If a laboratory value which is expected to have a numeric value for summary purposes, has a 
non-detectable level reported in the database, where the numeric value is missing, but typically 
a character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the 
comment field) is present, the number of significant digits in the observed values will be used to 
determine how much to add or subtract in order to impute the corresponding numeric value. 
o
Example 1: 2 Significant Digits =  ‘< x ‘ becomes x – 0.01
o
Example 2: 1 Significant Digit   =  ‘> x’ becomes x + 0.1
o
Example 3: 0 Significant Digits = ‘< x’ becomes x – 1    


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11.7.
Appendix 7: Premature Withdrawals & Handling of Missing 
Data
11.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion is defined in the protocol (Section 4.6) as completing 
all phases of the study including the follow-up visit.  The end of the study is 
defined as the last subject’s last visit.

A subject may withdraw from study treatment at any time at his/her own request, 
or may be withdrawn at any time at the discretion of the investigator for safety, 
behavioural or administrative reasons. If a subject withdraws from the study, 
he/she may request destruction of any samples taken, and the investigator must 
document this in the site study records. If applicable, the reason for withdrawal 
of consent. A withdrawn subject may be replaced with another subject who will 
be assigned to the same treatment randomization. If a subject withdraws from 
the study, he/she may request destruction of any samples taken, and the 
investigator must document this in the site study records. Additional 
subjects/cohorts may be enrolled to allow for evaluation of additional dose 
levels. All available data from subjects 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 by the use of a “blank” in subject listing 
displays. Unless all data for a specific visit are missing in which case the 
data is excluded from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to 
be missing data and should be displayed as such.
Outliers

Any subjects 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 Dates
Element
Reporting Detail
General
Partial dates will be displayed as captured in subject 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 


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Element
Reporting Detail
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 
missing.

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.


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11.7.2.3.
Handling of Missing Data for Statistical Analysis
Element
Reporting Detail
Imputation

No imputation will be carried out for any parameters


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11.8.
Appendix 8: Values of Potential Clinical Importance
11.8.1.
Laboratory Values
Haematology
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Hematocrit 
Ratio of 1
Male
0.54
Female
0.54
∆from BL
↓0.075
Hemoglobin 
g/L
Male
180
Female
180
∆from BL
↓25
Platelet Count 
x109/ L
100
550
While Blood Cell (WBC)
    Absolute Count
x109/ L
3
20
    Neutrophil Count
x109/ L
1.5
    Lymphocytes
x109/ L
0.8
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 (Fasting)
mmol/L
3
9
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


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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: [Remove footnotes for RAP development]
[2]
Represent standard ECG values of PCI for HV studies
[3]
Represent further subdivisions of ECG values for analysis whereby the RAP team needs to decide whether 
these need to be generated in addition to standard ECG values being flagged. IF not required, then delete.
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
NOTES: [Remove footnotes for RAP development]
Represent further subdivisions of BP & HR for analysis whereby the RAP team needs to decide whether these need to 
be generated in addition to standard absolute BP & HR values being flagged. IF not required, then delete.


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11.9.
Appendix 9: Pharmacokinetic / Pharmacodynamic Analyses
11.9.1.
Overview of Planned Pharmacokientic (PK) / Pharamcodynamic 
(PD) Analyses
The PK/PD analyses described in this appendix is purely for documentation purpose only 
and report is outside of scope of this RAP/CSR.
The PK/PD analyses will be based on the PK/PD population, unless otherwise specified.  
The relationship between drug pharmacokinetics and pharmacodynamic endpoints (e.g. 
TG AUC) will be explored.
The PK parameters are perhaps included AUC(0-∞), AUC(0-t), Cmax, and Cmin in Part 
1, AUC(0-∞) on Day 1, AUC(0-tau), Cmax, and Cmin on Days 1 and 14 in Part 2. PD 
parameters are %change from baseline (Day -1) of TG AUC(1-12) and TG AUC(2-5) as 
well as with the adjusted post dose TG values calculated AUC(1-12) and TG AUC(2-5). 
All summary tables and figures are for each part separately and all listings are for both 
parts combined into one, unless otherwise specified.
Exposure-Response Analysis between the PK parameters and PD parameter will be 
conducted separately for Part 1 and Part 2.
PK parameters are PK AUC and PK concentrations including Cmax and other 
concentrations as appropriate. The PD parameters are %change from baseline (Day -1) of 
TG AUC(1-12) and TG AUC(2-5) as well as with the adjusted post dose TG values 
calculated AUC(1-12) and TG AUC(2-5). 
Table 9 below provides an overview of the planned PK/PD analyses with full details of 
data displays being presented in Appendix 12: List of Data Displays.
Table 9
Overview of Planned PK/PD Analyses
PK Parameter / PD Parameter
Untransformed Stats Analysis
T
F
L
PK Parameter  / PD Parameter
Correlation between PD Parameter TG AUC and 
PK Parameters by Treatment and Day (in Part 2)
Y
Y
Emax Model Applied for PD Parameter TG AUC 
and PK Parameters by Treatment and Day (in Part 
2)
Y
Y
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.


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11.9.2.
Statistical Analyses of Postprandial Triglyceride
11.9.2.1.
Correlation Analysis
The correlation between PK parameters and PD parameters will be analysed by spearman 
method.
Summary and Figures of correlation between percent (%) change from baseline of TG 
AUC [AUC(1-12), AUC(2-5), as well as Corrected AUC(1-12) and Corrected AUC(2-5)] 
and PK parameters [AUC(0-inf), Cmax, Cmin on day 1 in part 1, AUC(0-inf) on day 1 in 
part 2, Cmax and Cmin on days 1 and 14 in part 2] by treatment and day will be 
produced.
Figure of the TG Level vs. dose by day may be also produced.
Sample code can be used as follows:
Proc corr data=analy Spearman;
   Var parameter1;
   with parameter2;
run;
11.9.2.2.
Exposure – Response Analysis
A 4 parameter Emax model will be applied between PD parameter and PK parameters.
The PK parameters are probably included AUC, Cmax, and other concentration as 
appropriate.
The PD parameter is percent (%) change from baseline in TG AUC.
The exposure-response analysis will be conducted separately for part 1 and part 2.
Analyses of percent (%) change from baseline in TG AUC data will be carried out using 
MIXED effect model. 
Emax Model description:
Primary Statistical Analyses
Endpoint(s)

Part 1: Percent change from baseline in TG AUC at Day 1

Part 2: Percent change from baseline in TG AUC at Day 1 and Day 14
Model Specification

First: A 4 parameter Emax model will be used as specified below:
Endpoint = E0 − Emax [ PK parameterm / (IC50m + PK parameterm) ] + Subject + random error


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Primary Statistical Analyses
where:

PK parameter are the PK parameters we would investigate: AUCLast, Cmax, Cmin and Clast

E0 is the percent change from baseline in TG AUC when the PK parameter is 0

Emax is the maximum achievable percent change from baseline in TG AUC

IC50 is the PK parameter level which achieves 50% of the Emax

m is the slope/hill constant
Sample SAS code will be provided later.
Depending upon the adequacy of model fitting some parameter may need to be analyzed on log scale (e.g. 
IC50, Emax).
If issues arise with the model fitting using a 4 parameter model then maybe made based on the data.
Model Checking & Diagnostics

Refer to Appendix 1: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

The results of the Emax model will be tabulated by part and day (in part 2). Tables will include the point 
estimates of the parameters, their 95% confidence interval and p-value. The IC50, IC90 (PK parameter 
level which achieves 90% of the Emax) and model fit diagnostics such as the AIC and R2 value will also 
be presented for each PK parameter.

The results of the Emax model will be presented graphically by part and day (in part 2). Predictions will 
be plotted against the raw values of percent change from baseline in TG AUC against the relevant PK 
parameter.


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11.10.
Appendix 10: Model Checking and Diagnostics for 
Statistical Analyses
11.10.1.
Statistical Analysis Assumptions
Dose Proportionality (Part 1 and Part 2)
Endpoint(s)

Part 1:
o
AUC(0-t), AUC(0-∞), and Cmax applied to all single dosing active 
treatments
o
AUC(0-∞) applied to multiple dosing active treatments

Part 2: AUC(0-∞) on Day 1, AUC0-τ and Cmax on Day 1 and Day 14
Analysis

Power Model

Model assumptions will be applied, but appropriate adjustments maybe made based on the 
data.

The Kenward and Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used.

Distributional assumptions underlying the model used for analysis will be examined by 
obtaining a normal probability plot of the residuals and a plot of the residuals versus the fitted 
values (i.e. checking the normality assumption and constant variance assumption of the model 
respectively) to gain confidence that the model assumptions are reasonable. 

If there are any departures from the distributional assumptions, alternative models will be 
explored using appropriate transformed data.
Accumulation Ratio (Part 2)
Endpoint(s)

(Ro, RCmax)
Analysis

Mixed Model

Model assumptions will be applied, but appropriate adjustments maybe made based on the 
data.

When the G matrix does not converge, the alternative variance covariance structure will be 
used.

The Kenward and Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used.

Distributional assumptions underlying the model used for analysis will be examined by 
obtaining a normal probability plot of the residuals and a plot of the residuals versus the fitted 
values (i.e. checking the normality assumption and constant variance assumption of the model 
respectively) to gain confidence that the model assumptions are reasonable. 

If there are any departures from the distributional assumptions, alternative models will be 
explored using appropriate transformed data.


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Steady State Assessment (Part 2)
Endpoint(s)

Ctrough in Part 2
Analysis

Mixed Model

Model assumptions will be applied, but appropriate adjustments maybe made based on the 
data.

When the G matrix does not converge, the alternative variance covariance structure will be 
used.

The Kenward and Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used.]

Distributional assumptions underlying the model used for analysis will be examined by 
obtaining a normal probability plot of the residuals and a plot of the residuals versus the fitted 
values (i.e. checking the normality assumption and constant variance assumption of the model 
respectively) to gain confidence that the model assumptions are reasonable. 

If there are any departures from the distributional assumptions, alternative models will be 
explored using appropriate transformed data.
Emax model for PK/PD (Part 1 and Part 2)
Endpoint(s)

Part 1: Percent change from baseline in TG AUC at Day 1

Part 2: Percent change from baseline in TG AUC at Day 1 and Day 14
Analysis

4 parameter Emax Model

Model assumptions will be applied, but appropriate adjustments maybe made based on the 
data.

Distributional assumptions underlying the model used for analysis will be examined by 
obtaining a normal probability plot of the residuals and a plot of the residuals versus the fitted 
values (i.e. checking the normality assumption and constant variance assumption of the model 
respectively) to gain confidence that the model assumptions are reasonable.

If there are any departures from the distributional assumptions, alternative models will be 
explored using appropriate transformed data


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11.11.
Appendix 11 – Abbreviations
11.11.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
Ae
Cumulative amount of unchanged drug excreted into the urine
AE
Adverse Event
ALT
Alanine aminotransferase
AUC
Area under the curve
AUC0-t
Area under the plasma concentration-time curve from time zero to time t
AUC0-tau
Area under the concentration-time curve from time zero (pre-dose) to the end of 
dosing interval
AUC0-∞
The area under the curve from time 0 extrapolated to infinite time
AUC0-24
The area under the curve from time 0 to 24 hour
AUCincr
Postprandial increase in triglyceride area under the curve
BCRP
Breast cancer resistance protein
BMI
Body mass index
BP
Blood pressure
BSFS
Bristol Stool Form Scale
BUN
Blood urea nitrogen
CI
Confidence Interval
Cmax
The maximum concentration
Clast
The last quantified concentration
CPMS
Clinical Pharmacology Modelling & Simulation
CS
Clinical Statistics
CSR
Clinical Study Report
CTR
Clinical Trial Register
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
DGAT
Diacylglycerol acyltransferase
DMPK
Drug Metabolism and Pharmacokinetics
DOB
Date of Birth
DP
Decimal Places
ECG
Electrocardiogram
eCRF
Electronic Case Record Form
GSK
GlaxoSmithKline
HDL
High-density lipoprotein
HR
Heart rate
IA
Interim Analysis
ICH
International Conference on Harmonisation
LDL
Low-density lipoprotein
LFT
Liver function test
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed Model Repeated Measures


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Abbreviation
Description
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PK
Pharmacokinetic
PKC
Pharmacokinetic Concentration (population)
PKP
Pharmacokinetic Parameter (population)
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RBC
Red blood cell
RD
Repeat-dose
RO
Observed accumulation ratio based on AUC(0-τ)
Rcmax
Observed accumulation ratio based on Cmax
Rs
Steady-state accumulation ration based on AUC(0-τ) on Day 14 and AUC0-∞ on 
Day 1
SAE
Serious Adverse Event
SD
Single-dose
SD
Standard deviation
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SOC
System Organ Class
SDTM
Study Data Tabulation Model
SOP
Standard Operation Procedure
t1/2
Elimination half-life
TA
Therapeutic Area
tmax
Time to maximum observed plasma concentration
TFL/TLF
Tables, Figures & Listings 
VLDL
Very-low density lipoprotein
VLDL-TG
Very-low density lipoprotein triglycerides
WBC
White blood cell
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
SAS
WinNonLin


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11.12.
Appendix 12: List of Data Displays
11.12.1.
General Data Display Numbering
The following general numbering convention will be applied for RAP displays: 
Section
Tables
Figures
Study Population
1.x
N/A
Safety
3.x
3.x
Pharmacokinetic
4.x
4.x
Pharmacodynamic
5.x
5.x
Pharmacokinetic/Pharmacodynamic
6.x
6.x
Section
Listing
ICH Listings
1 to x
Other Listings
y to z
11.12.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required an example 
mock-up displays provided in Appendix 13: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Efficacy
EFF_Fn
EFF_Tn
EFF_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
Pharmacokinetic
PK_Fn
PK_Tn
PK_Ln
Pharmacodynamic and / or Biomarker
PD_Fn
PD_Tn
PD_Ln
Pharmacokinetic / Pharmacodynamic
PKPD_Fn
PKPD_Tn
PK/PD_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL / TST ID / Example Shell’ or ‘Programming Notes’ column as 
‘[Non-Standard] + Reference.’
11.12.3.
Deliverable [Priority]
Delivery
Description
Headline
Headline Results (Not applied for this study)
SAC
Final Statistical Analysis Complete


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11.12.4.
General Note for Display
General note:
For any display where information needs to be presented on one row, please see below 
for how we will handle the 11 treatments in Part 1 and 3 treatments in Part 2.
The column for part 1 is:
On first page:
P1
(N=x)
Single Dose
A1
(N=x)
A2
(N=x)
A3
(N=x)
A4
(N=x)
A5
(N=x)
A6
(N=x)
On second page:
P1
(N=x)[1]
Multiple Dose
A7
(N=x)
A8
(N=x)
A10
(N=x)
A11
(N=x)
Note: [1] Placebo is repeated on both pages.
The column for part 2 is:
P2
(N=x)
B1
(N=x)
B1
(N=x)
B1
(N=x)
The “Total” column will be added on a case by case basis.
Please note: For PD parameter TG, P1 = matched placebo in part 1 excluding cohort 8
(‘Placebo exl. Cohort 8’ would be displayed in TFL). Placebo in cohort 8 will be 
presented separately in the display (‘Cohort 8 Placebo’ would be displayed in TFL).
Please note: For mock shells and anywhere which list treatment codes, please replace 
actual treatment dosing regimens in the Appendix 5, please update/remove footnote 
accordingly.  


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11.12.5.
Study Population
11.12.5.1. Study Population Tables
Study Population Tables
No.
Population
IDSL / TST ID/ 
Example Shell
Title
Programming Notes
((U)nique/(R)epeat)
Deliverable
Subject Disposition
1.1
1.2
Safety
ES8
Summary of Subject Status and 
Reason for Study Withdrawal (Part 
X)
ICH E3
(U)
SAC
1.3
Safety
SD1
Summary of Treatment Status and 
Reasons for Discontinuation of 
Study Treatment (Part 2)
ICH E3
(U)
Only for Part 2 since this table is required 
for all studies except single dose studies.
SAC
1.4
Screened 
Subjects
ES6
Summary of Screening Status and 
Reasons for Screen Failure
Journal Requirements
Used with Summary of Study 
Populations and Summary of Subject 
Disposition to create Consort diagram.
SAC
Protocol Deviation
1.5
1.6
Safety
DV1
Summary of Important Protocol 
Deviations (Part X)
ICH E3
(U)
SAC
Populations Analysed
1.8
1.9
Screened
Subject
SP1
Summary of Study Population (Part 
X)
IDSL
To display both pooling of subjects at 
placebo in part 1.
(1) Pooling of subjects at placebo for 
all cohorts
(2) Pooling of subjects at placebo 
SAC


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Study Population Tables
No.
Population
IDSL / TST ID/ 
Example Shell
Title
Programming Notes
((U)nique/(R)epeat)
Deliverable
except in cohort 8. Placebo in 
cohort 8.
Demographic and Baseline Characteristics
1.10
1.11
Safety
DM1
Summary of Demographic 
Characteristics (Part X)
ICH E3
(U)
SAC
11.12
11.13
Safety
DM5
Summary of Race and Racial 
Combinations
ICH E3
(U)
SAC
Prior and Concomitant Medications
1.14
1.15
Safety
MH1
Summary of Past Medical 
Conditions (Part X)
ICH E3
(U)
Required if medical condition data is 
collected.
MH1 depending on level of detail collected.
SAC
1.16
1.17
Safety
MH1
Summary of Current Medical 
Conditions (Part X)
ICH E3
(R)
Required if medical condition data is 
collected.
MH1 depending on level of detail collected.
SAC
1.18
1.19
Safety
CM1
Summary of Concomitant 
Medications (Part X)
ICH E3
(U)
SAC
Exposure and Treatment Compliance


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Study Population Tables
No.
Population
IDSL / TST ID/ 
Example Shell
Title
Programming Notes
((U)nique/(R)epeat)
Deliverable
1.20
1.21
Safety
EX1
Summary of Exposure to Study 
Treatment (Part X)
ICH E3
(U)
SAC
11.12.5.2. Safety Tables
Safety: Tables
No.
Population
IDSL / TST ID/ 
Example Shell
Title
Programming Notes 
((U)nique/(R)epeat)
Deliverable
Adverse Events (AEs)
3.1
3.2
Safety 
AE1
Summary of All Adverse Events by 
System Organ Class and Preferred 
Term (Part X)
ICH E3
(U)
SAC
3.3
3.4
Safety 
AE1
Summary of Adverse Events by 
System Organ Class 
Gastrointestinal (GI) and PT
ICH E3
(U)
by SOC and PT term, where SOC=GI.
SAC
3.5
3.6
Safety
AE3
Summary of Most Frequent Adverse 
Events by Overall Frequency
Most frequent adverse events are the 
frequency greater than 3.
3.7
3.8
Safety 
AE1
Summary of All Drug-Related 
Adverse Events by System Organ 
Class and Preferred Term
ICH E3
(R)
SAC
Serious Adverse Events (AEs)
3.9
3.10
Safety 
AE1
Summary of Serious Adverse 
Events by System Organ Class and 
ICH E3
(U)
SAC


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Safety: Tables
No.
Population
IDSL / TST ID/ 
Example Shell
Title
Programming Notes 
((U)nique/(R)epeat)
Deliverable
Preferred Term (Part X)
3.11
3.12
Safety 
AE1
Summary of Adverse Events 
Leading to Withdrawal from Study / 
Permanent Discontinuation of Study 
Treatment by System Organ Class 
and Preferred Term (Part X)
ICH E3
(R)
SAC
Laboratory: Chemistry
3.13
3.14
Safety
LB1
Summary of Chemistry Changes 
from Baseline (Part X)
ICH E3
(U)
Includes Baseline values.
Includes pre-specified parameters
repeated in conventional units.
SAC
Laboratory: Hematology
3.15
3.16
Safety
LB1
Summary of Hematology Changes 
from Baseline (Part X)
ICH E3
(R)
Includes Baseline values.
SAC
Laboratory: Urinalysis
3.17
3.18
Safety
LB1
Summary of Urine Concentration 
Changes from Baseline
ICH E3
(R)
Includes Baseline values.
SAC
3.19
3.20
Safety
LB2
Summary of Urinalysis Dipstick 
Results (Part X)
IDSL
(U)
As above for Chemistry, using dipstick 
categories.
SAC
Laboratory: Hepatobiliary (Liver)
3.21
3.22
Safety
LIVER1
Summary of Liver 
Monitoring/Stopping Event 
IDSL
SAC


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Safety: Tables
No.
Population
IDSL / TST ID/ 
Example Shell
Title
Programming Notes 
((U)nique/(R)epeat)
Deliverable
Reporting (Part X)
(U)
ECG
3.23
3.24
Safety
EG1
Summary of ECG Findings (Part X)
IDSL
(U)
As above for Chemistry, using ECG 
findings categories (and change from 
baseline categories, if applicable).
SAC
3.25
3.26
Safety
EG2
Summary of Change from Baseline 
in ECG Values by Visit (Part X)
IDSL
(U)
Includes Baseline values.
SAC
Vital Signs
3.31
3.32
Safety
VS1
Summary of Change from Baseline 
in Vital Signs by Visit (Part X)
ICH E3
(U)
Includes Baseline values.
SAC
3.33
3.34
Safety
VS3
Summary of Vital Signs Results by 
PCI Criteria (Part X)
IDSL
(U)
Recommended for studies with sufficiently 
large sample size or frequency of values of 
interest. 
SAC


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11.12.5.3. Safety Figures
Safety: Figures
No.
Population
IDSL / TST ID/ 
Example Shell
Title
Programming Notes 
((U)nique/(R)epeat)
Deliverable
Laboratory
3.1
3.2
Safety
LB8
Matrix Display of Maximum LFT 
(ALT, AST, ALP, and Total Bilirubin) 
Values
IDSL
(U)
SAC
3.3
3.4
Safety
Non-Standard 
Mock
SAFE_F1
Plot of Individual LFT (ALT, AST, 
ALP, and Total Bilirubin) Values vs. 
Study Time by Treatment Group 
and Test (Part X)
The name of X-axis is Days in Study. The 
name of Y-axis is the value of LFT (ALT, 
AST, ALP, and Total Bilirubin). One plot for 
each treatment group
SAC
11.12.5.4. Pharmacokinetic Tables
Pharmacokientic: Tables
No.
Population
IDSL / TST ID/ 
Example Shell
Title
Programming Notes 
((U)nique/(R)epeat)
Deliverable
Concentration-time
4.1
4.2
PKC
PK01
Summary of Plasma 
Pharmacokinetic Concentration-
Time Data by Treatment (Part X)
IDSL
(U)
SAC
4.3
PKC
PK01
Summary of Pharmacokinetic 
Trough Plasma Concentration-Time 
Data by Treatment (Part 2)
IDSL
(R)
SAC
Pharmacokinetic Parameters: Analyses


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Pharmacokientic: Tables
No.
Population
IDSL / TST ID/ 
Example Shell
Title
Programming Notes 
((U)nique/(R)epeat)
Deliverable
4.4
4.5
PKP
PK03
Summary of Derived 
Pharmacokinetic [units] by 
Treatment (Part X)
IDSL
(U)
All derived PK parameters were listed in 
Table 6 in the section. They are as follows:
Part 1: AUC(0-t), AUC(0-24), AUC(0-inf).
Part 2: AUC(0-tau), Ro and Rcmax, Rs,
            Ctrough.
Part 1 + Part 2 on Day 1: AUC(0-inf)
Part 1 + Part 2: Cmax on Day 1 in part 1 
and Days 1, 14 in part 2.
Tmax, t1/2, Ae, CLr on . on Day 1 in part 1 
and Day 14 in part 2
SAC
4.6
4.7
PKP
PK03
Summary of Log-Transformed 
Derived Pharmacokinetic [units] by 
Treatment (Part X)
IDSL
(U)
All Log-Transformed derived PK 
parameters were listed in Table 6.
SAC
4.8
4.9
PKP
Non-standard
Mock
PK_T1
Summary of Statistical Analysis of 
Dose Proportionality (Part X)
(U)
Please follow the sample code in the 
Section 8.1.3.2:.Statistical Analysis of
Pharmacokintic Parameters.
SAC
4.10
PKP
Non-standard
Mock
PK_T2
Summary of Statistical Analysis of 
Accumulation Ratio (Part 2)
(U)
For Ro, Rcmax
Please follow the sample code in the 
Section 8.1.3.2: Statistical Analysis of 
Pharmacokintic Parameters
SAC
4.11
PKP
Non-standard
Mock
PK_T3
Summary of Statistical Analysis of 
Assessment of Steady-State (Part 
2)
(U)
Please follow the sample code in the 
Section 8.1.3.2: Statistical Analysis of 
Pharmacokintic Parameters
SAC


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11.12.5.5. Pharmacokinetic Figures
Pharmacokientic: Figures
No.
Population
IDSL / TST ID/ 
Example Shell
Title
Programming Notes 
((U)nique/(R)epeat)
Deliverable
Concentration-time
4.1
4.2
PKC
PK16a
Individual Plasma Pharmacokinetic 
Concentration-Time Plots (Linear 
and Semi-log) (Part X)
IDSL
(U)
SAC
4.3
4.4
PKC
PK17
Mean Plasma Pharmacokinetic 
Concentration-Time Plots (Linear 
and Semi-log) (Part X)
IDSL
(U)
SAC
4.5
4.6
PKC
PK18
Median Plasma Pharmacokinetic 
Concentration-Time Plots (Linear 
and Semi-log) (Part X)
IDSL
(U)
SAC
11.12.5.6. Pharmacodynamic (and / or Biomarker) Tables:
Pharmacodynamic: Tables
No.
Population
IDSL / TST ID/ 
Example Shell
Title
Programming Notes 
((U)nique/(R)epeat)
Deliverable
Postprandial Triglyceride (TG)
5.1
5.2
PD
PD1
Summary of Absolute TG Values 
by Treatment, Day, and Time Point 
(Part X)
IDSL
(U)
Include baseline day time points
Footnote will be as follows:
Pooled placebo excludes cohort 8. 
Placebo in cohort 8 and active treatment in 
SAC


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Pharmacodynamic: Tables
No.
Population
IDSL / TST ID/ 
Example Shell
Title
Programming Notes 
((U)nique/(R)epeat)
Deliverable
cohort 8 are presented separately.
5.3
5.4
PD
PD1
Summary of Corrected TG Values 
by Treatment, Day, and Time Point 
(Part X)
IDSL
(U)
Please use the correction value which 
present in the Section 8.2.1.2 to adjust the 
TG values.
It will be displayed by Day in Part 1 (Day -
1 and Day 1)
It can be by Day in Part 2 (Day -1, Day 1 
and Day 14)
SAC
5.5
5.6
PD
PD4
Summary of TG AUC and 
Corrected TG AUC by Treatment 
and Day (Part X)
IDSL
(U)
Column name “Add Time Var.’ should be 
“Day”
SAC
5.7
5.8
PD
PD4
Summary of Percent (%) Change 
from Baseline in TG AUC and 
Corrected TG AUC (Part X)
IDSL
(U)
Column ‘Add Time Var.’ should be ‘Day 1 
– Day -1’ for Part 1; “Day 1 – Day -1” and 
“Day 14 – Day -1” for Part 2, respectively. 
Remove columns ‘N’ and ‘n’.
SAC
Biomark: Bristol Stool Form Scale (BSFS)
5.9
5.10
Safety
Non-standard 
Mock
PD_T1
Summary of Number of Subjects 
and Number of Bristol Stool Form 
Scale by Type and Day and 
Treatment (Part X)
(U)
SAC
5.11
5.12
Safety
Non-standard 
Mock
PD_T2
Summary of Total Number of 
Bristol Stool Form Scale by Day 
and Treatment (Part X)
(U)
SAC
Exploratory PD Labs


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Pharmacodynamic: Tables
No.
Population
IDSL / TST ID/ 
Example Shell
Title
Programming Notes 
((U)nique/(R)epeat)
Deliverable
5.13
Safety
LB1
Summary of Change from Baseline 
in Exploratory PD Labs Parameter 
(Part X)
ICH E3
(U)
SAC
11.12.5.7. Pharmacodynamic (and / or Biomarker) Figures:
Pharmacodynamic: Figures
No.
Population
IDSL / TST ID/ 
Example Shell
Title
Programming Notes 
((U)nique/Repeat)
Deliverable
Postprandial Triglyceride (TG)
5.1
5.2
PD
Non-standard
PD_F1
Mean (SD) of Absolute TG Values 
by Treatment, Day, and Time Point
Plot (Part X)
Non-standard (U)
For Part 1, Day -1 and Day 1 will be 
displayed in different pages but in the same 
plot.
For Part 2, Day -1, Day 1 and Day 14 will 
be displayed in different pages but in the 
same plot.
Name of X-axis is ‘Time Point (hr)’. Name 
of Y-axis is ‘Mean Absolute TG Values’
SAC
5.3
5.4
PD
Non-standard
PD_F1
Individual Absolute TG Values by 
Treatment, Day and Time Point 
(Part X)
Non-standard (U)
For Part 1, Day -1 and Day 1 will be 
displayed in different pages but in the same 
plot.
SAC


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Pharmacodynamic: Figures
No.
Population
IDSL / TST ID/ 
Example Shell
Title
Programming Notes 
((U)nique/Repeat)
Deliverable
For Part 2, Day -1, Day 1 and Day 14 will 
be displayed in different pages but in the 
same plot.
Name of X-axis is ‘Treatment’. Name of Y-
axis is ‘Absolute TG Values’
5.5
5.6
PD
Non-standard
PD_F1
Mean (SD) of Corrected TG 
Values by Treatment, Day, and 
Time Point Plot (Part X)
Non-standard (U)
For Part 1, Day -1 and Day 1 will be 
displayed .
For Part 2, Day -1, Day 1 and Day 14 will 
be displayed in different pages but in the 
same plot.
Name of X-axis is ‘Time Point (hr)’. Name 
of Y-axis is ‘Mean Corrected TG Values’
SAC
5.7
5.8
PD
Non-standard
PD_F1
Individual Corrected TG Values by 
Treatment, Day and Time Point 
(Part X)
Non-standard (U)
For Part 1, Day -1 and Day 1 will be 
displayed in different pages but in the same 
plot.
For Part 2, Day -1, Day 1 and Day 14 will 
be displayed in different pages but in the 
same plot.
Name of X-axis is ‘Treatment’. Name of Y-
axis is ‘Corrected TG Values’
SAC
5.9
5.10
PD
Non-standard
PD_F1
Mean (SD) of Percent (%) Change 
from Baseline of TG AUC 
(Corrected TG Values) by 
Treatment and Day Plot (Part X)
Non-standard (U)
For Percent (%) Change from Baseline of 
Corrected TG AUC in Part 1, there is Day 
1. For Part 2, Day 1, and Day 14 will be 
displayed in the same plot. Percent (%) 
Change from Baseline of Corrected TG 
AUC will be presented for TG AUC(1-
12),TG AUC(2-5) on different pages in the 
SAC


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Pharmacodynamic: Figures
No.
Population
IDSL / TST ID/ 
Example Shell
Title
Programming Notes 
((U)nique/Repeat)
Deliverable
same plot, respectively.
Name of X-axis is ‘Treatment’. Name of Y-
axis is ‘Mean Percent Change from 
Baseline in Corrected TG AUC (1-12)’ and 
‘Mean Percent Change from Baseline in 
Corrected TG AUC (2-5)’, respectively
Biomark: Bristol Stool Form Scale (BSFS) Figures
5.11
5.12
Safety
Non-standard 
Mock 
PD_F2
Number of Bristol Stool Form Scale 
by Type and Treatment Histogram 
Plot (Part X)
(U)
SAC
5.13
5.14
Safety
Non-standard 
Mock 
PD_F3
Number of Bristol Stool Form Scale 
by Type and Treatment Line Plot 
(Part X)
(U)
SAC
11.12.5.8. ICH Listings
Combined both parts into one listing by part. Similar will be applied all other listings unless otherwise specified.
ICH: Listings
No.
Population
IDSL / TST ID/ 
Example Shell
Title
Programming Notes 
((U)nique/(R)epeat)
Deliverable
Subject Disposition
1
Screened
ES7
Listing of Reasons for Screen 
Failure
(U)
SAC
ES2
Listing of Reasons for Study 
ICH E3


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ICH: Listings
No.
Population
IDSL / TST ID/ 
Example Shell
Title
Programming Notes 
((U)nique/(R)epeat)
Deliverable
2
Safety
Withdrawal
(U)
SAC
3
Safety
SD2
Listing of Reasons for Study 
Treatment Discontinuation 
ICH E3
(U)
Only for Part 2 since it is required for all 
studies except single dose studies.
SAC
4
Safety
BL1
Listing of Subjects for Whom the 
Treatment Blind was Broken
ICH E3
SAC
5
Safety
TA1
Listing of Planned and Actual 
Treatments
IDSL
Protocol Deviations
6
Safety
DV2
Listing of Important Protocol 
Deviations
ICH E3
(U)
SAC
7
Safety
IE3
Listing of Subjects with 
Inclusion/Exclusion Criteria 
Deviations
ICH E3
(U)
SAC
Demographic and Baseline Characteristics
8
Safety
DM2
Listing of Demographic 
Characteristics
ICH E3
(U)
SAC
9
Safety
DM9
Listing of Race
ICH E3
(U)
SAC
Prior and Concomitant Medications
10
Safety 
CP_CM3
Listing of Concomitant Medications
IDSL
(U)
SAC
Exposure and Treatment Compliance
11
Safety
EX3
Listing of Exposure Data
ICH E3  (U)
SAC


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ICH: Listings
No.
Population
IDSL / TST ID/ 
Example Shell
Title
Programming Notes 
((U)nique/(R)epeat)
Deliverable
Adverse Events
12
Safety
AE8
Listing of All Adverse Events
ICH E3  (U)
SAC
13
Safety
AE7
Listing of subject Numbers for 
Individual Adverse Events
ICH E3  
(U)
SAC
14
Safety
AE2
Listing of Relationship Between  
Adverse Event System Organ 
Classes, Preferred Terms, and 
Verbatim Text
IDSL  
(U)
SAC
Serious and Other Significant Adverse Events
15
Safety
AE8
Listing of Serious Adverse Events
ICH E3  
(U)
SAC
16
Safety
AE14
Listing of Reasons for Considering 
as a Serious Adverse Event
ICH E3  
(U)
SAC
17
Safety
AE8
Listing of Adverse Events Leading 
to Withdrawal from Study / 
Permanent Discontinuation of Study 
Treatment
ICH E3  
(U)
SAC
18
Safety
Non-standard
SAFE_L1
Listing of Pregnancy Results 
Mock example shell reference is SAFE_L1 
below
(U)
SAC
Hepatobiliary (Liver)
19
Safety
LIVER5
Listing of Liver Monitoring/Stopping 
Event Reporting
IDSL
(U)
SAC
All Laboratory
20
Safety
LB5
Listing of Laboratory Data for 
Subjects with Any Values of 
Potential Clinical Importance
ICH E3  
(U)
Display ALL labs for a subject who 
SAC


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ICH: Listings
No.
Population
IDSL / TST ID/ 
Example Shell
Title
Programming Notes 
((U)nique/(R)epeat)
Deliverable
experienced a value of potential clinical 
concern/importance.
21
Safety
LB5
Listing of Laboratory Values of 
Potential Clinical Importance
ICH E3
(U)
Only list the subject who has PCI value
SAC
ECG
22
Safety
CP_EG3
Listing of All ECG Data for Subjects 
with Any Value of Potential Clinical 
Importance
IDSL
Note: IDSL shell in development.
Required for ClinPharm studies only. 
Display ALL ECGs for a subject who 
experienced a value of potential clinical 
importance.
SAC
23
Safety
CP_EG3
Listing of All ECG Value of Potential 
Clinical Importance
IDSL
SAC
24
Safety
EG5
Listing of Abnormal ECG Findings
IDSL (U)
SAC
Vital Signs
25
Safety
CP_VS4
Listing of All Vital Signs Data for 
Subjects with Any Value of Potential 
Clinical Importance
IDSL
(U)
Display ALL Vital Signs for a subject who 
experienced a value of potential clinical 
importance.
SAC
26
Safety
CP_VS4
Listing of Vital Signs of Potential 
Clinical Importance
IDSL
(U)
SAC
Other Exams
27
Safety
Non-standard
SAFE_L2
Listing of Physical Exams
Mock example shell reference is SAFE_L2
below
(U)
SAC


CONFIDENTIAL
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ICH: Listings
No.
Population
IDSL / TST ID/ 
Example Shell
Title
Programming Notes 
((U)nique/(R)epeat)
Deliverable
11.12.5.9. Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / TST ID/ 
Example Shell
Title
Programming Notes 
((U)nique/(R)epeat)
Deliverable
Pharmacokinetic Concentrations
28
PKC
PK07
Listing of Plasma Pharmacokinetic 
Concentration-Time Data by 
Treatment
IDSL
(U)
Combined both parts into one listing by 
part. Similar will be applied all other listings 
unless otherwise specified.
SAC
29
PKC
PK07
Listing of Plasma Trough 
Concentration-Day/Time Data by 
Treatment
IDSL
(U)
Only for Part 2 since it is required for all 
studies except single dose studies.
Only include the following scheduled time 
points: pre-dose at days 2, 4, 5, 6, 12, 13, 
14, and 15 (or day 14 24 hours post-dose).
SAC
Pharmacokinetic Parameters
30
PKP
PK13
Listing of Derived Pharmacokinetic 
Parameters by Treatment
IDSL
(U)
Include all derived PK parameters
SAC


CONFIDENTIAL
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Non-ICH: Listings
No.
Population
IDSL / TST ID/ 
Example Shell
Title
Programming Notes 
((U)nique/(R)epeat)
Deliverable
31
PKP
Non-standard
Listing of SAS Output of Statistical 
Analysis of Dose Proportionality 
(Part 1)
(U)
Dump the SAS output from the PROC 
MIXED outputs and the details of modelling 
checking into the output.
SAC
32
PKP
Non-standard
Listing of SAS Output of Statistical 
Analysis of Dose Proportionality 
(Part 2)
(U)
Only for Part 2 on Day 1 and Day 14.
Dump the SAS output from the PROC 
MIXED outputs and the details of modelling 
checking into the output.
SAC
33
PKP
Non-standard
Listing of SAS Output of Statistical 
Analysis of Accumulation Ratio 
(Part 2)
(U)
Only for Part 2 on parameters Ro and 
Rcmax
Dump the SAS output from the PROC 
MIXED outputs and the details of modelling 
checking into the output.
SAC
34
PKP
Non-standard
Listing of SAS Output of Statistical 
Analysis of Assessment of Steady-
State (Part 2)
(U)
Only for Part 2 Ctrough values at pre-dose 
on days 2, 4, 5, 6, 12, 13, 14, and 15 (or 
day 14 24 post-dose).
Dump the SAS output from the PROC 
MIXED outputs and the details of modelling 
checking into the output.
SAC
Pharmacodynamic: Postprandial Triglyceride
35
PD
PD10
Listing of Postprandial TG Value 
Over Time by Treatment and Day
IDSL (U)
Include baseline values on day -1.
Include corrected TG values as well
SAC
36
PD
PD16
Listing of Individual TG AUC
IDSL
(U)
SAC


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Non-ICH: Listings
No.
Population
IDSL / TST ID/ 
Example Shell
Title
Programming Notes 
((U)nique/(R)epeat)
Deliverable
To Modify PD16 to add a column Time 
variable (Day). Replace the column from 
Baseline [analyte] (unit) to Weighted Mean 
(0-24h) with all derived TG AUC variable.
Biomarker: Bristol Stool Form Scale
37
Safety
Non-standard
PD_L1
Listing of Individual Bristol Stool 
Form Scale
(U)
SAC
Exploratory Pharmacodynamic Lab Parameters
38
Safety
LB5
Listing of Exploratory 
Pharmacodynamic Lab Parameters
ICH E3  
(U)
Remove Normal Range and PCI Flag 
columns
SAC