Clinical trial NCT03231943
Conditions: Infection, Human Immunodeficiency Virus HIV Infections
Keywords: FTIH Healthy Tolerability Dose-escalation HIV-1 Safety PK GSK3640254 Maturation inhibitor
Sponsor: ViiV Healthcare
Start date: 2017-09-19; Completion date: 2018-09-09
Enrollment: 78 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Human immuno deficiency virus 1 (HIV-1) infections continues to be a serious health threat throughout the world and development of medicines with new mechanism of action have an important role to play. GSK3640254 is a maturation inhibitor (MI) and can be effective in HIV-1 treatment. This randomized, 2-part, single and repeat increasing dose study will collect information on safety, tolerability and drug levels in the body of in healthy subjects for GSK3640254. The information collected in this study will help in further clinical development of GSK3640254, including a Phase IIA Proof of Concept (PoC) study in HIV-infected subjects. Approximately 16 healthy subjects will be randomized to receive single oral dose of GSK3640254 and placebo in Part 1 and approximately 56 healthy subjects will be randomized to receive repeat oral dose of GSK3640254 or placebo in Part 2. All doses will be given immediately after a moderate fat meal. Maximum duration of study participation will be approximately 12 weeks.

Detailed description:

Arms: arm 1: Eligible subjects will participate in cohort 1 or 2 and each of these two cohorts will contain up to four escalating doses of GSK3640254. In each cohort, 6 subjects will be randomized to receive single oral dose of GSK3640254 and 2 subjects will be randomized to receive placebo. Hence, each subject in cohort 1 and 2 will receive up to 3 escalating doses of GSK3640254 and one placebo in crossover manner. arm 2: Eligible subjects will participate in one of the 4 cohorts (3,4,5,6). In each cohort, 6 subjects will be randomized to receive a once-daily oral dose of GSK3640254 for 14 days. After the safety data of cohort 3-6 is available, 18 eligible subjects will be randomized to receive once daily oral dose of GSK3640254 for 14 days in expansion cohort. arm 3: Eligible subjects will participate in one of the 4 cohorts (3,4,5,6). In each cohort, 2 subjects will be randomized to receive a once-daily oral dose of placebo for 14 days. After the safety data of cohort 3-6 is available, 6 eligible subjects will be randomized to receive once daily oral dose of placebo for 14 days in expansion cohort.
Interventions: intervention 1: GSK3640254 intervention 2: Placebo
Intervention descriptions: intervention 1: GSK3640254 is a capsule available in 1 milligram (mg), 10 mg and 100 mg dosing strength. GSK3640254 capsule will be given via oral route during each dosing day with approximately 240 mL of water. intervention 2: Placebo capsule matching to the study treatment will be given via oral route during each dosing day with approximately 240 mL of water.

Protocol documents:
Prot_000.pdf: 
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TITLE PAGE
Protocol Title: A Double-Blind (Sponsor Unblinded), Randomized, Placebo-Controlled, 
Single and Repeated Dose Escalation Study to Investigate the Safety, Tolerability and 
Pharmacokinetics of GSK3640254 in Healthy Participants
Protocol Number: 207187 / 04
Short Title: GSK3640254 FTIH study in healthy volunteers 
Compound Number:
GSK3640254
Sponsor Name and Legal Registered Address: 
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information
 DO, MPH; 
Regulatory Agency Identifying Number(s): EudraCT number 2017-001367-21
Approval Date: 17-MAY-2018
Copyright 2018 ViiV Healthcare and the GlaxoSmithKline group of companies.  All 
rights reserved.  Unauthorised copying or use of this information is prohibited.
PPD
PPD


PPD
PPD
PPD


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 04
17-MAY-2018
Amendment 03
5-Dec-2017
Amendment 02
03-AUG-2017
Amendment 01
12-Jul-2017
Original Protocol
25-May-2017
Amendment 02; 03-Aug-2017
Overall Rationale for the Amendment: This amendment makes several notable 
changes to the protocol. First, details about the components of a full physical exam are 
described (including a neurologic exam); additionally, full physical exams now replace 
brief physical exams. Second, given the risk of neuropsychiatric events, a clinician (or 
qualified designee) administered Columbia Suicide Severity Rating Scale (CSSRS) has 
been incorporated into screening for all subjects (SAD and MAD); any subject with a 
positive (abnormal) response confirmed by the investigator will be excluded from 
participation. Additionally, the CSSRS has been incorporated into the on-treatment 
portion of the MAD only. Third, the emergence of any discontinuation criteria (including 
emergence of an SAE or emergence of any positive (abnormal) response confirmed by 
the investigator on the CSSRS during the on-treatment phase of the MAD) now requires 
discontinuation from the trial. More clarity is provided regarding the expected human 
effective dose range of GSK3640254 and the maximum single dose (200 mg if current 
assumptions are valid). Finally, the text regarding the 400 mg single dose in the event 
that exposures to GSK3640254 were lower than projected was removed.  
Amendment 03; 05-Dec-2017
The primary purpose of this protocol amendment (03) is to increase the maximum dose in 
the SAD part of the study from 200 mg to ≤ 700 mg, in relation to human exposure to 
GSK3640254 being approximately 70% lower than predicted based on animal data. 
Preliminary PK parameters for GSK3640254 following single dose administration of 1, 
3, and 10 mg show exposures that were lower along with a longer half-life than predicted 
based on animal data. The prediction for a 10 mg dose were a mean Cmax of 197 ng/mL, 
a mean AUC of 3430 ng.h/mL and a mean half-life of 15 hours. The observed Cmax was 
approximately 75% lower, the AUC was approximately 65% lower and the half-life was 
about 70% longer. Taking into consideration the actual human PK profile of 
GSK3640254 at 1, 3 and 10 mg, the minimally anticipated efficacious dose (X) has 
increased from 40 mg to 70 mg with an accumulation upon repeated once daily 
administration increasing from 50% to approximately 115%. In order to evaluate 
exposure anticipated at the maximum MAD dose of up to 4X, higher doses up to 9X will 
need to be evaluated in the SAD. Thus, this amendment is to enable the evaluation of the 
safety/tolerability and pharmacokinetics of single doses of GSK3640254 at doses ≤ 700 
mg in healthy volunteers continuing to participate in Cohorts 1 and 2. Specifically, the 


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proposed higher doses will be evaluated in Period 4 (Cohort 1, ≤ 400 mg; Cohort 2, ≤ 700 
mg). Other, non-major changes, have also been incorporated.
Amendment 04; 17-MAY-2018
The purpose of this protocol amendment (04) is to study a higher dose of 320 mg QD for 
14 days in the MAD part of the study (see Cohort 6 in Figure 1). The MAD 320 mg QD 
dose would explore steady-state Cmax values greater than those explored in the SAD 
study (which is not permitted by the current version of the protocol). This dose of 320 mg 
QD is four times the projected minimum effective dose (~80 mg QD) and is in line with 
the MAD PK stopping Criteria in the current approved protocol (amendment 03/ 05 
December 2017); specifically, the probability of any subject having an AUC > 61.1 
µg/mL is 42% (data through May 9, 2018). A MAD dose of 320 mg QD allows for a 
thorough evaluation of PK/QT relationship and a greater safety margin in subsequent 
clinical trials in patients. 
The totality of preliminary PK and safety/tolerability data to date shows the MAD 320 
mg QD dose is clinically and scientifically reasonable (see Section 3.2.2 for full details).
Specifically, GSK3640254 following single dose administration ultimately showed a 
plateauing of exposure at the 700 mg dose. On Day 14, the mean Cmax for the MAD 200 
mg dose (1841 ng/ml in Cohort 5) approximated that seen in the SAD at 400 and 700 mg 
doses (1881 and 1761 ng/ml, respectively). Since the current protocol does not permit a 
dose in the MAD to surpass the Cmax studied in the SAD, the ViiV/ GSK Dose 
Escalation Committee opened the Expansion Cohort (currently ongoing) with a 200 mg 
dose (See Figure 1) at the conclusion of Cohort 5. Briefly, there have been no significant 
clinical safety/tolerability findings in the SAD or MAD through May 7, 2018. 
Preliminary ongoing data review show no deaths or SAEs. There have been 4 individual 
AEs leading to discontinuation. There have been 10 individual AEs related to blinded 
study medication. Preliminary review of blinded safety data for the: 1) SAD show 17 
subjects experienced 60 individual AEs (58 Grade 1; Two Grade 2) and 2) MAD show 23 
subjects experienced 79 individual AEs (77 Grade 1; Two Grade 2). The two most 
frequent AE SOCs have been Nervous System and Gastrointestinal Disorders without a 
dose/AE relationship. Subjects recruited for the 320 mg QD Cohort will have the same 
inclusion/exclusion criteria, have the same study and subject stopping criteria, and 
undergo the same intensive safety evaluation as previously treated subjects in the MAD. 
Combined, based upon the preliminary safety and PK data gathered to date (see Section 
3.2.2 for full details) subjects will be adequately monitored.


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Section # 
and Name
Description of Change
Brief Rationale
Synopsis
Section 5.1 
Overall 
Design
Figure 1 changed and MAD 
Expansion Cohort Dose added
The actual doses for all Cohorts and 
Periods updated for the SAD and MAD
Section 3.2.2
Preliminary 
Safety and 
PK data in 
Current Study
Preliminary Safety and PK data 
from SAD and MAD updated/added
The clinical and PK data is needed to justify 
the rationale for supporting a proposed 
dose of 320 mg QD in the MAD (Cohort 6)
Section 3.3
Benefit Risk 
Assessment
Preliminary Safety and PK data 
from SAD and MAD updated/added
The clinical and PK data is needed to justify 
the rationale for supporting an unchanged 
benefit risk assessment for a proposed 
dose of 320 mg QD in the MAD (Cohort 6)
Section 5.1 
Overall 
Design (Part 
2 [MAD])
Preliminary Safety and PK data 
from SAD and MAD updated/added
The clinical and PK data is needed to justify 
the rationale for supporting a proposed 
dose of 320 mg QD in the MAD (Cohort 6)
Section 5.5.2
Predicted 
Human 
Effective 
Dose
Preliminary Safety and PK data 
from SAD and MAD updated/added
The clinical and PK data is needed to justify 
the rationale for supporting a proposed 
dose of 320 mg QD in the MAD (Cohort 6)
Throughout
Minor editorial and document 
formatting revisions
Minor, therefore not summarized


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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS...............................................................................................................9
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................13
3.
INTRODUCTION....................................................................................................20
3.1.
Study Rationale ..........................................................................................20
3.2.
Background ................................................................................................20
3.2.1.
Background Key Safety and PK data with a Prior 
Maturation Inhibitor (GSK3532795)..............................................21
3.2.2.
Preliminary Safety and PK data in Current Study (SAD 
doses 1 - 700 mg and MAD doses 50 – 200 mg daily).................22
3.3.
Benefit/Risk Assessment ............................................................................28
3.3.1.
Risk Assessment .........................................................................30
3.3.2.
Benefit Assessment.....................................................................32
3.3.3.
Overall Benefit:Risk Conclusion...................................................32
3.3.4.
Acute Monitoring in FTIH Studies ................................................32
4.
OBJECTIVES AND ENDPOINTS...........................................................................33
5.
STUDY DESIGN ....................................................................................................34
5.1.
Overall Design ............................................................................................34
5.2.
Number of Participants ...............................................................................37
5.3.
Participant and Study Completion...............................................................37
5.4.
Scientific Rationale for Study Design ..........................................................37
5.5.
Dose Justification........................................................................................38
5.5.1.
Predicted Human Pharmacokinetics ............................................38
5.5.2.
Predicted Human Effective Dose .................................................38
5.5.3.
Part 1 (SAD) Starting Dose and Dose Escalation.........................39
5.5.4.
Part 2 (MAD) Starting Dose and Dose Escalation........................41
5.5.5.
Dose Escalation Committee.........................................................42
5.5.6.
Anticipated Exposure and Safety Cover for a Range of 
Potential Doses............................................................................42
6.
STUDY POPULATION...........................................................................................44
6.1.
Inclusion Criteria.........................................................................................44
6.2.
Exclusion Criteria........................................................................................45
6.3.
Lifestyle Restrictions...................................................................................47
6.3.1.
Meals and Dietary Restrictions ....................................................47
6.3.2.
Drugs, Caffeine, Alcohol, and Tobacco........................................47
6.3.3.
Activity .........................................................................................48
6.4.
Screen Failures...........................................................................................48
7.
TREATMENTS.......................................................................................................49
7.1.
Treatments Administered............................................................................49
7.2.
Dose Modification .......................................................................................49
7.3.
Method of Treatment Assignment ...............................................................49
7.4.
Blinding.......................................................................................................50


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7.5.
Preparation/Handling/Storage/Accountability..............................................50
7.6.
Treatment Compliance................................................................................51
7.7.
Concomitant Therapy..................................................................................51
7.8.
Treatment after the End of the Study ..........................................................52
8.
DISCONTINUATION CRITERIA.............................................................................53
8.1.
Discontinuation of Study Treatment ............................................................53
8.1.1.
Liver Chemistry Stopping Criteria ................................................53
8.1.2.
QTc Stopping Criteria for Individual Participants..........................54
8.1.3.
PK Stopping Criteria for SAD and MAD .......................................54
8.1.4.
Clinical criteria for Stopping the Study .........................................54
8.1.5.
Rechallenge.................................................................................55
8.1.5.1.
Study Treatment Restart or Rechallenge....................55
8.2.
Withdrawal from the Study..........................................................................55
8.3.
Lost to Follow Up........................................................................................55
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................57
9.1.
Efficacy Assessments.................................................................................57
9.2.
Adverse Events...........................................................................................57
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................58
9.2.2.
Method of Detecting AEs and SAEs.............................................58
9.2.3.
Follow-up of AEs and SAEs.........................................................58
9.2.4.
Regulatory Reporting Requirements for SAEs .............................58
9.2.5.
Pregnancy ...................................................................................59
9.3.
Treatment of Overdose...............................................................................59
9.4.
Safety Assessments ...................................................................................59
9.4.1.
Physical Examinations.................................................................60
9.4.2.
Vital Signs....................................................................................60
9.4.3.
Electrocardiograms......................................................................60
9.4.3.1.
12-lead safety ECGs ..................................................60
9.4.3.2.
Cardiodynamic assessment (ECGs extracted 
from Holter recordings)...............................................60
9.4.4.
Clinical Safety Laboratory Assessments ......................................62
9.4.5.
Suicidal Risk Monitoring...............................................................63
9.4.6.
GI Toxicity Evaluation and Monitoring Plan..................................63
9.5.
Pharmacokinetics .......................................................................................66
9.6.
Pharmacodynamics ....................................................................................66
9.7.
Genetics .....................................................................................................67
10. STATISTICAL CONSIDERATIONS........................................................................68
10.1.
Sample Size Determination ........................................................................68
10.2.
Populations for Analyses ............................................................................68
10.3.
Statistical Analyses.....................................................................................69
10.3.1.
Safety Analyses...........................................................................69
10.3.2.
Other Analyses ............................................................................69
10.3.3.
Interim Analyses ..........................................................................70
10.3.4.
Final Analyses .............................................................................72
11. REFERENCES.......................................................................................................73
12. APPENDICES........................................................................................................75


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12.1.
Appendix 1: Abbreviations and Trademarks................................................75
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................78
12.3.
Appendix 3: Study Governance Considerations..........................................80
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................84
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................89
12.6.
Appendix 6: Genetics..................................................................................92
12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................93
12.8.
Appendix 8: Protocol Amendment History...................................................95


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1.
SYNOPSIS
Protocol Title: A Double-Blind (Sponsor Unblinded), Randomized, Placebo-Controlled, 
Single and Repeated Dose Escalation Study to Investigate the Safety, Tolerability and 
Pharmacokinetics of GSK3640254 in Healthy Participants
Short Title: GSK3640254 FTIH study in healthy participants
Rationale: The inhibition of maturation and release of human immunodeficiency virus-1 
(HIV-1) is a novel target for drug development, distinct from viral protease, reverse 
transcriptase and integrase. There are no maturation inhibitors (MI) approved for the 
treatment of HIV infection. GSK3640254 is a MI that displays in vitro evidence of low 
nanomolar potency against multiple HIV-1 Gag polymorphisms and a broad spectrum 
covering multiple HIV-1 subtypes, supporting compound development. The goal of this 
study is to gain information on the safety, tolerability, and pharmacokinetic properties of 
GSK3640254. This study will enable further clinical development of GSK3640254,
including a Phase IIA Proof of Concept (PoC) study in HIV-infected patients.
Objectives and Endpoints:
Objective
Endpoint
Primary

To investigate the safety and tolerability of 
GSK3640254 following single and repeated 
daily administration

GSK3640254 safety parameters:  adverse 
events; post-baseline values and changes 
over time of clinical laboratory evaluations 
(haematology, clinical chemistry, urinalysis), 
vital signs, and ECG parameters from pre-
dose values
Secondary

To describe the PK of GSK3640254 
following single and repeated daily 
administration

To examine dose proportionality following 
single and repeated doses of GSK3640254

To assess accumulation of GSK3640254

GSK3640254 PK parameters:
Part 1 (single dose): AUC(0-24), AUC(0-
tlast), AUC(0-inf), Cmax, C24, tmax, tlag, 
t1/2, Clast, tlast, CL/F.
Part 2 (Repeated QD doses for 14 days):  
Day 1: AUC(0-24), Cmax, C24, tmax, tlag
Day 14: AUC(0-), Cmax, C, tmax, t1/2, 
and CL/F

GSK3640254 Single dose: AUC (0-inf), 
Cmax. Repeat dose AUC(0-), Cmax, 
C

Accumulation ratios: R AUC(0-), R 


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Objective
Endpoint

To assess time to steady-state of 
GSK3640254
(Cmax), R (C)

Pre-dose concentrations on Day 2 -14 
(Part 2)
ECG= Electrocardiogram; AUC(0-24) = Area under the plasma concentration time curve from zero to 24; AUC(0-inf) = 
Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time; Cmax= Maximum 
observed concentration; tmax= Time of occurrence of Cmax; t1/2= Apparent terminal phase half-life; CL/F= Apparent 
oral clearance
Overall Design:
This study is a Phase 1, double-blind (sponsor-unblinded), randomized, placebo-
controlled, single- and repeat-dose escalation study of GSK3640254 in healthy 
participants.
A summary of the overall study design, including doses, sample size, and order, is 
presented in Figure 1; Schedule of Activities (SoA) tables are included in Section 2.
The proposed dosing schedule is designed to investigate single oral doses of 
GSK3640254 initially in Part 1 and then, at a suitable cross-over point (described below),
repeated once-daily oral dosing of GSK3640254 in Part 2. All doses will be administered 
immediately following a moderate fat meal (approximately 600 calories with 
approximately 30% of calories from fat), unless otherwise indicated.
Figure 1
Phase 1 Study in Healthy Participants using planned doses of 
GSK3640254
Note: A=active, P=placebo. The doses shown here were/are being completed. Amendment 04 proposes to 
evaluate a 320 mg Daily dose in MAD Cohort 6.


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Number of Participants:
A total of approximately 72 randomized participants will be targeted for the entire study. 
Part 1 will randomize approximately 16 participants, 8 participants in each of Cohort 1 
and Cohort 2. Part 2 will randomize approximately 56 participants, 8 participants in each 
of Cohorts 3 to 6 and 24 participants in the Expansion Cohort.
If participants prematurely discontinue the study in the single ascending dose (SAD),
they may be replaced at the discretion of the Sponsor in consultation with the 
investigator. The replacement participants will be assigned to the same treatment 
sequence, starting where the prior participant prematurely discontinued. Previously 
administered doses will not be repeated by replacement subjects if dose escalation criteria 
are met.
If participants prematurely discontinue the study in the MAD, they may be replaced at the 
discretion of the Sponsor in consultation with the investigator. The replacement
participants will be assigned to the same treatment in the same Cohort where the prior 
participant prematurely discontinued.
Treatment Groups and Duration:
Part 1 (SAD):
The SAD portion of the study will be conducted in an interlocking fashion with two 
separate cohorts of eight healthy participants each. Each of these two cohorts will contain 
up to four escalating doses of GSK3640254; no more than 8 doses will be assessed in 
Part 1. The interlocking design as shown in the schematic in Figure 1 and the 
randomization sequence will allow the 8 participants in each Cohort to potentially receive 
one of the two lowest and one of the two highest doses of GSK3640254. In each 
escalating dose period, six participants will be randomized to GSK3640254 and two 
participants will be randomized to placebo. Each participant will receive placebo once.
To conservatively assess safety in the SAD, within each period and Cohort, 2 out of the 8 
participants will serve as sentinel participants with one receiving GSK3640254 and the 
other receiving placebo (PBO or P in study design scheme). These sentinel participants
will be followed clinically for 24 hours after dose administration to monitor the 
emergence of adverse events. Assuring that there are no safety concerns upon 24 hour 
review of safety data (e.g. vital signs, ECGs, and adverse events) by the Principal 
Investigator (PI) for the sentinel participants, the remaining 6 participants will
subsequently be treated with either GSK3640254 or PBO according to randomization 
schedules.
Dose escalation in Part 1 will be determined by the ViiV Healthcare (VH)/
GlaxoSmithKline (GSK) study team and the PI based on the double-blind (sponsor-
unblinded) safety data and the PK data from the previous dosing period(s). Dose 
escalation will not exceed approximately 3-fold between doses up to approximately the 
predicted minimally effective dose (see Section 5.5) and will not exceed 2-fold thereafter. 
Twenty-four hour post-dose safety and PK data from a minimum of 4 participants 


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receiving GSK3640254 are required for dose escalation. Dose escalation will be guided 
by safety as well as the SAD PK stopping criteria. 
Continuous ECGs will be recorded on the day before dosing (Day -1), Day 1, and Day 2
for extraction of ECGs paired with PK sampling. 
Part 2 (MAD):
Part 2 (MAD) consists of four ascending repeat-dose cohorts (Cohorts 3 to 6), each with 
8 participants (active/PBO=6/2) who will receive a once-daily dose of GSK3640254 or 
PBO for 14 days. The earliest point at which Part 2 of the study will be conducted is once 
the single dose safety and preliminary PK data for the anticipated minimally effective 
dose have been evaluated in the SAD (see Figure 1, MAD). Dose escalation in Part 2 will 
be determined by the VH/GSK study team and the PI based on the double-blind (sponsor-
unblinded) safety and PK data (minimally up to 24 h post Day 14 dose) from the previous 
dosing period(s). Specifically, 14 days of safety and PK data from a minimum of four 
participants receiving active drug will be required for dose escalation. In this part of the 
MAD study, continuous ECGs will be recorded on the day before the first dose (Day -1) 
and Days 1, 2, 14, and 15 for extraction of ECGs paired with PK sampling. 
Part 2 also includes an Expansion Cohort to evaluate the rate of gastrointestinal (GI)
intolerability in 24 participants (active/PBO =18/6). The expansion cohort was conducted 
once the evaluation of the safety and PK from Cohorts 3 – 5 were available. The dose 
chosen was 200 mg (see Figure 1, MAD). 
Participants in both parts will have a screening visit within 28 days prior to first dose and 
a follow-up visit 7-14 days after the last dose. Maximum duration of study participation 
will be approximately 12 weeks.


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2.
SCHEDULE OF ACTIVITIES (SOA)
SAD Cohorts 1 and 2 Screening
Procedure
Screening (up to 28 days before Day 1)
Outpatient Visit
X
Informed Consent
X
Inclusion/Exclusion Criteria and 
Demography
X
Medical/medication/ drug/alcohol history
X
Full Physical Exam1
X
Columbia Suicide Severity Rating Scale 
(CSSRS)
X
Height, Weight, BMI
X
Vital signs
X
12 Lead ECG
X
Screening Holter
X
Pregnancy Test
X
Drug/alcohol/cotinine screen
X
HbsAg, HCV, HIV tests
X
Hem/Chem/Urine tests
X
1.  A Full Physical Exam will include at a minimum, assessments of the Skin, 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems.


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SAD Cohorts 1 and 2 On-Treatment: Before, During, and After Dosing in Each Period
Procedure
Periods 1 through 4
Follow-up 
(7-14 days 
post last 
dosing)
Day 
-2
Day 
-1
Day 1
Day 
2
Day 
3
Day 
4
Day 
5
Pre-
dose
0 
h
0.5 
h
1 
h
1.5 
h
2 
h
2.5 
h
3 
h
3.5 
h
4 
h
4.5 
h
5 
h
6 
h
8 
h
12 
h
24 
h
48 
h
72 
h
96 h
Admission to Unit
X
Outpatient Visit
X
Full Physical Exam1
X
X
X
X
Weight, BMI2
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
12-lead safety ECGs
X
X
X
X
X
X
X
X
X
X
X
X
X
Continuous ECG (full 
time matched baseline 
on Day-1)3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test
X
X4
Drug/alcohol/cotinine 
screen
X
Hem/Chem/Urine tests
X
X
X
X
X
Fasting Lipid test
X
X
X
Single Dosing with 
GSK3640254 following 
moderate fat meal
X
Plasma PK Sampling5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Event Review
<=================================================================================================================>
Con Med Review
<=================================================================================================================>
Furlough from Unit
X


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HCV=Hepatitis C; BMI= Body mass index; ECG= Electrocardiogram; PK= Pharmacokinetic, SAD=single ascending dose
Note:
1. A Full Physical Exam will include at a minimum, assessments of the Skin, Cardiovascular, Respiratory, Gastrointestinal and 
Neurological systems. A single exam can be performed on D-2 or D-1.
2. A BMI does not need to be measured at the time of measurement.
3. Additional safety ECGs may be printed at the discretion of the PI if prolongation in QT interval is suspected. The frequency of ECGs 
will support an exploratory endpoint (should clinical development continue) to evaluate the exposure-response relationship between 
GSK3640254 and QTcF. Once human PK data (e.g. Cmax) are available, the number of ECG time points may be reduced in 
subsequent dosing groups. At timepoints for ECG extraction, subjects will be supinely resting for at least 10 minutes. When ECG 
extractions coincide with safety ECGs, vital signs assessment and blood draws, procedures should be carried out in said order. 
4. This pregnancy test will be obtained approximately 37 days after the last dose of study treatment
5. The number of PK sampling time points may be reduced in subsequent dosing groups once human PK data are available.


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MAD Cohorts 3, 4, 5, 6 and the Expansion Cohort Screening
Procedure
Screening (up to 28 days before Day 1)
Outpatient Visit
X
Informed Consent
X
Inclusion/Exclusion Criteria and 
Demography
X
Medical/medication/ drug/alcohol history
X
Full Physical Exam1
X
CSSRS
X
Height, Weight, BMI
X
Vital signs
X
12 Lead ECG
X
Screening Holter
X
Drug/alcohol/cotinine screen
X
HbsAg, HCV, HIV tests
X
Hem/Chem/Urine tests
X
Pregnancy Test
X
1.  A Full Physical Exam will include at a minimum, assessments of the Skin, 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems.


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MAD Cohorts 3, 4, 5, 6 and the Expansion Cohort On-Treatment
Procedure
Follow-
up (7-14 
days 
post last 
dosing)
Day 
-2
Day 
-1
Day 
1
Day 
2
Day 
3
Day 
4
Day 
5
Day 
6
Day 
7
Day 
8
Day 
9
Day 
10
Day 
11
Day 
12
Day 
13
Day 
14
Day 
15
Day
16
Day 
17
Day 
18
0h
24h
48h
72h
96h
Admission to Unit
X
Outpatient Visit
X
Full Physical Exam1
X
X
X
X
X
X
X
CSSRS
X
X
Weight, BMI2
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
12-lead safety ECGs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Continuous ECG 
(full time matched 
baseline on Day-1)3
X
X
X
X
X
Drug/alcohol/cotinine 
screen
X
Hem/Chem/Urine 
tests
X
X
X
X
X
X
X
X
X
X
X
Fasting Lipid test
X
X
X
X
Pregnancy Test
X
X4
QD Dosing with 
GSK3640254 
following moderate 
fat meal
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Plasma PK 
Sampling5
X
X
X
X
X
X
X
X
X
X
X
X
X
Plasma Metabolite 
Sampling6
X
X
X
X


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Procedure
Follow-
up (7-14 
days 
post last 
dosing)
Day 
-2
Day 
-1
Day 
1
Day 
2
Day 
3
Day 
4
Day 
5
Day 
6
Day 
7
Day 
8
Day 
9
Day 
10
Day 
11
Day 
12
Day 
13
Day 
14
Day 
15
Day
16
Day 
17
Day 
18
0h
24h
48h
72h
96h
Urine Metabolite 
Sampling7
X
X
X
X
PGx Sampling (if 
participant consents)
X
Adverse Event 
Review
<=====================================================================================================================>
Con Med Review
<=====================================================================================================================>
Furlough from Unit
X
Note:
1. A Full Physical Exam will include at a minimum, assessments of the Skin, Cardiovascular, Respiratory, Gastrointestinal and 
Neurological systems. A single exam can be performed on D-2 or D-1.
2. A BMI does not need to be measured at the time of measurement.
3. ECG data extracted from the Continuous ECG will be assessed before PK sampling, prior to dosing and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4.5, 5, 
5.5, 6, 8, 12 h, and 24 h post dose on Day 1 and Day 14 and on corresponding timepoints on Day -1. At timepoints for ECG extraction, 
subjects will be supinely resting for at least 10 minutes. When ECG extractions coincide with safety ECGs, vital signs assessment and 
blood draws, procedures should be carried out in said order. The frequency of EKGs will support an exploratory endpoint to evaluate 
(should clinical development continue) the ER relationship between GSK3640254 and QTcF. Once human data (eg Cmax) is known, 
the number of EKG time points may be reduced.
4. This pregnancy test will be obtained approximately 37 days after the last dose of study treatment
5. Plasma PK samples for bioanalysis for GSK3640254 will be collected pre-dose according to the Time Window Allowances as 
indicated in the Study Reference Manual and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12 h on Day 1 and Day 14. On dosing days, 
plasma PK will be collected pre-dose. The number of PK sampling time points may be reduced in the initial MAD cohort as well as 
further in subsequent MAD dosing groups once human PK data are available in the SAD as well as in the initial MAD cohorts.
6. Plasma Metabolite samples for metabolite identification will be collected pre-dose according to the Time Window Allowances as 
indicated in the Study Reference Manual and at the same time points as for plasma PK samples on Day 1, Day 2 and Day 14, and Day 
15. Plasma metabolite samples will not be collected in the expansion cohort.


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7. Urine Metabolite Sampling for bioanalysis and metabolite identification will be collected pre-dose according to the Time Window 
Allowances as indicated in the Study Reference Manual and from time 0 up to 24 hours on Day 1 and Day 14. Urine samples will not 
be collected in the expansion cohort.


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3.
INTRODUCTION
3.1.
Study Rationale
This is a double-blind (sponsor-unblinded), randomised, placebo-controlled, first-time-in-
human (FTIH) study in a combined single- and multiple-dose protocol to investigate the 
safety, tolerability and PK of GSK3640254 in healthy participants. This study will enable 
further clinical development of GSK3640254, including a Phase IIA Proof of Concept 
(PoC) study in HIV-infected patients.
Infection with HIV-1 continues to be a serious health threat throughout the world, with 
more than one million infected individuals in the U.S. and more than 40 million 
worldwide. The now chronic exposure to combination anti-retroviral therapy (cART) has 
identified anti-retroviral (ARV)-associated long-term toxicities (e.g. central nervous 
system (CNS) or cardiovascular (CV)/metabolic effects, renal disease, etc.), creating a 
need to address and prevent these co-morbidities. Also, treatment failure remains a 
continuing concern in clinical care due to the presence and emergence of resistant strains 
and tolerability issues; in addition, the ageing HIV-1-infected population drives a need 
for drugs with fewer drug-drug interactions. In this environment, medicines with novel 
mechanisms of action (MoA) that can be used as part of the preferred cART regimen 
have an important role to play. However, to be successful, a new ARV agent must be 
safe, effective, provide a relatively high barrier to resistance, have low toxicity, have 
minimal drug-drug interactions, and preferably be a relatively low-dose once-a-day drug 
that can be combined with other agents as part of a fixed-dose regimen. GSK3640254, an 
HIV-1 maturation inhibitor, has the potential to meet such valued features for a new ARV 
medicine.
3.2.
Background
The inhibition of maturation and release of human immunodeficiency virus-1 (HIV-1) is 
a novel target for drug development, distinct from viral protease, reverse transcriptase or 
integrase. There are no MIs approved for the treatment of HIV infection. GSK3640254 is 
a MI that displays in vitro evidence of low nanomolar potency against multiple HIV-1 
Gag polymorphisms and a broad spectrum covering multiple HIV-1 subtypes, supporting 
compound development.
GSK3640254 is a next-generation HIV MI which is improved over existing/prior 
developmental MIs in the following ways: (1) it exhibits significantly improved pan-
genotypic coverage and potency against polymorphic variants; (2) in vitro data suggest
that GSK3640254 exhibits a higher barrier to emergence of resistant viruses (except for 
A364V); (3) GSK3640254 has improved potency in vitro toward all HIV-1 subtypes; and 
(4) it has a projected lower once-daily (QD) human dose (see dose rationale). Summaries 
of the pre-clinical studies are included in the Clinical Investigator's Brochure (CIB) 
[GlaxoSmithKline Document Number 2016N294821_00].


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3.2.1.
Background Key Safety and PK data with a Prior Maturation 
Inhibitor (GSK3532795)
Bristol-Myers Squibb (BMS), and later VH, developed a HIV-1 MI (GSK3532795), 
which was studied through Phase 2b studies in both treatment-naïve (AI468038) and 
experienced (AI468048) HIV-1 infected adults. In study AI468038, a greater number of 
participants who received GSK3532795 experienced gastrointestinal (GI) intolerability 
(specifically G1-2 diarrhoea and abdominal pain). A detailed examination of all GI 
adverse events (AEs) (regardless of Grade/Relationship) revealed a relationship with dose
[GlaxoSmithKline Document Number 2016N302783_00]. Ultimately, the rate of GI 
intolerability in the GSK3532795 dose groups in the Phase 2b study AI468038, helped 
lead to VH’s decision to end all trials and not progress to Phase 3 studies.
GI AEs were also previously observed in healthy participants in Phase 1 studies with 
varying doses, durations, and formulations of GSK3532795. First, in AI468049, the rates 
of GI AEs ranged from 33-67% across cohorts (single oral doses of GSK3532795 60 mg 
– 180 mg with food). Second, in AI468063, 65% of participants receiving GSK3532795 
180 mg QD with food developed diarrhea. Finally, in AI468052, 29% of participants who 
received GSK3532795 180 mg QD with food developed GI AEs. In all three studies, the 
most common GI AEs were abdominal pain and diarrhoea.
Aside from mild-moderate GI intolerability, two serious adverse events (SAEs) occurred 
in phase I study AI468044: one healthy participant had acute psychosis and another had 
suicidal ideation/homicidal ideation as diagnosed through an interview by a psychiatrist. 
The two participants received GSK3532795 240 mg twice daily (BID) and 240 mg QD 
for 3 days with food, respectively. These events were not observed in any other clinical 
study with GSK3532795. The most frequent neuropsychiatric AEs in studies with 
GSK3532795 were headache, dizziness and sleep abnormalities (e.g. insomnia, abnormal 
dreams).
The PK of GSK3532795 has been characterized in healthy participants at single doses 
from 10 mg to 180 mg and at multiple doses ranging from 10 mg to 240 mg, as well as at
doses ranging from 5 mg to 180 mg in HIV-1-infected participants. These doses were 
administered as various formulations (spray-dried dispersion suspension, micronized and 
non-micronized crystalline tablets and suspensions), as single and/or multiple doses, with 
and without food. Under fasted conditions, exposures to GSK3532795 increased in a less-
than-dose-proportional manner with significant overlap in exposures at doses ≥80 mg, 
likely due to the limited solubility of GSK3532795. The effect of food was minimal at 
lower doses (≤40 mg); however, following a single oral dose of 180 mg GSK3532795 
with food, exposures increased approximately 2-fold relative to fasted conditions. 
Assessment of data across multiple clinical trials suggested that administration of 
GSK3532795 with food resulted in dose-proportional increases in exposure up to doses 
of 240 mg and that food was necessary to achieve target efficacious concentrations of 
GSK3532795.


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3.2.2.
Preliminary Safety and PK data in Current Study (SAD doses 1 -
700 mg and MAD doses 50 – 200 mg daily)
Overall, there have been no major clinical safety/tolerability findings in the SAD (single 
doses up to 700 mg) or MAD (14 days of dosing up to 200 mg) through May 7, 2018. 
There have been 20 subjects treated in the blinded SAD and 33 subjects treated in the 
blinded MAD. Preliminary ongoing data review show no deaths or SAEs. There have 
been 4 individual AEs leading to discontinuation from the trial:

Blinded SAD 10 mg arm: Depression (Grade 2, not related). 

Blinded SAD 10 mg arm: Viral Infection (Grade 1, not related) lasting two days

Blinded SAD 100 mg arm: Viral Infection (Grade 1, not related) lasting seven 
days

Blinded MAD 200 mg arm: Rash Maculopapular (Grade 1, related). This rash 
occurred 8 days after receiving study medication and lasted for 6 days. There 
were no laboratory abnormalities. A Dermatology Consultant concluded this was 
a drug rash and the subject later received fexofenadine 180 mg once daily with a 
topical steroid cream.
There have been 10 individual AEs related to study medication (9 Grade 1; One Grade 
2):

Blinded SAD 10 mg arm: Dizziness

Blinded SAD 30 mg arm: Diarrhea and Abdominal Pain

Blinded SAD 700 mg arm: Diarrhea

Blinded MAD 50 mg arm: Headache (the only G2 related AE), Fatigue, and 
Transaminases Elevated. The subject with elevated transaminases had peak ALT 
of 83 IU/L on Day 16 after study medication. The remaining LFTs were normal 
throughout. An Ultrasound showed a subcapsular area of heterogenous 
echogenicity within segment 7, measuring approximately 35 x 23 x 36 mm. A 
follow up MRI was normal.

Blinded MAD 200 mg arm: Lethargy, Nausea, and Rash Maculopapular.
Preliminary review of blinded safety data (see Table 1) for the SAD 1 - 700 mg doses 
show 17 subjects experienced 60 individual AEs (58 Grade 1; Two Grade 2). The two 
most frequent AE SOCs have been Nervous System (16 individual AEs) and 
Gastrointestinal Disorders (11 individual AEs). The most frequent AEs have been 
Headache (10 individual AEs), Diarrhea and Contact Dermatitis (5 individual AEs each), 
and Dizziness (4 individual AEs). There were four Psychiatric individual AEs (three of 
which have occurred at 1 and 3 mg single blinded arms): Depression, Insomnia, and 
Nightmare (two individual AEs). There were no Cardiac AEs. There has been no 
dose/AE relationship.
Preliminary review of blinded safety data (see Table 2) for the MAD 50 – 200 mg (Daily 
for Fourteen Days) show 23 subjects experienced 79 individual AEs (77 Grade 1; Two 
Grade 2). The two most frequent AE SOCs have been Nervous System (25 AEs) and 
Gastrointestinal Disorders (12 individual AEs). The most frequent AEs have been 


2016N297505_04
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Headache (11 individual AEs), Dizziness (6 individual AEs), and Fatigue (5 individual 
AEs). There has been no clinically relevant GI or neurologic AE/dose relationship. One 
subject in the blinded 200 mg arm accounted for 13 individual AEs (5 of which were in 
the Neurologic SOC). There were three Psychiatric individual AEs: Agitation, Abnormal 
Dreams, and Nightmare. There was one Cardiac AE (palpitations in the 200 mg blinded 
dose).
There were no clinically significant abnormal fluctuations or trends in vital signs in the 
SAD or MAD. There were no abnormal clinically significant arrhythmias or QTcF 
prolongations observed for any subject in the SAD or MAD. There were no laboratory 
abnormality trends across doses that were clinically significant or associated with any 
symptoms.
Table 1
Summary Table (all AEs) in blinded SAD 1 - 700 mg doses
AEs by Blinded SAD Cohort/Period
SOC
PT
1 
m
g
3 
m
g
10 
mg
30 
mg
100 
mg
200 
mg
400 
mg
700 
mg
Nervous System Disorders
Dizziness
1
1
1
1
Headache
1
1
2
2
2
2
Parasthesia
1
Migraine
1
Gastrointestinal Disorders
Vomitting
2
Feces Soft
1
Diarrhea
1
1
2
1
Abdominal Pain
1
Feces 
Discolored
1
Feces Pale
1
Infections and Infestations
Nasopharyngitis
1
1
1
Oral Herpes
1
Viral Infection
1
1
Upper 
Respiratory Tract 
Infection
1
Respiratory, Thoracic, and 
Mediastinal Disorders
Nasal 
Obstruction
2
1
Cough
1
1
Oropharyngeal 
Pain
1
Hemoptysis
1
Skin and Subcutaneous 
Disorders
Contact 
Dermatitis
1
1
1
1
1


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AEs by Blinded SAD Cohort/Period
SOC
PT
1 
m
g
3 
m
g
10 
mg
30 
mg
100 
mg
200 
mg
400 
mg
700 
mg
Psychiatric Disorders
Depression
1
Insomnia
1
Nightmare
1
1
Injury, Poisoning, and 
Procedural Complications
Face Injury
1
Skin Abrasion
1
Contusion
1
Limb Injury
1
General Disorders and 
Administration Site Conditions
Catheter site 
pain
1
Vessel Puncture 
Site Bruise
1
Chest Pain
1
Investigations
Transaminases 
Increased
1
1
Musculoskeletal and 
Connective Tissue Disorders
Musculoskeletal 
Pain
1
Total AEs by Blinded SAD 
Cohort/Period
9
4
13
6
10
6
7
5
Table 2
Summary Table (all AEs) in blinded MAD 50 – 200 mg doses
AEs by Blinded MAD 
Cohort/Period
SOC
PT
50 mg 
100 mg
200 mg
Nervous System Disorders
Dizziness
1
2
3
Headache
4
2
5
Somnolence
1
Disturbance in 
Attention
2
Lethargy
2
Dizziness Postural
1
Hypoaesthesia
1
Dysgeusia
1
Gastrointestinal Disorders
Lip Dry
1
Mouth Ulceration
1


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25
AEs by Blinded MAD 
Cohort/Period
SOC
PT
50 mg 
100 mg
200 mg
Aphthous Ulcer
1
Abdominal Pain
1
1
Abdominal Distention
1
1
Glossodynia
1
Constipation
2
Nausea
1
Gastroesophageal 
Reflux Disease
1
General Disorders and Administration 
Site Conditions
Catheter site pain
1
Vessel Puncture Site 
Bruise
1
1
Fatigue
2
2
1
Feeling Cold
1
Catheter site Bruise
1
Skin and Subcutaneous Disorders
Contact Dermatitis
1
2
Blister
1
Dry Skin
1
Rash
1
Rash Maculopapular
1
Pruitis
1
Musculoskeletal and Connective Tissue 
Disorders
Back pain
1
1
2
Musculoskeletal 
Stiffness
1
Muscle Twitching
1
Injury, Poisoning, and Procedural 
Complications
Laceration
1
Contusion
1
1
2
Infections and Infestations
Hordeolum
1
Abscess
1
Oral Herpes
1
Psychiatric Disorders
Agitation
1
Abnormal Dreams
1
Nightmare
1


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26
AEs by Blinded MAD 
Cohort/Period
SOC
PT
50 mg 
100 mg
200 mg
Ear and Labyrinth Disorders
Ear Discomfort
1
Excessive Cerumen 
Production
1
Renal and Urinary Disorders
Pollakiuria
1
Dysuria
1
Respiratory, Thoracic, and Mediastinal 
Disorders
Epistaxis
1
Investigations
Transaminases 
Increased
1
Cardiac Disorders
Palpitations
1
Total AEs by Blinded MAD 
Cohort/Period
19
17
43
Preliminary PK parameters for GSK3640254 following single dose administration from 1 
to 700 mg are summarized in Table 3. GSK3640254 is slowly absorbed with maximum 
concentration observed on average 3-4 hours after dosing and slowly eliminated with an 
average half-life of 24 hours. Cmax and AUC increased in a close to dose proportional 
manner from 1 to 400 mg with a plateauing in exposure at the 700 mg dose. The 
maximum observed mean Cmax for the single dose administration (Table 3) is 1881 
ng/mL at the dose of 400 mg. The maximum observed mean AUC(0-inf) for the single 
dose administration (Table 3) is 43116 ng.hr/mL at the dose of 400 mg. The mean 
exposure observed at 700 mg is slightly lower than that at 400 mg single administration 
and thus we anticipate similar exposures with doses greater than 700 mg.


2016N297505_04
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Table 3
Summary of Preliminary PK Parameters Following Single Doses of 
GSK3640254 in study 207187
Dose
1 
mg
3 
mg
10 
mg
30 
mg
100 
mg
200 
mg
400 
mg
700 
mg
PK 
Parameter
Geometric Mean 
(CV%) [N]* 
Cmax
4.9 
(16) 
[6]
13.8 
(31) 
[6]
47
(30) 
[6]
129.8 
(21) 
[6]
372.1 
(72) 
[6]
578.9 
(27) 
[6]
1881
(50) 
[6]
1760.8 
(44) [6]
Tmax
3.5 
(2.5-
6) [6]
4.5 
(2-5) 
[6]
3.5 
(2.5-5) 
[6]
4 
(2.5-5)
[6]
3.8
(2-5)
[6]
3 
(2-4) 
[6]
3.3
(2-6) 
[6]
3.3 
(2-4.5) 
[6]
T1/2(z)
NC
22 
(14) 
[6]
25.8 
(17) 
[6]
23.3 
(16) 
[6]
23.9
(14) 
[6]
23.2
(17) 
[6]
23.3
(16) 
[6]
22.2
(28) 
[6]
AUC
NC
340 
(29) 
[6]
1229.3
(19) 
[6]
3008 
(26) 
[6]
8566.4 
(67) 
[6]
14978 
(41) 
[6]
43115.
7 (52) 
[6]
39972.5 
(50) [6]
* Tmax has been reported as Median (Min - Max)
AUC represents AUC(0-inf); NC: Not Computed
Units: Cmax in ng/mL, AUC in ng.h/mL, t1/2 and tmax in hours
Preliminary PK parameters on Day 1 and Day 14 for GSK3640254 following repeat dose 
administration of 50, 100 and 200 mg for 14 days are summarized in Table 4. The 
exposures on Day 14 are on average 2-3 folds higher than that on Day 1. Cmax and AUC 
on Day 14 tended to increase in a close to dose proportional manner from 50 to 200 mg. 
The maximum observed mean Cmax for the repeat dose administration is 1528 ng/mL at 
the dose of 200 mg on Day 14. The maximum observed mean AUC(0-24) for the repeat 
dose administration is 23046 ng.hr/mL at the dose of 200 mg on Day 14. 
The anticipated mean Cmax at a proposed dose of 320 mg based on the observed 
exposures (Table 4) using a dose proportionality model is predicted to be 1030 ng/mL on 
Day 1 and 2475 ng/mL for Day 14. The anticipated mean AUC(0-24) on Day 14 at a 
proposed dose of 320 mg based on observed exposures (Table 4) using a dose 
proportionality model is predicted to be 37942 ng.hr/mL. The probability of any subject 
exceeding the PK stopping criteria for MAD study with the dose of 320 mg repeat 
dosing, which is AUC(0-24) of 61100 ng.hr/mL based on LOAEL exposure in rat at 30 
mg/kg, is 42% based on data collected through 9th May. The probability of any subject 
exceeding the PK stopping criteria for SAD study with the dose of 320 mg repeat dosing, 
which is a Cmax of 7960 ng/mL based on minimal QT effects observed in one dog, is 
0.7% based on data collected through 9th May.


2016N297505_04
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Table 4
Summary of Preliminary PK Parameters Following Repeat Dose 
administration of GSK3640254 in study 207187
Day 1
Day 14 
Dose
Dose
50 mg
100 mg
200 mg
50 mg
100 mg
200 mg
PK Parameter
Geometric Mean (CV%) [N]* 
AUC (0-24)
2867.4 
(30) [6]
6826.2 
(23) [6]
8947.1 
(49) [NP]
6285.6 (34) 
[6]
17537.5 (14) 
[6]
23046.2 (36) 
[NP]
Cmax
214.5 
(24) [6]
535.6 
(23) [6]
689.2 
(40) [NP]
413.5 (32) 
[6]
1182 (10) [6] 1528.4 (30) 
[NP]
T1/2(z)
NC
NC
NC
24.5 (8) [6] 28.6 (19) [6]
21.9 (12) 
[NP]
Tmax
3.8 (3-5) 
[6]
4.3 (2-5) 
[6]
4 (1.5-
5.5) [NP]
3.8 (2.5-5) 
[6]
4 (1.5-4.5) 
[6]
3.5 (2-5) [NP]
* Tmax has been reported as Median (Min - Max)
Units: Cmax in ng/mL, AUC in ng.h/mL and Tmax in hours
NP: Not Printed as the expansion cohort is still running. This includes 6 active subjects from 
Cohort 5 and the subjects from expansion cohort 7 studied thruMay 9th, 2018.
NC: Not Computed
3.3.
Benefit/Risk Assessment
Based upon pre-clinical studies, the major risks are GI intolerability (e.g. abdominal pain 
and diarrhoea), prolongation of QTc, and neuropsychiatric safety. Reproduction of 
preclinical GI toxicity findings (e.g. single-cell parietal cell necrosis) would be unlikely 
during the limited dosing of GSK3640254 in this study. As noted in Section 3.3.1, one 
pre-clinical study did show one dog with an increased QTc interval when given a single 
dose of GSK3640254. Finally, the protocol will exclude potential participants from either 
SAD or MAD with any pre-existing psychiatric condition or positive (abnormal) 
response confirmed by the investigator on a clinician (or qualified designee) administered
CSSRS. The CSSRS assessment will also be administered by a clinician (or qualified 
designee) during the on-treatment portion of the MAD only.
Thus, to ensure the overall safety of participants (including, but not limited to, the risk of 
GI intolerability, QTc prolongation, and neuropsychiatric safety), this clinical trial will 
include healthy adults who will receive frequent clinical, ECG, and laboratory 
evaluations in-house during their participation in the trial.
The clinical data gathered through May 7, 2018 is summarized in Section 3.2.2 Overall, 
there have been no major clinical safety/tolerability findings in the SAD (single doses up 
to 700 mg) or MAD (14 days of dosing up to 200 mg). The proposed amendment seeks to 
evaluate a higher dose (320 mg Daily) in the MAD. The probability of the AUC(tau) 
exceeding the established PK stopping criteria is 42%. Subjects recruited for the 320 mg 
QD dose in Cohort 6 will have the same inclusion/exclusion criteria, have the same study 


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and subject stopping criteria, and undergo the same safety evaluation. Based upon the 
preliminary safety and PK data gathered to date (see Section 3.2.2) subjects will be 
adequately monitored.
ViiV Healthcare has assessed this study for any risks that may be posed to participants 
taking part. The proposed risk assessment and management plan for the study has been 
developed in accordance with the tenets of European Medicines Agency (EMEA) 
guidance on strategies to identify and mitigate risks for FTIH clinical trials with 
investigational medicinal products (EMEA/CHMP/SWP/28367/XX). 
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of GSK3640254 may be found in the CIB
[GlaxoSmithKline Document Number 2016N294821_00].


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3.3.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) GSK3640254
Cardiovascular (QT prolongation)
Pre-clinically, GSK3640254 inhibited cardiac 
hERG/IKr potassium, cardiac SCN5A sodium and L-
type calcium channel currents recorded from HEK 
293 cells stably transfected with cDNA from the ion 
channels. In a single-dose safety pharmacology 
study in telemeterized dogs, increases in QT 
interval (up to 20 ms) occurred primarily in one dog 
given 17 mg/kg. Later, there were no GSK3640254-
related effects on ECG parameters in dogs given up 
to 25 mg/kg/day for 4 weeks.
Protocol exclusion criteria based on screening 
Holter and ECG parameters and cardiac medical 
history.
Participants in the SAD/MAD will have a 24 hour 
holter monitor during the screening period and 
continuous ECGs during treatment; they will also 
have frequent clinical and VS evaluations (see 
SoA table).
Gastrointestinal intolerability and toxicity
Clinical signs indicative of gastrointestinal 
intolerability (sporadic vomiting and abnormal 
faeces beginning on Day 1 and continuing 
throughout the dosing periods) occurred mainly in 
dogs at 1 mg/kg/day. Additionally, toxicity findings 
of single-cell necrosis of parietal cells and/or chief 
cells were present in preclinical species. These 
findings were reversible. Finally, GI intolerability
(predominately abdominal pain and diarrhea) was 
seen with a structurally related compound 
GSK3532795 which was evaluated through Phase 
2b dosing. 
Protocol exclusion criterion based on pre-existing 
GI pathology or baseline GI signs/symptoms
Participants in the SAD and MAD will undergo 
intensive physical exam and laboratory testing. In 
addition, participants will undergo continuous 
evaluation for adverse events during their 
participation in the trial; there are clinical stopping 
criteria based upon incidence and intensity of 
treatment-emergent AEs. Finally, a general GI 
toxicity evaluation and monitoring plan will be 
available to guide the PI should GI AEs emerge 
(See Section 9.4).


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Neurologic/psychiatric safety
Two psychiatric SAEs in previous MI GSK3532795 
clinical program (acute psychosis, homicidal/suicidal 
ideation) at supratherapeutic doses were seen in 
healthy subjects in TQT study.
From a Neurologic and Psychiatric AE summary 
and PK/PD analysis for GSK3532795 across all 
studies mild G1 headache and G1 sleep 
abnormalities were the predominant AEs, with a 
trend for increasing neurologic and psychiatric AEs 
with increasing dose (based on TQT and P2b 
studies). No exposure-response relationship seen 
for select neurologic and psychiatric AEs (based on 
TQT and P2b studies)
CNS penetration data for GSK3532795 and 
GSK3640254 in rats demonstrate a similarly low 
brain distribution/penetration
Protocol exclusion criterion based on any pre-
existing psychiatric condition (including 
assessment using the CSSRS) for participants in 
both the SAD and MAD.
Participants in the SAD and MAD will undergo 
intensive physical exam and laboratory testing. In 
addition, participants will undergo continuous 
evaluation for adverse events during their 
participation in the trial; there are clinical stopping 
criteria based upon incidence and intensity of 
treatment-emergent AEs. 
Subjects will be housed throughout the MAD 14day 
component to ensure rapid diagnosis and 
management of any potential event.
Finally, participants in the MAD only will have 
assessment via a clinician (or qualified designee) 
administered CSSRS during the on-treatment 
portion of the study. In the event of a positive 
(abnormal) response confirmed by the investigator, 
the participant will discontinue from the trial and the 
PI/SI will arrange for urgent specialist psychiatric 
evaluation and management.


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3.3.2.
Benefit Assessment
This is a study in healthy participants; no medical benefit will be derived by volunteers’ 
participation. 
3.3.3.
Overall Benefit:Risk Conclusion
Given the preclinical profile of GSK3640254, the clinical profile of a structurally similar 
MI (GSK3532795), the preliminary clinical data gathered through May 7, 2018 and the 
planned clinical procedures and evaluations in this study, the potential risks to 
participants receiving GSK3640254 are low, evaluable, and manageable.  
3.3.4.
Acute Monitoring in FTIH Studies
Consistent with GSK/VH Guidance and CHMP guidelines for early phase studies, the 
study will be conducted in an accredited Phase 1 Clinical Research Unit with previous 
experience with first-time-in-human trials and immediate access to hospital facilities for 
the treatment of medical emergencies.


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4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To investigate the safety and tolerability of 
GSK3640254 following single and repeated 
daily administration

GSK3640254 safety parameters:  adverse 
events; post-baseline values and changes 
over time of clinical laboratory evaluations 
(haematology, clinical chemistry, urinalysis), 
vital signs, and ECG parameters from pre-
dose values
Secondary

To describe the PK of GSK3640254 
following single and repeated daily 
administration

To examine dose proportionality following 
single and repeated doses of GSK3640254 

GSK3640254 PK parameters:
Part 1 (single dose): AUC(0-24), AUC(0-
tlast), AUC(0-inf), Cmax, C24, tmax, tlag, 
t1/2, Clast, tlast, CL/F.  
Part 2 (Repeated QD doses for 14 days):  
Day 1: AUC(0-24), Cmax, C24, tmax, tlag
Day 14: AUC(0-), Cmax, C, tmax, t1/2, 
and CL/F

GSK3640254 Single dose: AUC (0-inf), 
Cmax. Repeat dose AUC(0-), Cmax, C

To assess accumulation of GSK3640254 

Accumulation ratios: R AUC(0-), R (Cmax), 
R (C)

To assess time to steady-state of 
GSK3640254 

Pre-dose concentrations on Day 2-14 (Part 
2)
Exploratory

To assess the exposure response 
relationship between GSK3640254 and 
safety parameter, including QTcF following 
single and repeated administration

To investigate the biotransformation of 
GSK3640254 in plasma and urine

As available, to assess the impact of food 
on the PK of GSK3640254 

Change-from-baseline QTcF (∆QTcF)

Provide samples of plasma and urine for the 
identification of any compound-derived 
metabolite(s)

GSK3640254 single dose Cmax, AUC(0-
inf), and C24
AUC(0-24) = Area under the plasma concentration time curve from zero to 24; AUC(0-inf) = Area under the 
concentration-time curve from time zero (pre-dose) extrapolated to infinite time; Cmax= Maximum observed 
concentration; tmax= Time of occurrence of Cmax; t1/2= Apparent terminal phase half-life; CL/F= Apparent oral 
clearance
Note: The exploratory endpoints may be analyzed once GSK3640254 clinical 
development continues.


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5.
STUDY DESIGN
5.1.
Overall Design
This study is a Phase 1, double-blind (sponsor-unblinded), randomized, placebo-
controlled, single- and repeat-dose escalation study to investigate the safety, tolerability, 
and PK of GSK3640254 in healthy participants. Approximately 72 healthy participants 
will be randomized in one of two parts: Part 1 (SAD) and Part 2 (MAD). The total 
number of cohorts in the SAD will be two; the total number of cohorts in the MAD will 
be five. The entire trial will be conducted in an inpatient clinical trial unit.
A summary of the overall study design, including proposed doses, sample size, and order, 
is presented in Figure 2; SoA tables are included in Section 2.
As described in detail below, the proposed dosing schedule is designed to investigate 
single doses of GSK3640254 initially in Part 1 and then, at a suitable cross-over point,
begin repeated once-daily dosing of GSK3640254 in Part 2. All doses will be 
administered immediately following a moderate fat meal (approximately 600 calories 
with approximately 30% of calories from fat), unless otherwise indicated.
Figure 2
Phase 1 Study in Healthy Participants using planned doses of 
GSK3640254
Note: A=active, P=placebo. The doses shown here were/are being completed. Amendment 04 proposes to 
evaluate a 320 mg Daily dose in MAD Cohort 6.
Study Design Details Part 1 (SAD):
The SAD portion of the study will be conducted in an interlocking fashion with two 
separate cohorts of eight healthy participants each. Each of these two cohorts will contain 
up to four escalating doses of GSK3640254. The interlocking design as shown in Figure 
2 and the randomization sequence in Table 5 will allow the 8 participants in each Cohort 


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to potentially receive one of the two lowest and one of the two highest doses of 
GSK3640254. In each escalating period and Cohort, 6 participants will be randomized to 
GSK3640254 and 2 participants will be randomized to placebo. Details of the starting 
dose and dose escalation can be found in Section 5.5.3.
Participants in Cohort 1 and Cohort 2 will follow the same randomization strategy with 
alternating ascending doses (Table 5). Two participants in either Cohort will be assigned 
to one of the four treatment sequences, and each participant will receive placebo once. 
Table 5
Description of treatment sequences in Cohort 1 and Cohort 2
Cohort 1
Period 1
Period 2
Period 3
Period 4
Sequence 1
Placebo
Dose 3
Dose 5
Dose 7
Sequence 2
Dose 1
Placebo
Dose 5
Dose 7
Sequence 3
Dose 1
Dose 3
Placebo
Dose 7
Sequence 4
Dose 1
Dose 3
Dose 5
Placebo
Cohort 2
Period 1
Period 2
Period 3
Period 4
Sequence 1
Placebo
Dose 4
Dose 6
Dose 8
Sequence 2
Dose 2
Placebo
Dose 6
Dose 8
Sequence 3
Dose 2
Dose 4
Placebo
Dose 8
Sequence 4
Dose 2
Dose 4
Dose 6
Placebo
Part 1 SAD: Sentinel Dosing
To conservatively assess safety, at the start of each dose period of the SAD, 2 out of the 8 
participants will serve as sentinel participants with one receiving GSK3640254 and the 
other receiving placebo. These sentinel participants will be followed clinically for 24 
hours after dose administration to monitor for emergence of adverse events. If there are 
no safety concerns, in the judgment of the PI, on review of the 24-hour safety data (e.g. 
vital signs, ECGs, and adverse events) for the sentinel participants, the remaining 6
participants will subsequently be administered either GSK3640254 or PBO according to 
randomization schedules.
Part 1 SAD: Dose Escalation
Dose escalation in Part 1 will be determined by the VH/GSK study team and the PI based 
on the double-blind (sponsor-unblinded) safety data and the PK data from the current and 


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previous dose(s). Dose escalation will not exceed approximately 3-fold between doses up
to approximately the predicted minimally effective dose and will not exceed 2-fold 
thereafter. Dose escalation in Part 1 will require (from the current dosing group) at least 
24 hours of safety and PK data from 4 participants receiving active drug. Dose escalation 
will be guided by safety as well as the SAD PK stopping criteria (see Section 8). Due to 
the alternating dosing periods between Cohort 1 and Cohort 2, a participant in either 
cohort will receive the next dose after approximately 3 or 4 weeks.
Part 2 (MAD):
Part 2 consists of four ascending repeat-dose cohorts (Cohorts 3 to 6), each with 8 
participants (active/PBO=6/2) who will receive a once-daily dose of GSK3640254 or 
PBO for 14 days. Details of the starting dose and dose escalations in Part 2 (MAD) are 
provided in Section 5.5.4.
The earliest point at which Part 2 (MAD) of the study will be initiated is once the single 
dose safety and preliminary PK data for the anticipated minimally effective dose has been 
evaluated in the SAD. The potential minimally effective dose for GSK3640254, noted as 
X, is anticipated to be that which is predicted to provide a steady state Ctrough ≥ 0.11 
g/mL in 95% of participants and will be re-estimated based on the PK data collected in 
the early doses in Part 1 (see Section 5.5.2 for further details). The initial dose in the 
MAD (Cohort 3) will be approximately half the anticipated minimally effective dose or 
0.5X. Dose escalation in the MAD will not exceed approximately 2-fold between cohorts
and will be driven by safety and PK stopping criteria (see Section 8). In addition, a dose 
will not be assessed in the MAD until the anticipated steady-state exposure (Cmax and 
AUC(0-) on Day 14) for that dose have been evaluated and shown not to have met 
safety stopping criteria in the SAD portion of the study (Part 1). However, as a plateau in 
exposure has been seen in the SAD between 400 mg and 700 mg, the highest dose in the 
MAD may be evaluating steady-state Cmax concentrations that are up to 50% greater
than previously observed in the SAD while not exceeding AUC already explored in the 
SAD. The 320 mg QD dose Cmax on Day 14 will not exceed the SAD PK stopping 
criteria (see Section 8).
Dose escalation in Part 2 will be determined by the VH/GSK study team and the PI based 
on the double-blind (sponsor-unblinded) safety and PK data (minimally up to 24 h post 
Day 14 dose) from the current and previous dosing cohort(s). Specifically, 14 days of 
safety and PK data (minimally up to 24 h post Day 14 dose) from a minimum of four 
participants in current cohort receiving active drug will be required for dose escalation.
Part 2 also includes an Expansion Cohort which was conducted at the conclusion of 
Cohort 5. VH’s prior and structurally similar MI (GSK3532795) ceased development in 
Phase 2b (due in part to a higher proportion of participants experiencing GI 
intolerability). GSK3532795, studied in Phase 1 studies of normal healthy volunteers 
showed diarrhoea of up to 65%. The Expansion Cohort will evaluate the rate of GI 
intolerability in 24 participants (active/PBO =18/6). The dose studied (200 mg) was 
previously studied doses in the MAD and did not meet safety or PK stopping criteria. 
While no formal statistical testing will be performed, a summary of GI AEs will be 
provided from: 1) 24 participants receiving one of the GSK3640254 doses studied 


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previously and 2) 14 participants receiving placebo across the entire MAD. These 
numbers of participants should provide sufficient clinical inference and better estimation 
of GI AEs frequency at a given dose (which can be used to inform subsequent dose 
selection/therapeutic index for HIV-1 infected participants).
Participants in both Part 1 and Part 2 will have a screening visit within 30 days prior to 
first dose and a follow-up visit 7-14 days after the last dose. Maximum duration of study 
participation will be approximately 12 weeks.
5.2.
Number of Participants
A total of approximately 72 healthy participants will be randomized in the trial: SAD 
(n~16) and MAD (n ~56). 
If participants prematurely discontinue the study in the SAD, they may be replaced at the 
discretion of the Sponsor in consultation with the investigator. The replacement
participants will be assigned to the same treatment sequence where the prior participant 
prematurely discontinued. Previously administered doses will not be repeated by 
replacement subjects if dose escalation criteria are met.
If participants prematurely discontinue the study in the MAD, they may be replaced at the 
discretion of the Sponsor in consultation with the investigator. The replacement
participants will be assigned to the same treatment in the same Cohort where the prior 
participant prematurely discontinued.
5.3.
Participant and Study Completion
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the last scheduled procedure shown in the Schedule of 
Activities.
The end of the study is defined as the date of the last visit of the last participant in the 
study.
5.4.
Scientific Rationale for Study Design
This study is a first time in human (FTIH) study that will assess the safety, tolerability, 
and PK of GSK3640254, an HIV-1 MI. The data gathered will inform subsequent clinical 
trials for GSK3640254, including a Phase 2a POC study in HIV-1-infected participants.
All doses of GSK3640254 in this study will be administered in the fed state, with dosing 
occurring within 5 minutes of completing a moderate fat meal, unless noted otherwise. 
Data with a previous MI, GSK3532795, demonstrated that food was necessary to achieve 
dose proportional PK and target efficacious concentrations (see Section 3.2.1). Given the 
structural similarities, including solubility limitations, between GSK3532795 and 
GSK3640254, administration of GSK3640254 with food in this study is expected to 
enhance both bioavailability and the likelihood for linear PK, allowing for a rigorous 
assessment of safety and tolerability across a larger exposure range than would be 
allowed in the fasted state. Finally, VH intends to administer GSK3640254 in the fed 


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state in a future Phase 2a POC study in HIV-infected participants; the current study will 
assess the safety, tolerability, and PK of GSK3640254 under the same conditions in 
healthy participants prior to dosing in HIV-infected participants. The impact of food on 
exposures to GSK3640254 will be assessed in a future Phase 1 study in healthy 
participants during clinical development.
In Part 2 of the study (MAD), doses potentially up to 4 times the minimally anticipated 
effective dose (~ 80 mg QD) are planned to be evaluated. In future studies in HIV-1-
infected participants, these doses/exposures may be evaluated to understand the 
relationship between GSK3640254 exposures and efficacy, duration of response, and 
resistance development (see Section 5.5.2). Furthermore, assessment of this 
dose/exposure range (anticipated to be the therapeutic exposure range in the target 
population) in healthy participants will inform safety and tolerability prior to exposing a 
more vulnerable HIV-1-infected population to GSK3640254 and will inform risk 
mitigation strategies for potential drug interactions.
This dose/exposure range in healthy participants is clinically reasonable based upon the 
preclinical profile of GSK3640254, the clinical profile of a prior MI (GSK3532795), and 
the planned inpatient evaluation for treatment emergent risks: including QT prolongation, 
GI intolerability/toxicity, and neuropsychiatric safety – which will frequently be 
monitored in this limited dosing duration setting.
5.5.
Dose Justification
5.5.1.
Predicted Human Pharmacokinetics
The pharmacokinetic profile for GSK3640254 in humans was predicted using allometric 
scaling across all species (mouse, rat, dog, and monkey), and was combined with Css-
MRT modeling to obtain the predicted human PK profile. Using this method, the IV 
plasma clearance in humans for GSK3640254 was projected to be low (0.47 mL/min/kg). 
The intravenous volume of distribution was assumed to be the same as in dogs or close to 
total body water (0.5 L/kg). The elimination half-life was anticipated to be around 15 
hours, leading to a small anticipated accumulation with once daily dosing of ~50%. The 
mean oral bioavailability in animals was 58% and assumed for exposure projections in 
humans. 
The emerging PK data are presented in Section 3.2.2.
5.5.2.
Predicted Human Effective Dose
Steady-state trough concentrations are typically the PK parameter of interest for efficacy 
for other antiretroviral classes such as protease inhibitors and integrase inhibitors. The 
minimum target steady state trough level for GSK3640254 was established using a value 
of 3 times the protein binding-adjusted EC90 (3xPBA-EC90) for one of the least sensitive 
variants, a triple-mutant polymorph (R361K/V362I/L363M), from a library of 36 gag/pr
genotyped viruses. This virus exhibited EC50, EC90 and 3x PBA EC90 values of 3, 7 
and 150 nM (0.11 g/mL), respectively. This 3xPBA-EC90 represents the anticipated 
minimal effective trough concentration of GSK3640254. 


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The potential minimally effective dose for GSK3640254 was initially estimated using the 
predicted human PK profile, assuming similar between-participant PK variability to that 
observed with GSK3532795 (Population PK model based on data from Phase 2b study 
AI468038, Metrum Research Group, 2016), to ensure that 95% of participants have 
steady state trough concentrations that exceed the target concentration of 0.11 g/mL
following once daily dosing of GSK3640254. This led to the prediction of a likely 
minimally effective once daily dose of approximately 40 mg, assuming 58% 
bioavailability. Following single administration of 1, 3 and 10 mg of GSK3640254 in this 
study, a pharmacokinetic model was fit through the concentration-time data and these 
population PK parameters were used along with the previously assumed PK variabilities. 
The updated minimally effective once daily dose was approximately 70 mg. At this dose, 
the mean repeat-dose Cmax is predicted to be approximately 0.544 g/mL, mean trough 
concentration is predicted to be approximately 0.238 g/mL and mean AUC is predicted 
to be approximately 8.91 g.h/mL (Table 8). The anticipated steady-state mean AUC is 
2.52-fold lower than the NOAEL in the rat, 6.86-fold lower than the LOAEL in the rat, 
and 8.23-fold lower than the LOAEL in the dog. The population PK model was further 
updated with all the concentration-time data available up to 9 May 2018 (excluding the 
700 mg SAD dose) and the population PK parameters including the between subject 
variabilities were used to provide the updated minimally effective once daily dose of 
approximately 80 mg.
The relationship between GSK3640254 exposure and efficacy, duration of antiviral 
response, and development of on-treatment resistance will be evaluated in future studies 
in HIV-1-infected participants where assessment of a range of exposures will be 
important to inform the therapeutic dose range of GSK3640254. One exposure parameter 
of interest is inhibitory quotient (IQ), where IQ = Ctrough/PBA-EC90. The IQs of other 
antiretrovirals at approved doses are approximately 19, 27, and 36 for dolutegravir 50 mg 
once daily, atazanavir 300 mg once daily with ritonavir, and lopinavir 400 mg twice daily 
with ritonavir, respectively [Van Lunzen, 2012 and Zhu, 2012]. For GSK3640254, the 
minimally effective dose provides a trough concentration of 0.11 ug/mL at steady state in 
95% of the participants and represents a geometric mean IQ of 7.92. To facilitate 
assessment of a range of GSK3640254 IQs in future studies in the target population, 
doses up to 4 times those of the minimally effective dose are planned for assessment in 
Part 2 (MAD) in healthy participants. These doses will be administered in accordance 
with PK and safety stopping criteria (see Section 8.1.3). Projected exposures at the 
highest anticipated once daily dose in the MAD include a mean repeat-dose Ctrough of 
1.02 ug/mL and an IQ of 27.8.
5.5.3.
Part 1 (SAD) Starting Dose and Dose Escalation
The starting oral dose of GSK3640254 in the SAD will be 1 mg. Assuming a 10-fold 
safety factor and a body weight of 60 kg, this starting dose is lower than that calculated 
based on the NOAEL in rat of 10 mg/kg (maximum recommended starting dose (MRSD)
= 9.6 mg) and the lowest observed adverse effect level (LOAEL) in dog of 1 mg/kg 
(MRSD = 3.24 mg), in the absence of a no observed adverse effect level (NOAEL) in dog
[Guidance for Industry estimating the maximum safe starting dose in initial clinical trials 
for therapeutics in adult healthy volunteers. FDA/CDER, July 2005]. Although a NOAEL 
was not established in the 4-week dog study due to the presence of gastric toxicity at all 


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doses, the gastric findings at 1 mg/kg/day (LOAEL) were minimal in severity, reversible,
and observed in only one dog.
Based on the predicted human PK, a 1 mg dose would provide a mean AUC(0-inf) of 
0.343 g.h/mL and a mean Cmax of 0.0197 g/mL. This predicted AUC(0-inf) is 65-fold 
lower than that observed in the rat at the NOAEL, 178-fold lower than that observed in 
the rat at the LOAEL, and 214-fold lower than that observed in the dog LOAEL. 
Dose escalations in Part 1 (SAD) will be governed in real-time by safety and PK stopping 
criteria (see Section 8.1.3 and Section 8.1.4). A dose will not be assessed in the MAD 
until the anticipated steady-state exposures (Cmax and AUC(0-) on Day 14) for that 
dose have been evaluated and shown not to have met PK or safety stopping criteria in the 
SAD portion of the study (Part 1). The maximum dose in the MAD is planned to be 
approximately 4X, where X is the minimally efficacious dose given once daily (see 
Section 5.5.2).  To account for anticipated accumulation of 115% upon repeat dosing, the 
highest dose in the SAD will be approximately 9X. This will allow single dose evaluation 
of the highest anticipated steady-state exposures before once daily administration of the 
highest MAD dose. Based on the assumptions described above, the anticipated maximum 
dose in Part 1 is a single dose of up to 700 mg. The predicted mean single dose Cmax of 
700 mg is 2.74 g/mL. Given different assumptions of with-in and between participant 
Cmax variability, the probabilities of any participant Cmax being above 7.96 g/mL, the 
SAD PK Stopping Criterion (Section 8.1.3), are illustrated in 6. All doses in the SAD are 
governed by safety and PK stopping criteria. A dose which has met formal clinical, QT, 
or PK stopping criteria will not be repeated in the SAD (or MAD).


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Table 6
Probability of any SAD participant (Cmax >7.96 µg/mL) for potential 
doses
Cmax Variability
Potential GSK3640254 SAD Doses
%CVw1
%CVb1
30mg
100mg
200mg 400mg
700mg
7.5
15
0
0
0
0
0
15
15
0
0
0
0
0.001
12.5
25
0
0
0
0
0.005
25
25
0
0
0
0
0.038
17.5
35
0
0
0
0.001
0.071
35
35
0
0
0
0.01
0.191
25
50
0
0
0
0.024
0.261
50
50
0
0
0.007
0.094
0.445
Note: 1, %CVw: within-participant coefficient of variation. %CVb: between-participant 
coefficient of variation
5.5.4.
Part 2 (MAD) Starting Dose and Dose Escalation
The initial dose in the MAD (Cohort 3) will be approximately half the likely minimally
effective dose, re-estimated based on the clinical PK data collected in the early doses of 
Part 1. Dose escalation in the MAD will not exceed approximately 2-fold between 
cohorts, and will be governed by both safety and MAD PK stopping criteria (see Section 
8.1.3 and Section 8.1.4). Given different assumptions for the between participant AUC 
variability (%CVb) and the current human PK prediction, the probability of any 
participant AUCtau in the MAD above 61.1 g.hr/mL, the MAD PK Stopping Criterion 
(Section 8.1.3), are illustrated in Table 7. 


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Table 7
Probability of any MAD participant (AUCtau > 61.1 µg.h/mL) for 
potential QD doses
AUC variability
Potential GSK3640254 QD MAD Doses
%CVb1
40mg
80mg
150mg
300mg
0.15
0
0
0
0.009
0.25
0
0
0
0.162
0.35
0
0
0
0.41
0.5
0
0
0.041
0.631
Note: 1, %CVb: between-participant coefficient of variation
5.5.5.
Dose Escalation Committee
This study will utilize a dose escalation committee made up of at least the following 
GSK/VH staff: PI, Sub-Investigator, Medical Monitor, pharmacokineticist, data manager, 
statistician, and study manager. The committee will evaluate data including but not
limited to: AEs, vital signs, laboratory findings, ECG parameters, and PK data. The 
blinding of personnel is discussed in Section 7.4.
5.5.6.
Anticipated Exposure and Safety Cover for a Range of Potential 
Doses
Projected steady-state exposures of GSK3640254 from potential doses in Part 2, taking 
into consideration the PK emerging from single doses of 1, 3 and 10 mg, are compared to 
target efficacious concentrations and preclinical toxicity exposures in Table 8. Predicted 
human exposure following multiple doses can be compared to the NOAEL and LOAEL 
in rats and only to a LOAEL in dogs. Findings in both species were GI related, limited 
and reversible (see Section 3.3.1 and the CIB for details).
Importantly, the doses listed here are nominal and are intended to demonstrate general 
concepts relating to factors of escalation. Dose escalation is exposure-based and the
specific doses in the SAD and MAD portions are subject to change based upon emerging 
clinical and PK data gathered in this study. As described above, dose escalations will be 
governed in real-time by safety and PK. A dose which has met formal clinical, QT, or PK 
stopping criteria (see Section 8) will not be repeated in the SAD or MAD.


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Table 8
Projected steady-state PK for a range of potential QD doses 
following fed administration and comparison to efficacy target and 
preclinical exposure
Parameter
40 mg
80 mg
150 mg
300 mg
Ctrough, ug/mL
Mean
0.136
0.272
0.509
1.019
Lower bound of 90% CI
0.0680
0.136
0.255
0.510
Ctrough/Ctarget
Mean
1.23
2.47
4.63
9.26
Lower bound of 90% CI
0.618
1.24
2.32
4.64
Cmax Day 1, ug/mL
Mean
0.157
0.314
0.588
1.18
Upper bound of 80% CI
0.360
0.720
1.35
2.70
Cmax Cover with
Rat NOAEL
6.59
3.293
1.756
0.878
Dog LOAEL
11.56
5.780
3.083
1.541
Cmax Day 14, ug/mL
Mean
0.311
0.622
1.17
2.33
Upper bound of 80% CI
0.484
0.968
1.82
3.63
Cmax Cover with
Rat NOAEL
4.90
2.448
1.306
0.653
Dog LOAEL
8.60
4.298
2.292
1.146
Mean AUC, ug.h/mL
Mean
5.09
10.2
19.1
38.17
Upper bound of 80% CI
7.26
14.5
27.2
54.49
AUC Cover with
Rat NOAEL
3.08
1.542
0.822
0.411
Rat LOAEL
8.41
4.205
2.243
1.12
Dog LOAEL
10.09
5.04
2.69
1.35
Note: The upper bound of the 80% CI is presented to capture the likely highest PK values in 6 subjects. The 
Cmax and AUC cover were computed as the ratio of Cmax or AUC in animal divided by the Upper Bound 
of the 80% CI predicted for humans. Ctarget = 3xPBA-EC90 (0.11 µg/mL). These predictions are taking 
into consideration the emerging PK observed after single administration of 1, 3 and 10 mg.


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6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1.
Participant must be 18 to 55 years of age inclusive, at the time of signing the 
informed consent.
Type of Participant and Disease Characteristics
2.
Participants who are overtly healthy as determined by medical evaluation including 
medical history and psychiatric history, physical examination, laboratory tests, and 
24 h Holter monitoring.
Weight
3.
Body weight 50.0kg (110lbs.) for men and 45.0kg (99lbs) for women and body 
mass index (BMI) within the range 18.5-32.0kg/m2 (inclusive).
Sex
4.
Male or female
a. Male participants:
A male participant must agree to use contraception as detailed in Appendix 5 of this
protocol during the treatment period and for at least 14 weeks following the last 
dose, corresponding to the time needed to eliminate study treatment for potential
genotoxic and teratogenic study treatments plus an additional 90 days 
(spermatogenesis cycle). In addition, male participants must refrain from donating 
sperm during this period.
b. Female participants: 
A female participant is eligible to participate if she is not a woman of childbearing 
potential (WOCBP) as defined in Appendix 5.
Informed Consent
5.
Capable of giving signed informed consent as described in Appendix 3 which
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.


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6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
Alanine transaminase (ALT) >1.5x upper limit of normal (ULN) 
2.
Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%). 
3.
Current or chronic history of liver disease, or known hepatic or biliary abnormalities.
4.
Pre-existing clinically relevant, in the opinion of the PI, gastro-intestinal pathology 
or diagnosis – e.g. irritable bowel syndrome, inflammatory bowel disease, and/or 
significant baseline signs and symptoms.
5.
Medical history of cardiac arrhythmias or cardiac disease or a family or personal 
history of long QT syndrome.
6.
Any known or suspected pre-existing psychiatric condition
7.
Any positive (abnormal) response confirmed by the investigator on a screening 
clinician (or qualified designee) administered CSSRS for either the SAD or MAD.
8.
Any other clinical condition (including but not limited to active substance use) or 
prior therapy that, in the opinion of the Investigator, would make the participant
unsuitable for the study; unable to comply with dosing requirements; or unable to 
comply with study visits; or a condition that could affect the absorption, distribution, 
metabolism or excretion of the drug.
Prior/Concomitant Therapy and Dietary Restriction
9.
Unable to refrain from the use of prescription or non-prescription drugs (with the 
exception of paracetamol), 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 
medication and for the duration of the study, unless in the opinion of the Investigator 
and VH Sponsor and Medical Monitor, the medication will not interfere with the 
study medications, procedures, or compromise participant safety (see Section 7.7).
10. Unwillingness to abstain from ingestion of any food or drink containing grapefruit 
and grapefruit juice, Seville oranges, blood oranges, or pomelos within 7 days prior 
to the first dose of study treatment(s) or until the end of the study.
Prior/Concurrent Clinical Study Experience
11. Participation in another concurrent clinical study or prior clinical study (with the 
exception of imaging trials) 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). 
12. Where participation in the study would result in donation of blood or blood products 
in excess of 500mL within 56 days.


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Diagnostic assessments
13. Presence of hepatitis B surface antigen (HBsAg), or positive hepatitis C antibody test 
result at screening or within 3 months prior to first dose of study treatment.
14. A positive pre-study drug/alcohol screen.
15. A positive test for a diagnostic HIV-1 PCR 
16. Exposure to more than four new chemical entities within 12 months prior to the first 
dosing day.
17. Exclusion criteria for screening ECG (a single repeat is allowed for eligibility 
determination):
Males
Females
Heart rate
<45 or >100bpm
<50 or >100bpm
PR Interval
<120 or >220msec
QRS duration
<70 or >120msec
QTcF interval 
>450msec
Note: A heart rate from 100 to 110bpm can be rechecked by ECG or vitals within 30 
minutes to verify eligibility.
18. Evidence of previous myocardial infarction (does not include ST segment changes 
associated with re-polarization).
19. Any conduction abnormality (including but not specific to left or right complete 
bundle branch block, AV block [2nd degree or higher], WPW syndrome).
20. Sinus Pauses >3 seconds.
21. Any significant arrhythmia which, in the opinion of the Investigator OR GSK/ViiV 
Medical monitor, will interfere with the safety for the individual participant.
22. Non-sustained or sustained ventricular tachycardia (3 consecutive ventricular 
ectopic beats).
Other Exclusions
23. History of regular alcohol consumption within 6 months of the study defined as: an 
average weekly intake of >14 units. One unit is equivalent to 8 g of alcohol: a half-
pint (~240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
24. Regular use of tobacco- or nicotine-containing products within 3 months prior to 
screening.
25. 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.


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6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions

Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit 
juice, pomelos, exotic citrus fruits, grapefruit hybrids, or their fruit juices from 7 
days before the start of study treatment until after the final PK sample in the study.

Unless otherwise indicated, all doses of GSK3640254 in this study will be 
administered in the fed state. The participants will fast for approximately 9.5 hours 
prior to dosing and will receive the moderate fat meal 30 minutes prior to dosing. 
Participants will eat this meal in 30 minutes or less. Dose administration will occur 
within 5 minutes of completion of meal consumption. Participants will not receive 
any further food until 4 hours post-dose. The moderate fat meal will contain about 
600 calories with approximately 30% of them coming from fat.

For food effect studies, water restrictions may be needed. No water is allowed from 2 
hours prior to dosing until 2 hours after dosing except for the glass of water needed 
to administer the study medication (e.g. 240 mL). Water is allowed ad libitum at all 
other times.

For the participants who may receive the study medication in fasted conditions, the 
participant will fast overnight (for at least 10 hours prior to dosing) and for an 
additional 4 hours after dosing. 

A snack and meal will be provided 4 hours and 10 hours, respectively, after dosing.

Meals on Day -1 will follow the Day 1 schedule.
6.3.2.
Drugs, Caffeine, Alcohol, and Tobacco

During each dosing session, participants will abstain from ingesting caffeine- or 
xanthine-containing products (eg, coffee, tea, cola drinks, and chocolate) for 24 
hours before admission to the unit (Day-2) until after collection of the final PK 
sample in each dosing session. Participants will be allowed to have caffeine or 
xanthine-containing products between dosing periods.

During each dosing session, participants will abstain from alcohol for 24 hours 
before admission to the unit (Day-2) until after collection of the final PK sample in 
each dosing session. Participants will be allowed to have alcohol products between 
dosing periods up to less than 14 units per week.

Use of tobacco products will not be allowed from screening until after the final 
follow-up visit.

Subjects must have a negative drug test at screening and must abstain from 
recreational drug use from screening until after the final follow-up visit.


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6.3.3.
Activity

Participants will abstain from strenuous exercise for 24 hours before each blood 
collection for clinical laboratory tests. Participants may participate in light 
recreational activities during studies (eg, watching television, reading).
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized. However, reserve participants only need to 
undergo the screening process once every 90 days; additionally, reserve participants will 
still be subject to Day -2 and -1 evaluations in routine fashion (as shown in the SoA
table). A minimal set of screen failure information is required to ensure transparent 
reporting of screen failure participants to meet the Consolidated Standards of Reporting 
Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility 
criteria that established screen failure, and any serious adverse events (SAEs).
Individuals who do not meet the criteria for participation in this study (screen failure) 
may not be rescreened.


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7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.
7.1.
Treatments Administered
Study Treatment Name:
GSK3640254
Placebo
Dosage formulation:
capsule
capsule
Unit dose strength(s):
1mg, 10mg, 100mg
placebo
Route of Administration 
oral
oral
Dosing instructions:
Study medication will be 
administered by the study 
personnel during each dosing 
day with approximately 240 mL 
of water
Study medication will be 
administered by the study 
personnel during each dosing 
day with approximately 240 mL 
of water
Packaging and Labelling
Study Treatment will be provided 
in HDPE bottles. Each bottle will 
be labelled as required per 
country requirement. 
Study Treatment will be provided 
in HDPE bottles. Each bottle will 
be labelled as required per 
country requirement.
Manufacturer
GSK, Harlow, UK
GSK, Harlow, UK
7.2.
Dose Modification
The decision to proceed to the next dose level in both Part 1 (SAD) and Part 2 (MAD) 
will be made by the VH/GSK study team and study investigator based on safety, 
tolerability, and preliminary PK data obtained from the prior dose level(s).
7.3.
Method of Treatment Assignment
Subjects will be assigned to study treatment in accordance with the randomization 
schedules generated by Clinical Statistics, prior to the start of the study, using validated 
internal software.
Each subject scheduled to receive study drug will receive a treatment allocation number 
when randomized. Study treatment will be dispensed at the study visits summarized in
(SoA).


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7.4.
Blinding
This will be a double-blind study with participants and the site staff blinded. The sponsor 
will be unblinded (meaning those staff may have access to unblinded data). For dose 
escalation, the VH/GSK study team physicians, statistician, and clinical pharmacokinetic 
staff will have access to unblinded data and present data at dose escalation meetings in a 
blinded fashion when interacting with site staff. Other VH/GSK staff will remain blinded 
unless unblinding becomes necessary. The blind may be broken if, in the opinion of the 
investigator, it is in the participant’s best interest for the investigator to know the study 
treatment assignment. The VH/GSK study team must be notified before the blind is 
broken unless identification of the study treatment is required for a medical emergency in 
which the knowledge of the specific blinded study treatment will affect the immediate 
management of the participant’s condition. In this case, the VH/GSK study team must be 
notified within 24 hours after breaking the blind. The date and reason that the blind was 
broken must be recorded in the source documentation and CRF, as applicable.
Participants will be randomized in a 3:1 ratio to receive study treatment (active 
drug:placebo) within a period or cohort. Investigators will remain blinded to each 
participant’s assigned study treatment throughout the course of the study.
Unblinded monitors and in the event of a Quality Assurance audit, the auditor(s) will be 
allowed access to un-blinded study treatment records at the site(s) to verify that 
randomization/dispensing has been done accurately.
A participant will be withdrawn if the participant’s treatment code is unblinded by the 
investigator or treating physician. The primary reason for discontinuation (the event or 
condition which led to the unblinding) will be recorded in the CRF.
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any participant with an SAE. If the SAE requires that an
expedited regulatory report be sent to one or more regulatory agencies, a copy of the 
report, identifying the participant’s treatment assignment, may be sent to investigators in
accordance with local regulations and/or GSK policy.
7.5.
Preparation/Handling/Storage/Accountability

The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.

Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment. All study treatments 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access 
limited to the investigator and authorized site staff.

The investigator is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation, and final disposition records).


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
Further guidance and information for the final disposition of unused study treatment 
are provided in the Study Reference Manual. 

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff. 

A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK.

Precaution will be taken to avoid direct contact with the study treatment.  A Material 
Safety Data Sheet (MSDS) describing occupational hazards and recommended 
handling precautions will be provided to the investigator. In the case of unintentional 
occupational exposure notify the monitor, Medical Monitor and/or GSK study 
contact.
7.6.
Treatment Compliance

Participants will be dosed at the site and they will receive study treatment directly 
from the investigator or designee, under medical supervision.  The date and time of 
each dose administered in the clinic will be recorded in the source documents.  The 
dose of study treatment and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person 
administering the study treatment.  Study site personnel will examine each 
participant’s mouth to ensure that the study treatment was ingested.
7.7.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrollment or receives during the study must be recorded along with:

reason for use

dates of administration including start and end dates

dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
Participants 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) before the start of study 
treatment until completion of the follow-up visit, unless, in the opinion of the investigator 
and sponsor, the medication will not interfere with the study or is needed to ensure the 
participant’s safety. 
Paracetamol, at doses of 2 grams/day, is permitted for use at any time during the study.


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7.8.
Treatment after the End of the Study
Participants will not receive any additional treatment from VH/GSK, or with 
GSK3640254, after the completion of the study because only healthy volunteers are 
eligible for study participation. 


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8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
A participant will be withdrawn from the study at any time:

At his or her own request

At the discretion of the Investigator or the Sponsor for safety (including lab 
abnormalities or intercurrent illness), psychiatric, compliance, or administrative 
reasons. 

Emergence of any positive (abnormal) response confirmed by the investigator on 
a clinician (or qualified designee) administered CSSRS during the on-treatment 
phase (MAD only)

Any SAE.

Termination of the study by GSK/VH. Safety data will be reviewed by the 
Sponsor in-stream by single case and collectively.  If a safety concerns arises, a 
decision about continuation of the study will be made. 

Loss of ability to freely provide consent due to treatment of either a psychiatric or 
physical (eg, infectious disease) illness

Unblinding by the PI for any reason

Repeat non-adherence by the participant with the requirements of the protocol or 
treatment (as determined by Investigator in consultation with the Medical 
Monitor)
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records.
If a participant withdraws from the study, he/she must complete a follow-up visit.
8.1.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology (in alignment with the Food 
and Drug Administration [FDA] premarketing clinical liver safety guidance). These 
protocol guidelines are in alignment with FDA premarketing clinical liver safety 
guidance: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Discontinuation of study treatment for abnormal liver tests should be considered by the 
investigator when a participant has an ALT 3xULN or if the investigator believes that it 
is in the best interest of the participant.
Details of liver safety follow-up procedures are described in Appendix 7.


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8.1.2.
QTc Stopping Criteria for Individual Participants

The Fridericia QT correction formula (QTcF) must be used for each individual 
participant to determine eligibility for and discontinuation from the study.  This 
formula may not be changed or substituted once the participant has been enrolled.
Safety ECGs and other non-protocol specified ECGs are an exception.  

The QTc should be based on single or averaged QTc values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period.  

A participant that meets either bulleted criterion below will be withdrawn from the 
study.

QTcF > 500msec,

Change from baseline: QTcF >60msec
See the SoA for data to be collected at the time of treatment discontinuation and follow-
up and for any further evaluations that need to be completed.
8.1.3.
PK Stopping Criteria for SAD and MAD
In the SAD, the PK stopping criterion is Cmax 7.96 µg/ml. This is based on the 
maximum concentration associated with minimal QT effects observed in one dog 
administered a single dose of 17 mg/kg GSK3640254 (7.96 ug/mL). If safety or PK 
stopping criteria are not met for the current/prior doses, dose escalation in Part 1 (SAD) 
will be stopped in the event that the Bayesian predicted probability is >50% that any 
participant’s Cmax for the next subsequent dose will exceed 7.96 µg/mL (the SAD PK 
stopping criteria).
In the MAD, the PK stopping criterion is AUC 61.1 µg.hr/mL. This is based on the 
LOAEL exposure (AUC = 61.1 ug.hr/mL) in the rat at 30 mg/kg. At the LOAEL in the 
rat, microscopic changes in the stomach of rats were observed. These changes were 
minimal and reversible following 4 weeks of dosing. The rat LOAEL AUC is slightly 
lower than the mean AUC observed in dogs at the LOAEL dose of 1 mg/kg/day (73.3 
µg.h/mL) where microscopic changes in the stomach were observed, and is 
approximately 3-fold higher than the AUC in rats at the NOAEL dose of 10 mg/kg/day. 
Dose escalation in Part 2 (MAD) will be stopped in the event that safety or PK stopping 
criteria are not met, but the Bayesian predicted probability is >50% that any participant’s
AUC(0-) on Day 14 in the subsequent dose will exceed the MAD PK stopping criteria.
8.1.4.
Clinical criteria for Stopping the Study
The planned dose escalation within study will be stopped (no new enrollments or further
administration of study drug) in the event of any one of the following. However, if any of 
the criteria are met, an optional cohort may be introduced to assess a lower tolerated 
dose. 

Two participants within the same Period (SAD) or Cohort (MAD) experience an 
AE of Grade 3 intensity assessed as related to GSK3640254, by the PI


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
One participant experiences an AE of Grade 4 intensity assessed as related to 
GSK3640254, by the PI

If greater than 25% of participants within the same Period (SAD) or Cohort 
(MAD) receiving GSK3640254 have a ≥ Grade 3 intensity AE or lab abnormality 
(with the exception of asymptomatic changes in lipid panel) or a ≥ Grade 2 
intensity rash with concurrent fever, transaminase elevation or eosinophilia. 

There is one Serious Adverse Event (SAE) or death assessed as related to 
GSK3640254, by the PI.

2 participants with confirmed QTcF ≥500 msec within the same Period (SAD) or 
Cohort (MAD)

2 participants with clinically significant, in the opinion of the PI, arrhythmias
within the same Period (SAD) or Cohort (MAD)
Finally, if a sentinel participant receiving GSK3640254 meets any of these clinical 
stopping criteria (G3 or G4 drug-related AE; a drug-related SAE or death; or a G2 rash 
with concurrent fever, transaminase elevation or eosinophilia), the rest of the Period 
(SAD) or Cohort (MAD) will not dose and further dose escalation will not occur (see 
Section 5.1). Of note, the intensity of AEs will be determined using DAIDS criteria (see 
Section 12.4 for further details)
8.1.5.
Rechallenge
8.1.5.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge is not allowed. Refer to Appendix 3 for full 
guidance. 
8.2.
Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, 
or may be withdrawn at any time at the discretion of the investigator for safety, 
behavioral, compliance or administrative reasons as described in detail in 
Section 8.1.

If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent.

If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records.

Refer to the SoA for data to be collected at the time of study discontinuation and
follow-up and for any further evaluations that need to be completed.
If a participant withdraws from the study, he/she must complete a follow-up visit.
8.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 


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The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 


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9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA.

Protocol waivers or exemptions are not allowed 

Immediate safety concerns will be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant will continue or discontinue 
study treatment.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the time frame defined in the SoA.

The maximum amount of blood collected from each participant over the duration of 
the study, including any extra assessments that may be required, will not exceed 500 
mL.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.

Time window allowances for all study assessments will be followed according to the 
time window allowances as indicated in the SRM.
9.1.
Efficacy Assessments
Not applicable.
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4. As described in Appendix 
4, intensity of AEs (and lab abnormalities) will be graded using the DAIDS Grading 
table. While the study population will consist of HIV-1 seronegative healthy volunteers, 
the DAIDS criteria will be used in later clinical trials (Phase 2a and beyond); 
additionally, the DAIDS criteria are have a more conservative grading scale relative to 
others (eg. CTCAE v 4.0). Thus, participant safety evaluation and monitoring will be 
more conservative.
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study,
or that caused the participant to discontinue the study treatment (see Section 8). 


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9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the signing of the ICF until the follow-up visit
at the time points specified in the SoA (Section 2).

All AEs will be collected from the start of treatment until the follow-up visit at 
the time points specified in the SoA (Section 2).

Medical occurrences that begin before the start of study treatment but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the case report form (CRF) not the AE section.

All SAEs will be recorded and reported to the sponsor or designee within 24 
hours, as indicated in Appendix 4. The investigator will submit any updated 
SAE data to the sponsor within 24 hours of it being available.

Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study 
participation, the investigator must promptly notify the sponsor.

The method of recording, evaluating, and assessing causality of AEs and SAEs 
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 4.
9.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
9.2.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs and AEs will be followed until the 
event is resolved, stabilized, otherwise explained, or the participant is lost to follow-up 
(as defined in Section 8.3). Further information on follow-up procedures is given in 
Appendix 4.
9.2.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are 
met. 

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study treatment 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 


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Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or 
other specific safety information eg, summary or listing of SAE) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.
9.2.5.
Pregnancy

Details of all pregnancies in female partners of male participants will be collected 
after the start of study treatment and until through the end of pregnancy (termination 
or delivery).

If a pregnancy is reported, the investigator will inform GSK within 24 hours of 
learning of the pregnancy and will follow the procedures outlined in Appendix 5.

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
9.3.
Treatment of Overdose
For this study, any dose of GSK3640254 greater than a planned dose level within a 20-
hour time period will be considered an overdose.
GSK does not recommend specific treatment for an overdose.  The investigator will use 
clinical judgment to treat any overdose.
In the event of an overdose, the investigator will:
1. Contact the Medical Monitor immediately.
2. Closely monitor the participant for AE/SAE and laboratory abnormalities until 
GSK3640254 can no longer be detected systemically (at least 5 days).
3. Obtain a plasma sample for PK analysis immediately and through 7 days if requested 
by the Medical Monitor (determined on a case-by-case basis).
4. Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.
9.4.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.


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9.4.1.
Physical Examinations

Consider further specifications (eg, for height and weight measurements, the 
participant is allowed to wear indoor, daytime clothing with no shoes) if 
appropriate for the study.

A complete physical examination will include, at a minimum, assessments of the 
Skin, Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. 
Height and weight will also be measured and recorded.

A brief physical examination will include, at a minimum, assessments of the 
skin, lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators will pay special attention to clinical signs related to previous 
serious illnesses.
9.4.2.
Vital Signs

Tympanic temperature, pulse rate, respiratory rate, and blood pressure will be 
assessed.

Blood pressure and pulse measurements will be assessed in semi-supine position
with a completely automated device. Manual techniques will be used only if an 
automated device is not available.

Blood pressure and pulse measurements will be preceded by at least 5 minutes 
of rest for the participant in a quiet setting without distractions (eg, television, 
cell phones).

Vital signs (to be taken before blood collection for laboratory tests) will consist 
of 1 pulse and 3 blood pressure measurements (3 consecutive blood pressure 
readings will be recorded at intervals of at least 1 minute). The average of the 3 
blood pressure readings will be recorded on the CRF.
9.4.3.
Electrocardiograms
9.4.3.1.
12-lead safety ECGs
Safety ECGs will be printed and interpreted on-site by the Investigator to ensure subject 
safety. Safety ECGs may be printed from the Global Instrumentation Holter device (see 
below). ECG parameters from safety ECGs will not be collected unless as part of an 
observed adverse events (e.g. 1st degree AV block with PR 240 msec). Refer to Section 
8.1.2 for QTc withdrawal criteria and additional QTc readings that may be necessary.
9.4.3.2.
Cardiodynamic assessment (ECGs extracted from Holter recordings)
The frequency of ECG data in the SAD and MAD arises from emerging literature 
suggesting frequent QT evaluation early in development may mitigate the need for a 
formal TQT study (Darpo, 2014). ECGs will be extracted as shown in the SOA from the 
SAD and the MAD component of the study, not including the extension cohort. Should 
clinical development of GSK3640254 continue, an exploratory objective of this study is 


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to assess the exposure-response relationship between GSK3640254 and QTcF following 
single and repeat dose administration. 
The 12-lead Holter and ECG equipment will be supplied and supported by iCardiac 
Technologies, Inc. All ECG data will be collected using a Global Instrumentation 
(Manlius, NY, USA) M12R ECG continuous 12 lead digital recorder.  The continuous 
12-lead digital ECG data will be stored onto SD memory cards.  ECGs to be used in the 
analyses will be selected at pre-determined time points as defined in the SOA, and will be 
read centrally by iCardiac Technologies, Inc.
The following principles will be followed in iCardiac’s core laboratory:

ECG analysts are blinded to the participant, visit and treatment allocation

Baseline and on-treatment ECGs for a particular participant will be over-read on the
same lead and will be analyzed by the same reader.

The primary analysis lead is lead II.  If lead II is not analyzable in any specific 
participants, then primary lead of analysis will be changed to another lead for the 
entire participant data set.
The following is a brief description of ECG analysis methods utilized by iCardiac’ core 
laboratory.
TQT Plus ECG Extraction Technique
Ten 14-second digital 12-lead ECG tracings will be extracted from the continuous Holter 
recordings using the ‘TQT Plus method’, a computer-assisted and statistical process 
utilized by iCardiac Technologies. The method enables extraction of ECGs with the 
lowest HR variability and noise within the protocol-specified extraction time window 
(e.g., the HR and QT changes from beat-to-beat in the range of <10%). At each protocol-
specified timepoint, 10 ECG replicates will be extracted from a 5-minute “ECG window” 
(typically, the last 5 minutes of the 15-minute period when the subject is maintained in a 
supine or semi-recumbent quiet position).
High-Precision QT Analysis
High-precision QT analysis will be performed on all analyzable (non-artifact) beats in the 
10 ECG replicates.  Statistical quality control procedures are used to review and assess all 
beats and identify “high” and “low” confidence beats using several criteria, including:

QT or QTc values exceeding or below certain thresholds (biologically unlikely).

RR values exceeding or below certain thresholds (biologically unlikely).

Rapid changes in QT, QTc or RR from beat to beat.
Measurements of all primary ECG parameters (QT, QTc, RR) in all recorded beats of all 
replicates that are deemed “high confidence” is performed using COMPAS software.  All 
low confidence beats are reviewed manually and adjudicated using pass-fail criteria.  The 
final QC assessment is performed by a cardiologist.  The beats found acceptable by 
manual review are included in the analysis.  The median QT, QTc, and RR value from 


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each extracted replicate is calculated, and then the mean of all available medians from a 
nominal timepoint is used as the subject’s reportable value at that timepoint.
Categorical T-wave morphology analysis (Table 9) and the measurement of PR and QRS 
intervals will be performed manually in 3 of the 10 ECG replicates at each timepoint.  
Each fiducial point (onset of P-wave, onset of Q-wave, offset of S-wave, and offset of T-
wave) is electronically marked.
Table 9
T-wave morphology categories (assessed manually)
Category
Description
Normal T-wave
Any T-wave not meeting any criterion below
Flat T-waves
T amplitude < 1 mm (either positive or negative) including flat 
isoelectric line
Notched T-wave (+)
Presence of notch(es) of at least 0.05 mV amplitude on ascending or 
descending arm of the positive T-wave
Biphasic
T-wave that contains a second component with an opposite phase 
that is at least 0.1 mV deep (both positive and negative/positive and 
polyphasic T-waves included)
Normal T-wave (-)
T amplitude that is negative, without biphasic T-wave or notches
Notched T-wave (-)
Presence of notch(es) of at least 0.05 mV amplitude on descending 
or ascending arm of the negative T-wave
In addition to the T-wave categorical analysis, the presence of abnormal U-waves is 
noted.
9.4.4.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency. 

The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 2 days after the last dose of study 
treatment will be repeated until the values return to normal or baseline or are no 
longer considered significantly abnormal by the investigator or medical monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology will be identified and the sponsor 
notified.


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
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.

If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in participant 
management or are considered clinically significant by the investigator (eg, SAE 
or AE or dose modification), then the results must be recorded in the CRF.
9.4.5.
Suicidal Risk Monitoring
GSK3640254 is not a CNS active drug nor is it being developed for a neurologic or 
psychiatric condition. However, given the risk of suicidal ideation identified with 
previous MI GSK3532795, all participants will undergo screening using the CSSRS 
administered by a clinician (or qualified designee); any positive (abnormal) response 
confirmed by the investigator, will exclude them from participating. Finally, participants 
in the MAD will have assessment by the CSSRS during the on-treatment phase of the 
study (see SoA table for details). As described in Section 8.1, any positive (abnormal) 
response confirmed by the investigator during the on-treatment phase will result in their 
discontinuation. In either case (screening or on-treatment) of positive (abnormal) 
response confirmed by the investigator, the PI/SI will arrange for urgent specialist 
psychiatric evaluation and management.
The definitions of behavioural suicidal events used in this scale are based on those used 
in the Columbia Suicide History Form [Posner, 2007]. Questions are asked on suicidal
behaviour, suicidal ideation, and intensity of ideation. Screening visit questions will be in 
relation to lifetime experiences and current experiences (within the past 2 months) and all 
subsequent questioning in relation to the last assessment.
9.4.6.
GI Toxicity Evaluation and Monitoring Plan
Pre-clinical toxicology studies in rats and dogs have suggested a potential for GI related 
toxicity with GSK3640254. This section provides general guidance to the Investigator on 
the evaluation and management of primarily upper gastrointestinal symptoms (Table 10). 
The Investigator may contact the GSK/VH Medical Monitor to discuss evaluation and 
management (including discontinuation of a participant) of any GI symptoms throughout 
the trial.


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Table 10
GI Toxicity Evaluation and Management
HISTORY
For symptoms of all grades, a thorough history forms the 
foundation of proper evaluation and management. The following 
are potential manifestations of some GI clinical syndromes that 
may occur (possibly in combination) during the clinical trial. 
Nausea and 
Vomiting
The investigator should attempt to identify the etiology of these 
symptoms (and whether it is intraperitoneal, extraperitoneal, 
medication related, infection related, or due to a metabolic disorder
(Hasler, 2012). Medications can cause nausea and vomiting 
acutely. 
Dyspepsia
The Investigator should identify the presence of red flags 
(odynophagia, unexplained weight loss, recurrent vomiting, GI 
bleeding, jaundice, palpable mass or adenopathy, or family history 
of GI malignancy). Symptoms of dyspepsia could include early 
satiety, bloating, or belching. Additionally, atypical symptoms of 
dyspepsia could include: pharyngitis, asthma, bronchitis, 
hoarseness, chest pain, or abdominal pain. 
Other Clinical 
Syndromes
Additional diagnostic criteria for other GI disorders potentially 
encountered in the clinical trial are available elsewhere (Rome 
Foundation, 2014).
PHYSICAL 
EXAMINATION
Physical examination should complement elements obtained from 
the history (Hasler, 2012). Acutely, the investigator may assess for 
signs of intravascular volume depletion (eg, orthostasis) and/or 
aspiration of vomitus as appropriate. Abdominal tenderness and 
guarding may indicate inflammation. The presence of fecal blood 
can indicate mucosal damage (eg, from an ulcer). Complete 
evaluation of dyspepsia should include an oral examination (poor 
dentition or pharyngeal erythema) and lungs for wheezing. 
DIAGNOSTIC 
EVALUATION 
AND 
MANAGEMENT
A major goal in the diagnostic evaluation of a participant with 
upper GI symptoms is to quickly arrive at a final diagnosis without 
exposing the participant to unnecessary (invasive) testing; 
Investigators should exercise good clinical judgment in this regard
(Soll, 2009). A major goal of therapy is directed at correcting the 
underlying identifiable medical or surgical abnormalities. 
Consultation (eg, gastroenterologist) is recommended as clinically 
indicated.


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Grade 1 symptoms
Participants may be treated symptomatically. If participants
develop dyspepsia alone, generally only limited and direct 
diagnostic testing should be performed. If the participant has 
dyspepsia they should limit alcohol, caffeine, chocolate, tobacco, 
and eating directly before bedtime. 
Grade 2 
symptomsa
Diagnostic testing may include but is not limited to the following 
(as clinically indicated):
Serum chemistries and assessment of hemoglobin if not recently 
performed. 
Testing for Helicobacter pylori
PCR for viruses (eg, CMV)
For participants who are infected with H. pylori discontinuation 
from the trial is necessary. Management should be targeted at 
addressing the underlying pathology.
Grade 3 
symptomsa
Diagnostic testing may include but is not limited to the following 
(as clinically indicated):

The testing outlined above in Grade 2

A barium swallow 

CT scan to identify gastrointestinal inflammation 

Upper endoscopy with biopsy as indicated (eg, mucosal injury
or the presence of red flags).
Management should be targeted at addressing the underlying 
pathology.
Grade 4 
symptomsa
Diagnostic testing may include but is not limited to the following 
(as clinically indicated):

The testing outlined above in Grade 2 and Grade 3

An acute abdominal series
Initial management can include correction of hemodynamic and 
electrolyte abnormalities as clinically indicated. After stabilization, 
management should be targeted at addressing the underlying 
pathology.
a.
For Grade 3-4 GI AEs related to active drug: the Investigator should consider discontinuing the partcipant from the 
study and performing an evaluation/management plan incorporating elements above. 


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9.5.
Pharmacokinetics

Whole blood samples of approximately 2 mL will be collected for measurement 
of plasma concentrations of GSK3640254 as specified in the SoA. An additional 
2 mL of whole blood samples will be collected for metabolite profiling at the 
same time points as the PK samples on Day 1, Day 2, Day 14 and Day 15, in 
MAD cohorts 3, 4, 5 and 6, as specified in the SoA. A maximum of 10 samples 
may be collected at additional time points during the study if warranted and 
agreed upon between the investigator and the sponsor. Instructions for the 
collection and handling of biological samples will be provided by the sponsor. 
The actual date and time (24-hour clock time) of each sample will be recorded.

Urine samples will be collected for 24 hours on Day 1 and Day 14 in MAD 
cohorts 3, 4, 5 and 6 for measurement of urine concentrations of GSK3640254 as 
specified in the SoA. 

The metabolite profiling of the plasma and urine samples will be conducted under 
separate protocols and results are reported separately according to the protocols.
Drug concentration information that would unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.
9.6.
Pharmacodynamics
Not applicable.


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9.7.
Genetics
A 10-mL blood sample for DNA isolation will be collected from participants who have 
consented to participate in the genetics analysis component of the study for the MAD 
portion of the study only. Participation is optional. Participants who do not wish to 
participate in the genetic research may still participate in the study.
In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent.
See Appendix 6 for Information regarding genetic research. Details on processes for 
collection and shipment and destruction of these samples can be found in SRM.


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10.
STATISTICAL CONSIDERATIONS
10.1.
Sample Size Determination
No formal statistical hypotheses are to be tested. Sample size is based on feasibility. No 
formal calculation of power or sample size for Parts 1 and 2 of the study has been 
performed. A sample size of approximately 8 participants per dose-cohort should be 
sufficient to provide useful estimates of both inter- and intra-participant variability for 
GSK3640254 PK parameters, and initial safety assessment.
As described in Section 5.1, an expansion cohort is included in this study in order to 
evaluate the rate of GI intolerability. No formal statistical testing will be performed. 
However, based on prior information from GSK3532795 studies, a conservative clinical 
estimate of GI AEs in those receiving placebo would be 10%; a sample size of 24 
participants on active and 14 participants on placebo would have 90% power to detect a 
45% difference between placebo and GSK3640254.
10.2.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled 
All participants who sign the ICF
Safety
All enrolled participants who take at least 1 dose of study treatment. 
Participants will be analyzed according to the treatment they actually 
received.
Pharmacokinetic 
Concentration 
The PK Concentration Population will include all participants who undergo 
plasma PK sampling and have evaluable PK assay results. This 
population will be used for the concentration listing. 
Pharmacokinetic Parameter
The PK Parameter Population will include all participants who undergo 
plasma PK sampling and have evaluable PK parameters estimated. This 
population will be used for PK parameter listing, plotting of the 
concentration-time data and PK parameter summary.


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10.3.
Statistical Analyses
10.3.1.
Safety Analyses
All safety analyses will be performed on the Safety Population and details will be 
provided in the Reporting and Analysis Plan (RAP). 
Endpoint
Statistical Analysis Methods
Primary
Safety data will be presented in tabular and or graphic format and summarized 
descriptively accordingly to GSK’s Integrated Data Standards Library (IDSL) 
standards
Exploratory
Will be described in the reporting and analysis plan 
AEs will be tabulated using MedDRA preferred terms. The number and percentage of 
participants experiencing each specific AEs (All AEs, Grade 2 or higher, and SAEs) will 
be tabulated by severity and by relationship to study product. For the calculations in these 
tables, each participant’s AEs will be counted once under the maximum severity or the 
strongest relationship to study product. AEs leading to withdrawal will also be 
summarized by treatment.
10.3.2.
Other Analyses
PK and safety response exploratory analyses will be described in the reporting and 
analysis plan. The population PK analysis and safety response analyses may be presented 
separately from the main clinical study report (CSR).
Pharmacokinetic Analyses
Plasma GSK3640254 concentration-time data will be analyzed by noncompartmental 
methods using WinNonlin Professional 5.2 or higher, Phoenix (Pharsight Corporation) or 
comparable software. Individual plasma PK parameters for each participant and dosing 
group will be determined, including:  

Part 1 (single dose): AUC (0-24), AUC(0-tlast), AUC (0-inf), Cmax, C24, tmax, 
tlag, t1/2, Clast, tlast, CL/F.  

Part 2 (Repeated QD doses for 14 days):  
o
Day 1: AUC(0-24), Cmax, C24, tmax, tlag
o
Day 14: AUC(0-), Cmax, C, tmax, t1/2, and CL/F. 
Statistical Analysis of Pharmacokinetic Data
Statistical analyses of the pharmacokinetic parameter data will be the responsibility of 
Clinical Statistics, GSK.


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Plasma GSK3640254 concentrations and PK data will be summarized by treatment and 
listed by participant. Unless stated otherwise, descriptive summaries will include number 
(n), mean, standard deviation (SD), coefficient of variation (%CV), median, minimum, 
and maximum for continuous variables, n and percent (%) for categorical variables, and 
geometric mean, 95% confidence interval (CI), and the between-participant CV (%CVb) 
for the log-transformed PK parameters.
Dose proportionality of selected single and repeated dose PK parameters will be assessed 
by the power model.
Accumulation will also be evaluated for each treatment by determining the ratio of Day 
14 (Part 2) to Day 1 AUC(0-) (R(AUC(0-)), Cmax (R(Cmax)), and C(R(C)). C24 on 
Day 1 will be taken as the Con that day.
Attainment of steady-state will be assessed by estimating the slope of pre-dose 
concentrations for GSK3640254 on Days 2-14 (Part 2). The final assessment of the slope 
will be determined by at least the last 3 pre-dose concentrations.
For the assessment of food effect (if conducted), the loge-transformed PK parameters will 
be separately analyzed using a mixed effect model with a fixed effect term for fed vs. 
fasted. Participant will be treated as a random effect in the model. Point estimates and 
their associated 90% confidence intervals CIs will be calculated for the difference in PK 
parameter values for the fed vs fasted comparisons. The point estimates and their 
associated 90% CIs will then be back-transformed to provide point estimates and 90% 
CIs for the ratios, fed/fasted in PK parameter values on the original scale. 
The details of the statistical analysis of PK data will be described in the RAP.
Pharmacokinetic/Safety Response Analyses
Pharmacokinetics/Safety Response analyses will be performed only if the GSK3640254 
development project is progressing forward. The endpoint for the potential impact of 
GSK3640254 on cardiac repolarization will be the change-from-baseline QTcF (∆QTc). 
A modelling approach will be used to describe the relationship between GSK3640254 
concentration and QTc data. 
The details of the PK/Safety Response analysis will be described in the RAP or in a 
separate analysis plan if the analysis is reported separately.
10.3.3.
Interim Analyses
There will be no formal interim analysis; however, all preliminary safety, tolerability, and 
available pharmacokinetic data will be reviewed internally at VH/GSK prior to each dose 
escalation or administration. Safety data (labs, vital signs, ECG, AEs, SAEs) will be 
reviewed by the PI/Sub-I and VH/GSK study team after completion of each dose level.
Dose escalation can only occur after PI/Sub-I and VH/GSK study team has found that the 
safety, PK profiles are supportive to proceed with the evaluation of the next higher dose 
level (See Section 5.5.5 Dose Escalation Committee).


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At each dose, the Bayesian probability of an individual exceeding the Cmax threshold in 
Part 1 and the Bayesian probability of an individual exceeding the AUC threshold in Part 
2 will be calculated and compared with 50%. This will be used to help selection of the 
next dose together with safety and tolerability data. The Bayesian probability will be 
based on Whitehead’s model shown below [Whitehead, 2001] using non-informative 
prior for model parameters.
[1]
Where 
is log-PK of -th participant to -th dose, 
is -th log-dose administered to -
th participant. 
and 
are population intercept and slope, respectively. 
is random 
effect of -th participant and 
is random error of i-th participant in -th dose.
When intra-participant variability cannot be estimated during PK predictions in Part 1 
(i.e., early on in the study when there is not sufficient information to estimate intra-
participant variability) and for conducting prediction of all doses in Part 2, the same 
Whitehead’s model will be used for Bayesian probability calculations as below.
                                                                [2]
Where yi is log-PK of i-th participant, di is the log-dose administered to i-th participant. θ1
and θ2 are population intercept and slope, respectively and i is random error of i-th
participant.
Bayesian model Operating Characteristics (OC)
In this part, we want to explore the operating characteristics of the 700mg dose for SAD. 
Given different assumptions of with-in and between participant Cmax variability (CV%),
and assuming dose proportionality (slope=1), data for 1000 trials were simulated based 
on Whitehead’s model [1]. Each simulated trial contains Cmax values for 6 subjects on 
treatment for doses ranging from 1mg to 400mg in SAD cohort 1 and cohort 2. 
For each simulate trial, we fitted the mixed effect Bayesian model based on mode [1]. In 
the following procedure, we calculated the Bayesian probability of an individual 
exceeding the Cmax threshold: 
We had 10000 iterations in the MCMC procedure. In each iteration, we obtained the 
estimated parameters 
and
(the estimated standard deviation of 
), Based on the estimation, a random sample for each subject, which represented the 
simulated exposure in the 700mg dose, was drawn from the distribution 
. We counted the number of iterations 
with any simulated 
exposure exceeding the Cmax threshold log(7.96). The Bayesian probability was 
calculated as 
.
For each trial, the Bayesian probability for the 700mg dose is calculated and compared 
with different thresholds (40%, 50% or 60%). Among those 1000 trials, the percentages 


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of trials with Bayesian probability below the thresholds, which stands for the percentage 
of trials that could be escalated to dose 700mg, are listed in Table 11.
Table 11
Percentage of trials with Bayesian probability less than the 
threshold (40%, 50% or 60%)
Cmax Variability
Probability Threshold
%CVw1
%CVb1
40%
50%
60%
7.5
15
100.0%
100.0%
100.0%
15
15
100.0%
100.0%
100.0%
12.5
25
99.9%
100.0%
100.0%
25
25
99.3%
99.5%
99.8%
17.5
35
95.6%
97.0%
98.5%
35
35
91.0%
94.0%
97.1%
25
50
75.7%
81.9%
85.2%
50
50
53.9%
66.8%
77.0%
Note: 1, %CVw: within-participant coefficient of variation. %CVb: between-participant coefficient of 
variation
Based on the table above, when with-in and between participant Cmax variability are 
small or moderate, the probability of successfully escalating to 700mg is high.
10.3.4.
Final Analyses
Final analysis will be performed after the completion of the study and final datasets 
authorization.
Data will be listed and summarized according to GSK reporting standards, where 
applicable. Listings will be sorted by participant, treatment and day; summaries will be 
presented by treatment, day, and time for each part.
Unless stated otherwise, descriptive summaries will include n, mean, standard deviation
(SD), coefficient of variation (%CV), median, minimum, and maximum, geometric mean 
with associated 95% confidence interval (CI), and the between-participant CV (%CVb) 
for continuous variables, whereas n and percent will be used as summary statistics for 
categorical variables.


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11.
REFERENCES
Darpo B., Garnett C., Benson C.T., Keirns J., Leishman D., et. al.  Cardiac safety 
research consortium: Can the thorough QT/QTc study be replaced by early QT 
assessment in routine clinical pharmacology studies? Scientific update and a research 
proposal for a path forward. Am Heart J 2014; 168:262-72.
GlaxoSmithKline Document Number 2016N294821_00.  GSK3640254 Investigator’s 
Brochure, Version 01. Effective Date Expected: 10 May 2017.
GlaxoSmithKline Document Number 2016N302783_00.  Clinical Study Report 
AI468038 (205891). Completion Date: 26 May 2016.
Guidance for Industry estimating the maximum safe starting dose in initial clinical trials 
for therapeutics in adult healthy volunteers. FDA/CDER, July 2005
Guidance for Industry: Drug Induced Liver Injury: Premarketing Clinical Evaluation. 
FDA/CDER and CBER, July 2009
Hasler WL Nausea, Vomiting, and Indigestion: Introduction. Chapter 39. Harrisons 
Principles of Internal Medicine 18th edition. 2012. McGraw Hill
James L.P. Pharmacokinetics of Acetaminophen - Protein Adducts ... Liver Failure. Drug 
Metab Disp, 37:1779-1784. 2009
Metrum Research Group. BMS-955176 Population Pharmacokinetics and Exposure-
response. Sponsored by Bristol Myers Squibb. Effective Date: 14 Nov 2016.
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification 
Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the 
FDA’s pediatric suicidal risk analysis of antidepressants. Am J Psychiatry. 
2007;164:1035-1043.
Rome Foundation. Rome III Diagnostic Criteria for Functional Gastrointestinal 
Disorders. Available: http://www.romecriteria.org/assets/pdf/19_RomeIII_apA_885-
898.pdf. Accessed Dec 22 2014.
Soll AH and Graham DY. Peptic Ulcer Disease. Chapter 40. Textbook of 
Gastroenterology. 5th edition. 2009. Blackwell Publishing.
Van Lunzen J, Maggiolo F, Arribas JR, et al. Once daily dolutegravir (S/GSK1349572) 
in combination therapy in antiretroviral-naïve adults with HIV: planned interim 48 weeks 
results from SPRING-1, a dose-ranging, randomised, phase 2b trial. The Lancet, 12(2): 
111-118. 2012.
Whitehead J. et al., Easy-to-implement Bayesian methods for dose-escalation studies in 
healthy participants, Biostatistics, 2, 47cs, 2, 47v 2001


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Zhu L, Liao S, Child M, et al. Pharmacokinetics and inhibitory quotient of 
atazanavir/ritonavir versus lopinavir/ritonavir in HIV-infected, treatment-naïve patients 
who participated in the CASTLE study. J Antimicrob Chemother. 67(2): 465-468. 2012.


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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
AE
Adverse Event
ARV
Anti-retroviral
AUC(0-)
Area under the curve (Area under the plasma 
drug concentration-time curve from pre-dose 
to the end of the dosing interval at steady 
state) 
AUC(0-24)
Area under the plasma concentration time 
curve from zero to 24
AUC(0-inf)
Area under the concentration-time curve 
from time zero (pre-dose) extrapolated to 
infinite time
AUC(0-tlast)
Area under the concentration-time curve 
from zero to time of last sample taken 
BID
Twice daily
BMI
Body mass index
BMS
Bristol-Myers Squibb
cART
Combination anti-retroviral therapy
CI
Confidence interval
CIB
Clinical Investigator's Brochure 
CL/F
Apparent oral clearance 
Cmax
Maximum observed concentration 
CNS
Central nervous system
CONSORT
Consolidated Standards of Reporting Trials 
CRF
Case report form
CSR
Clinical study report
CSSRS
Columbia Suicide Severity Rating Scale


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CV
Cardiovascular
CVb
Between-participant coefficient of variation
ECG
Electrocardiogram 
EMEA
European Medicines Agency
FDA
Food and Drug Administration 
FTIH
First-time-in-human
GCSP
Global Clinical Safety and 
Pharmacovigilance 
GI
Gastrointestinal
GSK
GlaxoSmithKline 
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C
HIV-1
Human immunodeficiency virus-1
ICF
Informed consent form 
IEC
Independent Ethics Committee 
IRB
Institutional Review Board 
LOAEL
Lowest observed adverse effect level
MAD
Multiple ascending dose
MI
Maturation inhibitors
MOA
Mechanisms of action
MSDS
Material Safety Data Sheet 
NOAEL
No observed adverse effect level
OC
Operating Characteristics
PBO
Placebo
PCR
Polymerase chain reaction


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PD
Pharmacodynamic 
PI
Principal Investigator 
PK
Pharmacokinetic 
POC
Proof of Concept
RAP
Reporting and Analysis Plan 
SAD
Single ascending dose
SAE
Serious Adverse Event 
SD
Standard deviation 
SOA
Schedule of activities
SRM
Study Reference Manual 
SUSAR
Suspected unexpected serious adverse 
reactions
t1/2
Apparent terminal phase half-life
tmax
Time of occurrence of Cmax 
ULN
Upper limit of normal 
VH
ViiV Healthcare
WOCBP
Women of Childbearing Potential 
Trademark Information
Trademarks owned by the 
GlaxoSmithKline group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
DAIDS
Phoenix
WinNonlin


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12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 12 will be performed by the central laboratory. 

Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either study treatment administration and/or 
response evaluation. If a local sample is required, it is important that the sample 
for central analysis is obtained at the same time. Additionally, if the local 
laboratory results are used to make either a study treatment decision or response 
evaluation, the results must be entered into the CRF.

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 6 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 12
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
MCV
MCH
%Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Clinical 
Chemistry1
BUN
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase
(SGOT)
Total and direct 
bilirubin
Creatinine
Sodium, 
Chloride, Bicarb
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase
(SGPT)
Total Protein
Glucose (non-
fasting)
Calcium, 
Magnesium, 
Phosphate
Alkaline 
phosphatase
Fasting Lipid 
Panel 
(Cholesterol, 
Triglycerides, 
HDL, LDL)
Routine 
Urinalysis

Specific gravity


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Laboratory 
Assessments
Parameters

pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte 
esterase by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

Breath alcohol and urine drug screen (to include at minimum: 
amphetamines, barbiturates, cocaine, opiates, cannabinoids and 
benzodiazepines)

Urine human chorionic gonadotropin (hCG) pregnancy test (as 
needed)2Serology and PCR [(HIV-1 diagnostic PCR, hepatitis B surface 
antigen [HBsAg], and hepatitis C virus antibody)] 
The results of each test must be entered into the CRF.
NOTES:
1.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 8.1.1. All events of ALT 3 × upper limit of normal (ULN) and bilirubin 2 × 
ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (INR) >1.5, if INR measured, 
which may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE (excluding studies of 
hepatic impairment or cirrhosis).
2.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC.
Analyte results that could unblind the study will not be reported to investigative sites or 
other blinded personnel until the study has been unblinded or the subject has undergone 
emergency unblinding.


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


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
Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative. 

Participants who are rescreened are required to sign a new ICF.
The ICF may contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research in accordance with SOP-GSKF-410. The 
investigator or authorized designee will explain to each participant the objectives of the 
exploratory research. Participants will be told that they are free to refuse to participate 
and may withdraw their consent at any time and for any reason during the storage period. 
A separate signature will be required to document a participant's agreement to allow any 
remaining specimens to be used for exploratory research. Participants who decline to 
participate will not provide this separate signature.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
Committee Structure
This study will utilize a dose escalation committee made up of the at least the following 
GSK/VH staff: Principle Investigator, Sub-Investigator, Medical Monitor, 
pharmacokineticist, data manager, statistician, and study manager. The committee will 
evaluate data including but not limited to: AEs, vital signs, laboratory findings, ECG 
parameters, and PK data.


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Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multi-center studies only in their entirety and 
not as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (eg, laboratory 
data). The investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years after study completion 
unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written 
approval of the sponsor. No records may be transferred to another location or 
party without written notification to the sponsor. 


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Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available.

Definition of what constitutes source data can be found in Study Reference 
Manual (SRM).
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study treatment development


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


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


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one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study using the DAIDS grading table (http://rsc.tech-res.com/docs/default-
source/safety/daids_ae_grading_table_v2_nov2014.pdf) and assign it to 1 of the 
following categories: 

Mild: no or minimal interference with usual social & functional activities 

Moderate: greater than minimal interference with usual social & functional activities

Severe: inability to perform usual social & functional activities. An AE that is 
assessed as severe should not be confused with an SAE. Severe is a category utilized 
for rating the intensity of an event; and both AE and SAE can be assessed as severe.

Life Threatening: inability to perform basic self-care functions
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.


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Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each AE/SAE.

A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to t GSK within 24 hours of 
receipt of the information.


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


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12.5.
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)
Women in the following categories are not considered WOCBP
1.
Premenarchal
2. Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment.
Contraception Guidance
Male participants
Male participants with female partners of child-bearing potential are eligible to 
participate if they agree to ONE of the following during the protocol-defined time 
frame in Section 6.1: 
Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 

Agree to use a male condom plus an additional method of contraception with a 
failure rate of <1% per year as described below when having penile-vaginal 
intercourse with a woman of childbearing potential 


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
Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of 
penile penetration during the protocol-defined time frame. 

Refrain from donating sperm for duration of study and for 14 weeks after study 
completion or from last dose.
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulationb

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.) 
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the participant.)
NOTES: 
a.
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants in clinical studies. 
b.
Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of 
the contraceptive method. In this case two highly effective methods of contraception should be utilized during the 
treatment period and for at least 38 days after the last dose of study treatment 


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Pregnancy Testing

Additional pregnancy testing should be performed at screening (both SAD and 
MAD) and prior to dosing in each period (SAD only) during the treatment period 
and at 37 days after the last dose of study treatment and as required locally 

Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected 
Collection of Pregnancy Information
Male participants with partners who become pregnant

Investigator will attempt to collect pregnancy information on any male participant’s 
female partner of a male study participant who becomes pregnant while participating 
in this study. This applies only to participants who receive study treatment.

After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy. 

Partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure. 


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12.6.
Appendix 6: Genetics
USE/ANALYSIS OF DNA

Genetic variation may impact an MAD participant’s response to therapy, 
susceptibility, severity and progression of disease. Variable response to therapy may 
be due to genetic determinants that impact drug absorption, distribution, metabolism, 
and excretion; mechanism of action of the drug; disease etiology; and/or molecular 
subtype of the disease being treated. Therefore, where local regulations and IRB/IEC 
allow, a blood sample will be collected for DNA analysis

DNA samples will be used for research related to study treatment and related 
diseases. They may also be used to develop tests/assays including diagnostic tests) 
related to study treatment. Genetic research may consist of the analysis of one or 
more candidate genes or the analysis of genetic markers throughout the genome [or 
analysis of the entire genome] (as appropriate)

DNA samples will be analyzed if it is hypothesized that this may help further 
understand the clinical data. 

DNA samples will be analyzed for clinical correlation related to study treatment. 
Additional analyses may be conducted if it is hypothesized that this may help further 
understand the clinical data. 

The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to study treatment or study treatments of this class. The 
results of genetic analyses may be reported in the clinical study report or in a 
separate study summary.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained while research on study treatment (or study treatments 
of this class) continues but no longer than 5 years or other period as per local 
requirements.


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12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments
The procedures listed below are to be followed if a participant meets the liver chemistry 
stopping criteria defined in Section 8.1.1:

Immediately withdraw the participant from study treatment

Notify the VH/GSK medical monitor within 24 hours of learning of the 
abnormality to confirm the participant’s study treatment cessation and follow-up.

Complete the “Safety Follow-Up Procedures” listed below.

Complete the liver event case report forms. If the event also meets the criteria of 
an SAE (see Appendix 4), the SAE data collection tool will be completed 
separately with the relevant details.
Safety Follow-Up Procedures for participants with ALT ≥ 3x ULN:

Monitor participants weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values.
Safety Follow-Up Procedures for participants with ALT ≥ 3xULN and total 
bilirubin ≥ 2xULN (>35% direct bilirubin); or ALT ≥ 3x ULN and INR1 > 1.5:

This event is considered an SAE (see Appendix 4). Serum bilirubin fractionation 
should be performed if testing is available. If fractionation is unavailable, urinary 
bilirubin is to be measured via dipstick (a measurement of direct bilirubin, which 
would suggest liver injury).

Make every reasonable attempt to have participants return to the clinic within 24 
hours for repeat liver chemistries, additional testing, and close monitoring (with 
specialist or hepatology consultation recommended).

Monitor participants twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values.
In addition, for all participants with ALT ≥ 3x ULN, every attempt must be made to 
also obtain the following:

Viral hepatitis serology including: 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.

Blood sample for pharmacokinetic (PK) analysis, obtained within 48 hours of last 
dose. 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 participant’s best approximation. If 
the date/time of the last dose cannot be approximated OR a PK sample cannot be 
collected in the time period indicated above, do not obtain a PK sample. 
Instructions for sample handling and shipping are included in the SPM.

Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).


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
Fractionate bilirubin, if total bilirubin ≥2xULN.

Assess eosinophilia

Record the appearance or worsening of clinical symptoms of hepatitis (fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or 
eosinophilia) on the AE CRF.

Record use of concomitant medications, acetaminophen, herbal remedies, other 
over the counter medications, or putative hepatotoxins on the Concomitant 
Medications CRF.

Record alcohol use on the Liver Events CRF.
The following are required for participants with ALT ≥ 3x ULN and bilirubin ≥ 2x 
ULN (>35% direct) but are optional for other abnormal liver chemistries:

Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney 
microsomal antibodies.

Serum acetaminophen adduct HPLC assay (quantifies potential acetaminophen 
contribution to liver injury in participants with definite or likely acetaminophen 
use in the preceding week [James, 2009].

Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to 
evaluate liver disease.

The Liver Imaging and/or Liver Biopsy CRFs are also to be completed if these 
tests are performed.


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12.8.
Appendix 8: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).
Amendment: 01; 12-JUL-2017
Overall Rationale for the Amendment: This amendment makes three changes to the 
protocol. First, the 24 h Holter Monitor at Day -2 in SAD and MAD has been removed. 
Second, language in the MAD Schedule of Analyses table, Footnote 1 changed from 
Holter to Continuous ECG. Finally, the protocol serum alcohol and drug screen has been 
changed to: 1) breath alcohol and 2) urine drug screen. 
Section # 
and Name
Description of Change
Brief Rationale
Section 2 
Schedule of 
Activities
Removed 24 h Holter Monitor at 
Day -2 in SAD and MAD
Since study participants will already have a 
Holter completed during screening, this 
amendment has removed the 24 h Holter 
Monitor at Day -2. This change does not 
affect the risk benefit ratio to participants.
Section 2
Schedule of 
Activities
Changed MAD Schedule of 
Analyses table Footnote 1 from 
Holter to Continuous ECG
This change in language reflects the use of 
the term Continuous ECG in the Schedule 
of Analysis table. This change does not 
affect the risk benefit ratio to participants.
Section 12.2
Clinical 
Laboratory 
Tests
Changed Serum alcohol and drug 
screen to: 1) breath alcohol and 2) 
urine drug screen
This change allows for improved participant 
convenience in the trial while still 
maintaining robust exclusion criteria. This 
change does not affect the risk benefit ratio 
to participants.
Amendment: 02; 3-AUG-2017
List of Specific Changes
Section # and Name
Description of Change
Brief Rationale
Synopsis
Figure 1 footnote removed and 
reference to a dose of 400 mg 
was removed.  
Figure 1 footnote removed and 
reference to a dose of 400 mg 
was removed. This change 
further addresses risk to 


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Section # and Name
Description of Change
Brief Rationale
participants.  
Section 2 Schedule of 
Analyses
The components of a Full 
Physical Exam are described 
to include at a minimum, 
assessments of the Skin, 
Cardiovascular, Respiratory, 
Gastrointestinal and 
Neurological systems. 
Additionally, full physical 
exams now replace brief 
physical exams.
To address the risk for 
neuropsychiatric events, a 
neurological evaluation will 
occur during scheduled full 
physical exams. This change 
further addresses risk to 
participants.
Section 2 Schedule of 
Analyses
A clinician (or qualified 
designee) administered 
CSSRS assessment has been 
added to the screening 
evaluation (SAD and MAD) 
and in the on-treatment phase 
of the MAD portion.
To address the risk of suicidal 
ideation identified with a similar 
asset, all participants will be 
screened with a clinician (or 
qualified designee) 
administered CSSRS. 
Additionally, the MAD portion 
of the trial will include use of 
the CSSRS during the on-
treatment phase. This change 
further addresses risk to 
participants.
Section 2 Schedule of 
Analyses
The fasting lipid panel is now 
separate from the routine 
chemistry panel.
The fasting lipid panel is now 
separate from the routine 
chemistry panel. This change 
does not affect the risk benefit 
ratio to participants.
Section 3.3 Benefit Risk 
Assessment
A clinician (or qualified 
designee) administered 
CSSRS assessment has been 
added to the screening 
evaluation for the entire study 
(SAD and MAD) and the on-
treatment phase of the MAD 
portion
To address the risk of suicidal 
ideation identified with 
previous MI GSK3532795, the 
MAD portion of the trial will 
include use of the CSSRS 
during the on-treatment phase. 
Also, the entire trial (SAD and 
MAD) will exclude any subject 
who has a positive (abnormal) 
response confirmed by the 
investigator on a clinician (or 
qualified designee) 
administered CSSRS at 
screening. These changes 
further address risk to 


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Section # and Name
Description of Change
Brief Rationale
participants.
Synopsis- Overall Design and 
Section 5.1 Overall Design
Reference to a dose of 400 mg 
was removed. Further clarity 
added to maximum dose in the 
SAD.
The anticipated maximum 
single dose of GSK3640254 in 
Part 1 will not exceed 6X, 
where X is the minimally 
efficacious dose given once 
daily and assuming 50% 
accumulation with repeat 
dosing. This maximum dose 
would allow exposure 
coverage of the highest 
anticipated MAD dose (4X). 
Based on current assumptions, 
the maximum dose in Part 1 
(SAD) is projected to be 200 
mg. These changes further 
address risk to participants.
Section 5.1
Figure 2 footnote removed and 
reference to a dose of 400 mg 
was removed.  
Figure 2 footnote removed and 
reference to a dose of 400 mg 
was removed. This change 
further addresses risk to 
participants.   
Section 5.4 Scientific Rationale 
for Study Design
Statement describing the 
rationale for the assessment of 
a therapeutic dose range in 
healthy subjects was added
To provide justification for 
assessment of an exposure 
range in healthy subjects that 
is anticipated to be the 
therapeutic exposure range in 
the target HIV-1-infected 
population. This change does 
not affect the risk benefit ratio 
to participants


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Section # and Name
Description of Change
Brief Rationale
Section 5.5.2 Predicted Human 
Efficacious Dose
Information regarding inhibitory 
quotient (IQ) has been added.
To provide justification for 
plans to assess doses up to 4 
times the anticipated minimally 
effective dose in healthy 
subjects. This change does not 
affect the risk benefit ratio to 
participants
Section 5.5.3
Part 1 (SAD) Starting Dose 
and Dose Escalation
Clarity on the maximum dose 
in the SAD provided.
The anticipated maximum 
single dose of GSK3640254 in 
Part 1 will not exceed 6X, 
where X is the minimally 
efficacious dose given once 
daily and assuming 50% 
accumulation with repeat 
dosing. This maximum dose 
would allow exposure 
coverage of the highest 
anticipated MAD dose (4X). 
Based on current assumptions, 
the maximum dose in Part 1 
(SAD) is projected to be 200 
mg.
Section 6.2 Exclusion Criteria
A clinician (or qualified 
designee) administered 
CSSRS assessment has been 
added as a screening 
evaluation for both the SAD 
and MAD.
To address the risk of suicidal 
ideation identified with 
previous MI GSK3532795, the 
entire trial (SAD and MAD) will 
exclude any subject who has a 
positive (abnormal) response 
confirmed by the investigator 
to the CSSRS at screening. 
This change further addresses 
risk to participants.
Section 8.1 Discontinuation of 
Study Treatment
Discontinuation criteria have 
been clarified to state a 
participant will be discontinued 
for any of the events described 
in this section. Two additional 
discontinuation criteria have 
been added: 1) Development 
of an SAE and 2) Emergence 
of any positive (abnormal) 
response confirmed by the 
investigator on the CSSRS 
during the on-treatment phase 
Emergence of these events 
now mandate discontinuation 
from the trial. This change 
further addresses risk to 
participants.


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Section # and Name
Description of Change
Brief Rationale
(MAD only)  
Section 9.4.5 Suicidal Risk 
Monitoring
Clarification of the use of a 
clinician (or qualified designee) 
administered CSSRS at 
screening (all subjects in SAD 
and MAD) and during the on-
treatment portion of the MAD 
has been added.
To address the risk of suicidal 
ideation identified with 
previous MI GSK3532795, the 
entire trial (SAD and MAD) will 
exclude any subject who has a 
positive (abnormal) response 
confirmed by the investigator 
to a clinician (or qualified 
designee) administered 
CSSRS at screening. The 
MAD portion of the trial will 
include use of the CSSRS 
administered by a clinician (or 
qualified designee) during the 
on-treatment phase of the 
study. A positive (abnormal) 
response confirmed by the 
investigator, at screening or 
on-treatment will result in the 
participant being excluded 
from participation (SAD or 
MAD) or discontinuing the 
study (MAD only), respectively. 
Subsequently the PI/SI will 
arrange for urgent specialist 
psychiatric evaluation and 
management. These changes 
further address risk to 
participants. 
Section 12.3
Study Governance
Clarification made that any 
substantial amendment will 
require approval from the 
MHRA before implementation.
Any substantial amendment to 
the protocol will require MHRA 
approval. This change does 
not affect the risk benefit ratio 
to participants


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Amendment: 03; 5-DEC-2017
Summary of Amendment Changes with Rationale:
The primary purpose of this protocol amendment (03) is to increase the maximum dose in 
the SAD part of the study from 200 mg to ≤ 700 mg, in relation to human exposure to 
GSK3640254 being approximately 70% lower than predicted based on animal data. 
Preliminary PK parameters for GSK3640254 following single dose administration of 1, 
3, and 10 mg show exposures that were lower along with a longer half-life than predicted 
based on animal data. The prediction for a 10 mg dose were a mean Cmax of 197 ng/mL, 
a mean AUC of 3430 ng.h/mL and a mean half-life of 15 hours. The observed Cmax was 
approximately 75% lower, the AUC was approximately 65% lower and the half-life was 
about 70% longer. Taking into consideration the actual human PK profile of 
GSK3640254 at 1, 3 and 10 mg, the minimally anticipated efficacious dose (X) has 
increased from 40 mg to 70 mg with an accumulation upon repeated once daily 
administration increasing from 50% to approximately 115%. In order to evaluate 
exposure anticipated at the maximum MAD dose of up to 4X, higher doses up to 9X will 
need to be evaluated in the SAD. Thus, this amendment is to enable the evaluation of the 
safety/tolerability and pharmacokinetics of single doses of GSK3640254 at doses ≤ 700 
mg in healthy volunteers continuing to participate in Cohorts 1 and 2. Specifically, the 
proposed higher doses will be evaluated in Period 4 (Cohort 1, ≤ 400 mg; Cohort 2, ≤ 700 
mg). Other, non-major changes, have also been incorporated.


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List of Specific Changes
Section # and Name
Description of Change
Brief Rationale
Title Page
The sponsor was changed 
back from GSK to VH.
VH is the sponsor of the study.
Sponsor Signatory Page
The Signatory was changed 
back from Harmony Garges to 
Max Lataillade.
Max Lataillade is the Sponsor.
Overall Design
The Doses for SAD, Period 4 
(Cohorts 1 and 2) were 
increase from 200 mg to ≤ 
400 and ≤ 700 mg, 
respectively in Figure 1. 
This is based upon a need to 
increase doses to attain the 
prior desired exposures. 
Preliminary review shows (dose 
proportional) exposures that 
have been approximately 70% 
lower than anticipated after 
single doses of 1, 3, and 10 
mg.
Section 2
SAD SoA Table
The Full PE can be performed 
on D-2 or D-1. A BMI does not 
need to be measured on D-1.
This flexibility improves the 
subject experience in the 
clinical trial without clinical or 
scientific consequence.
Section 2 
MAD SoA table
Only urine metabolite 
sampling will be performed. 
Next, plasma PK, plasma 
metabolite, and urine 
metabolite sampling will be 
determined by SRM time 
window allowances.
The Full PE can be performed 
on D-2 or D-1. A BMI does not 
need to be measured on D-1. 
A PGx sample will be drawn 
on D-1.
The SRM has been updated to 
reflect the time windows 
needed for accurate sampling.
This flexibility improves the 
subject experience in the 
clinical trial without clinical or 
scientific consequence.
Section 3.2.2
Preliminary Safety and PK data 
in Current Study (SAD doses 1, 
3, and 10 mg)
A new section summarizing 
preliminary safety/PK data for 
1, 3, and 10 mg SAD doses 
was added.
A new section needed to be 
added to describe emerging 
data.
Section 5.1
Overall Design
The Doses for SAD, Period 4 
(Cohorts 1 and 2) were 
increase from 200 mg to ≤ 
400 and ≤ 700 mg, 
This is based upon a need to 
increase doses to attain the 
prior desired exposures. 
Preliminary review shows  


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Section # and Name
Description of Change
Brief Rationale
respectively in Figure 2. 
exposures that have been 
approximately 70% lower than 
anticipated  after single doses 
of 1, 3, and 10 mg.
Sections 5.5.1 – 5.5.4
Predicted Human PK
Predicted Human Effective 
Dose
Part 1 and 2 Starting Dose and 
Dose Escalation
References to predicted 
human PK are changed to 
past tense and preliminary 
single dose data from 1, 3, 
and 10 mg are inserted. 
Projections for PK in the SAD 
and MAD have been re-
calculated. 
MAD dose escalation will not 
exceed approximately 2 fold.
Preliminary review shows (dose 
proportional) exposures that 
have been approximately 70% 
lower than anticipated after 
single doses of 1, 3, and 10 
mg. Thus, the PK parameters 
were re-estimated.
Dose escalation by 
approximately 2 fold in the 
MAD will minimize the pill 
burden encountered by 
participants taking study 
medication for 14 days.
Section 5.5.6
Anticipated Exposure and 
Safety Cover for a Range of 
Potential Doses
Projections for steady state 
PK were re-calculated based 
upon preliminary single dose 
data from the 1, 3, and 10 mg 
dose arms.
Preliminary review shows 
exposures that have been 
approximately 70% lower than 
anticipated after single doses of 
1, 3, and 10 mg. Thus, the 
steady state PK was re-
estimated
Section 6.4
Screen Failures
Text clarified to state reserve 
participants need to be 
screened once every 90 days 
These reserve participants still 
need to undergo evaluations 
on D-2 and D-1 as per the 
SoA table.
This additional text prevents 
reserve participants from 
undergoing excessive 
rescreening evaluations during 
the study.
Section 9
Study Assessments and 
Procedures
Time allowances for the study 
assessments will be followed 
according to the SRM. 
The SRM has been updated to 
reflect the time windows 
needed for accurate 
evaluations.
Section 9.5
Pharmacokinetics
Removal of urine PK profiling 
text.
Existing text, combined with the 
SRM, is sufficient for existing 
sampling.
Section 10.3.3
Bayesian Model Operating 
The Bayesian Model was re-
calculated using a max single 
The probability of successful 
escalation to a 700 mg single 
dose is needed if doses are to 


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Section # and Name
Description of Change
Brief Rationale
Characteristics 
dose of 700 mg.
increase as proposed.
Section 12.8
Appendix 8
The information from 
Amendment 2 was placed in 
this section.
Amendment 2 was previously 
approved.
Sponsor Name:
PREVIOUS TEXT
GlaxoSmithKline Research & Development Limited
REVISED TEXT
GlaxoSmithKline Research & Development Limited
ViiV Healthcare UK Limited
Sponsor Signatory:
PREVIOUS TEXT
Harmony P. Garges, MD
Global Medical Sciences
ViiV Healthcare 
REVISED TEXT
Harmony P. Garges, MD
Global Medical Sciences
ViiV Healthcare 
Max Lataillade, DO, MPH
VP, Clinical Development
ViiV Healthcare
Revision Chronology
PREVIOUS TEXT


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DOCUMENT HISTORY
Document
Date
Amendment 02
03-AUG-2017
Amendment 01
12-Jul-2017
Original Protocol
25-May-2017
REVISED TEXT
DOCUMENT HISTORY
Document
Date
Amendment 03
05-Dec-2017
Amendment 02
03-AUG-2017
Amendment 01
12-Jul-2017
Original Protocol
25-May-2017
1. 
SYNOPSIS
Overall Design
Figure 1 
Phase 1 Study in Healthy Participants using planned doses of 
GSK3640254
PREVIOUS TEXT
REVISED TEXT


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2.
SCHEDULE OF ACTIVITIES (SOA):
SAD Cohorts 1 and 2 On-Treatment: Before, During, and After Dosing in Each Period
PREVIOUS TEXT
Procedure
Periods 1 through 4
Follow-up 
(7-14 days 
post last 
dosing)
Day 
-2
Day 
-1
Day 1
Day 
2
Day 
3
Day 
4
Day 
5
Pre-
dose
0 
h
0.5 
h
1 
h
1.5 
h
2 
h
2.5 
h
3 
h
3.5 
h
4 
h
4.5 
h
5 
h
6 
h
8 
h
12 
h
24 
h
48 
h
72 
h
96 h
Admission to Unit
X
Outpatient Visit
X
Full Physical Exam1
X
X
X
Weight, BMI
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
12-lead safety ECGs
X
X
X
X
X
X
X
X
X
X
X
X
X
Continuous ECG (full 
time matched baseline 
on Day-1)2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test
X
X3
Drug/alcohol/cotinine 
screen
X
Hem/Chem/Urine tests
X
X
X
X
X
Single Dosing with 
GSK3640254 following 
moderate fat meal
X
Plasma PK Sampling4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Event Review
<=================================================================================================================>


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Con Med Review
<=================================================================================================================>
Furlough from Unit
X
HCV=Hepatitis C; BMI= Body mass index; ECG= Electrocardiogram; PK= Pharmacokinetic, SAD=single ascending dose
Note:
1. A Full Physical Exam will include at a minimum, assessments of the Skin, Cardiovascular, Respiratory, Gastrointestinal and 
Neurological systems.
2. Additional safety ECGs may be printed at the discretion of the PI if prolongation in QT interval is suspected. The frequency of ECGs 
will support an exploratory endpoint (should clinical development continue) to evaluate the exposure-response relationship between 
GSK3640254 and QTcF. Once human PK data (e.g. Cmax) are available, the number of ECG time points may be reduced in 
subsequent dosing groups. At timepoints for ECG extraction, subjects will be supinely resting for at least 10 minutes. When ECG 
extractions coincide with safety ECGs, vital signs assessment and blood draws, procedures should be carried out in said order. 
3. This pregnancy test will be obtained approximately 37 days after the last dose of study treatment
4. The number of PK sampling time points may be reduced in subsequent dosing groups once human PK data are available.
REVISED TEXT
Procedure
Periods 1 through 4
Follow-up 
(7-14 days 
post last 
dosing)
Day 
-2
Day 
-1
Day 1
Day 
2
Day 
3
Day 
4
Day 
5
Pre-
dose
0 
h
0.5 
h
1 
h
1.5 
h
2 
h
2.5 
h
3 
h
3.5 
h
4 
h
4.5 
h
5 
h
6 
h
8 
h
12 
h
24 
h
48 
h
72 
h
96 h
Admission to Unit
X
Outpatient Visit
X
Full Physical Exam1
X
X
X
X
Weight, BMI2
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
12-lead safety ECGs
X
X
X
X
X
X
X
X
X
X
X
X
X


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Continuous ECG (full 
time matched baseline 
on Day-1)3 2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test
X
X4 3
Drug/alcohol/cotinine 
screen
X
Hem/Chem/Urine tests
X
X
X
X
X
Fasting Lipid test
X
X
X
Single Dosing with 
GSK3640254 following 
moderate fat meal
X
Plasma PK Sampling5 4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Event Review
<=================================================================================================================>
Con Med Review
<=================================================================================================================>
Furlough from Unit
X
HCV=Hepatitis C; BMI= Body mass index; ECG= Electrocardiogram; PK= Pharmacokinetic, SAD=single ascending dose
Note:
1. A Full Physical Exam will include at a minimum, assessments of the Skin, Cardiovascular, Respiratory, Gastrointestinal and 
Neurological systems. A single exam can be performed on D-2 or D-1.
2.   A BMI does not need to be measured at the time of measurement.
3.  Additional safety ECGs may be printed at the discretion of the PI if prolongation in QT interval is suspected. The frequency of ECGs 
will support an exploratory endpoint (should clinical development continue) to evaluate the exposure-response relationship between 
GSK3640254 and QTcF. Once human PK data (e.g. Cmax) are available, the number of ECG time points may be reduced in subsequent 
dosing groups. At timepoints for ECG extraction, subjects will be supinely resting for at least 10 minutes. When ECG extractions coincide 
with safety ECGs, vital signs assessment and blood draws, procedures should be carried out in said order. 
4.   This pregnancy test will be obtained approximately 37 days after the last dose of study treatment
5.    The number of PK sampling time points may be reduced in subsequent dosing groups once human PK data are available.


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MAD Cohorts 3, 4, 5, 6 and the Expansion Cohort Screening
PREVIOUS TEXT 
Procedure
Follow-
up (7-14 
days 
post last 
dosing)
Day 
-2
Day 
-1
Day 
1
Day 
2
Day 
3
Day 
4
Day 
5
Day 
6
Day 
7
Day 
8
Day 
9
Day 
10
Day 
11
Day 
12
Day 
13
Day 
14
Day 
15
Day 
16
Day 
17
Day 
18
0h
24h
48h
72h
96h
Admission to Unit
X
Outpatient Visit
X
Full Physical Exam1
X
X
X
X
X
X
CSSRS
X
X
Weight, BMI
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
12-lead safety ECGs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Continuous ECG 
(full time matched 
baseline on Day-1)2
X
X
X
X
X
Drug/alcohol/cotinine 
screen
X
Hem/Chem/Urine 
tests
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test
X
X3
QD Dosing with 
GSK3640254 
following moderate 
fat meal
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Plasma PK 
Sampling4
X
X
X
X
X
X
X
X
X
X
X
X
X


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Procedure
Follow-
up (7-14 
days 
post last 
dosing)
Day 
-2
Day 
-1
Day 
1
Day 
2
Day 
3
Day 
4
Day 
5
Day 
6
Day 
7
Day 
8
Day 
9
Day 
10
Day 
11
Day 
12
Day 
13
Day 
14
Day 
15
Day 
16
Day 
17
Day 
18
0h
24h
48h
72h
96h
Plasma Metabolite 
Sampling5
X
X
X
X
Urine PK and 
Metabolite 
Sampling6
X
X
X
X
PGx Sampling (if 
participant consents)
X
Adverse Event 
Review
<=====================================================================================================================>
Con Med Review
<=====================================================================================================================>
Furlough from Unit
X
Note:
1. A Full Physical Exam will include at a minimum, assessments of the Skin, Cardiovascular, Respiratory, Gastrointestinal and 
Neurological systems.
2. ECG data extracted from the Continuous ECG will be assessed before PK sampling, prior to dosing and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4.5, 5, 
5.5, 6, 8, 12 h, and 24 h post dose on Day 1 and Day 14 and on corresponding timepoints on Day -1. At timepoints for ECG extraction, 
subjects will be supinely resting for at least 10 minutes. When ECG extractions coincide with safety ECGs, vital signs assessment and 
blood draws, procedures should be carried out in said order. The frequency of EKGs will support an exploratory endpoint to evaluate 
(should clinical development continue) the ER relationship between GSK3640254 and QTcF. Once human data (eg Cmax) is known, 
the number of EKG time points may be reduced.
3. This pregnancy test will be obtained approximately 37 days after the last dose of study treatment
4. Plasma PK samples for bioanalysis for GSK3640254 will be collected pre-dose (within 15 minutes prior to dosing) and 0.5,1, 1.5, 2, 
2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12 h on Day 1 and Day 14. On dosing days, plasma PK will be collected pre-dose. The number of PK 
sampling time points may be reduced in the initial MAD cohort as well as further in subsequent MAD dosing groups once human PK 
data are available in the SAD as well as in the initial MAD cohorts.


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5. Plasma Metabolite samples for metabolite identification will be collected pre-dose (within 15 minutes prior to dosing) and at the same 
time points as for plasma PK samples on Day 1, Day 2 and Day 14, and Day 15. Plasma metabolite samples will not be collected in the 
expansion cohort.
6. Urine PK and Metabolite Sampling for bioanalysis and metabolite identification will be collected pre-dose (within 1 hour prior to 
dosing) and from time 0 up to 24 hours on Day 1 and Day 14. Urine samples will not be collected in the expansion cohort.
REVISED TEXT
Procedure
Follow-
up (7-14 
days 
post last 
dosing)
Day 
-2
Day 
-1
Day 
1
Day 
2
Day 
3
Day 
4
Day 
5
Day 
6
Day 
7
Day 
8
Day 
9
Day 
10
Day 
11
Day 
12
Day 
13
Day 
14
Day 
15
Day 
16
Day 
17
Day 
18
0h
24h
48h
72h
96h
Admission to Unit
X
Outpatient Visit
X
Full Physical Exam1
X
X
X
X
X
X
X
CSSRS
X
X
Weight, BMI2
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
12-lead safety ECGs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Continuous ECG 
(full time matched 
baseline on Day-1)3 2
X
X
X
X
X
Drug/alcohol/cotinine 
screen
X
Hem/Chem/Urine 
tests
X
X
X
X
X
X
X
X
X
X
X
Fasting Lipid test
X
X
X
X
Pregnancy Test
X
X4 3


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Procedure
Follow-
up (7-14 
days 
post last 
dosing)
Day 
-2
Day 
-1
Day 
1
Day 
2
Day 
3
Day 
4
Day 
5
Day 
6
Day 
7
Day 
8
Day 
9
Day 
10
Day 
11
Day 
12
Day 
13
Day 
14
Day 
15
Day 
16
Day 
17
Day 
18
0h
24h
48h
72h
96h
QD Dosing with 
GSK3640254 
following moderate 
fat meal
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Plasma PK 
Sampling5 4
X
X
X
X
X
X
X
X
X
X
X
X
X
Plasma Metabolite 
Sampling6 5
X
X
X
X
Urine PK and
Metabolite 
Sampling7 6
X
X
X
X
PGx Sampling (if 
participant consents)
X
X
Adverse Event 
Review
<=====================================================================================================================>
Con Med Review
<=====================================================================================================================>
Furlough from Unit
X
Note:
1. A Full Physical Exam will include at a minimum, assessments of the Skin, Cardiovascular, Respiratory, Gastrointestinal and 
Neurological systems. A single exam can be performed on D-2 or D-1.
2. A BMI does not need to be measured at the time of measurement.
3. ECG data extracted from the Continuous ECG will be assessed before PK sampling, prior to dosing and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4.5, 5, 
5.5, 6, 8, 12 h, and 24 h post dose on Day 1 and Day 14 and on corresponding timepoints on Day -1. At timepoints for ECG extraction, 
subjects will be supinely resting for at least 10 minutes. When ECG extractions coincide with safety ECGs, vital signs assessment and 
blood draws, procedures should be carried out in said order. The frequency of EKGs will support an exploratory endpoint to evaluate 
(should clinical development continue) the ER relationship between GSK3640254 and QTcF. Once human data (eg Cmax) is known, 
the number of EKG time points may be reduced.


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4. This pregnancy test will be obtained approximately 37 days after the last dose of study treatment
5. Plasma PK samples for bioanalysis for GSK3640254 will be collected pre-dose (within 15 minutes prior to dosing) according to the 
Time Window Allowances as indicated in the Study Reference Manual and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12 h on Day 
1 and Day 14. On dosing days, plasma PK will be collected pre-dose. The number of PK sampling time points may be reduced in the 
initial MAD cohort as well as further in subsequent MAD dosing groups once human PK data are available in the SAD as well as in the 
initial MAD cohorts.
6. Plasma Metabolite samples for metabolite identification will be collected pre-dose (within 15 minutes prior to dosing) according to 
the Time Window Allowances as indicated in the Study Reference Manual and at the same time points as for plasma PK samples 
on Day 1, Day 2 and Day 14, and Day 15. Plasma metabolite samples will not be collected in the expansion cohort.
7. Urine PK and Metabolite Sampling for bioanalysis and metabolite identification will be collected pre-dose (within 1 hour prior to 
dosing) according to the Time Window Allowances as indicated in the Study Reference Manual and from time 0 up to 24 hours on 
Day 1 and Day 14. Urine samples will not be collected in the expansion cohort.


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ADDED TEXT
3.2.2
Preliminary Safety and PK data in Current Study (SAD doses 1, 3, 
and 10 mg)
Through Amendment 2 of the current protocol, preliminary review of blinded safety data 
for the 1, 3, and 10 mg doses of the ongoing study indicate no major clinically significant 
safety or tolerability concerns. There have been 5, 4 and 11 AEs (all non-serious) 
reported in the 1, 3, and 10 mg doses, respectively (n = 16 randomized subjects). All AEs 
were single reports, except for three cases of dizziness and three cases of contact 
dermatitis, related to ECG leads or intravenous cannula site. All AEs were Grade 1, apart 
from an AE of depression (Grade 2); this AE began eight days after receipt of study 
medication in Period 1 but was reported 43 days later. On further questioning, depression 
was associated with difficulty in sleeping and thoughts of self-harm. Immediate 
evaluation by a psychiatrist and GP uncovered long standing personal and family issues 
which pre-existed study entry. Given the psychosocial stressors, the depression was 
unrelated to study drug as determined by the investigator and the Sponsor. The subject 
was withdrawn from the study in order that treatment with anti-depressant medication 
could commence. A further subject withdrew from the study due to personal reasons. 
Only one AE (dizziness in the blinded 10 mg dosing arm) was identified as related to 
study medication. One subject in the blinded 3 mg arm dosing arm experienced three 
episodes of intermittent nightmares post dose, all reported as unrelated to study
medication. The subject had previously reported nightmares, but in-house, these had 
occurred more frequently. There have been no on-treatment clinically significant 
abnormalities in vital signs or ECGs. Finally, review of laboratory findings revealed one 
subject in the blinded 10 mg dosing arm whose Haematocrit decreased from 45.2% to 
41.8% (5 days after dosing). 
Preliminary PK parameters for GSK3640254 following single doses of 1, 3, and 10 mg 
are summarized in Table 1. GSK3640254 is slowly absorbed with
maximum 
concentration observed on average 3.5 hours after dosing and slowly eliminated with an 
average half-life of 26 hours. In general, exposures were lower along with a longer half-
life than predicted based on animal data (Sections 5.5.1 and 5.5.3). The observed Cmax is 
approximately 75% lower, the AUC is approximately 65% lower and the half-life is 
about 70% longer. The lower exposures may be due to a lower extent of absorption than 
the predicted based on the animal data.
Table 1  Summary of Preliminary PK Parameters Following Single Doses of 
GSK3640254 in study 207187
Dose of GSK3640254
1 mg
3 mg
10 mg
Parameters
N=6
N=6
N=6
Cmax, ng/mL
4.93 (16%)
13.8 (31%)
47.0 (30%)
Tmax, h
3.5 (2.5 – 6.0)
4.5 (2.0 – 5.0)
3.5 (2.5 – 5.0)


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T1/2z, h
NR
NR
25.8 (17%)
AUC, ng.h/mL
NR
NR
1230 (19%)
Note: Parameters are summarized as geometric mean (CVb%) except for Tmax 
presented as median (min-max).
NR: not reportable due to limited data in terminal phase and AUC extrapolated being 
greater than 40%.  
5.1
Overall Design
Figure 2
Phase 1 Study in Healthy Participants using planned doses of 
GSK3640254
PREVIOUS TEXT
REVISED TEXT


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Part 2 (MAD):
PREVIOUS TEXT
The earliest point at which Part 2 (MAD) of the study will be initiated is once the single 
dose safety and preliminary PK data for the anticipated minimally effective dose has been 
evaluated in the SAD. The potential minimally effective dose for GSK3640254, noted as 
X, is anticipated to be that which is predicted to provide a steady state Ctrough ≥ 0.11 
g/mL in 95% of participants and will be re-estimated based on the PK data collected in 
the early doses in Part 1 (see Section 5.5.2 for further details). The initial dose in the 
MAD (Cohort 3) will be approximately half the anticipated minimally effective dose or 
0.5X. Dose escalation in the MAD will not exceed 2-fold between cohorts and will be 
driven by safety and PK stopping criteria (see Section 8). In addition, a dose will not be 
assessed in the MAD until the anticipated steady-state exposure (Cmax and AUC(0-) on 
Day 14) for that dose have been evaluated and shown not to have met safety stopping 
criteria in the SAD portion of the study (Part 1).
REVISED TEXT
The earliest point at which Part 2 (MAD) of the study will be initiated is once the single 
dose safety and preliminary PK data for the anticipated minimally effective dose has been 
evaluated in the SAD. The potential minimally effective dose for GSK3640254, noted as 
X, is anticipated to be that which is predicted to provide a steady state Ctrough ≥ 0.11 
g/mL in 95% of participants and will be re-estimated based on the PK data collected in 
the early doses in Part 1 (see Section 5.5.2 for further details). The initial dose in the 
MAD (Cohort 3) will be approximately half the anticipated minimally effective dose or 
0.5X. Dose escalation in the MAD will not exceed approximately 2-fold between 
cohorts and will be driven by safety and PK stopping criteria (see Section 8). In addition, 
a dose will not be assessed in the MAD until the anticipated steady-state exposure (Cmax 
and AUC(0-) on Day 14) for that dose have been evaluated and shown not to have met 
safety stopping criteria in the SAD portion of the study (Part 1).
5.5.1. 
Predicted Human Pharmacokinetics
PREVIOUS TEXT
The pharmacokinetic profile for GSK3640254 in humans was predicted using allometric 
scaling across all species (mouse, rat, dog, and monkey), and was combined with Css-
MRT modeling to obtain the predicted human PK profile. Using this method, the IV 
plasma clearance in humans for GSK3640254 is projected to be low (0.47 mL/min/kg). 
The intravenous volume of distribution was assumed to be the same as in dogs or close to 
total body water (0.5 L/kg). The elimination half-life is anticipated to be around 15 hours, 
leading to a small anticipated accumulation with once daily dosing of ~50%. The mean
oral bioavailability in animals was 58% and assumed for exposure projections in humans. 
REVISED TEXT
The pharmacokinetic profile for GSK3640254 in humans was predicted using allometric 
scaling across all species (mouse, rat, dog, and monkey), and was combined with Css-


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MRT modeling to obtain the predicted human PK profile. Using this method, the IV 
plasma clearance in humans for GSK3640254 was is projected to be low (0.47 
mL/min/kg). The intravenous volume of distribution was assumed to be the same as in 
dogs or close to total body water (0.5 L/kg). The elimination half-life was is anticipated 
to be around 15 hours, leading to a small anticipated accumulation with once daily dosing 
of ~50%. The mean oral bioavailability in animals was 58% and assumed for exposure 
projections in humans. 
The emerging PK data obtained at the three lower single doses of 1, 3 and 10 mg are 
presented in Section 3.2.2.
5.5.2 
Predicted Human Effective Dose
PREVIOUS TEXT
The potential minimally effective dose for GSK3640254 was estimated using the 
predicted human PK profile, assuming similar between-participant PK variability to that 
observed with GSK3532795 (Population PK model based on data from Phase 2b study 
AI468038, Metrum Research Group, 2016), to ensure that 95% of participants have 
steady state trough concentrations that exceed the target concentration of 0.11 g/mL 
following once daily dosing of GSK3640254. This led to the prediction of a likely 
minimally effective once daily dose of approximately 40 mg, assuming 58% 
bioavailability. At this dose, the mean repeat-dose Cmax is predicted to be approximately
1.11 g/mL, mean trough concentration is predicted to be approximately 0.290 g/mL 
and mean AUC is predicted to be approximately 13.7 g.h/mL (Table 4). The anticipated 
steady-state mean AUC is 1.63-fold lower than the NOAEL in the rat, 4.46-fold lower 
than the LOAEL in the rat, and 5.35-fold lower than the LOAEL in the dog.
The relationship between GSK3640254 exposure and efficacy, duration of antiviral 
response, and development of on-treatment resistance will be evaluated in future studies 
in HIV-1-infected participants where assessment of a range of exposures will be 
important to inform the therapeutic dose range of GSK3640254. One exposure parameter 
of interest is inhibitory quotient (IQ), where IQ = Ctrough/PBA-EC90. The IQs of other 
antiretrovirals at approved doses are approximately 19, 27, and 36 for dolutegravir 50 mg 
once daily, atazanavir 300 mg once daily with ritonavir, and lopinavir 400 mg twice daily 
with ritonavir, respectively [Van Lunzen, 2012 and Zhu, 2012]. For GSK360254, the 
minimally effective dose provides a trough concentration of 0.11 ug/mL at steady state in 
95% of the participants and represents a geometric mean IQ of 7.92. To facilitate 
assessment of a range of GSK3640254 IQs in future studies in the target population, 
doses up to 4 times those of the minimally effective dose are planned for assessment in 
Part 2 (MAD) in healthy participants. These doses will be administered in accordance 
with PK and safety stopping criteria (see Section 8.1.3). Projected exposures at the 
highest anticipated once daily dose in the MAD include a mean repeat-dose Ctrough of 
0.87 ug/mL and an IQ of 23.7.
REVISED TEXT


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The potential minimally effective dose for GSK3640254 was initially estimated using the 
predicted human PK profile, assuming similar between-participant PK variability to that 
observed with GSK3532795 (Population PK model based on data from Phase 2b study 
AI468038, Metrum Research Group, 2016), to ensure that 95% of participants have 
steady state trough concentrations that exceed the target concentration of 0.11 g/mL 
following once daily dosing of GSK3640254. This led to the prediction of a likely 
minimally effective once daily dose of approximately 40 mg, assuming 58% 
bioavailability. After PK information were obtained following administration of 1, 3 
and 10 mg of GSK3640254 in this study, a pharmacokinetic model was fit through
these data and the observed PK profile was used along with the previously assumed 
variabilities. The updated minimally effective once daily dose is approximately 70 
mg. At this dose, the mean repeat-dose Cmax is predicted to be approximately 1.11 0.544
g/mL, mean trough concentration is predicted to be approximately 0.290 0.238 g/mL 
and mean AUC is predicted to be approximately 13.7 8.91 g.h/mL (Table 45). The 
anticipated steady-state mean AUC is 1.632.52-fold lower than the NOAEL in the rat, 
4.466.86-fold lower than the LOAEL in the rat, and 5.35 8.23-fold lower than the 
LOAEL in the dog.
The relationship between GSK3640254 exposure and efficacy, duration of antiviral 
response, and development of on-treatment resistance will be evaluated in future studies 
in HIV-1-infected participants where assessment of a range of exposures will be 
important to inform the therapeutic dose range of GSK3640254. One exposure parameter 
of interest is inhibitory quotient (IQ), where IQ = Ctrough/PBA-EC90. The IQs of other 
antiretrovirals at approved doses are approximately 19, 27, and 36 for dolutegravir 50 mg 
once daily, atazanavir 300 mg once daily with ritonavir, and lopinavir 400 mg twice daily 
with ritonavir, respectively [Van Lunzen, 2012 and Zhu, 2012]. For GSK360254, the 
minimally effective dose provides a trough concentration of 0.11 ug/mL at steady state in 
95% of the participants and represents a geometric mean IQ of 7.92. To facilitate 
assessment of a range of GSK3640254 IQs in future studies in the target population, 
doses up to 4 times those of the minimally effective dose are planned for assessment in 
Part 2 (MAD) in healthy participants. These doses will be administered in accordance 
with PK and safety stopping criteria (see Section 8.1.3). Projected exposures at the 
highest anticipated once daily dose in the MAD include a mean repeat-dose Ctrough of 
0.871.02 ug/mL and an IQ of 23.727.8.
5.5.3 
Part 1 (SAD) Starting Dose and Dose Escalation
PREVIOUS TEXT
Dose escalations in Part 1 (SAD) will be governed in real-time by safety and PK stopping 
criteria (see Section 8.1.3 and Section 8.1.4). A dose will not be assessed in the MAD 
until the anticipated steady-state exposures (Cmax and AUC(0-) on Day 14) for that 
dose have been evaluated and shown not to have met PK or safety stopping criteria in the 
SAD portion of the study (Part 1). The maximum dose in the MAD is planned to be 
approximately 4X, where X is the minimally efficacious dose given once daily (see 
Section 5.5.2).  To account for assumed accumulation of 50% upon repeat dosing, the 
highest dose in the SAD will be 6X. This will allow single dose evaluation of the highest 
anticipated steady-state exposures before once daily administration of the highest MAD 


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dose. Based on the assumptions described above, the anticipated maximum dose in Part 1 
is a single dose of 200 mg. The predicted mean single dose Cmax of 200 mg is 3.94 
g/mL. Given different assumptions of with-in and between participant Cmax variability, 
the probabilities of any participant Cmax being above 7.96 g/mL, the SAD PK Stopping 
Criterion (Section 8.1.3), are illustrated in Table 2. All doses in the SAD are governed by 
safety and PK stopping criteria. A dose which has met formal clinical, QT, or PK 
stopping criteria will not be repeated in the SAD (or MAD).
Table 2
Probability of any SAD participant (Cmax >7.96 µg/mL) for 
potential doses
Cmax Variability
Potential GSK3640254 SAD Doses
%CVw1
%CVb1
10mg
25mg
50mg 
100mg
200mg
250mg
300mg
12.5
25
0
0
0
0
0.034
0.211
0.593
25
25
0
0
0
0
0.122
0.405
0.754
17.5
35
0
0
0
0
0.181
0.486
0.772
35
35
0
0
0
0.013
0.363
0.636
0.831
25
50
0
0
0
0.016
0.436
0.692
0.861
50
50
0
0
0.005
0.101
0.591
0.792
0.905
Note: 1, %CVw: within-participant coefficient of variation. %CVb: between-participant coefficient of 
variation
REVISED TEXT
Dose escalations in Part 1 (SAD) will be governed in real-time by safety and PK stopping 
criteria (see Section 8.1.3 and Section 8.1.4). A dose will not be assessed in the MAD 
until the anticipated steady-state exposures (Cmax and AUC(0-) on Day 14) for that 
dose have been evaluated and shown not to have met PK or safety stopping criteria in the 
SAD portion of the study (Part 1). The maximum dose in the MAD is planned to be 
approximately 4X, where X is the minimally efficacious dose given once daily (see 
Section 5.5.2).  To account for assumedanticipated accumulation of 50115% upon repeat 
dosing, the highest dose in the SAD will be approximately 69X. This will allow single 
dose evaluation of the highest anticipated steady-state exposures before once daily 
administration of the highest MAD dose. Based on the assumptions described above, the 
anticipated maximum dose in Part 1 is a single dose of up to 700200 mg. The predicted 
mean single dose Cmax of 700200 mg is 3.942.74 g/mL. Given different assumptions of 
with-in and between participant Cmax variability, the probabilities of any participant 
Cmax being above 7.96 g/mL, the SAD PK Stopping Criterion (Section 8.1.3), are 


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illustrated in Table 2. All doses in the SAD are governed by safety and PK stopping 
criteria. A dose which has met formal clinical, QT, or PK stopping criteria will not be 
repeated in the SAD (or MAD).
Table 23
Probability of any SAD participant (Cmax >7.96 µg/mL) for 
potential doses
Cmax Variability
Potential GSK3640254 SAD Doses
%CVw1
%CVb1
10mg
25mg
50mg 
100mg
200mg
250mg
300mg
12.5
25
0
0
0
0
0.034
0.211
0.593
25
25
0
0
0
0
0.122
0.405
0.754
17.5
35
0
0
0
0
0.181
0.486
0.772
35
35
0
0
0
0.013
0.363
0.636
0.831
25
50
0
0
0
0.016
0.436
0.692
0.861
50
50
0
0
0.005
0.101
0.591
0.792
0.905
Note: 1, %CVw: within-participant coefficient of variation. %CVb: between-participant coefficient of 
variation


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Cmax Variability
Potential GSK3640254 SAD Doses
%CVw1
%CVb1
30mg
100mg
200mg 400mg
700mg
7.5
15
0
0
0
0
0
15
15
0
0
0
0
0.001
12.5
25
0
0
0
0
0.005
25
25
0
0
0
0
0.038
17.5
35
0
0
0
0.001
0.071
35
35
0
0
0
0.01
0.191
25
50
0
0
0
0.024
0.261
50
50
0
0
0.007
0.094
0.445
Note: 1, %CVw: within-participant coefficient of variation. %CVb: between-participant coefficient of 
variation
5.5.4. Part 2 (MAD) Starting Dose and Dose Escalation
PREVIOUS TEXT
The initial dose in the MAD (Cohort 3) will be approximately half the likely minimally
effective dose, re-estimated based on the clinical PK data collected in the early doses of 
Part 1. Dose escalation in the MAD will not exceed 2-fold between cohorts, and will be 
governed by both safety and MAD PK stopping criteria (see Section 8.1.3 and Section 
8.1.4). Given different assumptions for the between participant AUC variability (%CVb) 
and the current human PK prediction, the probability of any participant AUCtau in the 
MAD above 61.1 g.hr/mL, the MAD PK Stopping Criterion (Section 8.1.3), are 
illustrated in Table 3.
Table 3
Probability of any MAD participant (AUCtau > 61.1 µg.h/mL) for 
potential QD doses


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AUC variability
Potential GSK3640254 QD MAD Doses
%CVb1
25mg
50mg
100mg
110mg
120mg
130mg
140mg
0.25
0
0
0.056
0.144
0.269
0.466
0.65
0.35
0
0
0.224
0.378
0.525
0.684
0.81
0.5
0
0.019
0.514
0.653
0.736
0.829
0.876
Note: 1, %CVb: between-participant coefficient of variation
REVISED TEXT
The initial dose in the MAD (Cohort 3) will be approximately half the likely minimally
effective dose, re-estimated based on the clinical PK data collected in the early doses of 
Part 1. Dose escalation in the MAD will not exceed approximately 2-fold between 
cohorts, and will be governed by both safety and MAD PK stopping criteria (see Section 
8.1.3 and Section 8.1.4). Given different assumptions for the between participant AUC 
variability (%CVb) and the current human PK prediction, the probability of any 
participant AUCtau in the MAD above 61.1 g.hr/mL, the MAD PK Stopping Criterion 
(Section 8.1.3), are illustrated in Table 3.
Table 34
Probability of any MAD participant (AUCtau > 61.1 µg.h/mL) for 
potential QD doses
AUC variability
Potential GSK3640254 QD MAD Doses
%CVb1
25mg
50mg
100mg
110mg
120mg
130mg
140mg
0.25
0
0
0.056
0.144
0.269
0.466
0.65
0.35
0
0
0.224
0.378
0.525
0.684
0.81
0.5
0
0.019
0.514
0.653
0.736
0.829
0.876
Note: 1, %CVb: between-participant coefficient of variation


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AUC 
variability
Potential GSK3640254 QD MAD Doses
%CVb1
40mg
80mg
150mg
300mg
0.15
0
0
0
0.009
0.25
0
0
0
0.162
0.35
0
0
0
0.41
0.5
0
0
0.041
0.631
Note: 1, %CVb: between-participant coefficient of variation
5.5.6 Anticipated Exposure and Safety Cover for a Range of Potential 
Doses
PREVIOUS TEXT
Projected steady-state exposures of GSK3640254 from potential doses in Part 2 are compared to 
target efficacious concentrations and preclinical toxicity exposures in Table 4. Predicted human 
exposure following multiple doses can be compared to the NOAEL and LOAEL in rats and only to a 
LOAEL in dogs. Findings in both species were GI related, limited and reversible (see Section 3.3.1 
and the CIB for details).
Table 4
Projected steady-state PK for a range of potential QD doses 
following fed administration and comparison to efficacy target and 
preclinical exposure


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Parameter
10 mg
20 mg
40 mg
80 mg
120 mg
Ctrough, ug/mL
Mean
0.0725
0.145
0.290
0.580
0.870
Lower bound of 90% CI
0.0334
0.0668
0.134
0.267
0.401
Ctrough/Ctarget
Mean
0.659
1.32
2.64
5.27
7.91
Lower bound of 90% CI
0.304
0.607
1.215
2.43
3.64
Cmax Day 1, ug/mL
Mean
0.197
0.394
0.788
1.58
2.36
Upper bound of 80% CI
0.348
0.696
1.392
2.78
4.18
Cmax Cover with
Rat NOAEL
6.81
3.41
1.70
0.851
0.568
Dog LOAEL
12.0
5.98
2.99
1.49
0.996
Cmax Day 14, ug/mL
Mean
0.278
0.556
1.112
2.22
3.34
Upper bound of 80% CI
0.420
0.839
1.678
3.36
5.03
Cmax Cover with
Rat NOAEL
5.65
2.82
1.41
0.706
0.471
Dog LOAEL
9.92
4.96
2.48
1.24
0.826
Mean AUC, ug.h/mL
Mean
3.43
6.86
13.71
27.4
41.1
Upper bound of 80% CI
4.84
9.68
19.4
38.7
58.1
AUC Cover with
Rat NOAEL
4.63
2.31
1.16
0.58
0.386
Rat LOAEL
12.6
6.31
3.16
1.58
1.05
Dog LOAEL
15.1
7.57
3.79
1.89
1.26
Note: The upper bound of the 80% CI is presented to capture the likely highest PK values in 6 subjects. The 
Cmax and AUC cover were computed as the ratio of Cmax or AUC in animal divided by the Upper Bound 
of the 80% CI predicted for humans. Ctarget = 3xPBA-EC90 (0.11 µg/mL)
REVISED TEXT
Projected steady-state exposures of GSK3640254 from potential doses in Part 2, taking into 
consideration the PK emerging from single doses of 1, 3 and 10 mg, are compared to target 
efficacious concentrations and preclinical toxicity exposures in Table 45. Predicted human 
exposure following multiple doses can be compared to the NOAEL and LOAEL in rats and only to a 
LOAEL in dogs. Findings in both species were GI related, limited and reversible (see Section 3.3.1 
and the CIB for details).
Table 45
Projected steady-state PK for a range of potential QD doses 
following fed administration and comparison to efficacy target and 
preclinical exposure


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Parameter
40 mg
80 mg
150 mg
300 mg
Ctrough, ug/mL
Mean
0.136
0.272
0.509
1.019
Lower bound of 90% CI
0.0680
0.136
0.255
0.510
Ctrough/Ctarget
Mean
1.23
2.47
4.63
9.26
Lower bound of 90% CI
0.618
1.24
2.32
4.64
Cmax Day 1, ug/mL
Mean
0.157
0.314
0.588
1.18
Upper bound of 80% CI
0.360
0.720
1.35
2.70
Cmax Cover with
Rat NOAEL
6.59
3.293
1.756
0.878
Dog LOAEL
11.56
5.780
3.083
1.541
Cmax Day 14, ug/mL
Mean
0.311
0.622
1.17
2.33
Upper bound of 80% CI
0.484
0.968
1.82
3.63
Cmax Cover with
Rat NOAEL
4.90
2.448
1.306
0.653
Dog LOAEL
8.60
4.298
2.292
1.146
Mean AUC, ug.h/mL
Mean
5.09
10.2
19.1
38.17
Upper bound of 80% CI
7.26
14.5
27.2
54.49
AUC Cover with
Rat NOAEL
3.08
1.542
0.822
0.411
Rat LOAEL
8.41
4.205
2.243
1.12
Dog LOAEL
10.09
5.04
2.69
1.35
Note: The upper bound of the 80% CI is presented to capture the likely highest PK values in 6 subjects. The 
Cmax and AUC cover were computed as the ratio of Cmax or AUC in animal divided by the Upper Bound 
of the 80% CI predicted for humans. Ctarget = 3xPBA-EC90 (0.11 µg/mL). These predictions are taking 
into consideration the emerging PK observed after single administration of 1, 3 and 10 mg.
6.4 Screen Failures
PREVIOUS TEXT
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria that established screen failure, and 
any serious adverse events (SAEs).
Individuals who do not meet the criteria for participation in this study (screen failure) 
may not be rescreened.


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REVISED TEXT
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized. However, reserve participants only need to 
undergo the screening process once every 90 days; additionally, reserve participants 
will still be subject to Day -2 and -1 evaluations in routine fashion (as shown in the 
SoA table). A minimal set of screen failure information is required to ensure transparent 
reporting of screen failure participants to meet the Consolidated Standards of Reporting 
Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility 
criteria that established screen failure, and any serious adverse events (SAEs).
Individuals who do not meet the criteria for participation in this study (screen failure) 
may not be rescreened.
9
STUDY ASSESSMENTS AND PROCEDURES
ADDED TEXT

Time window allowances for all study assessments will be followed according to the 
time window allowances as indicated in the SRM.
9.5
Pharmacokinetics
PREVIOUS TEXT

Urine samples will be collected for 24 hours on Day 1 and Day 14 in MAD 
cohorts 3, 4, 5 and 6 for measurement of urine concentrations of GSK3640254 as 
specified in the SoA. After PK analysis, aliquots of 200 mL pooled urine samples 
(0-24 hour) will be used for metabolite profiling. A maximum of 2 samples may 
be collected at additional time points during the study if warranted and agreed 
upon between the investigator and the sponsor. Instructions for the collection and 
handling of biological samples will be provided by the sponsor. The actual start 
and stop date and time (24-hour clock time) as well as collected volume over 24 
hours will be recorded for urine sample. Details of PK urine sample collection, 
processing, storage procedures and shipping procedures are detailed in the SRM.
REVISED TEXT

Urine samples will be collected for 24 hours on Day 1 and Day 14 in MAD 
cohorts 3, 4, 5 and 6 for measurement of urine concentrations of GSK3640254 as 
specified in the SoA. After PK analysis, aliquots of 200 mL pooled urine samples 
(0-24 hour) will be used for metabolite profiling. A maximum of 2 samples may 
be collected at additional time points during the study if warranted and agreed 
upon between the investigator and the sponsor. Instructions for the collection and 
handling of biological samples will be provided by the sponsor. The actual start 
and stop date and time (24-hour clock time) as well as collected volume over 24 


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hours will be recorded for urine sample. Details of PK urine sample collection, 
processing, storage procedures and shipping procedures are detailed in the SRM.
10.3.3. Interim Analyses
PREVIOUS TEXT
In this part, we want to explore the operating characteristics of the 200mg dose. Given 
different assumptions of with-in and between participant Cmax variability (CV%), and 
assuming dose proportionality (slope=1), data for 1000 trials were simulated based on 
Whitehead’s model [1]. Each simulated trial contains Cmax values for 6 subjects on 
treatment for doses ranging from 1mg to 100mg in SAD cohort 1 and cohort 2. 
For each simulate trial, we fitted the mixed effect Bayesian model based on mode [1]. In 
the following procedure, we calculated the Bayesian probability of an individual 
exceeding the Cmax threshold: 
We had 10000 iterations in the MCMC procedure. In each iteration, we obtained the 
estimated parameters 
and
(the estimated standard deviation of 
), Based on the estimation, a random sample for each subject, which represented the 
simulated exposure in the 200mg dose, was drawn from the distribution 
. We counted the number of iterations 
with any simulated 
exposure exceeding the Cmax threshold log(7.96). The Bayesian probability was 
calculated as 
.
For each trial, the Bayesian probability for the 200mg dose is calculated and compared 
with different thresholds (40%, 50% or 60%). Among those 1000 trials, the percentages 
of trials with Bayesian probability below the thresholds, which stands for the percentage 
of trials that could be escalated to dose 200mg, are listed in Table 7.
Table 7
Percentage of trials with Bayesian probability less than the threshold 
(40%, 50% or 60%)


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Cmax Variability
Probability Threshold
%CVw1
%CVb1
40%
50%
60%
12.5
25
98.3%
98.8%
99.1%
25
25
93.9%
96.5%
98.4%
17.5
35
83.5%
87.3%
90.8%
35
35
69.4%
79.0%
86.3%
25
50
55.3%
63.0%
70.1%
50
50
33.8%
47.9%
58.9%
Note: 1, %CVw: within-participant coefficient of variation. %CVb: between-participant coefficient of 
variation
Based on the table above, when with-in and between participant Cmax variability are 
small or moderate, the probability of successfully escalating to 200mg is high.
REVISED TEXT
In this part, we want to explore the operating characteristics of the 200700mg dose for 
SAD. Given different assumptions of with-in and between participant Cmax variability
(CV%), and assuming dose proportionality (slope=1), data for 1000 trials were simulated 
based on Whitehead’s model [1]. Each simulated trial contains Cmax values for 6 
subjects on treatment for doses ranging from 1mg to 100400mg in SAD cohort 1 and 
cohort 2. 
For each simulate trial, we fitted the mixed effect Bayesian model based on mode [1]. In 
the following procedure, we calculated the Bayesian probability of an individual 
exceeding the Cmax threshold: 
We had 10000 iterations in the MCMC procedure. In each iteration, we obtained the 
estimated parameters 
and
(the estimated standard deviation of 
), Based on the estimation, a random sample for each subject, which represented the 
simulated exposure in the 200700mg dose, was drawn from the distribution 
. We counted the number of iterations 
with any simulated 
exposure exceeding the Cmax threshold log(7.96). The Bayesian probability was 
calculated as 
.
For each trial, the Bayesian probability for the 200700mg dose is calculated and 
compared with different thresholds (40%, 50% or 60%). Among those 1000 trials, the 
percentages of trials with Bayesian probability below the thresholds, which stands for the 
percentage of trials that could be escalated to dose 200700mg, are listed in Table 7.


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Table 78
Percentage of trials with Bayesian probability less than the threshold 
(40%, 50% or 60%)
Cmax Variability
Probability Threshold
%CVw1
%CVb1
40%
50%
60%
12.5
25
98.3%
98.8%
99.1%
25
25
93.9%
96.5%
98.4%
17.5
35
83.5%
87.3%
90.8%
35
35
69.4%
79.0%
86.3%
25
50
55.3%
63.0%
70.1%
50
50
33.8%
47.9%
58.9%
Note: 1, %CVw: within-participant coefficient of variation. %CVb: between-participant coefficient of 
variation
Cmax Variability
Probability Threshold
%CVw1
%CVb1
40%
50%
60%
7.5
15
100.0%
100.0%
100.0%
15
15
100.0%
100.0%
100.0%
12.5
25
99.9%
100.0%
100.0%
25
25
99.3%
99.5%
99.8%
17.5
35
95.6%
97.0%
98.5%
35
35
91.0%
94.0%
97.1%
25
50
75.7%
81.9%
85.2%
50
50
53.9%
66.8%
77.0%
Note: 1, %CVw: within-participant coefficient of variation. %CVb: between-participant coefficient of 
variation
Based on the table above, when with-in and between participant Cmax variability are 
small or moderate, the probability of successfully escalating to 200700mg is high.


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Amendment: 04; 17-May-2018
ADDED TEXT
Overall Rationale for the Protocol Amendment:
The purpose of this protocol amendment (04) is to study a higher dose of 320 mg QD for 
14 days in the MAD part of the study (see Cohort 6 in Figure 1). The MAD 320 mg QD 
dose would explore steady-state Cmax values greater than those explored in the SAD 
study (which is not permitted by the current version of the protocol). This dose of 320 mg 
QD is four times the projected minimum effective dose (~80 mg QD) and is in line with 
the MAD PK stopping Criteria in the current approved protocol (amendment 03/ 05 
December 2017); specifically, the probability of any subject having an AUC > 61.1 
µg/mL is 42% (data through May 9, 2018). A MAD dose of 320 mg QD allows for a 
thorough evaluation of PK/QT relationship and a greater safety margin in subsequent 
clinical trials in patients. 
The totality of preliminary PK and safety/tolerability data to date shows the MAD 320 
mg QD dose is clinically and scientifically reasonable (see Section 3.2.2 for full details). 
Specifically, GSK3640254 following single dose administration ultimately showed a 
plateauing of exposure at the 700 mg dose. On Day 14, the mean Cmax for the MAD 200 
mg dose (1841 ng/ml in Cohort 5) approximated that seen in the SAD at 400 and 700 mg 
doses (1881 and 1761 ng/ml, respectively). Since the current protocol does not permit a 
dose in the MAD to surpass the Cmax studied in the SAD, the ViiV/ GSK Dose 
Escalation Committee opened the Expansion Cohort (currently ongoing) with a 200 mg 
dose (See Figure 1) at the conclusion of Cohort 5. Briefly, there have been no significant 
clinical safety/tolerability findings in the SAD or MAD through May 7, 2018. 
Preliminary ongoing data review show no deaths or SAEs. There have been 4 individual 
AEs leading to discontinuation. There have been 10 individual AEs related to blinded 
study medication. Preliminary review of blinded safety data for the: 1) SAD show 17 
subjects experienced 60 individual AEs (58 Grade 1; Two Grade 2) and 2) MAD show 23 
subjects experienced 79 individual AEs (77 Grade 1; Two Grade 2). The two most 
frequent AE SOCs have been Nervous System and Gastrointestinal Disorders without a 
dose/AE relationship. Subjects recruited for the 320 mg QD Cohort will have the same 
inclusion/exclusion criteria, have the same study and subject stopping criteria, and 
undergo the same intensive safety evaluation as previously treated subjects in the MAD. 
Combined, based upon the preliminary safety and PK data gathered to date (see Section 
3.2.2 for full details) subjects will be adequately monitored.


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Section # 
and Name
Description of Change
Brief Rationale
Synopsis
Figure 1 changed and MAD 
Expansion Cohort Dose added
.The actual doses for all Cohorts and 
Periods updated for the SAD and MAD
Section 3.2.2
Preliminary Safety and PK data 
from SAD and MAD updated/added
The clinical and PK data is needed to justify 
the rationale for supporting a proposed 
dose of 320 mg QD in the MAD (Cohort 6)
Section 3.3
Benefit Risk 
Assessment
Preliminary Safety and PK data 
from SAD and MAD updated/added
The clinical and PK data is needed to justify 
the rationale for supporting an unchanged 
benefit risk assessment for a proposed 
dose of 320 mg QD in the MAD (Cohort 6)
Section 5.1 
Overall 
Design
Preliminary Safety and PK data 
from SAD and MAD updated/added
The clinical and PK data is needed to justify 
the rationale for supporting a proposed 
dose of 320 mg QD in the MAD (Cohort 6)
Section 5.5.2
Predicted 
Human 
Effective 
Dose
Preliminary Safety and PK data 
from SAD and MAD updated/added
The clinical and PK data is needed to justify 
the rationale for supporting a proposed 
dose of 320 mg QD in the MAD (Cohort 6)
List of Specific Changes
Overall Design:
PREVIOUS TEXT
A summary of the overall study design, including proposed doses, sample size, and order, 
is presented in Figure 1; Schedule of Activities (SoA) tables are included in Section 2.
REVISED TEXT
A summary of the overall study design, including proposed doses, sample size, and order, 
is presented in Figure 1; Schedule of Activities (SoA) tables are included in Section 2.
Figure 3
Phase 1 Study in Healthy Participants using planned doses of 
GSK3640254
PREVIOUS TEXT


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Note: A=active, P=placebo. The doses shown here are intended to demonstrate general concepts relating to 
factors of escalation. X represents the predicted minimally efficacious dose. Y (in the expansion cohort 
alone) represents a dose previously studied in the multiple ascending dose (MAD) cohorts that did not meet
the safety or PK stopping criteria. In Cohort 2 Period 4, a previous dose that was tolerated under fed 
conditions may be given under fasted conditions to assess food effect.
REVISED TEXT
Note: A=active, P=placebo. The doses shown here are were/are being completed. intended to demonstrate 
general concepts relating to factors of escalation. X represents the predicted minimally efficacious dose. Y 
(in the expansion cohort alone) represents a dose previously studied in the multiple ascending dose (MAD) 
cohorts that did not meet the safety or PK stopping criteria. In Cohort 2 Period 4, a previous dose that was 
tolerated under fed conditions may be given under fasted conditions to assess food effect. Amendment 04 
proposes to evaluate a 320 mg Daily dose in MAD Cohort 6.
Treatment Groups and Duration:


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Part 2 (MAD):
PREVIOUS TEXT
Part 2 also includes an Expansion Cohort to evaluate the rate of gastrointestinal (GI)
intolerability in 24 participants (active/PBO =18/6). The expansion cohort will be 
conducted once the evaluation of the safety and PK from Cohorts 3 – 6 are available. The 
dose Y mg (see Figure 1, MAD) will be one of the previously studied doses that met 
neither safety nor PK stopping criteria. 
REVISED TEXT
Part 2 also includes an Expansion Cohort to evaluate the rate of gastrointestinal (GI)
intolerability in 24 participants (active/PBO =18/6). The expansion cohort will be was
conducted once the evaluation of the safety and PK from Cohorts 3 – 6 are 5 were
available. The dose Y chosen was 200 mg (see Figure 1, MAD). will be one of the 
previously studied doses that met neither safety nor PK stopping criteria. 
PREVIOUS TEXT
3.2.2 Preliminary Safety and PK data in Current Study (SAD doses 1, 3, and 
10 mg)
Through Amendment 2 of the current protocol, preliminary review of blinded safety data 
for the 1, 3, and 10 mg doses of the ongoing study indicate no major clinically significant 
safety or tolerability concerns. There have been 5, 4 and 11 AEs (all non-serious) 
reported in the 1, 3, and 10 mg doses, respectively (n = 16 randomized subjects). All AEs 
were single reports, except for three cases of dizziness and three cases of contact 
dermatitis, related to ECG leads or intravenous cannula site. All AEs were Grade 1, apart 
from an AE of depression (Grade 2); this AE began eight days after receipt of study 
medication in Period 1 but was reported 43 days later. On further questioning, depression 
was associated with difficulty in sleeping and thoughts of self-harm. Immediate 
evaluation by a psychiatrist and GP uncovered long standing personal and family issues 
which pre-existed study entry. Given the psychosocial stressors, the depression was 
unrelated to study drug as determined by the investigator and the Sponsor. The subject 
was withdrawn from the study in order that treatment with anti-depressant medication 
could commence. A further subject withdrew from the study due to personal reasons. 
Only one AE (dizziness in the blinded 10 mg dosing arm) was identified as related to 
study medication. One subject in the blinded 3 mg arm dosing arm experienced three 
episodes of intermittent nightmares post dose, all reported as unrelated to study 
medication. The subject had previously reported nightmares, but in-house, these had 
occurred more frequently. There have been no on-treatment clinically significant 
abnormalities in vital signs or ECGs. Finally, review of laboratory findings revealed one 
subject in the blinded 10 mg dosing arm whose Haematocrit decreased from 45.2% to 
41.8% (5 days after dosing). 


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Preliminary PK parameters for GSK3640254 following single doses of 1, 3, and 10 mg
are summarized in Table 1. GSK3640254 is slowly absorbed with maximum
concentration observed on average 3.5 hours after dosing and slowly eliminated with an
average half-life of 26 hours. In general, exposures were lower along with a longer 
halflife than predicted based on animal data (Section 5.5.1 and Section 5.5.3). The 
observed Cmax is approximately 75% lower, the AUC is approximately 65% lower and 
the halflife is about 70% longer. The lower exposures may be due to a lower extent of 
absorption than predicted based on the animal data.
Table 1
Summary of Preliminary PK Parameters Following Single Doses of 
GSK3640254 in study 207187
Dose of GSK3640254
1 mg
3 mg
10 mg
Parameters
N=6
N=6
N=6
Cmax, ng/mL
4.93 (16%)
13.8 (31%)
47.0 (30%)
Tmax, h
3.5 (2.5 – 6.0)
4.5 (2.0 – 5.0)
3.5 (2.5 – 5.0)
T1/2z, h
NR
NR
25.8 (17%)
AUC, ng.h/mL
NR
NR
1230 (19%)
Note: Parameters are summarized as geometric mean (CVb%) except for Tmax presented as 
median (min-max).
NR: not reportable due to limited data in terminal phase and AUC extrapolated being greater 
than 40%.  
REVISED TEXT
3.2.2 Preliminary Safety and PK data in Current Study (SAD doses 1, 3, 
and - 7010 mg and MAD doses 50 – 200 mg daily)
Through Amendment 2 of the current protocol, preliminary review of blinded safety data 
for the 1, 3, and 10 mg doses of the ongoing study indicate no major clinically significant 
safety or tolerability concerns. There have been 5, 4 and 11 AEs (all non-serious) 
reported in the 1, 3, and 10 mg doses, respectively (n = 16 randomized subjects). All AEs 
were single reports, except for three cases of dizziness and three cases of contact 
dermatitis, related to ECG leads or intravenous cannula site. All AEs were Grade 1, apart 
from an AE of depression (Grade 2); this AE began eight days after receipt of study 
medication in Period 1 but was reported 43 days later. On further questioning, depression 
was associated with difficulty in sleeping and thoughts of self-harm. Immediate 
evaluation by a psychiatrist and GP uncovered long standing personal and family issues 
which pre-existed study entry. Given the psychosocial stressors, the depression was 
unrelated to study drug as determined by the investigator and the Sponsor. The subject 


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was withdrawn from the study in order that treatment with anti-depressant medication 
could commence. A further subject withdrew from the study due to personal reasons. 
Only one AE (dizziness in the blinded 10 mg dosing arm) was identified as related to 
study medication. One subject in the blinded 3 mg arm dosing arm experienced three 
episodes of intermittent nightmares post dose, all reported as unrelated to study 
medication. The subject had previously reported nightmares, but in-house, these had 
occurred more frequently. There have been no on-treatment clinically significant 
abnormalities in vital signs or ECGs. Finally, review of laboratory findings revealed one 
subject in the blinded 10 mg dosing arm whose Haematocrit decreased from 45.2% to 
41.8% (5 days after dosing). 
Preliminary PK parameters for GSK3640254 following single doses of 1, 3, and 10 mg
are summarized in Table 1. GSK3640254 is slowly absorbed with maximum
concentration observed on average 3.5 hours after dosing and slowly eliminated with an
average half-life of 26 hours. In general, exposures were lower along with a longer 
halflife than predicted based on animal data (Section 5.5.1 and Section 5.5.3). The 
observed Cmax is approximately 75% lower, the AUC is approximately 65% lower and 
the halflife is about 70% longer. The lower exposures may be due to a lower extent of 
absorption than predicted based on the animal data.
Overall, there have been no major clinical safety/tolerability findings in the SAD 
(single doses up to 700 mg) or MAD (14 days of dosing up to 200 mg) through May 
7, 2018. There have been 20 subjects treated in the blinded SAD and 33 subjects 
treated in the blinded MAD. Preliminary ongoing data review show no deaths or 
SAEs. There have been 4 individual AEs leading to discontinuation from the trial:

Blinded SAD 10 mg arm: Depression (Grade 2, not related). 

Blinded SAD 10 mg arm: Viral Infection (Grade 1, not related) lasting two 
days

Blinded SAD 100 mg arm: Viral Infection (Grade 1, not related) lasting 
seven days

Blinded MAD 200 mg arm: Rash Maculopapular (Grade 1, related). This 
rash occurred 8 days after receiving study medication and lasted for 6 days. 
There were no laboratory abnormalities. A Dermatology Consultant 
concluded this was a drug rash and the subject later received fexofenadine 
180 mg once daily with a topical steroid cream.
There have been 10 individual AEs related to study medication (9 Grade 1; One 
Grade 2):

Blinded SAD 10 mg arm: Dizziness

Blinded SAD 30 mg arm: Diarrhea and Abdominal Pain

Blinded SAD 700 mg arm: Diarrhea

Blinded MAD 50 mg arm: Headache (the only G2 related AE), Fatigue, and 
Transaminases Elevated. The subject with elevated transaminases had peak 
ALT of 83 IU/L on Day 16 after study medication. The remaining LFTs were 
normal throughout. An Ultrasound showed a subcapsular area of 


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heterogenous echogenicity within segment 7, measuring approximately 35 x 
23 x 36 mm. A follow up MRI was normal.

Blinded MAD 200 mg arm: Lethargy, Nausea, and Rash Maculopapular.
Preliminary review of blinded safety data (see Table 1) for the SAD 1 - 700 mg doses 
show 17 subjects experienced 60 individual AEs (58 Grade 1; Two Grade 2). The 
two most frequent AE SOCs have been Nervous System (16 individual AEs) and 
Gastrointestinal Disorders (11 individual AEs). The most frequent AEs have been 
Headache (10 individual AEs), Diarrhea and Contact Dermatitis (5 individual AEs 
each), and Dizziness (4 individual AEs). There were four Psychiatric individual AEs 
(three of which have occurred at 1 and 3 mg single blinded arms): Depression, 
Insomnia, and Nightmare (two individual AEs). There were no Cardiac AEs. There 
has been no dose/AE relationship.
Preliminary review of blinded safety data (see Table 2) for the MAD 50 – 200 mg 
(Daily for Fourteen Days) show 23 subjects experienced 79 individual AEs (77 
Grade 1; Two Grade 2). The two most frequent AE SOCs have been Nervous 
System (25 AEs) and Gastrointestinal Disorders (12 individual AEs). The most 
frequent AEs have been Headache (11 individual AEs), Dizziness (6 individual AEs), 
and Fatigue (5 individual AEs). There has been no clinically relevant GI or 
neurologic AE/dose relationship. One subject in the blinded 200 mg arm accounted 
for 13 individual AEs (5 of which were in the Neurologic SOC). There were three 
Psychiatric individual AEs: Agitation, Abnormal Dreams, and Nightmare. There 
was one Cardiac AE (palpitations in the 200 mg blinded dose).
There were no clinically significant abnormal fluctuations or trends in vital signs in 
the SAD or MAD. There were no abnormal clinically significant arrhythmias or 
QTcF prolongations observed for any subject in the SAD or MAD. There were no 
laboratory abnormality trends across doses that were clinically significant or 
associated with any symptoms.
Table 1: Summary Table (all AEs) in blinded SAD 1 - 700 mg doses
AEs by Blinded SAD Cohort/Period
SOC
PT
1 
m
g
3 
m
g
10 
mg
30 
mg
100 
mg
200 
mg
400 
mg
700 
mg
Nervous System Disorders
Dizziness
1
1
1
1
Headache
1
1
2
2
2
2
Parasthesia
1
Migraine
1
Gastrointestinal Disorders
Vomitting
2
Feces Soft
1
Diarrhea
1
1
2
1
Abdominal Pain
1
Feces Discolored
1


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Feces Pale
1
Infections and Infestations
Nasopharyngitis
1
1
1
Oral Herpes
1
Viral Infection
1
1
Upper 
Respiratory Tract 
Infection
1
Respiratory, Thoracic, and 
Mediastinal Disorders
Nasal 
Obstruction
2
1
Cough
1
1
Oropharyngeal 
Pain
1
Hemoptysis
1
Skin and Subcutaneous 
Disorders
Contact 
Dermatitis
1
1
1
1
1
Psychiatric Disorders
Depression
1
Insomnia
1
Nightmare
1
1
Injury, Poisoning, and 
Procedural Complications
Face Injury
1
Skin Abrasion
1
Contusion
1
Limb Injury
1
General Disorders and 
Administration Site Conditions
Catheter site 
pain
1
Vessel Puncture 
Site Bruise
1
Chest Pain
1
Investigations
Transaminases 
Increased
1
1
Musculoskeletal and 
Connective Tissue Disorders
Musculoskeletal 
Pain
1
Total AEs by Blinded SAD 
Cohort/Period
9
4
13
6
10
6
7
5
Table 2: Summary Table (all AEs) in blinded MAD 50 – 200 mg doses
AEs by Blinded MAD 
Cohort/Period


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SOC 
PT 
50 mg  
100 mg 
200 mg 
Nervous System Disorders 
Dizziness 
1 
2 
3 
  
Headache 
4 
2 
5 
  
Somnolence 
1 
  
  
Disturbance in 
Attention 
  
  
2 
  
Lethargy 
  
  
2 
  
Dizziness Postural 
  
  
1 
  
Hypoaesthesia
  
1
  
Dysgeusia 
  
  
1 
  
  
  
  
  
Gastrointestinal Disorders 
Lip Dry 
1 
  
  
  
Mouth Ulceration 
1 
  
  
  
Aphthous Ulcer 
1 
  
  
  
Abdominal Pain 
1 
  
1 
  
Abdominal Distention 
  
1 
1 
  
Glossodynia 
  
  
1 
  
Constipation 
  
  
2 
  
Nausea
  
1
Gastroesophageal 
Reflux Disease 
  
  
1 
  
  
  
  
  
General Disorders and Administration 
Site Conditions 
Catheter site pain 
  
  
1 
Vessel Puncture Site 
Bruise 
  
1 
1 
  
Fatigue 
2 
2 
1 
  
Feeling Cold 
1 
  
  
  
Catheter site Bruise 
  
  
1 
  
  
  
  
  
Skin and Subcutaneous Disorders 
Contact Dermatitis 
1 
  
2 
  
Blister 
  
1 
  
  
Dry Skin 
  
1 
  
  
Rash 
  
  
1 
  
Rash Maculopapular 
  
  
1 
  
Pruitis 
  
  
1 
  
  
  
  
  
Musculoskeletal and Connective Tissue 
Disorders 
Back pain 
1 
1 
2 
Musculoskeletal 
Stiffness 
1 
  
  
  
Muscle Twitching 
  
1 
  
  
  
  
  
  
Injury, Poisoning, and Procedural 
Complications 
Laceration 
  
  
1 
  
Contusion 
1 
1 
2 


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Infections and Infestations 
Hordeolum 
  
1 
  
  
Abscess 
  
1 
  
  
Oral Herpes
  
1
  
  
  
  
  
Psychiatric Disorders 
Agitation 
  
1 
  
  
Abnormal Dreams 
  
  
1 
  
Nightmare 
  
1 
  
  
  
  
  
  
Ear and Labyrinth Disorders 
Ear Discomfort 
  
  
1 
  
Excessive Cerumen 
Production 
  
  
1 
  
  
  
  
  
Renal and Urinary Disorders 
Pollakiuria 
  
  
1 
  
Dysuria 
  
  
1 
  
  
  
  
  
Respiratory, Thoracic, and Mediastinal 
Disorders 
Epistaxis 
1 
  
  
  
  
  
  
  
Investigations 
Transaminases 
Increased 
1 
  
  
  
  
  
  
  
Cardiac Disorders 
Palpitations 
  
  
1 
  
  
  
  
  
Total AEs by Blinded MAD Cohort/Period 
  
19 
17 
43 
 
Preliminary PK parameters for GSK3640254 following single dose administration 
from 1 to 700 mg are summarized in Table 3. GSK3640254 is slowly absorbed with 
maximum concentration observed on average 3-4 hours after dosing and slowly 
eliminated with an average half-life of 24 hours. Cmax and AUC increased in a close 
to dose proportional manner from 1 to 400 mg with a plateauing in exposure at the 
700 mg dose. The maximum observed mean Cmax for the single dose administration 
(Table 3) is 1881 ng/mL at the dose of 400 mg. The maximum observed mean 
AUC(0-inf) for the single dose administration (Table 3) is 43116 ng.hr/mL at the 
dose of 400 mg. The mean exposure observed at 700 mg is slightly lower than that at 
400 mg single administration and thus we anticipate similar exposures with doses 
greater than 700 mg. 
Table 13 
Summary of Preliminary PK Parameters Following Single Doses of 
GSK3640254 in study 207187 
 
Dose of GSK3640254 
 
1 mg 
3 mg 
10 mg 


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Parameters
N=6
N=6
N=6
Cmax, ng/mL
4.93 (16%)
13.8 (31%)
47.0 (30%)
Tmax, h
3.5 (2.5 – 6.0)
4.5 (2.0 – 5.0)
3.5 (2.5 – 5.0)
T1/2z, h
NR
NR
25.8 (17%)
AUC, ng.h/mL
NR
NR
1230 (19%)
Note: Parameters are summarized as geometric mean (CVb%) except for Tmax presented as median 
(min-max).
NR: not reportable due to limited data in terminal phase and AUC extrapolated being greater than 40%.  
Dose
1 mg
3 mg
10 mg
30 mg
100 mg
200 
mg
400 mg
700 mg
PK 
Param
eter
Geometric Mean 
(CV%) [N]* 
Cmax
4.9 
(16) [6]
13.8 
(31) [6]
47
(30) [6]
129.8 
(21) [6]
372.1 
(72) [6]
578.9 
(27) [6]
1881
(50) [6]
1760.8 
(44) [6]
Tmax
3.5 
(2.5-6) 
[6]
4.5 
(2-5) 
[6]
3.5 
(2.5-5) [6]
4 
(2.5-5) [6]
3.8
(2-5)
[6]
3 
(2-4) [6]
3.3
(2-6) [6]
3.3 
(2-4.5) [6]
T1/2(z)
NC
22 (14) 
[6]
25.8  
(17) [6]
23.3 (16) 
[6]
23.9
(14) [6]
23.2
(17) [6]
23.3
(16) [6]
22.2
(28) [6]
AUC
NC
340 
(29) [6]
1229.3
(19) [6]
3008 (26) 
[6]
8566.4 
(67) [6]
14978 
(41) [6]
43115.7 
(52) [6]
39972.5 
(50) [6]
* Tmax has been reported as Median (Min - Max)
AUC represents AUC(0-inf); NC: Not Computed
Units: Cmax in ng/mL, AUC in ng.h/mL, t1/2 and tmax in hours
Preliminary PK parameters on Day 1 and Day 14 for GSK3640254 following repeat 
dose administration of 50, 100 and 200 mg for 14 days are summarized in Table 4. 
The exposures on Day 14 are on average 2-3 folds higher than that on Day 1. Cmax 
and AUC on Day 14 tended to increase in a close to dose proportional manner from 
50 to 200 mg. The maximum observed mean Cmax for the repeat dose 
administration is 1528 ng/mL at the dose of 200 mg on Day 14. The maximum 
observed mean AUC(0-24) for the repeat dose administration is 23046 ng.hr/mL at 
the dose of 200 mg on Day 14. 
The anticipated mean Cmax at a proposed dose of 320 mg based on the observed 
exposures (Table 4) using a dose proportionality model is predicted to be 1030 
ng/mL on Day 1 and 2475 ng/mL for Day 14. The anticipated mean AUC(0-24) on 
Day 14 at a proposed dose of 320 mg based on observed exposures (Table 4) using a 


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dose proportionality model is predicted to be 37942 ng.hr/mL. The probability of 
any subject exceeding the PK stopping criteria for MAD study with the dose of 320 
mg repeat dosing, which is AUC(0-24) of 61100 ng.hr/mL based on LOAEL 
exposure in rat at 30 mg/kg, is 42% based on data collected through 9th May. The 
probability of any subject exceeding the PK stopping criteria for SAD study with 
the dose of 320 mg repeat dosing, which is a Cmax of 7960 ng/mL based on minimal 
QT effects observed in one dog, is 0.7% based on data collected through 9th May
2018.
Table 4
Summary of Preliminary PK Parameters Following Repeat Dose 
administration of GSK3640254 in study 207187 
Day 1 
Day 14 
Dose
Dose
50 mg
100 mg
200 mg
50 mg
100 mg
200 mg
PK 
Parameter
Geometric Mean (CV%) [N]* 
AUC l(0-24)
2867.4 (30) [6]
6826.2 (23) [6]
8947.1 (49) [NP]
6285.6 (34) [6]
17537.5 (14) [6] 23046.2 (36) [NP]
Cmax
214.5 (24) [6]
535.6 (23) [6]
689.2 (40) [NP]
413.5 (32) [6]
1182 (10) [6]
1528.4 (30) [NP]
T1/2(z)
NC
NC
NC
24.5 (8) [6]
28.6 (19) [6]
21.9 (12) [NP]
Tmax
3.8 (3-5) [6]
4.3 (2-5) [6]
4 (1.5-5.5) [NP]
3.8 (2.5-5) [6]
4 (1.5-4.5) [6]
3.5 (2-5) [NP]
* Tmax has been reported as Median (Min - Max)
Units: Cmax in ng/mL, AUC in ng.h/mL and Tmax in hours
NP: Not Printed as the expansion cohort is still running. This includes 6 active subjects from Cohort 5 and the subjects from 
expansion cohort 7 studied thruMay 9th, 2018.
NC: Not Computed
3.3 
Benefit/Risk Assessment
ADDED TEXT
The clinical data gathered through May 7, 2018 is summarized in Section 3.2.2. 
Overall, there have been no major clinical safety/tolerability findings in the SAD 
(single doses up to 700 mg) or MAD (14 days of dosing up to 200 mg). The proposed 
amendment seeks to evaluate a higher dose (320 mg Daily) in the MAD. The 
probability of the AUC(tau) exceeding the established PK stopping criteria is 42%. 
Subjects recruited for the 320 mg QD dose in Cohort 6 will have the same 
inclusion/exclusion criteria, have the same study and subject stopping criteria, and 
undergo the same safety evaluation. Based upon the preliminary safety and PK data 
gathered to date (see Section 3.2.2) subjects will be adequately monitored.
3.3.3 Overall Benefit:Risk Conclusion


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PREVIOUS TEXT
Given the preclinical profile of GSK3640254, the clinical profile of a structurally similar 
MI (GSK3532795), and the planned clinical procedures and evaluations in this study, the 
potential risks to participants receiving GSK3640254 are low, evaluable, and 
manageable.  
ADDED TEXT
Given the preclinical profile of GSK3640254, the clinical profile of a structurally similar 
MI (GSK3532795), the preliminary clinical data gathered through May 7, 2018 and 
the planned clinical procedures and evaluations in this study, the potential risks to 
participants receiving GSK3640254 are low, evaluable, and manageable.  
5.1    Figure 2
    Phase 1 Study in Healthy Participants using planned 
doses of GSK3640254
PREVIOUS TEXT
Note: A=active, P=placebo. The doses shown here are intended to demonstrate general concepts relating to 
factors of escalation. X represents the predicted minimally efficacious dose. Y (in the expansion cohort 
alone) represents a dose previously studied in the multiple ascending dose (MAD) cohorts that did not meet
the safety or PK stopping criteria. In Cohort 2 Period 4, a previous dose that was tolerated under fed 
conditions may be given under fasted conditions to assess food effect.
REVISED TEXT


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Note: A=active, P=placebo. The doses shown here are were/are being completed. intended to demonstrate 
general concepts relating to factors of escalation. X represents the predicted minimally efficacious dose. Y 
(in the expansion cohort alone) represents a dose previously studied in the multiple ascending dose (MAD) 
cohorts that did not meet the safety or PK stopping criteria. In Cohort 2 Period 4, a previous dose that was 
tolerated under fed conditions may be given under fasted conditions to assess food effect. Amendment 04 
proposes to evaluate a 320 mg Daily dose in MAD Cohort 6.
Study Design Details Part 1 (SAD):
PREVIOUS TEXT
The SAD portion of the study will be conducted in an interlocking fashion with two 
separate cohorts of eight healthy participants each. Each of these two cohorts will contain 
up to four escalating doses of GSK3640254. The interlocking design as shown in Figure 
2 and the randomization sequence in Table will allow the 8 participants in each Cohort to 
potentially receive one of the two lowest and one of the two highest doses of 
GSK3640254. In each escalating period and Cohort, 6 participants will be randomized to 
GSK3640254 and 2 participants will be randomized to placebo. Details of the starting 
dose and dose escalation can be found in Section 5.5.3.
Participants in Cohort 1 and Cohort 2 will follow the same randomization strategy with 
alternating ascending doses (Table 2). Two participants in either Cohort will be assigned 
to one of the four treatment sequences, and each participant will receive placebo once. 
Table 2
Description of treatment sequences in Cohort 1 and Cohort 2
REVISED TEXT
The SAD portion of the study will be conducted in an interlocking fashion with two 
separate cohorts of eight healthy participants each. Each of these two cohorts will contain 
up to four escalating doses of GSK3640254. The interlocking design as shown in Figure 
2 and the randomization sequence in Table will allow the 8 participants in each Cohort to 


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potentially receive one of the two lowest and one of the two highest doses of 
GSK3640254. In each escalating period and Cohort, 6 participants will be randomized to 
GSK3640254 and 2 participants will be randomized to placebo. Details of the starting 
dose and dose escalation can be found in Section 5.5.3.
Participants in Cohort 1 and Cohort 2 will follow the same randomization strategy with 
alternating ascending doses (Table 25). Two participants in either Cohort will be assigned 
to one of the four treatment sequences, and each participant will receive placebo once. 
Table 25
Description of treatment sequences in Cohort 1 and Cohort 2
Part 2 (MAD):
PREVIOUS TEXT
The earliest point at which Part 2 (MAD) of the study will be initiated is once the single 
dose safety and preliminary PK data for the anticipated minimally effective dose has been 
evaluated in the SAD. The potential minimally effective dose for GSK3640254, noted as 
X, is anticipated to be that which is predicted to provide a steady state Ctrough ≥ 0.11 
g/mL in 95% of participants and will be re-estimated based on the PK data collected in 
the early doses in Part 1 (see Section 5.5.2 for further details). The initial dose in the 
MAD (Cohort 3) will be approximately half the anticipated minimally effective dose or 
0.5X. Dose escalation in the MAD will not exceed approximately 2-fold between cohorts
and will be driven by safety and PK stopping criteria (see Section 8). In addition, a dose 
will not be assessed in the MAD until the anticipated steady-state exposure (Cmax and 
AUC(0-) on Day 14) for that dose have been evaluated and shown not to have met 
safety stopping criteria in the SAD portion of the study (Part 1).
Part 2 also includes an Expansion Cohort which will be conducted at the conclusion of
the traditional MAD, once the evaluation of the safety and PK from Cohorts 3-6 is
available. VH’s prior and structurally similar MI (GSK3532795) ceased development in
Phase 2b (due in part to a higher proportion of participants experiencing GI
intolerability). GSK3532795, studied in Phase 1 studies of normal healthy volunteers
showed diarrhoea of up to 65%. The Expansion Cohort will evaluate the rate of GI
intolerability in 24 participants (active/PBO =18/6). The dose to be studied (Y) will be
one of the previously studied doses in the MAD that did not meet the safety or PK
stopping criteria. While no formal statistical testing will be performed, a summary of GI
AEs will be provided from: 1) 24 participants receiving one of the GSK3640254 doses
studied previously and 2) 14 participants receiving placebo across the entire MAD. These
numbers of participants should provide sufficient clinical inference and better estimation
of GI AEs frequency at a given dose (which can be used to inform subsequent dose
selection/therapeutic index for HIV-1 infected participants).
REVISED TEXT


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The earliest point at which Part 2 (MAD) of the study will be initiated is once the single 
dose safety and preliminary PK data for the anticipated minimally effective dose has been
evaluated in the SAD. The potential minimally effective dose for GSK3640254, noted as 
X, is anticipated to be that which is predicted to provide a steady state Ctrough ≥ 0.11 
g/mL in 95% of participants and will be re-estimated based on the PK data collected in 
the early doses in Part 1 (see Section 5.5.2 for further details). The initial dose in the 
MAD (Cohort 3) will be approximately half the anticipated minimally effective dose or 
0.5X. Dose escalation in the MAD will not exceed approximately 2-fold between cohorts
and will be driven by safety and PK stopping criteria (see Section 8). In addition, a dose 
will not be assessed in the MAD until the anticipated steady-state exposure (Cmax and 
AUC(0-) on Day 14) for that dose have been evaluated and shown not to have met 
safety stopping criteria in the SAD portion of the study (Part 1). However, as a plateau 
in exposure has been seen in the SAD between 400 mg and 700 mg, the highest dose 
in the MAD may be evaluating steady-state Cmax concentrations that are up to 
50% greater than previously observed in the SAD while not exceeding AUC already 
explored in the SAD. The 320 mg QD dose Cmax on Day 14 will not exceed the SAD
PK stopping criteria (see Section 8). 
Part 2 also includes an Expansion Cohort which will be was conducted at the conclusion 
of the traditional MAD Cohort 5. once the evaluation of the safety and PK from Cohorts 
3-6 is available. VH’s prior and structurally similar MI (GSK3532795) ceased 
development in Phase 2b (due in part to a higher proportion of participants experiencing 
GIintolerability). GSK3532795, studied in Phase 1 studies of normal healthy volunteers
showed diarrhoea of up to 65%. The Expansion Cohort will evaluate the rate of GI
intolerability in 24 participants (active/PBO =18/6). The dose to be studied (Y200 mg) 
will be one of the was previously studied doses in the MAD that and did not meet the
safety or PK stopping criteria. While no formal statistical testing will be performed, a 
summary of GI AEs will be provided from: 1) 24 participants receiving one of the 
GSK3640254 doses studied previously and 2) 14 participants receiving placebo across 
the entire MAD. These numbers of participants should provide sufficient clinical 
inference and better estimation of GI AEs frequency at a given dose (which can be used 
to inform subsequent dose selection/therapeutic index for HIV-1 infected participants).
5.4 
Scientific Rationale for Study Design
PREVOUS TEXT
In Part 2 of the study (MAD), doses potentially up to 4 times the minimally anticipated
effective dose (X) are planned to be evaluated. In future studies in HIV-1-infected
participants, these doses/exposures will be evaluated to understand the relationship
between GSK3640254 exposures and efficacy, duration of response, and resistance
development (see Section 5.5.2). Furthermore, assessment of this dose/exposure range
(anticipated to be the therapeutic exposure range in the target population) in healthy
participants will inform safety and tolerability prior to exposing a more vulnerable HIV-
1-infected population to GSK3640254 and will inform risk mitigation strategies for
potential drug interactions.


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REVISED TEXT
In Part 2 of the study (MAD), doses potentially up to 4 times the minimally anticipated 
effective dose (X ~ 80 mg QD) are planned to be evaluated. In future studies in HIV-1-
infected participants, these doses/exposures will may be evaluated to understand the 
relationship between GSK3640254 exposures and efficacy, duration of response, and 
resistance development (see Section 5.5.2). Furthermore, assessment of this 
dose/exposure range (anticipated to be the therapeutic exposure range in the target 
population) in healthy participants will inform safety and tolerability prior to exposing a 
more vulnerable HIV-1-infected population to GSK3640254 and will inform risk 
mitigation strategies for potential drug interactions.
5.5.1 Predicted Human Pharmacokinetics
PREVIOUS TEXT
The emerging PK data obtained at the three lower single doses of 1, 3 and 10 mg are 
presented in Section 3.2.2.
REVISED TEXT
The emerging PK data obtained at the three lower single doses of 1, 3 and 10 mg are 
presented in Section 3.2.2.
5.5.2 Predicted Human Effective Dose
PREVIOUS TEXT
The potential minimally effective dose for GSK3640254 was initially estimated using the 
predicted human PK profile, assuming similar between-participant PK variability to that 
observed with GSK3532795 (Population PK model based on data from Phase 2b study 
AI468038, Metrum Research Group, 2016), to ensure that 95% of participants have 
steady state trough concentrations that exceed the target concentration of 0.11 g/mL 
following once daily dosing of GSK3640254. This led to the prediction of a likely 
minimally effective once daily dose of approximately 40 mg, assuming 58% 
bioavailability. Following single administration of 1, 3 and 10 mg of GSK3640254 in this 
study, a pharmacokinetic model was fit through the concentration-time data and these 
population PK parameters were used along with the previously assumed PK variabilities. 
The updated minimally effective once daily dose is approximately 70 mg. At this dose, 
the mean repeat-dose Cmax is predicted to be approximately 0.544 g/mL, mean trough 
concentration is predicted to be approximately 0.238 g/mL and mean AUC is predicted 
to be approximately 8.91 g.h/mL (Table5). The anticipated steady-state mean AUC is 
2.52-fold lower than the NOAEL in the rat, 6.86-fold lower than the LOAEL in the rat, 
and 8.23-fold lower than the LOAEL in the dog.


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The relationship between GSK3640254 exposure and efficacy, duration of antiviral 
response, and development of on-treatment resistance will be evaluated in future studies 
in HIV-1-infected participants where assessment of a range of exposures will be 
important to inform the therapeutic dose range of GSK3640254. One exposure parameter 
of interest is inhibitory quotient (IQ), where IQ = Ctrough/PBA-EC90. The IQs of other 
antiretrovirals at approved doses are approximately 19, 27, and 36 for dolutegravir 50 mg 
once daily, atazanavir 300 mg once daily with ritonavir, and lopinavir 400 mg twice daily 
with ritonavir, respectively [Van Lunzen, 2012 and Zhu, 2012]. For GSK360254, the 
minimally effective dose provides a trough concentration of 0.11 ug/mL at steady state in 
95% of the participants and represents a geometric mean IQ of 7.92. To facilitate 
assessment of a range of GSK3640254 IQs in future studies in the target population, 
doses up to 4 times those of the minimally effective dose are planned for assessment in 
Part 2 (MAD) in healthy participants. These doses will be administered in accordance 
with PK and safety stopping criteria (see Section 8.1.3). Projected exposures at the 
highest anticipated once daily dose in the MAD include a mean repeat-dose Ctrough of 
1.02 ug/mL and an IQ of 27.8.
REVISED TEXT
The potential minimally effective dose for GSK3640254 was initially estimated using the 
predicted human PK profile, assuming similar between-participant PK variability to that 
observed with GSK3532795 (Population PK model based on data from Phase 2b study 
AI468038, Metrum Research Group, 2016), to ensure that 95% of participants have 
steady state trough concentrations that exceed the target concentration of 0.11 g/mL 
following once daily dosing of GSK3640254. This led to the prediction of a likely 
minimally effective once daily dose of approximately 40 mg, assuming 58% 
bioavailability. Following single administration of 1, 3 and 10 mg of GSK3640254 in this 
study, a pharmacokinetic model was fit through the concentration-time data and these 
population PK parameters were used along with the previously assumed PK variabilities. 
The updated minimally effective once daily dose is was approximately 70 mg. At this 
dose, the mean repeat-dose Cmax is predicted to be approximately 0.544 g/mL, mean 
trough concentration is predicted to be approximately 0.238 g/mL and mean AUC is 
predicted to be approximately 8.91 g.h/mL (Table 58). The anticipated steady-state 
mean AUC is 2.52-fold lower than the NOAEL in the rat, 6.86-fold lower than the 
LOAEL in the rat, and 8.23-fold lower than the LOAEL in the dog. The population PK 
model was further updated with all the concentration-time data available up to 9 
May 2018 (excluding the 700 mg SAD dose) and the population PK parameters 
including the between subject variabilities were used to provide the updated 
minimally effective once daily dose of approximately 80 mg.
The relationship between GSK3640254 exposure and efficacy, duration of antiviral 
response, and development of on-treatment resistance will be evaluated in future studies 
in HIV-1-infected participants where assessment of a range of exposures will be 
important to inform the therapeutic dose range of GSK3640254. One exposure parameter 
of interest is inhibitory quotient (IQ), where IQ = Ctrough/PBA-EC90. The IQs of other 
antiretrovirals at approved doses are approximately 19, 27, and 36 for dolutegravir 50 mg 
once daily, atazanavir 300 mg once daily with ritonavir, and lopinavir 400 mg twice daily 
with ritonavir, respectively [Van Lunzen, 2012 and Zhu, 2012]. For GSK3640254, the 


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minimally effective dose provides a trough concentration of 0.11 ug/mL at steady state in 
95% of the participants and represents a geometric mean IQ of 7.92. To facilitate 
assessment of a range of GSK3640254 IQs in future studies in the target population, 
doses up to 4 times those of the minimally effective dose are planned for assessment in 
Part 2 (MAD) in healthy participants. These doses will be administered in accordance 
with PK and safety stopping criteria (see Section 8.1.3). Projected exposures at the 
highest anticipated once daily dose in the MAD include a mean repeat-dose Ctrough of 
1.02 ug/mL and an IQ of 27.8.
5.5.3. Part 1 (SAD) Starting Dose and Dose Escalation
PREVIOUS TEXT
Table 3
Probability of any SAD participant (Cmax >7.96 µg/mL) for potential 
doses
REVISED TEXT
Table 36
Probability of any SAD participant (Cmax >7.96 µg/mL) for potential 
doses
5.5.4 Part 2 (MAD) Starting Dose and Dose Escalation
PREVIOUS TEXT
The initial dose in the MAD (Cohort 3) will be approximately half the likely minimally
effective dose, re-estimated based on the clinical PK data collected in the early doses of 
Part 1. Dose escalation in the MAD will not exceed approximately 2-fold between 
cohorts, and will be governed by both safety and MAD PK stopping criteria (see Section 
8.1.3 and Section 8.1.4). Given different assumptions for the between participant AUC 
variability (%CVb) and the current human PK prediction, the probability of any 
participant AUCtau in the MAD above 61.1 g.hr/mL, the MAD PK Stopping Criterion 
(Section 8.1.3), are illustrated in Table 4. 
Table 15
Probability of any MAD participant (AUCtau > 61.1 µg.h/mL) for 
potential QD doses
REVISED TEXT
The initial dose in the MAD (Cohort 3) will be approximately half the likely minimally
effective dose, re-estimated based on the clinical PK data collected in the early doses of 
Part 1. Dose escalation in the MAD will not exceed approximately 2-fold between 
cohorts, and will be governed by both safety and MAD PK stopping criteria (see Section 
8.1.3 and Section 8.1.4). Given different assumptions for the between participant AUC 
variability (%CVb) and the current human PK prediction, the probability of any 


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participant AUCtau in the MAD above 61.1 g.hr/mL, the MAD PK Stopping Criterion 
(Section 8.1.3), are illustrated in Table 71. 
Table 167
Probability of any MAD participant (AUCtau > 61.1 µg.h/mL) for 
potential QD doses
5.5.6.
Anticipated Exposure and Safety Cover for a Range of Potential 
Doses
PREVIOUS TEXT
Projected steady-state exposures of GSK3640254 from potential doses in Part 2, taking 
into consideration the PK emerging from single doses of 1, 3 and 10 mg, are compared to 
target efficacious concentrations and preclinical toxicity exposures in Table5. Predicted 
human exposure following multiple doses can be compared to the NOAEL and LOAEL 
in rats and only to a LOAEL in dogs. Findings in both species were GI related, limited 
and reversible (see Section 3.3.1 and the CIB for details).
Table 17
Projected steady-state PK for a range of potential QD doses 
following fed administration and comparison to efficacy target and preclinical 
exposure
REVISED TEXT
Projected steady-state exposures of GSK3640254 from potential doses in Part 2, taking 
into consideration the PK emerging from single doses of 1, 3 and 10 mg, are compared to 
target efficacious concentrations and preclinical toxicity exposures in Table 5828. 
Predicted human exposure following multiple doses can be compared to the NOAEL and 
LOAEL in rats and only to a LOAEL in dogs. Findings in both species were GI related, 
limited and reversible (see Section 3.3.1 and the CIB for details).
Table 188
Projected steady-state PK for a range of potential QD doses 
following fed administration and comparison to efficacy target and preclinical 
exposure
9.4.3.2.
Cardiodynamic assessment (ECGs extracted from Holter 
recordings)
High-Precision QT Analysis
PREVIOUS TEXT
Categorical T-wave morphology analysis (Table 6) and the measurement of PR and QRS 
intervals will be performed manually in 3 of the 10 ECG replicates at each timepoint.  
Each fiducial point (onset of P-wave, onset of Q-wave, offset of S-wave, and offset of T-
wave) is electronically marked.


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Table 19
T-wave morphology categories (assessed manually)
REVISED TEXT
Categorical T-wave morphology analysis (Table 69) and the measurement of PR and 
QRS intervals will be performed manually in 3 of the 10 ECG replicates at each 
timepoint.  Each fiducial point (onset of P-wave, onset of Q-wave, offset of S-wave, and 
offset of T-wave) is electronically marked.
Table 209
T-wave morphology categories (assessed manually)
9.4.6. GI Toxicity Evaluation and Management
PREVIOUS TEXT
Pre-clinical toxicology studies in rats and dogs have suggested a potential for GI related 
toxicity with GSK3640254. This section provides general guidance to the Investigator on 
the evaluation and management of primarily upper gastrointestinal symptoms (Table 7). 
The Investigator may contact the GSK/VH Medical Monitor to discuss evaluation and 
management (including discontinuation of a participant) of any GI symptoms throughout 
the trial.
Table 21
GI Toxicity Evaluation and Management
REVISED TEXT
Pre-clinical toxicology studies in rats and dogs have suggested a potential for GI related 
toxicity with GSK3640254. This section provides general guidance to the Investigator on 
the evaluation and management of primarily upper gastrointestinal symptoms (Table 7
10). The Investigator may contact the GSK/VH Medical Monitor to discuss evaluation 
and management (including discontinuation of a participant) of any GI symptoms 
throughout the trial.
Table 2210
GI Toxicity Evaluation and Management
10.3.3.
Interim Analyses
Bayesian model Operating Characteristics (OC)
PREVIOUS TEXT
For each trial, the Bayesian probability for the 700mg dose is calculated and compared 
with different thresholds (40%, 50% or 60%). Among those 1000 trials, the percentages 
of trials with Bayesian probability below the thresholds, which stands for the percentage 
of trials that could be escalated to dose 700mg, are listed in Table 115.
Table 23
Percentage of trials with Bayesian probability less than the 
threshold (40%, 50% or 60%)


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REVISED TEXT
For each trial, the Bayesian probability for the 700mg dose is calculated and compared 
with different thresholds (40%, 50% or 60%). Among those 1000 trials, the percentages 
of trials with Bayesian probability below the thresholds, which stands for the percentage
of trials that could be escalated to dose 700mg, are listed in Table 811 .
Table 2411
Percentage of trials with Bayesian probability less than the 
threshold (40%, 50% or 60%)

SAP_001.pdf: 
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Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
 
 
Title 
: Reporting and Analysis Plan for Study 207187: A Double-
Blind (Sponsor Unblinded), Randomized, Placebo-
Controlled, Single and Repeated Dose Escalation Study to 
Investigate the Safety, Tolerability and Pharmacokinetics of 
GSK3640254 in Healthy Participants 
Compound Number  : GSK3640254 
Effective Date  
: 08-SEP-2018 
 
Description: 
• 
The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 207187. 
• 
This RAP is intended to describe the safety, tolerability, and pharmacokinetic 
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. 
 
RAP Author(s): 
Approver 
Date 
Approval Method 
 
Manager, Statistician (PAREXEL, Clinical 
Statistics) 
07-SEP-2018 
eSignature 
 
Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited. 
 
RAP Team Approvals: 
Approver 
Date 
Approval Method 
 
Clinical Development Manager (ID, CPSSO) 
31-AUG-2018 
eSignature 
PPD
PPD


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Physician Product Lead(Clinical Development, 
VH Healthcare) 
04-SEP-2018 
eSignature 
  
Manager (Clinical Pharmacology Modeling and 
Simulation, GSK) 
07-SEP-2018 
eSignature 
  
Clinical Pharmacologist (Clinical Pharmacology 
Modeling and Simulation, GSK) 
07-SEP-2018 
eSignature 
  
Lead Statistician (ID, Clinical Statistics) 
04-SEP-2018 
eSignature 
 
Principal Programmer (ID, Clinical Statistics) 
31-AUG-2018 
eSignature 
 
 DQL (ID, Data Management) 
03-SEP-2018 
eSignature 
 
Clinical Statistics and Clinical Programming Line Approvals: 
Approver 
Date 
Approval Method 
 
Statistics Leader (ID, Clinical Statistics) 
(Delegate for 
 
04-SEP-2018 
eSignature 
 
04-SEP-2018 
eSignature 
Programming Manager (ID, Clinical 
Programming) 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 6 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 6 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 6 
2.2. 
Study Objective(s) and Endpoint(s)............................................................... 6 
2.3. 
Study Design ................................................................................................ 7 
2.4. 
Statistical Hypotheses................................................................................... 8 
3. 
PLANNED ANALYSES ............................................................................................ 9 
3.1. 
Interim Analyses ........................................................................................... 9 
3.2. 
Final Analyses .............................................................................................. 9 
4. 
ANALYSIS POPULATIONS ................................................................................... 10 
4.1. 
Protocol Deviations ..................................................................................... 11 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 12 
5.1. 
Study Treatment & Sub-group Display Descriptors ..................................... 12 
5.2. 
Baseline Definitions .................................................................................... 13 
5.3. 
Other Considerations for Data Analyses and Data Handling 
Conventions ................................................................................................ 14 
6. 
STUDY POPULATION ANALYSES ....................................................................... 15 
6.1. 
Overview of Planned Study Population Analyses ........................................ 15 
6.2. 
Display Details ............................................................................................ 16 
6.2.1. 
Subject Disposition ...................................................................... 16 
6.2.2. 
Protocol Deviations ...................................................................... 16 
6.2.3. 
Populations Analysed .................................................................. 16 
6.2.4. 
Demographic and Baseline Characteristics .................................. 16 
6.2.5. 
Concomitant Medications ............................................................. 16 
6.2.6. 
Exposure and Treatment Compliance .......................................... 17 
7. 
SAFETY ANALYSES ............................................................................................. 18 
7.1. 
Overview of Planned Safety Analysis .......................................................... 18 
7.2. 
Display Details ............................................................................................ 20 
7.2.1. 
Adverse Events Analysis ............................................................. 20 
Adverse Events of Special Interest: ............................................................................. 21 
7.2.2. 
Clinical Laboratory Safety Analyses ............................................. 21 
7.2.3. 
Other Safety Analyses ................................................................. 23 
7.2.3.1. 
Electrocardiograms..................................................... 23 
7.2.3.2. 
Vital Signs .................................................................. 23 
7.2.3.3. 
Hepatobiliary (Liver) ................................................... 23 
8. 
PHARMACOKINETIC ANALYSES ......................................................................... 24 
8.1. 
Pharmacokinetic Analyses .......................................................................... 24 
8.1.1. 
Endpoint / Variables ..................................................................... 24 
8.1.1.1. 
Drug Concentration Measures .................................... 24 
8.1.1.2. 
Derived Pharmacokinetic Parameters......................... 24 


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8.1.2. 
Summary Measure ...................................................................... 25 
8.1.3. 
Population of Interest ................................................................... 25 
8.1.4. 
Statistical Analyses / Methods ..................................................... 25 
8.1.4.1. 
Statistical Methodology Specification .......................... 26 
8.1.5. 
Food Effect Assessment .............................................................. 29 
9. 
POPULATION PHARMACOKINETIC (POPPK) ANALYSES .................................. 30 
10. REFERENCES ....................................................................................................... 31 
11. APPENDICES ........................................................................................................ 32 
11.1. 
Appendix 1: Protocol Deviation Management and Definitions for PK 
Parameter Population ................................................................................. 32 
11.2. 
Appendix 2: Schedule of Activities .............................................................. 33 
11.2.1. 
Protocol Defined Schedule of Events ........................................... 33 
11.3. 
Appendix 3: Assessment Windows ............................................................. 40 
11.4. 
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................ 41 
11.4.1. 
Study Phases .............................................................................. 41 
11.4.1.1. Study Phases for Concomitant Medication ................. 41 
11.4.2. 
Treatment Emergent Flag for Adverse Events ............................. 42 
11.4.3. 
Adverse Events Assignment to Treatment Period for Part 
1 .................................................................................................. 42 
11.4.4. 
Concomitant Medication Assignment to Treatment Period 
for Part 1 ...................................................................................... 42 
11.5. 
Appendix 5: Data Display Standards & Handling Conventions .................... 44 
11.5.1. 
Reporting Process ....................................................................... 44 
11.5.2. 
Reporting Standards .................................................................... 44 
11.5.3. 
Reporting Standards for Pharmacokinetic .................................... 45 
11.6. 
Appendix 6: Derived and Transformed Data ............................................... 47 
11.6.1. 
General ........................................................................................ 47 
11.6.2. 
Study Population .......................................................................... 47 
11.6.3. 
Safety .......................................................................................... 47 
11.6.4. 
Pharmacokinetic .......................................................................... 50 
11.6.5. 
Pharmacodynamic (and / or Biomarker) ....................................... 50 
11.7. 
Appendix 7: Reporting Standards for Missing Data ..................................... 51 
11.7.1. 
Premature Withdrawals ................................................................ 51 
11.7.2. 
Handling of Missing Data ............................................................. 51 
11.7.2.1. Handling of Missing and Partial Dates ........................ 51 
11.8. 
Appendix 8: Values of Potential Clinical Importance ................................... 53 
11.8.1. 
Laboratory Values ........................................................................ 53 
11.8.2. 
ECG ............................................................................................. 53 
11.8.3. 
Vital Signs .................................................................................... 54 
11.9. 
Appendix 9: Population Pharmacokinetic (PopPK) Analyses ...................... 55 
11.10. Appendix 10: Pharmacokinetic / Pharmacodynamic Analyses .................... 56 
11.11. Appendix 11: Abbreviations & Trade Marks ................................................ 57 
11.11.1. Abbreviations ............................................................................... 57 
11.11.2. Trademarks ................................................................................. 57 
11.12. Appendix 12: List of Data Displays.............................................................. 58 
11.12.1. Data Display Numbering .............................................................. 58 
11.12.2. Mock Example Shell Referencing ................................................ 58 
11.12.3. Deliverables ................................................................................. 58 


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11.12.4. Study Population Tables .............................................................. 59 
11.12.5. Safety Tables ............................................................................... 61 
11.12.6. Safety Figures ............................................................................. 67 
11.12.7. Pharmacokinetic Tables ............................................................... 67 
11.12.8. Pharmacokinetic Figures ............................................................. 70 
11.12.9. Pharmacokinetic / Pharmacodynamic Figures ............................. 72 
11.12.10. ICH Listings ................................................................................. 73 
11.12.11. Non-ICH Listings .......................................................................... 79 
 


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1. 
INTRODUCTION 
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol: 207187 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
There were no changes or deviations to the originally planned statistical analysis 
specified in the protocol amendment 3 Dated: 05/DEC/2017.  
2.2. 
Study Objective(s) and Endpoint(s) 
Objectives 
Endpoints 
Primary Objectives 
Primary Endpoints 
• 
To investigate the safety and 
tolerability of GSK3640254 following 
single and repeated daily 
administration 
• 
GSK3640254 safety parameters: adverse events; post-
baseline values and changes over time of clinical 
laboratory evaluations (haematology, clinical chemistry, 
urinalysis), vital signs, and ECG parameters from predose 
values 
Secondary Objectives 
Secondary Endpoints 
• 
To describe the PK of GSK3640254 
following single and repeated daily 
administration 
• 
GSK3640254 PK parameters:  
 
Part 1 (single dose): AUC(0-24), AUC(0-tlast), AUC(0-inf), 
Cmax, C24, tmax, tlag, t1/2, Clast, tlast, CL/F. 
 
Part 2 (Repeated QD doses for 14 days): 
Day 1: AUC(0-24), Cmax, C24, tmax, tlag 
Day 14: AUC(0-τ), Cmax, Cτ, tmax, t1/2, and CL/F 
• 
To examine dose proportionality 
following single and repeated doses 
of GSK3640254 
• 
GSK3640254 Single dose: AUC(0-inf), Cmax.  
• 
Repeat dose AUC(0-τ), Cmax, Cτ 
• 
To assess accumulation of 
GSK3640254 
• 
Accumulation ratios: R AUC(0-τ), R(Cmax), R (Cτ) 
• 
To assess time to steady-state of 
GSK3640254 
• 
Pre-dose concentrations on Day 2 -14 (Part 2) 
Exploratory Objectives 
Exploratory Endpoints 
• 
To assess the exposure response 
relationship between GSK3640254 
and safety parameter, including QTcF 
following single and repeated 
administration 
• 
Change-from-baseline QTcF (∆QTcF) 
• 
To investigate the biotransformation 
of GSK3640254 in plasma and urine 
• 
Provide samples of plasma and urine for the identification 
of any compound derived metabolite(s) 
• 
As available, to assess the impact of 
food on the PK of GSK3640254 
• 
GSK3640254 single dose Cmax, AUC(0-inf), and C24 
Note: The exploratory endpoints may be analyzed once GSK3640254 clinical development 
continues. 


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2.3. 
Study Design 
Overview of Study Design and Key Features 
 
Design 
Features 
• 
Two part, Phase 1, double-blind (sponsor-unblinded), randomized, placebo 
controlled, single- and repeat-dose escalation study. 
Part 1 (SAD): 
• 
SAD portion will be conducted in an interlocking fashion with 2 separate cohorts of 8 
healthy participants each. Each of these 2 cohorts will contain up to 4 escalating 
doses of GSK3640254.  
• 
In each escalating period and Cohort, 6 participants will be randomized to 
GSK3640254 and 2 participants will be randomized to placebo.  
• 
Participants in Cohort 1 and Cohort 2 will follow the same randomization strategy 
with alternating ascending doses with 4-period crossover, placebo-controlled. 
 
Part 2 (MAD): 
• 
Part 2 consists of 4 ascending repeat-dose cohorts (Cohorts 3 to 6), each with 8 
participants (active/PBO=6/2) who will receive a once-daily dose of GSK3640254 or 
PBO for 14 days.  
• 
Part 2 also includes an Expansion Cohort which will be conducted at the conclusion 
of cohort 5. 
• 
The Expansion Cohort will evaluate the rate of GI intolerability in 24 participants 
(active/PBO =18/6).  
Dosing 
Part 1 (SAD): 
• 
The dose for Part 1 Cohort 1 of this study were 1 mg for Period 1, 10 mg for Period 
2, 100 mg for Period 3 and 400 mg for Period 4. 
• 
The dose for Part 1 Cohort 2 of this study will be 3 mg for Period 1, 30 mg for Period 
2, 200 mg for Period 3 and 700 mg for Period 4. 
 
Part 2 (MAD): 
• 
The dose for Part 2 of this study were 50 mg for Cohort 3, 100 mg for Cohort 4, 200 
mg for Cohort 5 and the expansion cohort, and 320 mg for cohort 6. 


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Overview of Study Design and Key Features 
All doses were administered in fed condition.   
Time & Events 
• 
Refer to Appendix 2: Schedule of Activities 
Treatment 
Assignment 
Part 1 (SAD): 
• 
Participants in either Cohort 1 or Cohort 2 will be assigned to 1 of the 4 treatment 
sequences in a cross-over, and each participant will receive placebo once. 
  
 
 
Part 2 (MAD): 
• 
In Cohorts 3 to 6, 8 participants per cohort (active/PBO=6/2) will receive a once-daily 
dose of GSK3640254 or PBO for 14 days.  
• 
In the Expansion Cohort, 24 participants (active/PBO=18/6) will receive a once-daily 
dose (200 mg) of GSK3640254 or PBO for 14 days 
Interim 
Analysis 
• 
All preliminary safety, tolerability, and available PK data were reviewed internally at 
VH/GSK prior to each dose escalation. Safety data (labs, vital signs, ECG, AEs, 
SAEs) were reviewed by the PI/Sub-I and VH/GSK study team after completion of 
each dose level. 
 
2.4. 
Statistical Hypotheses 
The main purpose of this study is to assess the safety, tolerability and PK of single and 
repeated oral doses of GSK3640254 in healthy volunteers. No formal hypotheses are to 
be tested and no statistical testing will be performed. 


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3. 
PLANNED ANALYSES 
3.1. 
Interim Analyses 
All preliminary safety, tolerability, and available PK data were reviewed internally at 
VH/GSK prior to each dose escalation. Safety data (labs, vital signs, ECG, AEs, SAEs) 
will be reviewed by the PI/Sub-I and VH/GSK study team after completion of each dose 
level. 
At each dose, the Bayesian probability of an individual exceeding the Cmax stopping 
criteria in Part 1 and the Bayesian probability of an individual exceeding the AUC 
stopping criteria in Part 2 will be calculated and compared with 50%. This will be used to 
help selection of the next dose together with safety and tolerability data. The Bayesian 
probability will be based on Whitehead’s model shown below [Whitehead, 2001] using 
non-informative prior for model parameters. 
                                        𝑦𝑦𝑖𝑖𝑖𝑖= 𝜃𝜃1 + 𝜃𝜃2𝑑𝑑𝑖𝑖𝑖𝑖+ 𝑠𝑠𝑖𝑖+ 𝜖𝜖𝑖𝑖𝑖𝑖                                                         [1] 
Where 𝑦𝑦𝑖𝑖𝑗𝑗 is log-PK of 𝑖𝑖-th participant to 𝑗𝑗-th dose, 𝑑𝑑𝑖𝑖𝑖𝑖  is 𝑗𝑗-th log-dose administered to 𝑖𝑖-
th participant. 𝜃𝜃1 and 𝜃𝜃2 are population intercept and slope, respectively. 𝑠𝑠𝑖𝑖 is random 
effect of 𝑖𝑖-th participant and 𝜖𝜖𝑖𝑖𝑖𝑖 is random error of 𝑖𝑖-th participant in 𝑗𝑗-th dose. Note that, 
from the first to the second dose in Part 1 of the study, we will assume that the PK is 
dose-proportional for the model. 
When intra-participant PK variability cannot be estimated early in Part 1 (i.e., early on in 
the study when there is not sufficient information to estimate intra-participant variability) 
and for conducting prediction of all doses in Part 2, the same Whitehead’s model will be 
used for Bayesian probability calculations as below. 
                                         𝑦𝑦𝑖𝑖= 𝜃𝜃1 + 𝜃𝜃2𝑑𝑑𝑖𝑖+ 𝜖𝜖𝑖𝑖                                                                [2] 
Where yi is log-PK of i-th participant, di is the log-dose administered to i-th participant. θ1 
and θ2 are population intercept and slope, respectively and εi is random error of i-th 
participant. Note that, from the first to the second dose in Part 2 of the study, we will 
assume that the PK is dose-proportional for the model. 
 
3.2. 
Final Analyses 
The final planned primary analyses will be performed after the completion of the 
following sequential steps: 
1. All participants have completed the study as defined in the protocol  
2. All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management. 
3. All criteria for unblinding the randomization codes have been met.  
4. Randomization codes have been distributed according to RandAll NG procedures. 


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Data will be listed and summarized according to GlaxoSmithKline reporting standards, 
where applicable.  Listings will be sorted by subject, day and time, noting treatment; 
summaries will be presented by treatment, day, and time. Unless stated otherwise, 
descriptive summaries will include n, mean, standard deviation (SD), coefficient of 
variation (%CV), median, minimum, and maximum for continuous variables, whereas n 
and percent will be used as summary statistics for categorical variables, and 
geometric mean, 95% confidence interval (CI), and the between-participant CV (%CVb) 
for the log-transformed PK parameters.  Baseline or predose assessment is the last 
available assessment prior to time of the first dose unless it is specified otherwise.  If 
there are multiple assessments collected on the same scheduled time, the average of these 
assessments will be used.  For tabulated safety summaries, only the scheduled 
assessments will be included in the summary tables.  Version 9.3 or higher of the SAS 
system will be used to analyse the data as well as to generate tables, figures, and listings. 
 
4. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses Evaluated 
Screened  
• 
All participants who were screened for eligibility 
• 
Study Population 
Enrolled  
• 
All participants who passed screening and entered the 
study. 
• 
Note screening failures (who never passed screening 
even if rescreened) and participants screened but never 
enrolled into the study (Reserve, Not Used) are 
excluded from the Enrolled population, as they did not 
enter the study. 
• 
Study Population 
Safety 
• 
All randomized participants who received at least one 
dose of study treatment. 
• 
This population will be based on the treatment the 
subject actually received for each respective 
cohort/period . 
• 
Study Population 
• 
Safety  
Pharmacokinetic 
(PK)  
Concentration 
• 
Part 1 (SAD) 
The PK Concentration Population will include all 
participants who undergo plasma PK sampling and have 
at least one evaluable concentration during the single 
dose phase of the study Part 1.  
• 
Part 2 (MAD) 
The PK Concentration Population will include all 
participants who undergo plasma PK sampling and have 
at least one evaluable concentration during the repeat 
dose phase of the study Part 2.  
 
• 
PK concentration 
Listing 
• 
PK individual 
concentration-time 
data plots 
Pharmacokinetic 
(PK) Parameter 
• 
Part 1 (SAD) 
The PK Parameter Population will include all 
participants who undergo plasma PK sampling and have 
evaluable PK parameters estimated during the single 
dose phase of the study Part 1.  
• 
Part 2 (MAD) 
The PK Parameter Population will include all 
• 
PK parameter 
listing 
• 
PK mean/median 
concentration-time 
data plots 
• 
PK parameter 


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Population 
Definition / Criteria 
Analyses Evaluated 
participants who undergo plasma PK sampling and have 
evaluable PK parameters estimated during the repeat 
dose phase of the study Part 2.  
 
summary 
• 
Dose 
proportionality 
• 
Accumulation ratio 
analysis and 
steady state 
analysis for Part 2 
Refer to Appendix 12: List of Data Displays which details the population used for each display. 
 
4.1. 
Protocol Deviations 
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed. 
Protocol deviations will be tracked by the study team throughout the conduct of the 
study, in accordance with the Protocol Deviation Management Plan Version 002 (09-
May-2018). 
o Data will be reviewed prior to freezing the database to ensure all important 
deviations are captured and categorised on the protocol deviations dataset.  
o This dataset will be the basis for the summaries and listings of protocol 
deviations. 
A separate listing of all inclusion/exclusion criteria deviations will also be provided. This 
listing will be based on data as recorded on the inclusion/exclusion page of the eCRF. 


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5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
5.1. 
Study Treatment & Sub-group Display Descriptors 


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Treatment Group Descriptions 
RandAll NG 
Data Displays for Reporting  
Code 
Description 
Description 
Header 
Order in 
TLF  
Part 1 
P/PS 
Placebo/Placebo Sentinel 
Placebo SD 
SD PBO 
9 
D1/ D1S 
GSK3640254 Dose Level 1/ GSK3640254 
Dose Level 1 sentinel 
GSK3640254 1 mg 
SD 
SD 1mg 
1 
D2/ D2S 
GSK3640254 Dose Level 2/ GSK3640254 
Dose Level 2 sentinel 
GSK3640254 3 mg 
SD 
SD 3mg 
2 
D3/ D3S 
GSK3640254 Dose Level 3/ GSK3640254 
Dose Level 3 sentinel 
GSK3640254 10 mg 
SD 
SD 10mg 
3 
D4/ D4S 
GSK3640254 Dose Level 4/ GSK3640254 
Dose Level 4 sentinel 
GSK3640254 30 mg 
SD 
SD 30mg 
4 
D5/ D5S 
GSK3640254 Dose Level 5/ GSK3640254 
Dose Level 5 sentinel 
GSK3640254 100 mg 
SD 
SD 100mg 
5 
D6/ D6S 
GSK3640254 Dose Level 6/ GSK3640254 
Dose Level 6 sentinel 
GSK3640254 200 mg 
SD 
SD 200mg 
6 
D7/ D7S 
GSK3640254 Dose Level 7/ GSK3640254 
Dose Level 7 sentinel 
GSK3640254 400 mg 
SD 
SD 400mg 
7 
D8/ D8S 
GSK3640254 Dose Level 8/ GSK3640254 
Dose Level 8 sentinel 
GSK3640254 700 mg 
SD 
SD 700mg 
8 
Part 2 
RP 
Placebo Repeated Dose 
Placebo RD 
RD PBO 
5 
R1 
GSK3640254 Repeat Dose Level 1 
GSK3640254 50 mg 
RD 
RD 50mg 
1 
R2 
GSK3640254 Repeat Dose Level 2 
GSK3640254 100 mg 
RD 
RD 100mg 
2 
R3 
GSK3640254 Repeat Dose Level 3 
GSK3640254 200 mg 
RD 
RD200 
mg 
3 
R4 
GSK3640254 Repeat Dose Level 4 
GSK3640254 320 mg 
RD 
RD 320mg 
4 
R5 
GSK3640254 Repeat Dose Level for 
Expansion Cohort 
GSK3640254 200 mg 
RD 
RD200 
mg 
3 
NOTES: 
• 
Order represents treatments being presented in TFL, as appropriate. 
• 
Placebo is pooled by part 
5.2. 
Baseline Definitions 
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
latest pre-dose assessment with a non-missing value, including those from unscheduled 
visits. If time is not collected, Day 1 assessments are assumed to be taken prior to first 
dose and used as baseline. 
Parameter 
Study Assessments Considered as Baseline 
Baseline Used in Data 
Display 
Screening 
Day -2 
Day -1 
Day 1 
(Pre-Dose) 
Lab 
X 
X 
 
 
Day -2 in each period 
ECG 
X 
X 
X 
X 
Day 1(Pre-Dose) in each 
period 


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Parameter 
Study Assessments Considered as Baseline 
Baseline Used in Data 
Display 
Screening 
Day -2 
Day -1 
Day 1 
(Pre-Dose) 
Vital Signs  X 
 
X 
 
Day -1 in each period 
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing. 
5.3. 
Other Considerations for Data Analyses and Data Handling 
Conventions 
Other considerations for data analyses and data handling conventions are outlined in the 
appendices: 
Section 
Component 
12.3 
Appendix 3: Assessment Windows 
12.4 
Appendix 4: Study Phases and Treatment Emergent Adverse Events 
12.5 
Appendix 5: Data Display Standards & Handling Conventions 
12.5 
Appendix 6: Derived and Transformed Data 
12.7 
Appendix 7: Reporting Standards for Missing Data 
12.8 
Appendix 8: Values of Potential Clinical Importance 
 


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6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Study Population Analyses 
The study population analyses will be based on the Safety population, unless otherwise 
specified. 
Study population analyses including analyses of subject’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure and treatment compliance will be based on GSK Core Data Standards.  
Details of the planned displays are presented in Appendix 12: List of Data Displays. 
Table 1 provides an overview of the planned study population analyses, with full details 
of data displays being presented in Appendix 12. 
Table 1 
Overview of Planned Study Population Analyses 
Display Type 
Data Displays Generated 
Table 
Figure 
Listing 
Subject Disposition 
Subject Disposition 
Y 
 
 
Reasons for Screening Failures 
Y 
 
Y[1] 
Study Treatment Discontinuation 
Y 
 
Y 
Reasons for Subject Withdrawal 
 
 
Y 
Protocol Deviations 
Important[3] Protocol Deviations 
Y 
 
Y 
Subjects with Inclusion/Exclusion Criteria Deviations 
 
 
Y[2] 
Populations Analysed 
Study Populations and Exclusions 
Y 
 
 
Subjects Excluded from Any Population 
 
 
Y 
Subjects for whom the Treatment Blind was Broken 
 
 
Y[4] 
Demographic and Baseline Characteristics 
Demographic Characteristics 
Y 
 
Y 
Race and Racial Combinations 
Y 
 
Y  
Summary of Age Ranges 
Y 
 
 
Concomitant Medications 
Concomitant Medications[5] 
Y 
 
Y 
Exposure and Treatment Compliance 
Study Treatment Overall Compliance 
Y 
 
 
Exposure to Study Treatment 
Y 
 
Y 
Meal data 
 
 
Y 
NOTES : 
• 
Y = Yes display generated. 
1. Conditional displays, if data is available listing will be generated. 
2. Listing of subjects excluded from any population will be generated only. 
3. All protocol deviations will be listed, with important protocol deviations summarized. 
4. Listing will be created for part 2 when data is available. 
5. Provide summary table if more than 10 conmeds 
 


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6.2. 
Display Details 
6.2.1. 
Subject Disposition 
The disposition table will consist of all subjects in the safety population.   
The number and percentage of subjects who failed screening and were, therefore, not 
entered into the study, overall and by reason, will be summarized. A listing of the screen 
failure record for all subjects who failed screening, including the reasons for screen 
failure will be produced.  
Reasons for study treatment discontinuation will be summarized for each treatment group 
and overall.  A by-subject listing of reasons for study withdrawal and a by-subject listing 
of reasons for study treatment discontinuation will be produced.  
6.2.2. 
Protocol Deviations 
The number and percentage of subjects who had important protocol deviations defined in 
Section 4.1 will be summarized by treatment group and overall. 
A listing of all protocol deviations will be produced. 
Subjects with inclusion and exclusion deviations will be listed.  
6.2.3. 
Populations Analysed 
The number of subjects who were enrolled into the study, and the number of subjects 
within each analysis population (Safety and PK) will be summarized for each treatment 
group and overall.  
Subjects excluded from any population and subjects for whom the Treatment Blind was 
broken will be listed. 
6.2.4. 
Demographic and Baseline Characteristics 
The demographic and baseline characteristics age, sex, race, ethnicity, height, weight, 
BMI will be summarized by treatment group and overall for the safety population.  The 
count, mean, standard deviation, median, minimum, and maximum value will be 
computed for age, BMI, height, and weight.  
A by-subject listing of demographic and baseline characteristics will also be produced.  
Summaries of race and racial combinations will be produced for each treatment group 
and overall.  A listing of race by subject will also be produced. 
Summaries of age ranges will be produced for each treatment group and overall.   
6.2.5. 
Concomitant Medications 
Medications will be coded using the GSK Drug v1.4 coding dictionary. 


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Concomitant medications will be summarised by GSK-Drug Anatomical Therapeutic 
Chemical (ATC) classification level 1 (body system) and ingredient if there are more 
than 10 concomitant medications. Drugs that are composed of a combination of 
ingredients will be displayed according to the ATC classifications of the ingredients, not 
of the combination. A by-subject listing will also be conducted. 
6.2.6. 
Exposure and Treatment Compliance  
The complete dosing experience will be listed for all subjects for both Part 1 and Part 2. 
The total duration of exposure (number of days on study drug), and cumulative dose will 
be summarized by treatment group for Part 2. 
For subjects who completed the 14-day treatment period in Part 2 of the study, the 
expected number of doses is 14.  For subjects who permanently discontinued the study 
treatment and/or withdrew from the study, the expected number of doses during the 
treatment period will be calculated using “Days on study drug” where “Days on study 
drug” is Last Dose Date – First Dose Date +1.  
A summary of study medication compliance will be produced by treatment group for Part 
2: 0%, >0-<100%, 100%, >100%. The compliance will be calculated for the whole study 
treatment period as the percentage of cumulative dose [100*(actual cumulative dose) / 
(expected cumulative dose for the subject’s treatment duration)]. For subjects who 
completed the 14-day treatment period in Part 2, the expected cumulative dose of 
GSK3640254 taken during the treatment period is as follows: 
• For subjects who received 50 mg GSK3640254, the expected cumulative dose is 
700 mg GSK3640254  
• For subjects who received 100 mg GSK3640254, the expected cumulative dose is 
1400 mg GSK3640254  
• For subjects who received 200 mg GSK3640254, the expected cumulative dose is 
2800 mg GSK3640254  
• For subjects who received 320 mg GSK3640254, the expected cumulative dose is 
4480 mg GSK3640254  
For subjects who permanently discontinued study treatment or withdrew early from the 
study, the expected cumulative dose of GSK3640254 taken during the treatment period 
will be calculated as follows: 
• For subjects who received 50 mg GSK3640254, the expected cumulative dose is 
50 mg*(Last Dose Date – First Dose Date +1) 
• For subjects who received 100 mg GSK3640254, the expected cumulative dose is 
100 mg*(Last Dose Date – First Dose Date +1) 
• For subjects who received 200 mg GSK3640254, the expected cumulative dose is 
200 mg*(Last Dose Date – First Dose Date +1) 


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• For subjects who received 320 mg GSK3640254, the expected cumulative dose is 
320 mg*(Last Dose Date – First Dose Date +1) 
The actual cumulative dose of GSK3640254 for all subjects is the sum of all doses, in 
mg, of study drug consumed for the duration of the study.   
A by-participant listing of the meal data will also be generated including start and stop 
date and time of meal, dosing time, type of meal and whether the totality of the meal was 
ingested. 
 
7. 
SAFETY ANALYSES 
7.1. 
Overview of Planned Safety Analysis 
The safety analyses will be based on the safety population, unless otherwise specified. 
Safety data are the primary endpoints of the study, will be presented in tabular and 
summarized and listed descriptively accordingly to GSK’s Integrated Data Standards 
Library (IDSL)standards. Details of the planned displays are presented in Appendix 12: 
List of Data Displays. 
 
Table 2 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 12. 
Table 2 
Overview of Planned Safety Analyses 
Display Type 
Absolute 
Change from Baseline 
Summary 
Individual 
Summary 
Individual 
T 
F 
F 
L 
T 
F 
F 
L 
Adverse Events (AEs) 
AEs Overview 
Y 
 
 
 
 
 
 
 
All AEs 
 
 
 
Y 
 
 
 
 
All Adverse Events by 
Maximum Grade and 
SOC and PT 
Y 
 
 
 
 
 
 
 
All Drug-Related AEs 
 
 
 
Y 
 
 
 
 
Drug-Related Adverse 
Events by Maximum 
Grade and SOC and 
PT 
Y 
 
 
 
 
 
 
 
Serious AEs 
 
 
 
Y 
 
 
 
 
Serious AEs by SOC 
and PT (Subjects & 
No. of Occurrences) 
Y 
 
 
 
 
 
 
 
Drug Related Serious 
Adverse Events  
 
 
 
 
Y 
 
 
 
 
Fatal AEs 
 
 
 
Y 
 
 
 
 
Non-Fatal SAEs 
 
 
 
Y 
 
 
 
 


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Display Type 
Absolute 
Change from Baseline 
Summary 
Individual 
Summary 
Individual 
T 
F 
F 
L 
T 
F 
F 
L 
Grade 2- 4 Adverse 
Events 
 
 
 
Y 
 
 
 
 
AEs of Special Interest 
Y 
 
 
Y 
 
 
 
 
Adverse Events 
Leading to Withdrawal 
from Study/Permanent 
Discontinuation of 
Study Treatment 
Y 
 
 
Y 
 
 
 
 
Subject Numbers for 
Individual AEs 
 
 
 
Y 
 
 
 
 
Common Adverse 
Events and Common 
Non-Serious Adverse 
Events By Overall 
Frequency 
Y 
 
 
 
 
 
 
 
Relationship of 
Adverse Event System 
Organ Classes, 
Preferred Terms, and 
Verbatim Text 
 
 
 
Y 
 
 
 
 
Laboratory Values 
Clinical Chemistry 
Y 
 
 
Y 
Y 
 
 
 
Hematology 
Y 
 
 
Y 
Y 
 
 
 
Urinalysis 
Y 
 
 
Y 
 
 
 
 
Clinical Chemistry  
Value of Potential 
Clinical Importance 
 
 
 
Y 
 
 
 
 
Hematology Values of 
Potential Clinical 
Importance 
 
 
 
Y 
 
 
 
 
Urinalysis Values of 
Potential Clinical 
Importance 
 
 
 
Y 
 
 
 
 
Worst Case Chemistry 
Lab Results by 
Maximum Grade Post-
Baseline Relative to 
Baseline 
Y 
 
 
 
 
 
 
 
Worst Case 
Hematology Lab 
Results by Maximum 
Grade Post-Baseline 
Relative to Baseline 
Y 
 
 
 
 
 
 
 
Worst Case Urine Lab 
Results by Maximum 
Grade Post-Baseline 
Relative to Baseline 
Y 
 
 
 
 
 
 
 
Lab Results Identified 
 
 
 
Y 
 
 
 
 


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Display Type 
Absolute 
Change from Baseline 
Summary 
Individual 
Summary 
Individual 
T 
F 
F 
L 
T 
F 
F 
L 
as Adverse Events 
Treatment Emergent 
Laboratory Toxicities 
Y 
 
 
 
 
 
 
 
Subjects with grades 2 
or higher laboratory 
toxicities 
 
 
 
Y 
 
 
 
 
ECG 
ECG Findings 
Y 
 
 
Y 
 
 
 
 
Abnormal ECG 
Findings 
 
 
 
Y 
 
 
 
 
ECG Values 
Y 
 
 
 
Y 
 
 
 
All ECG Values for 
Subjects with a Value 
of PCI 
 
 
 
Y 
 
 
 
 
Maximum Increase in 
QTc Values Post-
Baseline Relative to 
Baseline by Category 
 
 
 
 
Y 
 
 
 
Mean (95% CI) 
Change from Baseline 
in QTc interval by Time 
and Treatment 
 
 
 
 
 
Y 
 
 
Vital Signs 
Vital Values 
Y 
 
 
Y 
Y 
 
 
 
All Vital Signs for 
Subjects with Values of 
PCI 
 
 
 
Y 
 
 
 
 
Hepatobiliary (Liver) 
Liver 
Monitoring/Stopping 
Event Reporting 
Y 
 
 
 
 
 
 
 
Summary of 
Hepatobiliary 
Laboratory 
Abnormalities 
Y 
 
 
 
 
 
 
 
NOTES : 
• 
T = Table, F = Figure, L = Listing, 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.      
                                                                                                                                
7.2. 
Display Details 
7.2.1. 
Adverse Events Analysis   
All adverse event (AE) data will be summarized, sorted by the system organ class and 
preferred term assigned by MedDRA version 21.0, and presented by treatment group.  
The following summaries will be provided: 


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• 
Adverse events overview 
• 
All adverse events by maximum grade and SOC and PT 
• 
Drug related adverse events by maximum grade and SOC and PT 
• 
Serious adverse events by SOC and PT (Subjects & No. of Occurrences) 
• 
Adverse events of Special Interest 
• 
Adverse events leading to withdrawal from study/permanent discontinuation of study 
treatment  
• 
Common (>= 5%) adverse events by overall frequency  
• 
Common (>= 5%) non-serious adverse events by overall frequency 
The following listings will be provided: 
• 
All adverse events 
• 
Drug related adverse events 
• 
Serious adverse events  
• 
Drug related serious adverse events 
• 
Fatal adverse events 
• 
Non-fatal serious adverse events 
• 
Grade 2 - 4 Adverse Events 
• 
Adverse events of special interest 
• 
Adverse events leading to withdrawal from study/permanent discontinuation of study 
treatment 
• 
Subject Numbers for Individual AEs 
• 
Relationship of Adverse Event System Organ Classes, Preferred Terms, and 
Verbatim Text                                                                                                                                                
Adverse Events of Special Interest: 
A comprehensive list of MedDRA terms based on clinical review will be used to identify 
each type of GI event (Nausea and Vomiting, Dyspepsia etc.). [Changes to the MedDRA 
dictionary may occur between the start of the study and the time of reporting and/or 
emerging data from on-going studies may highlight additional adverse events of special 
interest, therefore the list of terms to be used for each event of interest and the specific 
events of interest will be based on the safety review team (SRT) agreements in place at 
the time of reporting.]  
7.2.2. 
Clinical Laboratory Safety Analyses 
Laboratory evaluations including the analyses of chemistry laboratory tests, hematology 
laboratory tests and urinalysis will be based on GSK Core Data Standards.  


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Haematology, clinical chemistry and urinalysis parameters collected are listed below.   
Protocol Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count  
RBC Indices: 
MCV 
MCH 
%Reticulocytes 
WBC count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC Count 
Hemoglobin 
Hematocrit 
Clinical 
Chemistry 
BUN 
Potassium 
Aspartate 
Aminotransferase 
(AST)/ Serum 
Glutamic-Oxaloacetic 
Transaminase (SGOT) 
Total bilirubin 
 
Creatinine 
Sodium, Chloride, 
Bicarb 
Alanine 
Aminotransferase 
 (ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase (SGPT) 
Total Protein 
 
Glucose (non-
fasting) 
Calcium, 
Magnesium, 
Phosphate 
Alkaline phosphatase 
Fasting Lipid 
Panel 
(Cholesterol, 
Triglycerides, 
HDL, LDL) 
Routine 
Urinalysis 
• 
Specific gravity 
• 
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte 
esterase by dipstick 
• 
Microscopic examination (if blood or protein is abnormal) 
 
The following summaries will be provided: 
• 
Laboratory values for hematology, clinical chemistry, and urinalysis by visit and by 
treatment 
• 
Laboratory values change from baseline for hematology and clinical chemistry by 
visit and by treatment group 
• 
The number and percentage of subjects with on-treatment laboratory abnormalities 
worsened from baseline by maximum grade for haematology, clinical chemistry and 
urinalysis. 
• 
Treatment emergent laboratory toxicities 
The following listings will be provided: 


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• 
Laboratory values for haematology, clinical chemistry, and urinalysis  
• 
Laboratory values of potential clinical importance for hematology, clinical chemistry 
and urinalysis (potential clinical importance criteria are specified in Section 12.8.1) 
• 
Laboratory results identified as adverse events 
• 
Subjects with grades 2 or higher laboratory toxicities  
 
7.2.3. 
Other Safety Analyses 
7.2.3.1. 
Electrocardiograms 
A summary of the number and percentage of subjects of all ECG findings will be 
displayed by treatment.  Additionally, summary statistics of ECG values and change from 
baseline in ECG values will be presented. Maximum QTc values and maximum increase 
in QTc values post-baseline relate to baseline will be summarized by category.  Mean 
(95% CI) change from baseline in QTcF interval will be plotted by time and treatment. A 
by-subject listing of ECG findings for all subjects will be listed. Abnormal ECG findings 
and all ECG values for subjects with a value of potential clinical importance will be listed 
(potential clinical importance criteria are specified in Section 12.8.2).   
7.2.3.2. 
Vital Signs 
Vital sign values and change from baseline will be summarized. A by-subject listing of 
vital signs for all subjects will be produced. All vital signs for subjects with values of 
potential clinical importance will be listed (potential clinical importance criteria are 
specified in Section 12.8.3) 
7.2.3.3. 
 Hepatobiliary (Liver) 
Liver monitoring/stopping event reporting will be summarized by treatment group.  A 
summary of hepatobiliary laboratory abnormalities will be produced. 
 


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8. 
PHARMACOKINETIC ANALYSES 
8.1. 
 Pharmacokinetic Analyses 
The pharmacokinetic (PK) analyses will be based on the “PK Concentration” and “PK 
Parameter” population, unless otherwise specified.  
As an overview, individual, mean and median plasma GSK3640254 concentration-time 
profiles will be plotted by treatment and day (linear and semi-linear profiles). PK 
sampling times will be related to the start of the dosing date/time. Actual sampling times 
will be used to calculate all of the non-compartmental pharmacokinetic parameters. 
Individual concentrations of GSK3640254 in plasma will be listed and summarised by 
treatment and nominal time. Details of the planned displays are presented in Appendix 
12: List of Data Displays. 
Table 3 provides an overview of the planned analyses, with full details being presented in 
Appendix 12.  
Table 3 
Overview of Planned Pharmacokinetic Analyses 
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 
PK Concentrations 
Plasma Drug 
Concentrations 
 
 
 
Y 
 Y 
Y 
Y 
 
 
 
 
Y 
Y 
 
PK Parameters 
PK Parameters 
 
 
 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
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.     
 
8.1.1. 
Endpoint / Variables 
8.1.1.1. 
Drug Concentration Measures 
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 12.5.3 
Reporting Standards for Pharmacokinetic) 
8.1.1.2. 
Derived Pharmacokinetic Parameters 
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
WinNonlin. All calculations of non-compartmental parameters will be based on actual 
sampling times. Pharmacokinetic parameters listed will be determined from the plasma 
concentration-time data, as data permits. 
Parameter 
Parameter Description 


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AUC(0-inf) 
Area under the concentration-time curve extrapolated to infinity will be calculated as:  
AUC = AUC(0-t) + C(t) / λ_z 
AUC(0-
tlast) 
Area under the concentration-time curve from time zero to the time of the last quantifiable 
concentration (C(t)) will be calculated using the linear trapezoidal rule for each incremental 
trapezoid and the log trapezoidal rule for each decremental trapezoid. 
AUC(0-24) 
Area under the plasma concentration time curve from zero to 24 
AUC(0-τ) 
Area under the curve (Area under the plasma drug concentration-time curve 
from pre-dose to the end of the dosing interval at steady state) 
%AUCex 
The percentage of AUC (0-inf) obtained by extrapolation (%AUCex) will be calculated as: 
[AUC(0-inf) – AUC(0-t)] / AUC(0-inf) x 100 
Cmax 
Maximum observed concentration, determined directly from the concentration-time data. 
C24 
Concentration at 24 hours post-dose on Day 1 
Clast 
Last quantifiable concentration 
Cτ 
Pre-dose (trough) concentration at the end of the dosing interval 
tmax 
Time to reach Cmax, determined directly from the concentration-time data. 
t½ 
Apparent terminal half-life will be calculated as: t½ = ln2 / λ _z 
tlag 
Absorption lag time 
tlast 
Time of last quantifiable concentration 
CL/F  
Apparent oral clearance 
NOTES:  
• 
Additional parameters may be included as required. 
8.1.2. 
Summary Measure 
•  Part 1 (single dose): AUC (0-24), AUC(0-tlast), AUC (0-inf), Cmax, C24, tmax, 
tlag, t1/2, Clast, tlast, CL/F.   
• Part 2 (Repeated QD doses for 14 days):   
o Day 1: AUC(0-24), Cmax, C24, tmax, tlag 
o Day 14: AUC(0-τ), Cmax, Cτ, tmax, t1/2, and CL/F.  
8.1.3. 
Population of Interest  
The primary pharmacokinetic analyses will be based on the Pharmacokinetic Parameter 
population, unless otherwise specified. 
8.1.4. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK Data Standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 8.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. 
 


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8.1.4.1. 
Statistical Methodology Specification 
Dose Proportionality-Power model: 
Part 1, and 2: 
Dose proportionality of GSK3640254 following single-dose administration in Part 
1 and following single-dose and repeat-dose administration inPart 2 of the study will be 
assessed separately using the power model (Smith, 2000) as 
described below: 
y = α * 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝛽𝛽 
where y denotes the PK parameter being analyzed [for Part 1: AUC(0-∞), AUC(0-24), 
and Cmax. For Part 2: AUC(0-24),  Cmax on Day1; 
AUC(0-τ), Cmax, 𝐶𝐶τ on Day 14] . Dose proportionality implies that β=1 and will be 
assessed by estimating β along with its confidence interval. The exponent, β, in the 
power model will be estimated by regressing the 𝑙𝑙𝑙𝑙𝑙𝑙𝑒𝑒-transformed PK parameter on 𝑙𝑙𝑙𝑙𝑙𝑙𝑒𝑒 
dose. 
log(y) = log(α) + β * log(dose) 
The power model will be fitted by restricted maximum likelihood (REML) using SAS 
Proc Mixed. For Part 1, a power model with subject as the random effect will be fitted. If 
the model does not converge then a fixed effect power model will be fitted. For Part 2, a 
fixed effect power model will be fitted. The mean slope will be estimated from the power 
model and the corresponding 90% confidence interval calculated. Intra-subject CV% 
calculated from the model will be presented in the table. Point estimates and confidence 
intervals for the slope will be reported to 4 decimal places with no rounding. 
Part 1, 
An example of SAS code is included here for the power model approach. 
ODS output solutionf=stat 
Proc Mixed; 
class subject; 
model logPKvar = logdose /cl alpha=0.1 solution ddfm=kr; 
random intercept /subject=subject type=un; 
run; 
If the above model still does not converge, then use: 
ODS output solutionf=stat 


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Proc Mixed; 
model logPKvar = logdose /cl alpha=0.1 solution ddfm=kr; 
run; 
Part 2, 
ODS output solutionf=stat 
Proc Mixed; 
model logPKvar = logdose /cl alpha=0.1 solution ddfm=kr; 
run; 
 
Dose Proportionality-ANOVA Model 
Part 1, and 2: 
Additionally, dose proportionality may be assessed by pair-wise analysis of variance 
(ANOVA) using the SAS Mixed model procedure if power model does not show dose 
proportionality. A reference dose of 3 mg for all parts, and will be used and the other 
doses would be treated as test dose. PK parameters will be normalized to the reference 
dose and then log-transformed prior to the analysis. Point estimates and 90% confidence 
intervals for AUC and Cmax will be reported to 4 decimal places with no rounding. 
An example of SAS code is also included here for the ANOVA approach. 
ODS output solutionf=stat;  
Proc Mixed; 
class treatment; /* treatments are different dose groups */ 
model logdnPKvar = treatment/ddfm=kr; 
lsmeans treatment; /* assuming one ref and four test treatments */ 
estimate 'test1 vs ref' treatment -1 1 0 0 0 /cl alpha=0.1; 
estimate 'test2 vs ref' treatment -1 0 1 0 0/cl alpha=0.1; 
run; 
Individual and box plot of dose-normalized plasma GSK3640254 PK parameters by 
treatment will be generated. 
 
Accumulation Ratio Analysis 
Part 2: 


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An ANOVA with a random effect term for subject and fixed effect terms for day will be 
performed by dose on the loge-transformed PK parameters (AUC(0-τ), Cτ, and Cmax). 
Day will be treated as a class variable in the model. The accumulation ratio of 
GSK3640254 will be estimated by calculating the ratio of the geometric least squares 
(GLS) means of PK parameters between Day 14 and Day 1 for Cohort 3,4,5, 6 and 
expansion, and the corresponding 90% CI for each dose. 
An example of SAS code is included here. 
ODS output solutionf=stat; 
Proc Mixed; 
by dose; 
class subject day; 
model logPKpar = day / ddfm=kr; 
random subject; 
lsmeans day; 
estimate 'Day X vs Day 1' day -1 1/cl alpha=0.1; 
run; 
Comparative plots of individual plasma GSK3640254 PK estimates will be generated 
by dose group [AUC(0-τ) ), Cτ, and Cmax on Day 14 versus AUC(0-24), C24 and Cmax 
on Day 1] on linear and semi-logarithmic scales. The accumulation ratio will also be 
listed and summarized along with other PK parameters. 
 
Steady State Assessment 
Part 2 
Predose concentrations on Day 2 through 14 and Cτ on day 14 from Cohort 3, 4, 5, 6 and 
expansion of Part 2 of the study will be plotted versus day by treatment (dose). An 
ANOVA with terms for subject as a random effect and day as a fixed effect will be 
performed by dose 
on the loge-transformed C0 and Cτ. Day will be treated as a continuous variable in the 
model. Achievement of plasma GSK3640254 steady state will be assessed by visual 
inspection of plots and calculating the point estimate and 90% CI of the slope of the 
linear regression of Days 2-14 for Cohort 3, 4, 5,6 and expansion of Part 2 of pre-dose C0 
and Cτ versus Day by dose group. To claim that steady state is reached, the pre-dose 


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concentration slope estimate is close to zero or the 90% CI for the slope estimate includes 
zero. 
An example of SAS code to assess achievement of steady-state is 
included here. 
ODS output solutionf=stat; 
Proc Mixed; 
by dose; 
where (Day in (10,11,12,13,14, 15)); 
class subject; 
model logCtau = Day/cl alpha=0.1 solution; 
random intercept/subject=subject type=un; 
run; 
The same analysis will be repeated with C0 data by dropping one earlier day at time 
between day 2-14, and the results will be presented in the same table. 
 
 
8.1.5. 
Food Effect Assessment  
As the study did not administer GSK in fasted conditions, the food effect evaluation can’t 
be performed.  


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9. 
POPULATION PHARMACOKINETIC (POPPK) 
ANALYSES 
The population PK analysis and pharmacodynamic analyses will be presented separately 
from the main clinical study report (CSR). 


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10. 
REFERENCES 
 
• GlaxoSmithKline Document Number 2016N297505_00: A Double-Blind (Sponsor 
Unblinded), Randomized, Placebo-Controlled, Single and Repeated Dose Escalation 
Study to Investigate the Safety, Tolerability and Pharmacokinetics of GSK3640254 in 
Healthy Participants. Effective Date: 03-MAY-2017 
• Whitehead J. et al., Easy-to-implement Bayesian methods for dose-escalation studies 
in healthy participants, Biostatistics, 2, 47cs, 2, 47v 2001 
 


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11. 
APPENDICES 
11.1. 
Appendix 1: Protocol Deviation Management and Definitions 
for PK Parameter Population 
 
A subject meeting any of the following criteria will be excluded from the PK Parameter 
Summary Population: 
Number  
Exclusion Description 
01 
Failure of any inclusion/exclusion criteria, but subject is 
still enrolled 
 


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11.2. 
Appendix 2: Schedule of Activities 
11.2.1. 
Protocol Defined Schedule of Events 
 
SAD Cohorts 1 and 2 Screening 
Procedure 
Screening (up to 28 days before Day 1) 
Outpatient Visit 
X 
Informed Consent 
X 
Inclusion/Exclusion Criteria and 
Demography 
X 
Medical/medication/ drug/alcohol history 
X 
Full Physical Exam1 
X 
Columbia Suicide Severity Rating Scale 
(CSSRS) 
X 
Height, Weight, BMI 
X 
Vital signs 
X 
12 Lead ECG 
X 
Screening Holter 
X 
Pregnancy Test 
X 
Drug/alcohol/cotinine screen 
X 
HbsAg, HCV, HIV tests 
X 
Hem/Chem/Urine tests 
X 


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SAD Cohorts 1 and 2 On-Treatment: Before, During, and After Dosing in Each Period 
Procedure 
Periods 1 through 4 
Follow-up 
(7-14 days 
post last 
dosing) 
Day 
-2 
Day 
-1 
Day 1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Pre-
dose 
0 
h 
0.5 
h 
1 
h 
1.5 
h 
2 
h 
2.5 
h 
3 
h 
3.5 
h 
4 
h 
4.5 
h 
5 
h 
6 
h 
8 
h 
12 
h 
24 
h 
48 
h 
72 
h 
96 h 
Admission to Unit 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Outpatient Visit 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
Full Physical Exam1 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
X 
Weight, BMI 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Vital signs 
  
X 
  
  
  
X 
  
X 
  
  
  
  
X 
  
X 
  
X 
X 
X 
X 
X 
X 
12-lead safety ECGs 
X 
X 
X 
  
  
X 
  
X 
  
  
  
X 
  
  
X 
  
X 
X 
X 
X 
X 
X 
Continuous ECG (full 
time matched baseline 
on Day-1)2 
  
X 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
Pregnancy Test 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X3 
Drug/alcohol/cotinine 
screen 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Hem/Chem/Urine tests 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X 
  
X 
X 
Single Dosing with 
GSK3640254 following 
moderate fat meal 
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Plasma PK Sampling4 
  
  
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Adverse Event Review 
<=================================================================================================================> 
Con Med Review 
<=================================================================================================================> 
Furlough from Unit 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
HCV=Hepatitis C; BMI= Body mass index; ECG= Electrocardiogram; PK= Pharmacokinetic, SAD=single ascending dose 
Note: 


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1. A Full Physical Exam will include at a minimum, assessments of the Skin, Cardiovascular, Respiratory, Gastrointestinal and 
Neurological systems. 
2. Additional safety ECGs may be printed at the discretion of the PI if prolongation in QT interval is suspected. The frequency of ECGs 
will support an exploratory endpoint (should clinical development continue) to evaluate the exposure-response relationship between 
GSK3640254 and QTcF. Once human PK data (e.g. Cmax) are available, the number of ECG time points may be reduced in 
subsequent dosing groups. At timepoints for ECG extraction, subjects will be supinely resting for at least 10 minutes. When ECG 
extractions coincide with safety ECGs, vital signs assessment and blood draws, procedures should be carried out in said order.  
3. This pregnancy test will be obtained approximately 37 days after the last dose of study treatment 
4. The number of PK sampling time points may be reduced in subsequent dosing groups once human PK data are available.


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MAD Cohorts 3, 4, 5 and the Expansion Cohort Screening 
Procedure 
Screening (up to 28 days before Day 1) 
Outpatient Visit 
X 
Informed Consent 
X 
Inclusion/Exclusion Criteria and 
Demography 
X 
Medical/medication/ drug/alcohol history 
X 
Full Physical Exam1 
X 
CSSRS 
X 
Height, Weight, BMI 
X 
Vital signs 
X 
12 Lead ECG 
X 
Screening Holter 
X 
Drug/alcohol/cotinine screen 
X 
HbsAg, HCV, HIV tests 
X 
Hem/Chem/Urine tests 
X 
Pregnancy Test 
X 
1.  A Full Physical Exam will include at a minimum, assessments of the Skin, 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems.


 
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MAD Cohorts 3, 4, 5 and the Expansion Cohort On-Treatment 
Procedure 
  
Follow-
up (7-14 
days 
post last 
dosing) 
Day 
-2 
Day 
-1 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
6 
Day 
7 
Day 
8 
Day 
9 
Day 
10 
Day 
11 
Day 
12 
Day 
13 
Day 
14 
Day 
15 
Day 
16 
Day 
17 
Day 
18 
0h 
24h 
48h 
72h 
96h 
Admission to Unit 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Outpatient Visit 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
Full Physical Exam1 
  
X 
  
  
  
  
  
X 
  
  
  
  
  
X 
  
  
X 
  
  
X 
X 
CSSRS 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Weight, BMI 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Vital signs 
  
X 
X 
X 
  
 X 
  
 X 
  
X 
  
X  
  
 X 
  
X 
  
  
X 
  
X 
12-lead safety ECGs 
X 
X 
X 
X 
X 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
X 
X 
X 
X 
X 
Continuous ECG 
(full time matched 
baseline on Day-1)2 
  
X 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
X 
X 
  
  
  
  
Drug/alcohol/cotinine 
screen 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Hem/Chem/Urine 
tests 
X 
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
X 
Pregnancy Test 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X3 
QD Dosing with 
GSK3640254 
following moderate 
fat meal 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
  
Plasma PK 
Sampling4 
  
  
X 
X 
X 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
X 
X 
 X 
X 
  
Plasma Metabolite 
Sampling5 
  
  
X 
X 
  
  
  
  
  
  
  
  
  
  
  
X 
X 
  
  
  
  


 
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Procedure 
  
Follow-
up (7-14 
days 
post last 
dosing) 
Day 
-2 
Day 
-1 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
6 
Day 
7 
Day 
8 
Day 
9 
Day 
10 
Day 
11 
Day 
12 
Day 
13 
Day 
14 
Day 
15 
Day 
16 
Day 
17 
Day 
18 
0h 
24h 
48h 
72h 
96h 
Urine PK and 
Metabolite 
Sampling6 
  
  
X 
X 
  
  
  
  
  
  
  
  
  
  
  
X 
X 
  
  
  
  
PGx Sampling (if 
participant consents) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Adverse Event 
Review 
<=====================================================================================================================> 
Con Med Review 
<=====================================================================================================================> 
Furlough from Unit 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
Note: 
1. A Full Physical Exam will include at a minimum, assessments of the Skin, Cardiovascular, Respiratory, Gastrointestinal and 
Neurological systems. 
2. ECG data extracted from the Continuous ECG will be assessed before PK sampling, prior to dosing and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4.5, 5, 
5.5, 6, 8, 12 h, and 24 h post dose on Day 1 and Day 14 and on corresponding timepoints on Day -1. At timepoints for ECG extraction, 
subjects will be supinely resting for at least 10 minutes. When ECG extractions coincide with safety ECGs, vital signs assessment and 
blood draws, procedures should be carried out in said order. The frequency of EKGs will support an exploratory endpoint to evaluate 
(should clinical development continue) the ER relationship between GSK3640254 and QTcF. Once human data (eg Cmax) is known, 
the number of EKG time points may be reduced. 
3. This pregnancy test will be obtained approximately 37 days after the last dose of study treatment 
4. Plasma PK samples for bioanalysis for GSK3640254 will be collected pre-dose (within 15 minutes prior to dosing) and 0.5,1, 1.5, 2, 
2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12 h on Day 1 and Day 14. On dosing days, plasma PK will be collected pre-dose. The number of PK 
sampling time points may be reduced in the initial MAD cohort as well as further in subsequent MAD dosing groups once human PK 
data are available in the SAD as well as in the initial MAD cohorts. 
5. Plasma Metabolite samples for metabolite identification will be collected pre-dose (within 15 minutes prior to dosing) and at the same 
time points as for plasma PK samples on Day 1, Day 2 and Day 14, and Day 15. Plasma metabolite samples will not be collected in the 
expansion cohort. 


 
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6. Urine PK and Metabolite Sampling for bioanalysis and metabolite identification will be collected pre-dose (within 1 hour prior to 
dosing) and from time 0 up to 24 hours on Day 1 and Day 14. Urine samples will not be collected in the expansion cohort. 
 


 
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11.3. 
Appendix 3: Assessment Windows 
Not applicable. 


 
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11.4. 
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events 
11.4.1. 
Study Phases 
Assessments and events will be classified according to the time of occurrence relative to 
start and/or stop date of the study treatment. 
Study Phase 
Definition 
Pre-Treatment  
Date ≤ (First) Study Treatment Start Date 
On-Treatment 
(First) Study Treatment Start Date < Date ≤ (Last) Study Treatment Stop Date + 5 
days 
Post-Treatment 
Date > (Last) Study Treatment Stop Date + 5 days 
 
Study epoch of follow-up data for Part 1will be summarized in following way: 
Follow-up from Period 1will be counted in Period 1 summary; 
Follow-up from Period 2 will be counted in Period 2 summary; 
Follow-up from Period 3 will be counted in Period 3 summary; 
Follow-up from final follow-up will be counted in Period 4 summary. 
 
11.4.1.1. 
Study Phases for Concomitant Medication 
Study Phase 
Definition 
Prior 
If medication end date is not missing and is before 28 days prior to screening visit 
Concomitant 
Any medication that is not a prior 
NOTES:  
• 
Please refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and partial 
dates for concomitant medication. Use the rules in this table if concomitant medication date is 
completely missing. 


 
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11.4.2. 
Treatment Emergent Flag for Adverse Events 
Flag 
Definition 
Treatment 
Emergent 
• 
If AE onset date is on or after treatment start date & on or before treatment stop 
date.  
• 
Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment Stop Date  
• 
For Part 1: AE onset is during one period and worsens during a later period it 
would be counted in both periods. For the initial period, the logic would be as 
above. For the later period the logic would use the treatment dates associated with 
the later period 
• 
Treatment Period Start Date ≤ AE Worsening Date ≤ Study Treatment Stop Date  
NOTES:  
• 
If the study treatment stop date is missing, then the AE will be considered to be On-Treatment. 
• 
Time of study treatment dosing and start/stop time of AEs should be considered, if collected. 
 
11.4.3. 
Adverse Events Assignment to Treatment Period for Part 1  
Adverse events (AEs) will be assigned to a treatment period and corresponding treatment 
received in that treatment period after the imputations defined in RAP section 12.7.2 have 
been performed. 
• Treatment Period 1: all AEs with start date/time at the time of or after 
administration in Treatment Period 1 and before administration in Treatment 
Period 2  
• Treatment Period 2: all AEs with start date/time at the time of or after 
administration in Treatment Period 2 and before administration in Treatment 
Period 3  
• Treatment Period 3: all AEs with start date/time at the time of or after 
administration in Treatment Period 3 and before administration in Treatment 
Period 4  
• Treatment Period 4: all AEs with start date/time at the time of or after 
administration in Treatment Period 4 
Thus, AEs occurring during the 1st washout will be assigned to the treatment received in 
Treatment Period 1, AEs occurring during the 2th washout will be assigned to the 
treatment received in Treatment Period 2, AEs occurring during the 3rd washout will be 
assigned to the treatment received in Treatment Period 3 and AEs occurring during final 
follow-up will be assigned to the treatment received in Treatment Period 4. 
11.4.4. 
Concomitant Medication Assignment to Treatment Period for Part 
1 
Concomitant medications (CMs) will be assigned to a treatment period and 
corresponding treatment received in that treatment period after the imputations defined in 
RAP section 12.7.2 have been performed. 


 
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• Treatment Period 1: all CMs with start date/time at the time of or after 
administration in Treatment Period 1 and before administration in Treatment 
Period 2  
• Treatment Period 2: all CMs with start date/time at the time of or after 
administration in Treatment Period 2 and before administration in Treatment 
Period 3  
• Treatment Period 3: all CMs with start date/time at the time of or after 
administration in Treatment Period 3 and before administration in Treatment 
Period 4  
• Treatment Period 4: all CMs with start date/time at the time of or after 
administration in Treatment Period 4  
Thus, CMs occurring during the 1st washout will be assigned to the treatment received in 
Treatment Period 1, CMs occurring during the 2th washout will be assigned to the 
treatment received in Treatment Period 2, CMs occurring during the 3rd washout will be 
assigned to the treatment received in Treatment Period 3, and CMs occurring during 
follow-up will be assigned to the treatment received in Treatment Period 4. 


 
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11.5. 
Appendix 5: Data Display Standards & Handling 
Conventions 
11.5.1. 
Reporting Process 
Software 
• 
The currently supported versions of SAS software will be used. 
Reporting Area 
HARP Server 
: US1SALX00259 
HARP Compound 
: 3640254 
Analysis Datasets  
• 
Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.13 & ADaM IG 
Version 1.0]. If the Study Data Standardization Plan (SDSP) exists for a study, ensure the CDISC 
versions are consistent. 
Generation of RTF Files 
• 
RTF files will be generated for SAC. 
11.5.2. 
Reporting Standards 
General 
• 
The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx): 
• 
4.03 to 4.23: General Principles 
• 
5.01 to 5.08: Principles Related to Data Listings 
• 
6.01 to 6.11: Principles Related to Summary Tables 
• 
7.01 to 7.13: Principles Related to Graphics  
• 
Do not include subject level listings in the main body of the GSK Clinical Study Report. All subject level 
listings should be located in the modular appendices as ICH or non-ICH listings 
• 
Statistical analyses of the pharmacokinetic parameter data will be the responsibility of Clinical 
Statistics, GSK. 
Formats 
• 
GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected, unless otherwise stated. 
• 
Numeric data will be reported at the precision collected on the eCRF. 
• 
The reported precision from non eCRF sources will follow the IDSL statistical principles but may be 
adjusted to a clinically interpretable number of DP’s.  
Planned and Actual Time 
• 
Reporting for tables, figures and formal statistical analyses: 
• 
Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated. 
• 
The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate. 
• 
Reporting for Data Listings:  
• 
Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1). 
• 
Unscheduled or unplanned readings will be presented within the subject’s listings.  
Unscheduled Visits 


 
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• 
Unscheduled visits will not be included in summary tables and/or figures. 
• 
All unscheduled visits will be included in listings. 
Descriptive Summary Statistics 
Continuous Data 
Refer to IDSL Statistical Principle 6.06.1 
Categorical Data 
N, n, frequency, % 
Graphical Displays 
• 
Refer to IDSL Statistical Principals 7.01 to 7.13. 
Plasma GSK3640254 concentrations and PK data  
• 
Will be summarized by treatment and listed by participant. Unless stated otherwise, descriptive 
summaries will include number (n), mean, standard deviation (SD), coefficient of variation (%CV), 
median, minimum, and maximum for continuous variables, n and percent (%) for categorical variables, 
and geometric mean, 95% confidence interval (CI), and the between-participant CV (%CVb) for the log-
transformed PK parameters. 
Between-subject coefficient of variation (%CVb)  
• 
Untransformed Data: 100 * (SD/Mean) 
• 
Transformed Data: 100 * (sqrt(exp(SDlog2)-1)), where SDlog indicates the standard deviation of log-
transformed data. 
• 
Within subject coefficient of variation (%CVw) will be calculated according to the  
following method: 
CVw(%) = SQRT(exp(MSE) – 1)×100 and MSE is the residual mean squared error from the model. 
CVw represents a pooled measure of within-subject variability across the treatments. 
 
11.5.3. 
Reporting Standards for Pharmacokinetic 
Pharmacokinetic Concentration Data 
PC Windows Non-
Linear (WNL) File 
PC WNL file (CSV format) for the non-compartmental analysis by Clinical 
Pharmacology Modelling and Simulation function will be created according to 
[Insert document name].  
Note: Concentration values will be imputed as per GUI_51487 
Descriptive Summary 
Statistics, Graphical 
Displays and Listings 
Refer to IDSL PK Display Standards. 
Refer to IDSL Statistical Principle 6.06.1. 
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only.  
NONMEM/Pop PK 
File 
Not applicable. 
 
 
 
Pharmacokinetic Parameter Derivation 
PK Parameter to be 
Derived by 
Programmer 
The following PK parameters will be derived by the Programmer: C24, AUC/Dose, 
Cmax/Dose, Ratio of accumulation 
Pharmacokinetic Parameter Data 
Is NQ impacted PK 
Parameters Rule 
Being Followed 
[Modify as required] 
No.  
OR  
Yes, refer to [Standards for Handling NQ Impacted PK Parameters]. 
Descriptive Summary 
Refer to IDSL PK Display Standards. 


 
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Statistics, Graphical 
Displays and Listings 
Refer to [Insert document name]  
 


 
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11.6. 
Appendix 6: Derived and Transformed Data 
11.6.1. 
General 
Multiple Measurements at One Analysis Time Point 
• 
Mean of the measurements will be calculated and used in any derivation of summary statistics but if 
listed, all data will be presented. 
• 
Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance summary 
tables. 
Study Day 
• 
Calculated as the number of days from First Dose Date: 
• 
Ref Date = Missing              → Study Day = Missing  
• 
Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date 
• 
Ref Data ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1     
 
11.6.2. 
Study Population 
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. 
 
11.6.3. 
Safety 
Adverse Events 
 
• 
Gastrointestinal nonspecific symptoms and therapeutic procedures 
Abdominal discomfort 


 
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Abdominal distension 
Abdominal pain 
Abdominal pain lower 
Abdominal pain upper 
Abdominal symptom 
Abdominal tenderness 
Abnormal faeces 
Aerophagia 
Anorectal discomfort 
Bowel movement irregularity 
Change of bowel habit 
Constipation 
Defaecation disorder 
Defaecation urgency 
Diarrhoea 
Discoloured vomit 
Epigastric discomfort 
Eructation 
Faecal volume decreased 
Faecal volume increased 
Faeces hard 
Faeces soft 
Flatulence 
Frequent bowel movements 
Gastrointestinal pain 
Gastrointestinal sounds abnormal 
Gastrointestinal toxicity 
Infrequent bowel movements 
Nausea 
Non-cardiac chest pain 
Oesophageal discomfort 
Oesophageal pain 
Vomiting 
Anorectal swelling 
Antacid therapy 
Antidiarrhoeal supportive care 
Antiemetic supportive care 
Breath odour 
Chest pain 
Colonic lavage 
Dysphagia 
Early satiety 
Gastritis prophylaxis 
Gastrointestinal disorder therapy 


 
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Gastrointestinal tract irritation 
Gastrooesophageal reflux prophylaxis 
Glycogenic acanthosis 
Hypovolaemia 
Laxative supportive care 
Malabsorption 
Mucous stools 
Pernicious anaemia 
Post procedural constipation 
Post procedural diarrhoea 
Post-tussive vomiting 
Probiotic therapy 
Procedural nausea 
Procedural vomiting 
Prophylaxis against diarrhoea 
Prophylaxis of nausea and vomiting 
Regurgitation 
Retching 
Steatorrhoea 
Vomiting projectile 
 
ECG Parameters 
RR Interval 
• IF RR interval (msec) is not provided directly, then RR can be derived as : 
[1] If QTcB is machine read & QTcF is not provided, then : 
𝑅𝑅𝑅𝑅= ቈ൬𝑄𝑄𝑄𝑄
𝑄𝑄𝑄𝑄𝑄𝑄𝑄𝑄൰
2
቉ ∗1000 
[2] If QTcF is machine read and QTcB is not provided, then:  
𝑅𝑅𝑅𝑅= ቈ൬𝑄𝑄𝑄𝑄
𝑄𝑄𝑄𝑄𝑄𝑄𝑄𝑄൰
3
቉ ∗1000 
• 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 :  
𝑄𝑄𝑄𝑄𝑄𝑄𝑄𝑄= 
𝑄𝑄𝑄𝑄
ට𝑅𝑅𝑅𝑅
1000
 
𝑄𝑄𝑄𝑄𝑄𝑄𝑄𝑄= 
𝑄𝑄𝑄𝑄
3ට𝑅𝑅𝑅𝑅
1000
 
 
 
 


 
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11.6.4. 
Pharmacokinetic 
General 
• 
The PK Plasma Concentration Population will include all subjects who undergo plasma PK sampling 
and have evaluable PK assay results for the study drug. 
• 
Data from subjects who have major protocol deviations will be excluded from PK concentration 
summary, PK parameter summary and statistical comparisons but will be included in the Listing and 
flagged. 
• 
This population will be used for listing PK concentrations, parameters, calculating PK parameters and 
plotting of individual concentration-time files. 
• 
If during clinical phase, 3 consecutive samples in any phase i.e.(Absorption, Distribution and 
Metabolism / Excretion) are found to be missing then data for that subject will not be included in PK and 
statistical analysis and only the concentration data of that subject(s) will be presented 
• 
Calculation of Pharmacokinetic Parameter Values Not Described in Section 9 (refer to GUI_51487 
for pharmacokinetic analysis information) 
 
11.6.5. 
Pharmacodynamic (and / or Biomarker) 
Not applicable. 
 
 


 
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11.7. 
Appendix 7: Reporting Standards for Missing Data 
11.7.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
• Subject study completion was defined as complete all phases of the study 
including the follow-up visit. 
• Withdrawn subjects may be replaced in the study, if applicable, at the discretion 
of the sponsor in consultation with the investigator. 
• 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. 
• All subjects who withdraw prematurely from the study/study drug will be 
documented and the reason for their withdrawal recorded in the final Clinical 
Pharmacology Study Report (CPSR). 
• In the event that the study is prematurely discontinued, all available data will be 
listed and a review carried out by the study team to assess which statistical 
analyses are still considered appropriate. 
 
11.7.2. 
Handling of Missing Data 
Element 
Reporting Detail 
General 
• 
Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument: 
o These data will be indicated by the use of a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table.  
o Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such. 
Outliers 
• 
Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report. 
11.7.2.1. 
Handling of Missing and Partial Dates 
Element 
Reporting Detail 
General 
• 
Partial dates will be displayed as captured in subject listing displays. 
Adverse 
Events 
• 
The eCRF allows for the possibility of partial dates (i.e., only month and year) to be 
recorded for AE start and end dates; that is, the day of the month may be missing. In 
such a case, the following conventions will be applied for calculating the time to onset 
and the duration of the event: 
o Missing Start Day: First of the month will be used unless this is before the start 
date of study treatment; in this case the study treatment start date will be used and 
hence the event is considered On-treatment as per Appendix 4: Study Phases 
and Treatment Emergent Adverse Events. 
o Missing Stop Day: Last day of the month will be used, unless this is after the stop 
date of study treatment; in this case the study treatment stop date will be used. 
• 
Completely missing start or end dates will remain missing, with no imputation applied. 


 
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Element 
Reporting Detail 
Consequently, time to onset and duration of such events will be missing. 
Concomitant 
Medications 
• 
Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention: 
o If the partial date is a start date, a '01' will be used for the day and 'Jan' will be 
used for the month 
o If the partial date is a stop date, a '28/29/30/31' will be used for the day (dependent 
on the month and year) and 'Dec' will be used for the month. 
• 
The recorded partial date will be displayed in listings. 


 
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11.8. 
Appendix 8: Values of Potential Clinical Importance 
11.8.1. 
Laboratory Values 
Division of AIDS (DAIDS, Version 2.0, November 2014 )AE grade 2 and above of lab 
abnormalities will be listed by subject, period/treatment, visit, and actual date and time. 
Haematology 
Laboratory Parameter 
 
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Hematocrit  
Ratio of 1 
Male 
 
0.54 
Female 
 
0.54 
∆ from BL 
↓0.075 
 
Hemoglobin  
g/L 
 
Male 
 
180 
Female 
 
180 
∆ from BL 
↓25 
 
Lymphocytes  
x109/ L 
 
0.8 
 
Neutrophil Count  
x109/ L 
 
1.5 
 
Platelet Count  
x109/ L 
 
100 
550 
White Blood Cell Count (WBC) 
x109/ L 
 
3 
12 
Clinical Chemistry 
Laboratory Parameter 
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Albumin  
g/L 
 
30 
 
Bicarbonates 
mmol/L 
 
18 
32 
BUN 
mmol/L 
 
 
>9 
Creatinine 
µmol/L 
∆ from BL 
 
↑ 44.2 
Glucose 
mmol/L 
 
3 
9 
Potassium 
mmol/L 
 
3 
5.5 
Sodium 
mmol/L 
 
130 
150 
Total CO2 
mmol/L 
 
18 
32 
Total Protein 
g/L 
∆ from BL 
< -15 
>15 
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 
Total Bilirubin  
µmol/L 
High 
≥ 1.5xULN 
 
11.8.2. 
ECG 
ECG Parameter 
Units 
Clinical Concern Range 
Lower 
Upper 
Absolute 


 
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ECG Parameter 
Units 
Clinical Concern Range 
Lower 
Upper 
PR Interval 
msec 
< 120 
> 200 
QRS Duration 
msec 
< 60 
> 120 
QT Interval 
msec 
< 320 
> 450 
QTc Interval (Bazett) 
msec 
< 320 
> 450 
QTc Interval (Fridericia) 
msec  
< 320 
> 450 
RR Interval 
msec 
< 600 
> 1200 
Change from Baseline 
Increase from Baseline QTc 
msec 
 
>60 
11.8.3. 
Vital Signs 
Vital Sign Parameter 
(Absolute) 
Units 
Clinical Concern Range 
Lower 
Upper 
Systolic Blood Pressure 
mmHg 
< 85 
> 140 
Diastolic Blood Pressure 
mmHg 
< 45 
> 90 
Heart Rate 
bpm 
< 40 
> 100 
 
 


 
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11.9. 
Appendix 9: Population Pharmacokinetic (PopPK) Analyses 
Not Appicable. 


 
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11.10. 
Appendix 10: Pharmacokinetic / Pharmacodynamic 
Analyses 
The PK/PD analysis will be conducted if data is available. 


 
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11.11. 
Appendix 11: Abbreviations & Trade Marks 
11.11.1. 
Abbreviations 
Abbreviation 
Description 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
CPMS 
Clinical Pharmacology Modelling & Simulation 
CSR 
Clinical Study Report 
CTR 
Clinical Trial Register 
CVb / CVw 
Coefficient of Variation (Between) / Coefficient of Variation (Within) 
DBF 
Database Freeze 
DBR 
Database Release 
DP 
Decimal Places 
eCRF 
Electronic Case Record Form 
GSK 
GlaxoSmithKline 
IA 
Interim Analysis 
ICH 
International Conference on Harmonization 
IDSL 
Integrated Data Standards Library 
IP 
Investigational Product 
PCI 
Potential Clinical Importance  
PD 
Pharmacodynamic 
PDMP 
Protocol Deviation Management Plan 
PK 
Pharmacokinetic 
PopPK 
Population PK 
QC 
Quality Control 
QTcF 
Fridericia’s QT Interval Corrected for Heart Rate 
QTcB 
Bazett’s QT Interval Corrected for Heart Rate 
RAP 
Reporting & Analysis Plan 
SAC 
Statistical Analysis Complete 
SDSP 
Study Data Standardization Plan 
SDTM 
Study Data Tabulation Model 
TFL 
Tables, Figures & Listings  
VH 
ViiV healthcare 
11.11.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
None 
 
DAIDS 
 
 
Phoenix 
 
 
WinNonlin 
 
 
SAS 


 
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11.12. 
Appendix 12: List of Data Displays 
11.12.1. 
Data Display Numbering 
The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Figures 
Study Population 
1.1 to 1.n 
1.1 to 1.n 
Safety 
3.1 to 3.n 
3.1 to 3.n 
Pharmacokinetic 
4.1 to 4.n 
4.1 to 4.n 
Phamacokinetic/Pharmacodynamic 
 
5.1 to 5.n 
Section 
Listings 
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 example mock-up 
displays provided in 2: Example Mock Shells for Data Displays. 
Section 
Figure 
Table 
Listing 
Study Population 
POP_Fn 
POP_Tn 
POP_Ln 
Safety 
SAFE_Fn 
SAFE_Tn 
SAFE_Ln 
Pharmacokinetic 
PK_Fn 
PK_Tn 
PK_Ln 
NOTES:  
• 
Non-Standard displays are indicated in the ‘IDSL /  Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’ 
 
11.12.3. 
Deliverables 
Delivery  
Description 
SAC  
Final Statistical Analysis Complete 
 


 
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11.12.4. 
Study Population Tables 
Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Part 1 
Subject Disposition 
1.1. 
Safety 
ES4 
 
Summary of Subject Disposition at Each Study Epoch - Part 1 
ICH E3 
SAC  
1.2. 
Safety 
ES1A 
Summary of Subject Status and Reason for Study Withdrawal – 
Part 1 
ICH E3, FDAAA, EudraCT 
SAC 
1.3. 
Safety 
ES6 
Summary of Screening Status and Reasons for Screen Failure - 
Part 1 
ICH E3 
SAC  
1.4. 
Safety 
SD1 
Summary of Treatment Status and Reasons for Discontinuation 
of Study – Part 1 
The treatment group column will 
indicate the treatment that the 
subject was taking at the time of 
discontinuation 
SAC 
Protocol Deviation 
1.5. 
Safety 
DV1 
Summary of Important Protocol Deviations - Part 1 
ICH E3, Only the total column will 
appear 
SAC 
Population Analysed 
1.6. 
Safety 
SP1 
Summary of Study Populations - Part 1 
 
SAC  
Demographic and Baseline Characteristics 
1.7. 
Safety 
DM3 
Summary of Demographic Characteristics - Part 1 
ICH E3, FDAAA, EudraCT 
SAC 
1.8. 
Enrolled 
DM11 
Summary of Age Ranges - Part 1 
EudraCT, only the total column will 
appear 
SAC 


 
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Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
1.9. 
Safety 
DM5 
Summary of Race and Racial Combinations - Part 1 
ICH E3, FDA, FDAAA, EudraCT, only 
the total column will appear 
SAC 
Prior and Concomitant Medications 
1.10. 
Safety 
CM1 
Summary of Concomitant Medications – Part 1 
only the total column will appear  
SAC 
Exposure and Treatment Compliance 
1.11. 
Safety 
EX1 
Summary of Exposure to Study Drug– Part 1 
ICH E3 
For ClinPharm, a listing often 
substitutes for a table. 
SAC 
Part 2 
Subject Disposition 
1.12. 
Safety 
ES4 
 
Summary of Subject Disposition at Each Study Epoch - Part 2 
ICH E3 
SAC  
1.13. 
Safety 
ES1 
Summary of Subject Status and Reason for Study Withdrawal – 
Part 2 
ICH E3, FDAAA, EudraCT 
SAC 
1.14. 
Safety 
ES6 
Summary of Screening Status and Reasons for Screen Failure - 
Part 2 
ICH E3 
SAC  
1.15. 
Safety 
SD1 
Summary of Treatment Status and Reasons for Discontinuation 
of Study– Part 2 
 
SAC 
Protocol Deviation 
1.16. 
Safety 
DV1 
Summary of Important Protocol Deviations - Part 2 
ICH E3 
SAC 
Population Analysed 
1.17. 
Safety 
SP1 
Summary of Study Populations - Part 2 
IDSL 
 
SAC  


 
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Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Demographic and Baseline Characteristics 
1.18. 
Safety 
DM1  
Summary of Demographic Characteristics - Part 2 
ICH E3, FDAAA, EudraCT 
SAC 
1.19. 
Enrolled 
DM11 
Summary of Age Ranges - Part 2 
EudraCT 
SAC 
1.20. 
Safety 
DM5 
Summary of Race and Racial Combinations - Part 2 
ICH E3, FDA, FDAAA, EudraCT 
SAC 
Prior and Concomitant Medications 
1.21. 
Safety 
CM1 
Summary of Concomitant Medications – Part 2 
ICH E3 
 
SAC 
Exposure and Treatment Compliance 
1.22. 
Safety 
EX1  
Summary of Exposure to Study Drug – Part 2 
 
SAC 
 
11.12.5. 
Safety Tables 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Part 1 
Adverse Events (AEs) 
3.1.  
Safety 
AE13 
Adverse Event Overview – Part 1 
the counting of events and the 
percentages will be based on 
the number of subjects on each 
treatment, so subjects will 
appear in more than one 
treatment category 
SAC 


 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.2.  
Safety 
 
AE5A 
Summary of All Adverse Events by Maximum Grade by System 
Organ Class and Preferred Term - Part 1 
ICH E3 
 
SAC 
3.3.  
Safety 
AE5A 
Summary of All Drug-Related Adverse Events by Maximum 
Grade by System Organ Class and Preferred Term  – Part 1 
ICH E3, 3.2. 
SAC 
Serious and Other Significant Adverse Events 
3.4.  
Safety 
AE16 
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Participants and Occurrences) – 
Part 1 
FDAAA, EudraCT 
 
SAC 
3.5.  
Safety 
AE5A 
Summary of Adverse Events of Special Interest by Maximum 
Grade by System Organ Class and Preferred Term – Part 1 
 
SAC 
3.6.  
Safety 
AE1 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study – 
Part 1 
IDSL 
SAC 
3.7.  
Safety 
AE3 
Summary of Common (>=5%) Adverse Events by Overall 
Frequency – Part 1 
ICH E3 
SAC 
3.8.  
Safety 
AE15 
Summary of Common (>=5%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Subjects 
and Occurrences) – Part 1 
FDAAA, EudraCT 
SAC 
Laboratory: Chemistry  
3.9.  
Safety 
LB1 
Summary of Clinical Chemistry Data – Part 1 
Will have Non-fasting Glucose 
and fasting Glucose results 
separately. 
SAC 
3.10. 
Safety 
LB1 
Summary of Clinical Chemistry Changes from Baseline – Part 1 
ICH E3, Non-fasting Glucose test 
results will not be included since the 
baseline values are fasting results.  
SAC  


 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.11. 
Safety 
LB16 
Summary of Worst Case Clinical Chemistry Results by 
Maximum Grade Increase Post-Baseline Relative to Baseline – 
Part 1 
ICH E3, (reference study 204953 
Table 2.11) 
SAC 
3.12. 
Safety 
LB2 
Summary of Treatment Emergent Clinical Chemistry Toxicities – 
Part 1 
(reference study mid200207 Table 
2.16) 
SAC 
Laboratory: Hematology 
3.13. 
Safety 
LB1 
Summary of Hematology Data – Part 1 
 
SAC 
3.14. 
Safety 
LB1 
Summary of Hematology Changes from Baseline – Part 1 
ICH E3 
SAC 
3.15. 
Safety 
LB16 
Summary of Worst Case Hematology Results by Maximum 
Grade Increase Post-Baseline Relative to Baseline – Part 1 
ICH E3, 3.11 
SAC 
3.16. 
Safety 
LB2 
Summary of Treatment Emergent Hematology Toxicities – Part 
1 
 
SAC 
Laboratory: Urinalysis 
3.17. 
 Safety 
UR1 
Summary of Urine Data – Part 1 
 
SAC 
3.18. 
Safety 
LB1 
Summary of Urine Concentration Changes from Baseline– Part 
1 
ICH E3 
 
SAC 
3.19. 
Safety 
LB16 
Summary of Worst Case Urinalysis by Maximum Grade Increase 
Post-Baseline Relative to Baseline – Part 1 
ICH E3 
SAC 
Laboratory: Hepatobiliary (Liver) 
3.20. 
 Safety 
LIVER1 
Summary of Liver Monitoring/Stopping Event Reporting – Part 1 
 
SAC 
3.21. 
 Safety 
LIVER10 
Summary of Hepatobiliary Laboratory Abnormalities – Part 1 
 
 
SAC 
ECG 
3.22. 
 Safety 
EG1 
Summary of ECG Findings – Part 1 
 
SAC 


 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.23. 
Safety 
EG10 
Summary of Maximum QTc Values Post-Baseline Relative to 
Baseline by Category – Part 1 
ICH E14 
SAC 
3.24. 
Safety 
EG2 
Summary of Change from Baseline for ECG Values – Part 1 
 
SAC 
3.25. 
Safety 
EG11 
Summary of Maximum Increase in QTc Values Post Baseline 
Relative to Baseline by Category – Part 1 
ICH E14 
SAC 
Vital Signs 
3.26. 
Safety 
VS1 
Summary of Change from Baseline in Vital Signs – Part 1 
ICH E 3, 3.11 
SAC 
3.27. 
Safety 
VS6 
Summary of Vital Sign Results by Maximum Grade Increases 
Post-Baseline Relative to Baseline – Part 1 
IDSL 
SAC 
Part 2 
Adverse Events (AEs) 
3.28. 
Safety 
AE13 
Adverse Event Overview – Part 2 
 
SAC 
3.29. 
Safety 
 
AE5A 
Summary of All Adverse Events by Maximum Grade by System 
Organ Class and Preferred Term - Part 2 
ICH E3 
 
SAC 
3.30. 
Safety 
AE5A 
Summary of All Drug-Related Adverse Events by Maximum 
Grade by System Organ Class and Preferred Term  – Part 2 
ICH E3, 3.2. 
SAC 
Serious and Other Significant Adverse Events 
3.31. 
Safety 
AE16 
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Participants and Occurrences) – 
Part 2 
FDAAA, EudraCT 
 
SAC 
3.32. 
Safety 
AE5A 
Summary of Adverse Events of Special Interest by Maximum 
Grade by System Organ Class and Preferred Term – Part 2 
 
SAC 


 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.33. 
Safety 
AE1 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study – 
Part 2 
IDSL 
SAC 
3.34. 
Safety 
AE3 
Summary of Common (>=5%) Adverse Events by Overall 
Frequency – Part 2 
ICH E3 
SAC 
3.35. 
Safety 
AE15 
Summary of Common (>=5%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Subjects 
and Occurrences) – Part 2 
FDAAA, EudraCT 
 
SAC 
Laboratory: Chemistry  
3.36. 
Safety 
LB1 
Summary of Clinical Chemistry Data – Part 2 
Will have Non-fasting Glucose 
and fasting Glucose results 
separately. 
SAC 
3.37. 
Safety 
LB1 
Summary of Clinical Chemistry Changes from Baseline  – Part 2 
Non-fasting Glucose test results 
will not be included since the 
baseline values are fasting 
results.  
SAC  
3.38. 
Safety 
LB16 
Summary of Worst Case Clinical Chemistry Results by 
Maximum Grade Increase Post-Baseline Relative to Baseline – 
Part 2 
(reference study 204953 Table 2.11) 
SAC 
3.39. 
Safety 
LB2 
Summary of Treatment Emergent Clinical Chemistry Toxicities – 
Part 2 
(reference study mid200207 Table 
2.16) 
SAC 
Laboratory: Hematology 
3.40. 
Safety 
LB1 
Summary of Hematology Data – Part 2 
 
SAC 
3.41. 
Safety 
LB1 
Summary of Hematology Changes from Baseline – Part 2 
 
SAC 
3.42. 
Safety 
LB16 
Summary of Worst Case Hematology Results by Maximum 
Grade Increase Post-Baseline Relative to Baseline – Part 2 
3.11 
SAC 


 
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No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.43. 
Safety 
LB2 
Summary of Treatment Emergent Hematology Toxicities – Part 
2 
 
SAC 
Laboratory: Urinalysis 
3.44. 
 Safety 
UR1 
Summary of Urine Data – Part 2 
 
SAC 
3.45. 
Safety 
LB1 
Summary of Urine Concentration Changes from Baseline– Part 
2 
ICH E3 
 
SAC 
3.46. 
Safety 
LB16 
Summary of Worst Case Urinalysis by Maximum Grade Increase 
Post-Baseline Relative to Baseline – Part 2 
ICH E3 
SAC 
Laboratory: Hepatobiliary (Liver) 
3.47. 
 Safety 
LIVER1 
Summary of Liver Monitoring/Stopping Event Reporting – Part 2 
 
SAC 
3.48. 
 Safety 
LIVER10 
Summary of Hepatobiliary Laboratory Abnormalities – Part 2 
 
 
SAC 
ECG 
3.49. 
 Safety 
EG1 
Summary of ECG Findings – Part 2 
 
SAC 
3.50. 
Safety 
EG10 
Summary of Maximum QTc Values Post-Baseline Relative to 
Baseline by Category – Part 2 
ICH E14 
SAC 
3.51. 
Safety 
EG2 
Summary of Change from Baseline for ECG Values – Part 2 
 
SAC 
3.52. 
Safety 
EG11 
Summary of Maximum Increase in QTc Values Post Baseline 
Relative to Baseline by Category – Part 2 
ICH E14 
SAC 
Vital Signs 
3.53. 
Safety 
VS1 
Summary of Change from Baseline in Vital Signs – Part 2 
3.11 
SAC 
3.54. 
Safety 
VS6 
Summary of Vital Sign Results by Maximum Grade Increases 
Post-Baseline Relative to Baseline – Part 2 
IDSL 
SAC 


 
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11.12.6. 
Safety Figures 
Safety : Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Part 1 
ECG 
3.1.  
Safety 
mid200207 
Figure 2.6 
Plot of Mean (95% CI) Change from Baseline  in QTcF Interval 
by Treatment and Time – Part 1 
(reference study mid200207 Figure 
2.6) 
SAC  
Part  2 
ECG 
3.2.  
Safety 
mid200207 
Figure 2.6 
Plot of Mean (95% CI) Change from Baseline in QTcF Interval 
by Treatment and Time – Part 2 
(reference study mid200207 Figure 
2.6) 
SAC  
11.12.7. 
Pharmacokinetic Tables 
Pharmacokinetic : Tables 
No. 
Population 
IDSL / TST 
ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Part 1 
PK Concentration Data 
4.1.  
PK 
Concentration 
PKCT1 
Summary of Plasma GSK3640254 PK Concentration-Time Data 
by Treatment and by Day – Part 1 
 
SAC  
PK Derived Parameters 
4.2.  
PK Parameter 
PKPT1 
Summary of Untransformed Derived Plasma GSK3640254 PK 
Parameters by Treatment – Part 1 
 
SAC  


 
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Pharmacokinetic : Tables 
No. 
Population 
IDSL / TST 
ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
4.3.  
PK Parameter 
PKPT3 
Summary of Loge-transformed Derived Plasma GSK3640254  
PK Parameters by Treatment – Part 1 
 
SAC  
PK Statistical Analysis Table 
4.4.  
PK Parameter 
mid200207 
Table 3.5 
Summary Results of Single Dose Proportionality Assessment 
Using Power Model – Part 1 
(reference study mid200207 Table 
3.5) 
SAC  
4.5.  
PK Parameter 
mid200207 
Table 3.5 
Summary Results of Single Dose Proportionality Assessment 
Using ANOVA – Part 1 
(reference study mid200207 Table 
3.5) 
SAC  
Part 2 
PK Concentration Data 
4.6.  
PK 
Concentration 
PKCT1 
Summary of Plasma GSK3640254 PK Concentration-Time Data 
by Treatment and by Day – Part 2 
 
SAC  
PK Derived Parameters 
4.7.  
PK Parameter 
PKPT1 
Summary of Untransformed Derived Plasma GSK3640254  PK 
Parameters by Treatment – Part 2 
 
SAC  
4.8.  
PK Parameter 
PKPT3 
Summary of Loge-transformed Derived Plasma GSK3640254  
PK Parameters by Treatment – Part  2 
 
SAC  
PK Statistical Analysis Table 
4.9.  
PK Parameter 
mid200207 
Table 3.5 
Summary Results of Repeat Dose Day 1 Dose Proportionality 
Assessment Using Power Model – Part 2 
 
SAC 
4.10. 
PK Parameter 
mid200207 
Table 3.5 
Summary Results of Repeat Dose Day 14 Dose Proportionality 
Assessment Using Power Model – Part 2 
 
SAC 
4.11. 
PK Parameter 
mid200207, 
Table 3.7 
Summary Results of Repeat Dose Day 1 Dose Proportionality 
Assessment Using ANOVA – Part 2 
 
SAC  


 
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No. 
Population 
IDSL / TST 
ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
4.12. 
PK Parameter 
mid200207, 
Table 3.7 
Summary Results of Repeat Dose Day 14 Dose Proportionality 
Assessment Using ANOVA – Part 2 
 
SAC  
4.13. 
PK Parameter 
mid200207, 
Table 3.9 
Summary Results of Steady-State GSK3640254 Concentrations 
Assessment – Part 2 
One for each treatment 
SAC  
4.14. 
PK Parameter 
mid200207, 
Table 3.10 
Summary Results of GSK3640254 PK Parameter Treatment 
Comparisons – Accumulation Ratio – Part 2  
One for each treatment 
SAC  


 
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11.12.8. 
Pharmacokinetic Figures 
Pharmacokinetic : Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Part 1 
PK Concentration Plots 
4.1.  
PK Concentration 
PKCF6 
Individual Plasma GSK3640254 Concentration-Time Plots 
(Linear and Semi-Log) by Treatment – Part 1 
Overlay all individual profile within 
each treatment with all days profiles 
SAC  
4.2.  
PK Parameter 
PKCF2 
Mean Plasma GSK3640254 Concentration-Time Plots 
(Linear and Semi-Log) – Part 1 
 
SAC  
4.3.  
PK Parameter 
PKCF3 
Median Plasma GSK3640254  Concentration-Time Plots 
(Linear and Semi-Log) – Part 1 
 
SAC  
PK Derived Parameters Plots 
4.4.  
PK Parameter 
mid200207 
Figure 3.4 
Individual and Box Plot of Plasma GSK3640254 PK 
Parameters (Linear and Semi-Log) by Treatment– Part 1 
Include all treatments & all of the 
PK parameters.  
SAC  
4.5.  
PK Parameter 
GSK1265744/ 
LAI117020, 
Figure 3.6 
Comparative Plots of Individual Plasma GSK3640254 PK 
Parameters (Linear and Semi-Log) by Treatment – Part 1 
By Treatment, connect individual 
data. Also geometric mean overlay 
with a thicker line for Part 1 subjects 
SAC  
Part 2 
PK Concentration Plots 
4.6.  
PK Concentration 
PKCF6 
Individual Plasma GSK3640254 Concentration-Time Plots 
(Linear and Semi-Log) by Treatment and by Day – Part 2 
Overlay all individual profile within 
each treatment with all days profiles 
SAC  
4.7. .  
PK Parameter 
PKCF2 
Mean Plasma GSK3640254 Concentration-Time Plots 
(Linear and Semi-Log) by Day – Part 2 
 
SAC  
4.8.  
PK Parameter 
PKCF3 
Median Plasma GSK3640254 Concentration-Time Plots 
(Linear and Semi-Log) by Day – Part 2 
 
SAC  
PK Derived Parameters Plots 


 
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Pharmacokinetic : Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
4.9.  
PK Parameter 
mid200207 
Figure 3.4 
Individual and Box Plot of Plasma GSK3640254  PK 
Parameters (Linear and Semi-Log) by Treatment and by 
Day – Part 2 
Include all treatments & all of the 
PK parameters.  
SAC  
4.10. 
PK Parameter 
GSK1265744/ 
LAI117020, 
Figure 3.6 
Comparative Plots of Individual Plasma GSK3640254 PK 
Parameters (Linear and Semi-Log) by Treatment – Part 1 
By Treatment, connect individual 
data. Also geometric mean overlay 
with a thicker line for Part 1 subjects 
SAC  


 
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11.12.9. 
Pharmacokinetic / Pharmacodynamic Figures 
Pharmacokinetic / Pharmacodynamic : Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PK Concentration Data/ECG 
5.1.  
PK 
Concentratio
n 
mid200207, 
Figure 3.6 
Scatter Plot of Individual QTcF Change from Baseline vs Time 
Matched GSK3640254 PK Concentration  
All Subjects assume the placebo 
subjects with 0 concentrations 
All Time-matched Concentrations 
SAC  


 
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11.12.10. ICH Listings 
ICH : Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Part 1 
Subject Disposition 
1.  
Screening 
ES7 
Listing of Reasons for Screen Failure – Part 1 
 
SAC  
2.  
Safety 
ES3 
Listing of Reasons for Study Withdrawal – Part 1 
ICH E3 
SAC  
Protocol Deviations 
3.  
Safety 
DV2A 
Listing of Important Protocol Deviations – Part 1 
ICH E3 
SAC  
4.  
Safety 
IE4 
Listing of Subjects with Inclusion/Exclusion Criteria Deviations – 
Part 1 
ICH E3, Listing also includes analysis 
population exclusions. 
SAC  
Populations Analysed 
5.  
Screening 
SP3A 
Listing of Subjects Excluded from Any Population – Part 1 
ICH E3 
SAC  
6.  
Safety 
BL2 
Listing of Subjects for Whom the Treatment Blind was Broken – 
Part 1 
ICH E3 
SAC  
Demographic and Baseline Characteristics 
7.  
Safety 
DM4 
Listing of Demographic Characteristics – Part 1 
ICH E3 
SAC  
8.  
Safety 
DM10 
Listing of Race – Part 1 
ICH E3 
SAC  
Concomitant Medications 
9.  
Safety 
CM2 
Listing of Concomitant Medications – Part 1 
 
SAC  
Exposure and Treatment Compliance 
10.  
Safety 
EX3 
Listing of Exposure Data – Part 1 
ICH E3 
SAC  
11.  
Safety 
Non-Standard 
Listing of Meal Data – Part 1 
 
SAC 
Adverse Events 


 
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No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
12.  
Safety 
AE9CP 
Listing of All Adverse Events – Part 1 
ICH E3 
SAC  
13.  
Safety 
AE9CP 
Listing of All Drug Related Adverse Events – Part 1 
 
SAC 
14.  
Safety 
AE9CP 
Listing of Serious Adverse Events – Part 1 
 
SAC  
15.  
Safety 
AE9CP 
Listing of Drug Related Serious Adverse Events – Part 1 
 
SAC  
16.  
Safety 
AE9CP 
Listing of Fatal  Adverse Events – Part 1 
ICH E3 
SAC 
17.  
Safety 
AE9CP 
Listing of non-Fatal  Serious Adverse Events – Part 1 
ICH E3 
SAC 
18.  
Safety 
AE14 
Listing of Reasons for Considering as a Serious Adverse Event – 
Part 1 
ICH E3 
SAC 
19.  
Safety 
AE9CP 
Listing of Grade 2 ~4 Adverse Events – Part 1 
 
SAC  
20.  
Safety 
AE9CP 
Listing of Adverse Event of Special Interest – Part 1 
 
SAC 
21.  
Safety 
AE9CP 
Listing of Adverse Events Leading to Permanent Discontinuation 
of Study Drug or Withdrawal from Study – Part 1 
ICH E3 
SAC  
22.  
Safety 
AE7 
Listing of Subject Numbers for Individual Adverse Events  – Part 
1 
ICH E3 
SAC 
23.  
Safety 
AE2 
Relationship of Adverse Event System Organ Classes, Preferred 
Terms, and Verbatim Text – Part 1 
IDSL 
SAC  
Laboratory Values 
24.  
Safety 
LB6 
Listing of Clinical Chemistry Data – Part 1 
Glucose (non-fasting) results 
will be shown in listings with 
the fasting/non-fasting flag. 
 
SAC  
25.  
Safety 
LB6 
Listing of Hematology Data – Part 1 
 
SAC  
26.  
Safety 
UR2a 
Listing of Urinalysis Data – Part 1 
 
SAC  
27.  
Safety 
LB6 
Listing of All Clinical Chemistry Data for Subjects with Any Value 
of Potential Clinical Importance – Part 1 
ICH E3 
SAC  


 
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ICH : Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
28.  
Safety 
LB6 
Listing of All Hematology Data for Subjects with Any Value of 
Potential Clinical Importance –Part 1 
ICH E3 
SAC  
29.  
Safety 
UR2a 
Listing of Urinalysis Data for Subjects with Abnormalities of 
Potential Clinical Concern – Part 1 
ICH E3 
SAC 
30.  
Safety 
LB6 
Listing of Clinical Chemistry Values of Potential Clinical 
Importance – Part 1 
IDSL 
SAC  
31.  
Safety 
LB6 
Listing of Hematology Values of Potential Clinical Importance –
Part 1 
IDSL 
SAC  
32.  
Safety 
UR2a 
Listing of Urinalysis Values of Potential Clinical Concern – Part 1 
IDSL 
SAC 
33.  
Safety 
LB14 
Listing of Laboratory Data with Character Results – Part 1 
ICH E3 
SAC 
34.  
Safety 
HAI114885 
Table 10.14 
Listing of Lab Results Identified as Adverse Events – Part 1 
 
SAC 
35.  
Safety 
mid200207 
Table 2.17 
Listing of Grade 2 or Higher Treatment Emergent Clinical 
Chemistry Data Toxicities – Part 1 
 
SAC  
36.  
Safety 
mid200207 
Table 2.17 
Listing of Grade 2 or Higher Treatment Emergent Hematology 
Data Toxicities – Part 1 
 
SAC  
ECG 
37.  
Safety 
EG6 
Listing of ECG Findings – Part 1 
 
SAC  
38.  
Safety 
EG6 
Listing of Abnormal ECG findings –Part 1 
 
SAC  
39.  
Safety 
EG4 
Listing of All ECG Values for Subjects with a Value of Potential 
Clinical Importance – Part 1 
 
SAC  
Vital Signs 
40.  
Safety 
VS5 
Listing of Vital Signs – Part 1 
 
SAC  


 
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ICH : Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
41.  
Safety 
VS5 
Listing of All Vital Signs for Subjects with Values of Potential 
Clinical Importance – Part 1 
 
SAC  
Part 2 
Subject Disposition 
42.  
Screening 
ES7 
Listing of Reasons for Screen Failure – Part 2 
 
SAC  
43.  
Safety 
ES2 
Listing of Reasons for Study Withdrawal – Part 2 
 
SAC  
Protocol Deviations 
44.  
Safety 
DV2 
Listing of Important Protocol Deviations – Part 2 
 
SAC  
45.  
Safety 
IE3 
Listing of Subjects with Inclusion/Exclusion Criteria Deviations – 
Part 2 
Listing also includes analysis 
population exclusions. 
SAC  
Populations Analysed 
46.  
Screening 
SP3 
Listing of Subjects Excluded from Any Population – Part 2 
 
SAC 
47.  
Safety 
BL1 
Listing of Subjects for Whom the Treatment Blind was Broken – 
Part 2 
 
SAC  
Demographic and Baseline Characteristics 
48.  
Safety 
DM2 
Listing of Demographic Characteristics – Part 2 
 
SAC  
49.  
Safety 
DM9 
Listing of Race – Part 2 
 
SAC  
Concomitant Medications 
50.  
Safety 
CM2 
Listing of Concomitant Medications – Part 2 
 
SAC 
Exposure and Treatment Compliance 
51.  
Safety 
EX3 
Listing of Exposure Data – Part 2 
 
SAC 
52.  
Safety 
Non-Standard 
Listing of Meal Data – Part 1 
 
SAC 
Adverse Events 


 
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ICH : Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
53.  
Safety 
AE8CP 
Listing of All Adverse Events – Part 2 
 
SAC  
54.  
Safety 
AE8CP 
Listing of All Drug Related Adverse Events – Part 2 
 
SAC 
55.  
Safety 
AE8CP 
Listing of Serious Adverse Events – Part 2 
 
SAC  
56.  
Safety 
AE8CP 
Listing of Drug Related Serious Adverse Events – Part 2 
 
SAC  
57.  
Safety 
AE8CP 
Listing of Fatal Adverse Events – Part 2 
ICH E3 
SAC 
58.  
Safety 
AE8CP 
Listing of non-Fatal Serious Adverse Events – Part 2 
ICH E3 
SAC 
59.  
Safety 
AE14 
Listing of Reasons for Considering as a Serious Adverse Event – 
Part 2 
ICH E3 
SAC 
60.  
Safety 
AE8CP 
Listing of Grade 2 ~ 4 Adverse Events – Part 2 
 
SAC  
61.  
Safety 
AE8CP 
Listing of Adverse Event of Special Interest – Part 2 
 
SAC 
62.  
Safety 
AE8CP 
Listing of Adverse Events Leading to Permanent Discontinuation 
of Study Drug or Withdrawal from Study – Part 2 
ICH E3 
SAC  
63.  
Safety 
AE7 
Listing of Subject Numbers for Individual Adverse Events – Part 
2 
ICH E3 
SAC 
64.  
Safety 
AE2 
Relationship of Adverse Event System Organ Classes, Preferred 
Terms, and Verbatim Text – Part 2 
IDSL 
SAC  
Laboratory Values 
65.  
Safety 
LB6 
Listing of Clinical Chemistry Data – Part 2 
Glucose (non-fasting) results 
will be shown in listings with 
the fasting/non-fasting flag. 
SAC  
66.  
Safety 
LB6 
Listing of Hematology Data – Part 2 
 
SAC  
67.  
Safety 
UR2a 
Listing of Urinalysis Data – Part 2 
 
SAC  
68.  
Safety 
LB6 
Listing of All Clinical Chemistry Data for Subjects with Any Value 
of Potential Clinical Importance – Part 2 
ICH E3 
SAC  


 
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ICH : Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
69.  
Safety 
LB6 
Listing of All Hematology Data for Subjects with Any Value of 
Potential Clinical Importance – Part 2 
ICH E3 
SAC  
70.  
Safety 
UR2a 
Listing of Urinalysis Data for Subjects with Abnormalities of 
Potential Clinical Concern – Part 2 
ICH E3 
SAC 
71.  
Safety 
LB6 
Listing of Clinical Chemistry Values of Potential Clinical 
Importance – Part 2 
IDSL 
SAC  
72.  
Safety 
LB6 
Listing of Hematology Values of Potential Clinical Importance – 
Part 2 
IDSL 
SAC  
73.  
Safety 
UR2a 
Listing of Urinalysis Values of Potential Clinical Concern – Part 2 
IDSL 
SAC 
74.  
Safety 
LB14 
Listing of Laboratory Data with Character Results – Part 2 
ICH E3 
SAC 
75.  
Safety 
HAI114885 
Table 10.14 
Listing of Lab Results Identified as Adverse Events – Part 2 
 
SAC 
76.  
Safety 
mid200207 
Table 2.17 
Listing of Grade 2 or Higher Treatment Emergent Clinical 
Chemistry Data Toxicities – Part 2 
 
SAC  
77.  
Safety 
mid200207 
Table 2.17 
Listing of Grade 2 or Higher Treatment Emergent Hematology 
Data Toxicities – Part 2 
 
SAC  
ECG 
78.  
Safety 
EG5 
Listing of ECG Findings – Part 2 
 
SAC  
79.  
Safety 
EG5 
Listing of Abnormal ECG findings –Part 2 
 
SAC  
80.  
Safety 
EG3 
Listing of All ECG Values for Subjects with a Value of Potential 
Clinical Importance – Part 2 
 
SAC  
Vital Signs 
81.  
Safety 
VS4 
Listing of Vital Signs – Part 2 
 
SAC  
82.  
Safety 
VS4 
Listing of All Vital Signs for Subjects with Values of Potential 
Clinical Importance – Part 2 
 
SAC  


 
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11.12.11. Non-ICH Listings 
Non-ICH : Listings 
No. 
Population 
IDSL / TST 
ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Part 1 
PK Concentration Data 
83.  
PK 
Concentration 
PKCL1X 
Listing of Plasma GSK3640254 PK Concentration-Time Data – 
Part 1 
 
SAC  
84.  
PK Parameter 
PKPL1X 
Listing of Derived Plasma GSK3640254 PK Parameters – Part 1 
 
SAC  
PK Statistical Analysis 
85.  
PK Parameter 
SAS output 
of Table 4.4 
SAS Output of Summary Results of Single Dose Day 1 Dose 
Proportionality Assessment Using Power Model – Part 1 
 
SAC  
86.  
PK Parameter 
SAS output 
of Table 4.5 
SAS Output of Summary Results of Single Dose Day 1 Dose 
Proportionality Assessment Using ANOVA – Part 1 
 
SAC  
Part 2 
PK Concentration Data 
87.  
PK 
Concentration 
PKCL1X 
Listing of Plasma GSK3640254 PK Concentration-Time Data – 
Part 2 
 
SAC 
88.  
PK Parameter 
PKPL1X 
Listing of Derived Plasma GSK3640254 PK Parameters – Part 2 
 
SAC  
PK Statistical Analysis 
89.  
PK Parameter 
SAS output 
of Table 4.9 
SAS Output of Summary Results of Repeat Dose Day 1 Dose 
Proportionality Assessment Using Power Model – Part 2 
 
SAC 
90.  
PK Parameter 
SAS output 
of Table 
4.10 
SAS Output of Summary Results of Repeat Dose Day 14 Dose 
Proportionality Assessment Using Power Model – Part 2 
 
SAC 


 
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Non-ICH : Listings 
No. 
Population 
IDSL / TST 
ID / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
91.  
PK Parameter 
SAS output 
of Table 
4.11 
SAS Output of Summary Results of Repeat Dose Day 1 Dose 
Proportionality Assessment Using ANOVA – Part 2 
 
SAC  
92.  
PK Parameter 
SAS output 
of Table 
4.12 
SAS Output of Summary Results of Repeat Dose Day 14 Dose 
Proportionality Assessment Using ANOVA – Part 2 
 
SAC  
93.  
PK Parameter 
SAS output 
of Table 
4.13 
SAS Output of Summary Results of Steady-State GSK3640254 
Concentrations Assessment – Part 2 
 
SAC  
94.  
PK Parameter 
SAS output 
of Table 
4.14 
SAS Output of Summary Results of GSK3640254 PK Parameter 
Treatment Comparisons – Accumulation Ratio – Part 2  
 
SAC  
 
 
 


 
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Example Shells 
Non-Standard 1 
 
Protocol: AAA111111  
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 
of xx 
Population: Safety 
 
 
Listing x 
Listing of Meal Data (Safety Population) 
 
 
 
{Inv./} 
Subj. 
 
{Age(y)/ 
Sex/ 
Race} 
 
Trt. 
 
Visit/Pl.
Time 
 
Start 
Date/Star
t Time of 
Meal  
 
Stop 
Date/Sto
p Time 
of Meal  
Start 
Date/Star
t Time of 
Dosing 
 
Meal  
Type 
 
Totality 
of the 
Meal 
been 
Ingested
? 
 
Proporti
onal of 
the Meal 
Consumed
? 
 
 
 
 
 
 
 
 
 
 
36/ 
M/ 
Mixed Race 
A 
PART1 
P1D1/PRED
OSE 
/09:00 
 
9/09:10  
 
/09:30 
 High Fat 
Meal 
  No 
76-
100% 
 
 
 
 
 
 
 
   
 
 
 
 
PPD
PPD