Clinical trial NCT03045861
Conditions: Infection, Human Immunodeficiency Virus HIV Infections
Sponsor: GlaxoSmithKline
Start date: 2017-03-17; Completion date: 2018-04-23
Enrollment: 33 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
GSK2838232 is a novel HIV-1 maturation inhibitor (MI) that is being developed for the treatment of HIV-1 infection in combination with other antiretroviral therapy (ART). This study will be a 10-day monotherapy, open-label, adaptive, dose ranging, repeat-dose study. This study will be conducted in two Parts (Part A and Part B) consisting single daily doses of GSK2838232 and Cobicistat from Day 1 to Day 10. This proof of concept open-label study will be aimed to characterize the acute antiviral activity, pharmacokinetics (PK), the relationship between PK and antiviral activity, and safety of GSK2838232/cobi administered across a range of doses over 10 days in HIV-1 infected patients. A cohort of 10 subjects will be studied in Part I followed by interim (go/no-go) analysis of Part A data. On completion of an interim analysis of part A data, further cohorts of 8 subjects will then be studied in Part B in a parallel design in two or more cohorts (depending upon the data obtained in Part A). Approximately 34 HIV-1 infected treatment-naive subjects will be enrolled during the study. Subjects in both parts 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 6 Weeks.

Detailed description:

Arms: arm 1: During Part A (Cohort 1), subjects will receive a single dose of GSK2838232 100 mg and Cobicistat 150 mg once daily each morning with a light breakfast meal and 240 mL of water from Day 1 to Day 10. Subjects will be followed up to Day 22. arm 2: During Part B (Cohort 2), subjects will receive a single dose of GSK2838232 200 mg and Cobicistat 150 mg once daily each morning with a light breakfast meal and 240 mL of water from Day 1 to Day 10. Subjects will be followed up to Day 22. arm 3: During Part B (Cohort 3), subjects will receive a single dose of GSK2838232 50 mg and Cobicistat 150 mg once daily each morning with a light breakfast meal and 240 mL of water from Day 1 to Day 10. Subjects will be followed up to Day 22. arm 4: During Part B (Cohort 4), subjects will receive a single dose of GSK2838232 20 mg and Cobicistat 150 mg once daily each morning with a light breakfast meal and 240 mL of water from Day 1 to Day 10. Subjects will be followed up to Day 22.
Interventions: intervention 1: GSK2838232 intervention 2: Cobicistat
Intervention descriptions: intervention 1: GSK2838232 capsules will be supplied as swedish orange, unmarked capsule (50 mg), and white, unmarked capsules (10 mg) in high-density polyethylene bottles. intervention 2: Cobicistat tablets 150 mg will be supplied as an orange, round, biconvex, film-coated tablet in bulk containers for individualized dosing.

Protocol documents:
Prot_000.pdf: 
2015N227852_03
CONFIDENTIAL
The GlaxoSmithKline group of companies
200911
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A Phase 2a, Multicenter, Randomized, Adaptive, Open-label,  
Dose Ranging Study to Evaluate the Antiviral Effect, Safety, 
Tolerability and Pharmacokinetics of Cobicistat-boosted 
GSK2838232 Monotherapy Over 10 Days in HIV-1 Infected 
Adults
Compound Number:
GSK2838232
Development Phase:
IIA
Effective Date:
15-JUN-2017
Protocol Amendment Number:  03
Author (s):
         PTS, Ware, UK
         GCSP, Stockley Park, UK
         Infectious Diseases, Clinical, Upper Providence, PA, US
         Clinical Statistics, GSK, Upper Providence, PA, US
        HIV DPU, Clinical RTP, NC, US
         Virology, HIV DPU, RTP, NC, US
         CPMS, GSK, RTP, NC, US
         HIV DPU, RTP, NC, US
        Clinical Pharmacology, ViiV Healthcare, RTP, NC, US
         PCPS, GSK, Upper Providence, PA, US
        PCPS, GSK, Upper Providence, PA, US
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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Revision Chronology
GlaxoSmithKline 
Document Number
Date
Version
2015N227852_00
2016-NOV-09
Original
2015N227852_01
2017-APR-26
Amendment No. 1
Amendment 1 includes minor updates to Inclusion-Exclusion (IE) criteria, including 
clarification on use of pre- or post-exposure prophylaxis, and removal of exclusionary 
requirements related to concomitant medications and tobacco and alcohol use during the 
study. Guidance around relevant habits is included in the Lifestyle section of the protocol 
and adjustments were made to reduce restrictions on these requirements. Modifications 
were also made to the pharmacokinetics sampling, allowing for the 12 h PK collection 
timepoint on Day 1 and 10 to be optional. Minor alterations were made regarding the 
order of screening procedures, including the Holter monitoring requirements. 
Visit/procedure windows were included to allow more flexibility with scheduling of 
assessments. Furthermore, the serial ECG collection (up to 6h post-dose) was removed on 
Day 5. Finally, the post-study care guidance was updated to include an option for subjects 
to receive reimbursement for marketed ART for a limited period after completion of 
study treatment and follow up. Minor clarifications, reformatting of tables, re-numbering 
of sections and correction of typographical errors were also made throughout this 
amendment.
2015N227852_02
2017-MAY-24
Amendment No. 2
Amendment 2 includes expansion of the eligible subject population to allow treatment 
experienced HIV-1 infected patients, in addition to treatment naive patients. Patients with 
a treatment history of a prior maturation inhibitor will still be ineligible. Slight 
modifications were made to include flexible language for enrolment into Part B to allow 
prioritization of one dose cohort or to open randomization into Part B cohorts in a parallel 
fashion. Also the upper limit of the BMI inclusion criteria was increased from 31 to 35 
kg/m2.
2015N227852_03
2017-JUN-15
Amendment No. 3
Amendment 3 includes modification to the protocol Inclusion Criteria (#6) to ensure 
exclusion of treatment-experienced patients with limited remaining treatment options.
 
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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time 
Phone Number 
and email 
address
After-hours 
Phone/Cell/
Pager Number
Fax Number
Site Address
Primary 
Medical 
Monitor/SAE 
contact 
information 
Pharmaceutical 
Product 
Development 
(PPD) Safety 
Hotline 
PPD, 929 North 
Front Street, 
Wilmington, NC 
28401
Secondary 
Medical Monitor
MD
GlaxoSmithKline
1250 St 
Collegeville Rd 
Collegeville, PA 
19426
Sponsor Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the
clinical trial application.   
Regulatory Agency Identifying Number(s):  116,094
 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 200911
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date
 
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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 200911........................................................9
2.
INTRODUCTION....................................................................................................13
2.1.
Study Rationale ..........................................................................................13
2.2.
Brief Background ........................................................................................13
2.2.1.
Preclinical Summary....................................................................14
2.2.2.
Clinical Summary of Safety and Pharmacokinetics ......................19
2.2.2.1.
Clinical Summary of Safety.........................................19
2.2.2.2.
Study 204953 (completed); Pharmacokinetic 
Data ...........................................................................20
2.2.2.3.
Overall Summary/Conclusions of PK data..................23
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................25
4.
STUDY DESIGN ....................................................................................................26
4.1.
Overall Design ............................................................................................26
4.2.
Type and Number of Subjects.....................................................................27
4.3.
Design/Dose Justification............................................................................28
4.3.1.
GSK2838232 with Ritonavir.........................................................28
4.3.2.
GSK2838232 with Cobicistat .......................................................29
4.3.3.
Interim Analysis ...........................................................................29
4.4.
Benefit:Risk Assessment ............................................................................30
4.4.1.
Risk Assessment .........................................................................31
4.4.2.
Benefit Assessment.....................................................................33
4.4.3.
Overall Benefit:Risk Conclusion...................................................33
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............33
5.1.
Inclusion Criteria.........................................................................................34
5.2.
Exclusion Criteria........................................................................................36
5.3.
Screening/Baseline/Run-in Failures............................................................38
5.4.
Withdrawal/Stopping Criteria.......................................................................39
5.4.1.
Liver Chemistry Stopping Criteria ................................................39
5.4.1.1.
Study Treatment Restart or Rechallenge....................40
5.4.2.
QTc Stopping Criteria ..................................................................40
5.5.
Stopping criteria based on Adverse Events.................................................41
5.6.
Subject and Study Completion....................................................................41
6.
STUDY TREATMENT ............................................................................................41
6.1.
Investigational Product and Other Study Treatment....................................41
6.2.
Treatment Assignment................................................................................42
6.3.
Planned Dose Adjustments.........................................................................42
6.4.
Blinding.......................................................................................................42
6.5.
Preparation/Handling/Storage/Accountability..............................................42
6.6.
Compliance with Study Treatment Administration.......................................43
6.7.
Treatment of Study Treatment Overdose....................................................43
6.8.
Treatment after the End of the Study ..........................................................44
6.9.
Lifestyle and/or Dietary Restrictions............................................................44
6.9.1.
Meals and Dietary Restrictions ....................................................44
 
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6.9.2.
Alcohol, Caffeine and Exercise ....................................................44
6.10.
Contraception .............................................................................................44
6.11.
Concomitant Medications and Non-Drug Therapies....................................45
6.11.1.
Permitted Medications and Non-Drug Therapies..........................45
6.11.2.
Prohibited Medications and Non-Drug Therapies.........................45
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................45
7.1.
Time and Events Table...............................................................................47
7.2.
Visit Windows .............................................................................................49
7.3.
Screening and Critical Baseline Assessments ............................................49
7.3.1.
Holter Monitoring (Screening criteria)...........................................49
7.4.
Efficacy.......................................................................................................50
7.4.1.
HIV-1 RNA Sampling ...................................................................50
7.4.2.
Lymphocyte Subsets by Flow Cytometry .....................................50
7.5.
Safety .........................................................................................................50
7.5.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........50
7.5.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................51
7.5.1.2.
Method of Detecting AEs and SAEs ...........................51
7.5.1.3.
Follow-up of AEs and SAEs........................................51
7.5.1.4.
Cardiovascular and Death Events ..............................52
7.5.1.5.
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ................52
7.5.1.6.
Regulatory Reporting Requirements for SAE..............53
7.5.2.
Pregnancy ...................................................................................53
7.5.3.
Physical Exams ...........................................................................53
7.5.4.
Vital Signs....................................................................................54
7.5.5.
Electrocardiogram (EGC).............................................................54
7.5.6.
Clinical Safety Laboratory Assessments ......................................54
7.6.
Pharmacokinetics .......................................................................................56
7.6.1.
Blood Sample Collection..............................................................56
7.6.2.
Sample Analysis ..........................................................................56
7.7.
Biomarker(s)/Pharmacodynamic Markers ...................................................56
7.7.1.
Viral Genotyping and Phenotyping...............................................56
7.8.
Genetics .....................................................................................................56
7.9.
Value Evidence and Outcomes...................................................................57
8.
DATA MANAGEMENT ...........................................................................................57
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................57
9.1.
Hypotheses.................................................................................................57
9.2.
Sample Size Considerations.......................................................................57
9.2.1.
Sample Size Assumptions ...........................................................57
9.2.2.
Sample Size Sensitivity................................................................58
9.2.3.
Sample Size Re-estimation or Adjustment...................................59
9.3.
Data Analysis Considerations .....................................................................59
9.3.1.
Analysis Populations....................................................................59
9.3.2.
Interim Analysis ...........................................................................59
9.4.
Key Elements of Analysis Plan ...................................................................60
9.4.1.
Primary Analyses.........................................................................60
9.4.1.1.
Safety Analyses..........................................................60
9.4.1.2.
Efficacy Analyses .......................................................60
 
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9.4.1.3.
Pharmacokinetic Analyses..........................................61
9.4.2.
Secondary Analyses ....................................................................61
9.4.2.1.
Pharmacokinetic/Pharmacodynamic Analyses ...........61
9.4.2.2.
Viral Genotyping and Phenotyping Analyses ..............62
10. STUDY GOVERNANCE CONSIDERATIONS........................................................62
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............62
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................62
10.3.
Quality Control (Study Monitoring) ..............................................................63
10.4.
Quality Assurance.......................................................................................63
10.5.
Study and Site Closure ...............................................................................63
10.6.
Records Retention......................................................................................64
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................65
10.8.
Review Committees....................................................................................65
11. REFERENCES.......................................................................................................66
12. APPENDICES........................................................................................................68
12.1.
Appendix 1: Abbreviations and Trademarks................................................68
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................71
12.3.
Appendix 3: Liver Safety – Study Treatment Restart or Rechallenge 
Guidelines...................................................................................................74
12.4.
Appendix 4: Genetic Research ...................................................................75
12.5.
Appendix 5: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................78
12.5.1.
Definition of Adverse Events........................................................78
12.5.2.
Definition of Serious Adverse Events...........................................79
12.5.3.
Definition of Cardiovascular Events .............................................81
12.5.4.
Recording of AEs and SAEs ........................................................81
12.5.5.
Evaluating AEs and SAEs............................................................82
12.5.6.
Reporting of SAEs to GSK...........................................................83
12.6.
Appendix 6: Collection of Pregnancy Information........................................85
12.7.
Appendix 7: Country Specific Requirements...............................................86
12.8.
Appendix 8: Division Of AIDS Table For Grading The Severity Of 
Adult And Pediatric Adverse Events Version 1.0, December 2004; 
Clarification August 2009............................................................................87
12.9.
Appendix 9: Toxicity Management ............................................................106
12.10. Appendix 10: Protocol Amendment Changes............................................111
12.10.1. AMENDMENT 1.........................................................................111
12.10.2. AMENDMENT 2.........................................................................129
12.10.3. AMENDMENT 3.........................................................................137
 
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1.
PROTOCOL SYNOPSIS FOR STUDY 200911
Rationale
GSK2838232 is a novel human immunodeficiency virus (HIV-1) maturation inhibitor 
that is being developed for the treatment of HIV-1 in combination with other 
antiretrovirals.
Three clinical studies of GSK2838232 (n=53 healthy subjects) have been completed thus 
far. One study (Study 204953) completed at the end of 2016 and analysis of the data is 
ongoing. Healthy subjects have received GSK2838232 or placebo in single or repeated 
dose designs, to a maximum single dose of 250 mg or repeated dose (for 11 days) of 
200 mg QD, in combination with ritonavir (RTV). 
Study HMI116787 (completed November 2013) was the First Time in Human study of 
GSK2838232 and assessed safety and tolerability of escalating doses (5 mg to 100 mg), 
food effect, and the impact of steady-state ritonavir on GSK2838232 pharmacokinetics 
(PK). Following successful completion of 3-month toxicology studies in rat and dog in 
2014, clinical studies 200912 and 200207 were initiated. These were double-blind, 
placebo-controlled, single (Study 200912) and repeat-dose (Study 200207) escalation 
studies to investigate the safety, tolerability, and PK of GSK2838232 alone and when co-
administered with ritonavir 100 mg once daily (QD) for 8-11 days. Further assessment of 
an alternative formulation was also an objective in Study 200912.
Both studies were prematurely terminated/completed in March/April 2015 because of 
concerns over cardiovascular (CV) toxicity, in particular a clinical CV serious adverse 
event (SAE) whereby the Food and Drug Administrating (FDA) imposed a clinical hold. 
Following submission of long-term (6-month rat, 9-month dog) chronic toxicology data 
and follow up to the clinical SAE in November 2015, the hold was released in January 
2016 and Study 204953 was initiated.
Study 204953 investigated the safety and PK of GSK2838232 in single and repeat-doses 
as well as the suitability of a new, capsule formulation. Doses of up to 250 mg 
GSK2838232/100 mg RTV (as single doses) or 200 mg GSK2838232/100 mg RTV (QD 
for 11 days) were studied. The final cohort of the study assessed unboosted GSK2838232 
(200mg BID) for 11 days. The study completed at the end of 2016 and the data analys is 
ongoing.
These studies have shown GSK2838232 with or without RTV to be well tolerated and, 
together with daily RTV dosing (“boosting”), demonstrate a PK profile suitable for 
progression to HIV patients in this Phase IIa proof of concept 10-day, monotherapy study 
design.  However, potential concerns over protease resistance necessitate a change to a 
pharmacoenhancer without antiviral effects in this study of GSK2838232 monotherapy. 
Therefore, for Study 200911, cobicistat (Tybost,150 mg QD) will be substituted for RTV.  
The objective of Study 200911 is to understand the safety, PK and HIV antiviral profile 
of GSK2838232/cobicistat (GSK2838232/cobi) when given to HIV-infected, treatment 
naive, otherwise healthy adults. Approximately 10 HIV-1 infected subjects will be 
enrolled into Part A. If warranted by an interim safety, virology, and PK data analysis, 
 
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approximately 8 subjects will be enrolled in each of between two and four Cohorts in Part 
B.
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

To evaluate antiviral activity of 
GSK2838232/cobi in HIV-1 infected 
patients during 10 days of 
monotherapy.

Change from baseline (Day 1) in plasma HIV-1 
RNA 

To assess safety and tolerability of 
GSK2838232/cobi when administered 
as monotherapy over 10 days.

Safety and tolerability parameters, including 
adverse event, concurrent medication, clinical 
laboratory, electrocardiogram (ECG) and vital 
signs assessments.

To characterize the pharmacokinetics 
of GSK2838232 in HIV-1 infected 
patients following GSK2838232/cobi 
dosing for 10 days.

GSK2838232 PK parameters following dose 
administration, as follows:
Day 1: area under the plasma concentration time 
curve AUC(0-24), maximum observed 
concentration (Cmax), time to maximum 
observed concentration (tmax), concentration at 
24 hours post dose (C24), absorption lag time 
(tlag); 
Following last repeat administration on Day 10:  
AUC(0-), pre-dose concentration (C0),
concentration at end of dosing interval (C), 
Cmax, tmax, t½, and apparent oral clearance 
(CL/F), if data permit
Secondary

To explore the relationship between 
GSK2838232 exposure and change 
in plasma HIV-1 RNA

GSK2838232 PK parameters Day 10 AUC(0-), 
Cmax, Cwith Day 11 HIV-1 RNA change from 
baseline

To assess the immunologic effect of 
GSK2838232/cobi when 
administered over 10 days in HIV-1 
infected adults

Change from baseline in CD4+ cell count to Day 
11

To explore the relationship between 
GSK2838232 exposure and safety or 
immunologic parameters, if 
appropriate.

GSK2838232 PK parameters on Day 10: 
AUC(0-), Cmax, Cwith Day 11 change from 
baseline in CD4+ cell count
 
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Objectives
Endpoints

To assess the development of viral 
resistance (genotypic and 
phenotypic) over 10 days and 
correlate with viral response, if 
appropriate.

Emergence of drug resistance mutations, if 
appropriate

To estimate GSK2838232 
accumulation and to assess 
attainment of steady state following 
administration of GSK2838232/cobi 
for 10 days in HIV infected subjects.

Accumulation:
GSK2838232 PK accumulation ratios (R): Day 
10 AUC(0-), Cmax, and Ccompared to Day 1 
AUC(0-24), Cmax, and C24, respectively

Steady State:
pre-morning dose concentrations (C0) on Days 2 
through 11 

To examine dose proportionality of 
GSK2838232 pharmacokinetic 
parameters following 
GSK2838232/cobi dosing for 10 days
in HIV infected subjects.

Day 1 AUC(0-24), Cmax, and C24, and Day 10 
AUC(0-), Cmax, and Cat different dose levels 
for the assessment of dose proportionality
Note: Other exploratory objectives and endpoints will be specified in the RAP
Design, Treatment Arms and Duration
Approximately 34 HIV-1 infected subjects will be enrolled overall. 
This study is a 10-day monotherapy, open-label, adaptive, dose ranging, repeat-dose 
study and will be conducted as two parts with an interim (go/no-go) analysis performed 
after Part A (Table 1). Part A, Cohort 1 will evaluate a safe and well-tolerated dose level 
of GSK2838232 that has been tested (with RTV) in prior Phase I studies and that targets 
a high inhibitory quotient (IQ) value. Following the completion of an interim analysis of 
those data and according to criteria defined later in the protocol, further cohorts of 8 
subjects will then be studied in Part B in two or more cohorts (depending upon the data 
obtained in Part A). 
The totality of this data will provide a full dose-response of GSK2838232 over a wide 
dose range to explore the safety and PK/pharmacodynamics (PD) relationship of 
GSK2838232 in HIV-1 infected subjects and facilitate choice of doses for Phase IIb 
studies.
 
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Table 1
Study Design for 200911
Part A: GSK2838232/cobi 
Once Daily x 10 days1
Part B: GSK2838232/cobi 
Once Daily x 10 days1,2
Cohort
N
232 Dose
(mg)
Cohort
N
232 Dose 
(mg)
1
10
100
2
8
200
3
8
50
4
8
20
1. 
Part A Cohort 1 safety/PK/virology data will be evaluated at interim, prior to initiating other cohorts in Part B. All 
doses will be given with 150 mg cobicistat.
2. 
Part B GSK2838232 doses are an illustration of the projected doses per cohort. The actual doses for each cohort 
and number of cohorts are subject to modification based upon safety, PK and antiviral activity data from Cohort 1 
(Part A). More doses/cohorts (including potential removal of cobi co-dosing) may be added (the maximum dose in 
Part B would likely not exceed 200 mg with cobicistat unless overall plasma exposure [as AUC and Cmax] was 
lower in HIV infected subjects than in healthy subjects at the same dose level).
The possibility that an additional, unboosted GSK2838232 monotherapy cohort will be 
assessed in Part B is dependent on analysis of the PK data from Study 204953 where 
unboosted GSK2838232 at a dose of 200 mg twice daily (BID) was assessed and Study 
205820, which plans to evaluate GSK2838232 at a dose of 500mg once daily (QD). 
Subjects in both parts 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 6 weeks.
HIV Drug Resistance: Following cessation of GSK2838232/cobi dosing for 10 days, 
there will be prolonged exposure to waning plasma concentrations of GSK2838232, 
because of the long t½ (i.e., in the “tail” of the PK profile). However, based on in vitro 
resistance passage data with GSK2838232 [and unlike with many other ARV therapies], 
there appears to be a limited likelihood of developing maturation resistance mutations in 
HIV-infected subjects due to its virologic profile. 
Analysis
The primary objectives of this study are to investigate the safety, tolerability, PK and 
antiviral activity of 10 days repeated doses of GSK2838232/cobi in HIV-1 infected 
otherwise healthy subjects. Descriptive summaries will be provided for safety, PK, and 
HIV viral load data.
 
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2.
INTRODUCTION
GSK2838232 is a novel human immunodeficiency virus (HIV)-1 maturation inhibitor 
(MI) that is being developed for the treatment of HIV-1 infection in combination with 
other antiretrovirals (ART).
2.1.
Study Rationale
This ‘proof of concept (PoC)’ open-label study is being conducted to characterize the 
acute antiviral activity, pharmacokinetics (PK), the relationship between PK and antiviral 
activity, and safety of GSK2838232 given with 150 mg once daily (QD) cobicistat 
(GSK283232/cobi), administered across a range of doses over 10 days in HIV-1 infected 
patients. A two-part adaptive and dose ranging design is to be applied in this study. Data 
from this study will be utilized to select doses for further studies in Phase IIb.
2.2.
Brief Background
Combination antiviral therapy with inhibitors of HIV protease, integrase, entry and 
reverse transcriptase (RT) has demonstrated significant improvement in acquired 
immunodeficiency syndrome (AIDS)-related morbidity and mortality over the last 10-15 
years. Emerging multi-class drug resistant viral strains and long-term toxicities warrant 
development of new classes of antiretroviral therapies targeting various parts of the HIV-
1 viral life cycle [Wainburg, 2010]. The inhibition of maturation of HIV-1 is a novel 
target for drug development, distinct from viral protease RT or integrase [Saxena, 2012; 
Qian, 2009]. HIV maturation is the final cleavage step of the capsidSp1 (transcription 
factor) polyprotein that generates the functional capsid p24 protein. This mechanism of 
action results in accumulation of the uncleaved p25 protein with subsequent improper 
assembly of the HIV core, resulting in a non-infectious virion. Gel-based mechanism of 
action studies suggest that compound GSK2838232 acts as a maturation inhibitor. 
Western Blot analysis shows inhibition of capsid-Sp1 cleavage and accumulation of p25 
in the presence of GSK2838232.
Prior validation of this target was demonstrated with the HIV maturation inhibitor known 
as bevirimat (BVM; [Martin, 2007a; Martin, 2007b; Martin, 2008; NORVIR, 2013]). 
BVM reached Phase II studies in HIV patients; however, only modest reductions in 
plasma HIV-1 ribonucleic acid (RNA) concentrations were observed in Phase IIa 
monotherapy studies [Mahmood, 2006; Martin, 2007] and a pattern of polymorphic 
(differential) antiviral activity [Wainburg, 2010] led to termination of BVM development. 
The average decrease from baseline to Day 14 plasma HIV-1 ribonucleic acid (RNA) was 
0.54 and 0.70 log10 copies/mL for 200 mg and 300 mg twice daily regimens (Table 2); 
all subjects achieved plasma BVM concentrations above the in vitro EC90. Responders, 
classified based on 5 polymorphisms in HIV-1 gag (at positions 369, 370, and 371), 
achieved an average 1.15 log10 copies/mL reduction in plasma HIV-1 RNA, while an 
average 0.17 log10 copies/mL reduction was achieved for non-responders.
 
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Table 2
Summary of Bevirimat Antiviral Response and PK in a 14-day 
Monotherapy Study in HIV-infected Adults
BVM dosage 
regimen
Mean (SD) viral load 
change from 
baseline to Day 14
2IQ
Plasma BVM 
1Cmin (g/mL)
Plasma BVM 
1Cmax 
(g/mL)
Plasma BVM 
1AUC(0-) 
(g.h/mL)
200 mg BID
(N=14)
-0.54 (0.64)
1.70
46
(41, 51)
58
(53, 64)
632
(571, 699)
300 mg BID
(N=18)
-0.70 (0.77)
2.67
72
(65, 80)
91
(84, 99)
973
(890, 1064)
1.
Cmin, Cmax, and AUC reported as geometric mean (95% CI).
2.
IQ=geometric mean Cmin/in vitro EC90; reported EC90=27 g/mL; all subjects achieved IQ 1.
        AUC(0-) = Area under the concentration-time curve over the dosing interval; BVM = Bevirimat; CI = Confidence 
interval; Cmax = Maximum plasma concentration; Cmin = Minimum plasma concentration; EC90 = 50% protection 
against resistant mutant HIV infection; IQ = Inhibitory quotient; SD = Standard deviation.
Early clinical data for BMS955176, a second generation maturation inhibitor, have been 
recently presented [Nowicka-Sans, 2015]. In a 10-day monotherapy trial in HIV-infected 
patients, plasma HIV-1 RNA was reduced at doses of between 40 mg and 120 mg QD. 
All doses were well tolerated. The maximum change, seen between 10 and 12 days after 
starting dosing, was about 1.5 log10, which is substantially better than the effect 
demonstrated with BVM and may indicate the maximum expected clinical effect of 
inhibiting this viral target.
Although BMS955176 is currently in Phase II studies in HIV-infected patients, there are 
no maturation inhibitors approved for the treatment of HIV infection.  The uncertainties 
of early drug development and continuing need for novel ART, especially for heavily 
treated/experienced HIV-infected persons, support continued compound development. 
GSK2838232’s low nanomolar in vitro potency against multiple HIV-1 gag 
polymorphisms and broader spectrum across multiple HIV-1 subtypes indicates it has 
utility in this setting.
2.2.1.
Preclinical Summary
Nonclinical pharmacology
Virology
GSK2838232, in vitro, is an inhibitor of HIV maturation by preventing the cleavage of 
the HIV gag structural subunit p25 to p24. GSK2838232 is a potent antiviral agent with a 
mean 50% maximal inhibitory concentration (50% maximal inhibitory concentration 
[IC50]) value of 1.6 nM (range: 0.8 to 4.3 nM) when tested in a panel of 26 HIV-1 
isolates with various polymorphic gag genotypes in peripheral blood mononuclear cells 
(PBMCs), suggesting that GSK2838232 can inhibit a broad spectrum of HIV isolates. In 
another PBMC assay, GSK2838232 showed potent antiviral activity in 59 of 60 isolates 
with IC50 values ranging from 0.22 to 5.1 nM. GSK2838232 also inhibited HIV-1 strains 
containing the consensus Sp1 QVT region or the V370A polymorphism in MT4 cells
(IC50 = 0.73 to 0.81 nM). 
 
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In an MT2 cell-based assay utilizing recombinant viruses harboring gag and protease 
from subjects before and after a protease inhibitor (PI) based regimen, GSK2838232 
inhibited 12 of 15 viruses with a mean IC50 value of 1.7 nM (range = 0.4 to 3 nM). The 
remaining 3 viruses were not inhibited by GSK2838232 up to the top concentrations 
tested at 400 nM. There was no correlation of PI sensitivity and susceptibility to 
GSK2838232. GSK2838232 resistance mutations were selected for by serial passage of 
virus in a SupT1 cell-based assay with increasing concentrations of GSK2838232. In the 
lab strain NL4-3 and gag/protease recombinant viruses, the resistance mutation A364V 
arose and resistance confirmed by site-directed mutagenesis. This resistance mutation 
maintains susceptibility to other classes of anti-retrovirals including PIs and non-
nucleoside RT inhibitors.
GSK2838232 was tested in vitro in combination with two marketed PIs, atazanavir and 
darunavir. Using a dose-wise additivity model, GSK2838232A showed additive anti-viral 
activity with both PIs.
Secondary Pharmacology
In a secondary pharmacology study, GSK2838232 was tested against a panel of 
receptors, ion channels and transporters and demonstrated no significant effect (IC50 of 
1 M). It is important to note that the selectivity for antiviral activity of GSK2828232 
compared to all tested off-target activities was >100-fold, and the potential for organ 
toxicity was characterized in the nonclinical toxicology studies (see below).
In safety pharmacology studies in male rats, there were no hemodynamic changes or 
neurobehavioral effects following single oral doses up to 300 mg/kg. A single oral dose 
of GSK2838232 at 30 mg/kg or 300 mg/kg produced reversible increases in respiratory 
tidal volume (32% and 36%, respectively) and derived minute volume (17% and 26%, 
respectively) at 6 hours after dosing. These doses did not produce any effect on 
respiratory rate, airway resistance or body temperature. There were no respiratory effects 
in rats given 5 mg/kg (mean maximum plasma concentration [Cmax] 0.12 g/mL; AUC0-24
1.0 g.h/mL based on Day 1 of the 4-week repeat dose study). These findings were not 
considered to suggest a safety concern in humans.
GSK2838232 at the maximum feasible concentration, limited by solubility, of 4.09 M 
(3.31 g/mL) caused no inhibition of human ether-a-gogo related gene (hERG) tail 
current in Human Embryonic Kidney 293 cells stably transfected with hERG cDNA, 
indicating a low probability for interaction at the hERG channel.
In conscious telemetered male dogs (n=4), a single oral dose of GSK2838232 at 
60 mg/kg (Cmax 0.59 g/mL; AUC0-24 8.7 g.h/mL based on Day 1 exposure data from 
the 4-week oral repeat dose toxicity study) was associated with one episode of 
non-sustained ventricular tachycardia in one dog lasting ~1.2 seconds. There were no 
effects on arterial pressures, heart rate, or electrocardiogram (ECG) interval durations. An 
investigative safety pharmacology cardiovascular study was conducted in telemetered 
dogs given 60 mg/kg/day for 4 weeks with serial monitoring by echocardiography, 
cardiac biomarkers, qualitative and quantitative electrocardiology, microscopy, and 
transmission electron microscopy (TEM) of the heart. 
 
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There were no changes in echocardiography endpoints, ECG intervals, ECG waveforms, 
arterial pressures, heart rates, serum cTpnI, N-terminal prohormone of brain natriuretic 
peptide (NTproBNP), or in heart tissue as assessed by TEM. With routine microscopy, 
one treated dog had a single focus of degeneration/necrosis of the tunica media 
(moderate) in an extramural artery and another treated dog had localised, mixed-cell 
inflammation (mild) along the epicardium of the coronary groove. Both changes have 
been reported in normal beagles and were considered of uncertain relationship to 
treatment in the absence of changes in any other structural or functional cardiovascular 
endpoints. The 28-day exposures were similar to the previous 4-week toxicity study in 
dogs: the Cmax range at 60 mg/kg/day in this investigative safety pharmacology study was 
0.542 to 2.00 g/mL and range of AUC0-24 was 6.04 to 35.7 g.h/mL. In subsequent 
repeat-dose studies in dogs treated for up to 9 months with up to 70 mg/kg/day, no
changes were evident in cardiac biomarkers (including cTpnI and NTproBNP), functional 
(including ECG waveform) or structural (including microscopic evaluation) 
cardiovascular endpoints at slightly higher exposures than those achieved than in 
previous studies. The end of the 9-month study, gender averaged Cmax at 70 mg/kg/day 
was 1.95 g/mL and AUC0-24 was 38.8 g.h/mL. These studies support an absence of 
GSK2838232-related functional or structural effects on the heart in preclinical testing. 
The No Observed Adverse Effect Level (NOAEL) was established at 20 mg/kg/day (on 
the basis of mild hepatic findings) with an associated area under the curve at 24 hours 
(AUC24) of 16.2 g.hr/mL and Cmax 0.847 g/mL.
Pharmacokinetics and product metabolism in animals
The PK of GSK2838232 were investigated in the mouse, rat, and dog. The oral 
bioavailability of GSK2838232 was low to moderate (~6% to 40%) depending on the 
species and formulation. Plasma and blood clearance were low and the volume of 
distribution at steady state was high relative to total body water. The half-life of 
GSK2838232 was short in the mouse and rat, but moderate in the dog. Systemic exposure 
of GSK2838232 generally increased in a less than dose-proportional manner.  In rats, 
there were no differences in systemic exposure between single and repeat-dose 
administration, or between males and females.  In a 7-day study in dogs, systemic 
exposures were generally similar between males and females and after single and repeat 
dosing; however, in a 4-week study, systemic exposures were higher in females than in 
males in the high-dose group (60 mg/kg/day) and higher after repeat dosing than after a 
single dose. The distribution of radioactivity in male pigmented rats following a single 
oral administration of [14C] GSK2838232 at a target dose level of 20 mg/kg showed 
radioactivity was rapidly absorbed and widely distributed throughout the body with all 
tissues, except the brain and spinal cord. There were no tissues that retained detectable 
levels of radioactivity at 28 days post dose. In a bile duct canulated rat study, 30% of the 
administered dose was excreted in the bile as an acylglucuronide. In the same study, 
unchanged drug and metabolites were eliminated primarily in the bile and feces, while a 
mean of <1% of the dose was eliminated in urine.
In vitro, GSK2838232 is highly protein bound (>99.9%) and has low passive 
permeability. In vivo evidence suggests active uptake of GSK2838232 by transporters in 
the rat liver. 
 
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After single oral doses of 5, 100, or 300 mg/kg, the average liver to plasma ratio was 51, 
17, and 10, respectively. After 7 days of dosing at 30, 100, or 300 mg/kg/day, liver to 
blood ratios ranged from 10 to 16.
In the 13-week repeat dose studies in dogs given 35 mg/kg BID (70 mg/kg/day), heart 
tissue collected at necropsy had GSK2838232 concentrations 2.5 to 5-times higher than 
the 24-hour post-dose plasma concentrations, similar to the previous 4-week CV 
investigative findings.  In the 13-week repeat dose studies in rats given 300 mg/kg/day, 
heart tissue collected at necropsy had GSK2838232 concentrations approximately 3 times 
higher than the 24-hour post-dose plasma concentrations, similar to the previous 7-day 
findings.  Overall GSK2838232 did not appear to be highly concentrated in heart tissue 
after repeat dosing and suggests that accumulation upon chronic dosing is unlikely.
Routes of metabolism identified in liver microsomal incubations and rat, dog, and human 
hepatocytes were N-dealkylation, oxidation, oxidative deamination, and glucuronidation, 
alone or in combination, with no human-specific metabolites detected.  N-dealkylated 
products and glucuronidation were observed in rat plasma and the bile. In general, in 
vitro metabolite profiles of the nonclinical species and human were qualitatively similar, 
such that all metabolites of [14C] GSK2838232 observed in human hepatocyte 
incubations were observed in rat and/or dog. Minor to trace levels of potential aldehydes 
metabolites formed as a result of N-dealkylation and oxidative deamination were
observed in rat, dog and humans.  
GSK2838232 did not show evidence for glutathione adduct formation in rat or human 
liver microsomes.  Data from pooled human liver microsomes along with recombinant 
cytochrome P450 (CYP) enzymes suggest that in vitro the oxidative metabolism of 
GSK2838232 was primarily mediated by CYP3A4.  Preliminary in vitro investigations 
showed GSK2838232 did not inhibit CYP1A2, 2C9, 2C19, 2D6, 3A4 and was not a 
metabolism-dependent inhibitor of CYP3A4. No drug interaction risk was identified for 
co-administrated substrates of UGT1A1, 1A3, 1A6, 1A9, 2B7, and 2B15, OAT1, OAT3, 
OATP1B1, OATP1B3 or OCT2 at a clinical dose of 200 mg GSK2838232/ritonavir 
(predicted Cmax 0.32 µM). Extrapolation of the clinical risk (using FDA and EMA 
regulatory guidance) did indicate a risk for GSK2838232-mediated inhibition of 
UGT1A4 and of gut contributions of CYP3A4, P-gp, and BCRP at the same clinical 
exposure; however, the potential for clinically significant interactions via these 
mechanisms is predicted to be low (<2 fold change in AUC). GSK2838232 did show 
weak induction of CYP3A4 enzyme activity. However, based on the maximum predicted 
plasma concentrations and high protein binding, the potential for clinically significant 
drug interactions through CYP3A4 induction by GSK2838232 appears to be low.
The inclusion of cobicistat as a CYP3A4 inhibitor pharmacoenhancer in this Phase IIa 
study in place of ritonavir is unlikely to produce a significantly different profile of 
GSK2838232 ADME (and therefore systemic exposure); however, there have been no 
preclinical studies conducted with GSK2838232 and cobicistat to date.  
Toxicology
GSK2838232 administered by oral gavage in repeat dose studies up to 6 months duration 
resulted in no adverse treatment-related effects in rats given up to 300 mg/kg/day QD. 
 
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In dogs given up to 70 mg/kg/day (35 mg/kg/day BID), adverse liver effects were noted 
at this dose in the 9-month repeat dose study.  Though isolated, low grade changes in 
heart rate and cardiac troponin I (cTnI) had been noted in 4-week toxicity studies in rats 
and dogs; however, there were no treatment-related structural or functional 
cardiovascular changes in studies of 3 months and greater duration as assessed by 
echocardiography, ECG, microscopy, and cardiac biomarkers, indicating an absence of 
GSK2838232-related functional or structural effects on the heart in preclinical testing. 
Only non-adverse treatment-related changes were noted in the definitive 6-month rat 
study, which included occasional salivation in animals given 300mg/kg/day and minimal 
clinical pathology changes without histologic correlates (transient clinical chemistry 
changes at 5 mg/kg/day and reversible urine chemistry changes at 300 mg/kg/day). The 
NOAEL in this study was considered to be 300 mg/kg/day (mean AUC[0-t] 
21.3 g.h/mL, mean Cmax 1.77 g/mL [Week 26 values for males and females 
combined]).  
As noted above, dogs given GSK2838232 at 70 mg/kg/day for 9 months had minimal to 
moderate pigmentation (consistent with bile) with minimal to mild mixed cell infiltration 
in the liver and isolated mild increases in alanine aminotransferase (ALT) activity.  These 
findings were considered adverse, but were reversible after the 6-week off-dose period.  
The NOAEL for this dog study was considered to be the mid-dose level of 20 mg/kg/day 
(mean AUC[0-t] 16.2 g.h/mL, mean Cmax 0.847 g/mL [Week 39 values for males and 
females combined]).
Data from genotoxicity assessments suggest that GSK2838232 does not present a 
genotoxic hazard to humans.
During discussions with the FDA regarding the resolution of the clinical hold, the 
Agency recommended that the sporadic cardiovascular changes observed in the early (1-
month) rat GLP study at the highest dose level (300 mg/kg/day) should be considered 
when defining the NOAEL and establishing a safe dose of GlaxoSmithKline (GSK) for 
the initiation of this study protocol.  Accordingly, for the initial PK studies, the reference 
dose level of 30 mg/kg/day in the 1-month rat study was initially used to define the 
NOAEL and therefore the values for fold cover at maximum projected mean exposure 
and Cmax in human subjects were lower, at >2.5-fold.  However, based on the 
cumulative clinical safety data through Cohort 5 of Study 204953, the designated 
NOAEL for the most sensitive species (i.e., 20 mg/kg/day in the 9-month dog study 
based on liver endpoints) is currently used for assessing fold-cover for projected clinical 
dosing in this study.
The inclusion of cobicistat as a CYP3A4 inhibitor pharmacoenhancer in this Phase IIa
study in place of ritonavir is unlikely to produce a significantly different profile of 
GSK2838232 ADME (and therefore systemic exposure and toxicity); however, there 
have been no preclinical studies conducted with GSK2838232 and cobicistat to date.  
Full details of non-clinical and clinical data may be found in the current Investigator’s 
Brochure (IB) [GSK Document Number 2012N151889_03].
 
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2.2.2.
Clinical Summary of Safety and Pharmacokinetics
To date, GSK2838232 has been evaluated in three completed clinical studies with or 
without ritonavir (RTV) (GSK2838232/r). A fourth study (204953) completed late 2016 
and data analysis is ongoing. Full details of the clinical results can be found in the 
Investigator’s Brochure.
2.2.2.1.
Clinical Summary of Safety
As of November 2016 fifty-three subjects had been exposed to GSK2838232 in 3 
completed studies. One study (204953) completed in late 2016 and the analysis of results 
are ongoing (63 subjects were exposed to GSK2838232/r or placebo so far in this study).  
Overall, drug-related adverse events have been few and mild, and included headache, 
dizziness, fatigue, nausea, and palpitations and anxiety.  Similarly, treatment-emergent 
laboratory abnormalities have also been few and mostly grade 1.  There have been no 
discernible patterns, thus far, in terms of AEs or laboratory abnormalities.
One subject in study 200912 discontinued treatment with RTV due to an AE.  A 47-year-
old female who developed right upper quadrant abdominal pain, nausea and flatulence 
associated with grade 4 elevations in ALT and aspartate aminotransferase, and grade 2 
elevations in total bilirubin (BIL). She was diagnosed with a common bile duct 
obstruction due to gallstones that spontaneously resolved. The Investigator assessed this 
AE as unrelated to study treatment.
Due to sporadic CV-related safety signals in the early animal studies (see Section 2.2.2), 
intense CV monitoring was in place for all four studies.  
One AE occurred in HMI116787 that was initially considered a CV AE but after further 
evaluation was considered not to be of cardiac etiology.  Two CV AEs occurred in 
200207 that were initially considered possibly related to GSK2838232 exposure.  
However, further evaluation confirmed that there is a low likelihood that these events 
were due to GSK2838232 exposure.  A summary of each event is provided in the IB.
In Study 204953, there have been a small number of CV-related events of any sort: There 
have  been no serious adverse drug reactions, and no clinically significant drug-related 
abnormal findings for 12-lead ECGs, vital signs, safety laboratory results (including 
cardiac troponin I), or telemetry.  The following cardiovascular AEs were observed 
during the course of the study but were not considered to be caused by GSK2838232 
exposure:

In Part 1A (Cohort 1), Period 2, a subject was withdrawn due to an AE (low 
hemoglobin) prior to GSK2838232 exposure Day -2.  A replacement subject 
was brought in, but was not dosed with GSK2838232 or placebo because during 
the 2-day RTV run-in, on Day -1, the replacement subject met the stopping 
criteria for telemetry due to as brief occurrence of asymptomatic, NSVT prior to 
the first dose of GSK2838232 or placebo.  Because the subject was excluded 
from the study prior to the first dose of investigational drug, the NSVT was not 
considered to be a serious and unexpected adverse drug reaction that would 
qualify for IND safety reporting.  
 
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
In Part 1A (Cohort 1), Period 3 (Period “3A” for the purpose of differentiating 
between 100 mg GSK2838232/r vs. 200 mg GSK2838232/r), one subject was 
discontinued prior to the first dose of study drug due to a series of 
cardiovascular findings (pre-ventricular contractions on telemetry).  None of the 
findings were abnormal or atypical, but the investigator determined that this 
would not be a good etiology to have in a subject about to receive 
investigational drug.  Because the event occurred prior to first dose of 
investigational drug, the finding was not considered to be due to GSK2838232 
exposure.  

In Part 1A (Cohort 1), Period 3 (Period “3A” for the purpose of differentiating 
between 100 mg GSK2838232/r vs. 200 mg GSK2838232/r), one subject who 
had already been dosed on 2 previous occasions (with either GSK2838232 or 
placebo) was dosed for 2 days with RTV, and then on 05 May 2016 was dosed 
with either GSK2838232/r or placebo/r as scheduled. On the following day (06 
May 2016), the subject experienced an asymptomatic, 6-beat run of NSVT, 
which was classified at the time as an SAE. Further monitoring, including 
continuous Holter monitoring revealed no further events. The subject had no 
troponin elevation throughout the study. After additional investigation it was 
determined that the NSVT had occurred after the subject had received placebo 
the previous day. Although the subject had received active on the two prior 
visits, the protocol allowed for sufficient washout between each dose.  
Therefore, because the subject had received placebo prior to experiencing the 
NSVT, the event was not considered to be due to GSK2838232 exposure or a 
serious and unexpected suspected adverse reaction that would qualify for IND 
safety reporting.

In Part 2 (Cohort 6, 200mg/r), a 40 year old male enrolled in the study with no
significant medical history experienced an asymptomatic ventricular triplet 
(NSVT) while asleep at 5:33am on Day 8 (of 11 days worth of dosing) 
approximately 21 hours after receiving 200 mg GSK2838232/r on the previous 
day at 8.25am. This event was noted by the site staff and the subject was 
assessed and found to have no associated clinical symptoms or complaints. The 
GSK medical monitor was notified.  Because the subject was not symptomatic 
and this did not meet protocol-defined stopping criteria, the study was not 
unblinded at the time, and the subject was allowed to continue dosing. Dosing 
in the study is now complete and no further events have been noted. It was the 
assessment of the site PI and the GSK safety/monitoring team that a ventricular 
triplet can be seen in healthy volunteers on continuous Holter monitoring.
Therefore neither the PI nor GSK considered this event to be a serious and 
unexpected suspected adverse reaction.
2.2.2.2.
Study 204953 (completed); Pharmacokinetic Data
Study 204953 investigated the safety, tolerability, and PK of escalating doses of 
GSK2838232 as micronized API, with 100 mg RTV, initially as single doses and then as 
repeated doses for 11 days.  
 
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In addition, it evaluated the relative bioavailability of a single fasted dose of micronized 
API powder blend in capsules with RTV compared to powder-in-bottle for oral 
suspension with RTV and the effect of a normal fat meal on the bioavailability of a single 
dose of GSK2838232 in the capsule formulation with RTV.  It will evaluate 
GSK2838232 exposure after repeated doses of unboosted GSK2838232 in the capsule 
formulation. Noncompartmental PK analysis was performed using scheduled sample 
times.  The anaylsis of data from this study is ongoing; preliminary results are presented.
Pharmacokinetic analysis was performed on GSK2838232 plasma concentration-time 
data using nominal time following single doses of 50, 100, and 250 mg in combination 
with RTV in Part 1A of Study 204953 (Table 3).  On average, GSK2838232 Cmax 
values were reached 4-6 hours after dosing.  Terminal half-life values ranged from 15 to 
28 hours across the three dose levels.  Overall, broad dose proportionality was observed 
for Cmax and AUC(0-) values with ascending single doses of GSK2838232 (50, 100, 
and 250 mg with 100 mg RTV).
Table 3
Summary of Preliminary Pharmacokinetic Parameter Values after 
Single Doses of GSK2838232 in Combination with 100 mg Ritonavir 
(Study 204953, Part 1A)
Dose (mg)
n
t½ 
(h)
tlag 
(h)
tmax 
(h)
Cmax 
(ng/mL)
AUC(0-) 
(ng.h/mL)
50
8
22.7
(17%)
(17.2-28.5)
0.188
(138%)
(0-0.5)
3.63
(41%)
(2.5-6.0)
17.2
(43%)
(8.7-27.9)
458.6
(33%)
(210.6-662.0)
100
6
18.0
(14%)
(15.8-22.3)
0.167
(155%)
(0-0.5)
6.00
(59%)
(2.5-12.0)
25.2
(20%)
(17.5-31.5)
890.5
(20%)
(619.1-1053)
250
5
17.3
(6.4%)
(15.5-18.6)
0
(-)
(0-0)
5.50
(71%)
(2.0-12.0)
60.7
(23%)
(40.8-73.1)
1731
(29%)
(1222-2505)
Data are presented as mean (CV) (minimum-maximum).
Study 204953 Part 1B was an open label, 2x2+1 three-period, crossover design, 
evaluating the relative bioavailability of the micronized API GSK2838232 powder blend 
in capsules compared to the PiB reference formulation for the first two periods, with the 
assessment of food effect on the capsule formulation in Period 3.  
The relative bioavailability of the micronized powder blend in 50 mg hand-filled capsules 
compared to the micronized API as PiB for oral suspension was assessed as 100 mg 
GSK2838232 single doses with 100 mg RTV after two pre-doses (48 h) in the fasted state 
in a randomized crossover design in 12 subjects in the first two periods of Part 1B of 
Study 204953. Preliminary geometric mean AUC(0-) and Cmax values were 
approximately 45% and 60% higher, respectively, after administration in the capsule 
formulation compared to oral suspension from PiB (Table 4).
 
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Table 4
Preliminary Assessment of Relative Bioavailability of Capsule 
Formulation vs. Powder-in-Bottle Formulation of GSK2838232 (Study 
204953, Part 1B)
Parameter
Test
Reference
n
Ratio of Geometric 
Least Square Means
90% CIof Ratio
AUC(0-) 
Capsule
PiB
12
1.43
(1.194,1.702)
Cmax 
Capsule
PiB
12
1.58
(1.312,1.900)
PiB = powder-in-bottle.
The potential food effect with the capsule formulation was assessed as 100 mg 
GSK2838232 single doses with 100 mg RTV after two pre-doses (48 h) in the fasted state 
and with a normal fat meal in a non-randomized crossover design (fasted in either Period 
1 or 2, fed in Period 3).  Eleven subjects provided data for both dietary conditions.   
Preliminary geometric mean AUC(0-) and Cmax values were approximately 60% 
higher after administration in the capsule formulation with a normal fat meal compared to 
the fasted state (Table 5).
Table 5
Preliminary Assessment of the Effect of a Normal Fat Meal on 
GSK2838232 Exposure when Administered as a Capsule 
Formulation with Ritonavir (Study 204953, Part 1B)
Parameter
n
Capsule – food
Geometric mean
Capsule –
fasted
Geometric 
mean
Ratio of geometric 
means 
(food/fasted)
AUC(0-) (ng.h/mL)
11
2414
1539
1.57
Cmax (ng/mL)
11
76.9
47.2
1.63
Repeat dose PK parameter values in Study 204953 Part 2 were determined on Day 1 and 
Day 11 using nominal time in Part 2 of Study 204953 (Table 6). After the Day 11 dose of 
GSK2838232 with RTV, exposure (Cmax, AUC[0-]) appeared to increase 
proportionally with the increase in dose level with the PiB and capsule formulations. 
 
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Table 6
Summary of Preliminary Pharmacokinetic Parameter Values on 
Day 1 and Day 11 during Repeated Dosing of GSK2838232 in 
Combination with 100 mg Ritonavir (Study 204953, Part 2)
Dose 
(mg)
n
t½ 
(h)
tlag 
(h)
tmax 
(h)
Cmax 
(ng/mL)
AUC(0-) 
(ng.h/mL)
C
(ng/mL)
Study Day 1
20
(PiB)
6
-
0.417
(49%)
(0-0.5)
3.67
(11%)
(3.0-4.0)
12.2
(47%)
(5.8-20.8)
189.4
(40%)
(83.7-284.4)
6.1
(39%)
(2.5-8.9)
50
(PiB)
6
-
0.167
(155%)
(0-0.5)
3.00
(51%)
(2.0-6.0)
18.7
(40%)
(9.0-25.9)
288.7
(39%)
(138.6-380.2)
9.5
(35%)
(5.1-12.6)
100
(capsules)
6
-
0.167
(155%)
(0-0.5)
2.25
(23%)
(1.5-3.0)
48.4
(32%)
(28.1-69.6)
664.1
(31%)
(422.5-932.7)
21.6
(33%)
(12.8-29.3)
200
(capsules)
6
-
0.083
(245%)
(0-0.5)
2.50
(25%)
(2.0-3.5)
79.4
(38%)
(50.8-125)
1124
(39%)
(636.7-1794)
38.9
(36%)
(21.7-58.6)
Study Day 11
20
(PiB)
6
19.2
(16%)
(15.1-
24.2)
-
5.00
(32%)
(2.5-6.0)
27.4
(38%)
(11.3-40.4)
474.3
(31%)
(214.3-613.2)
15.3
(30%)
(7.1-19.2)
50
(PiB)
6
27.3
(52%)
(15.2-
50.4)
-
3.50
(46%)
(1.5-6.0)
58.0
(24%)
(40.9-78.0)
1113
(23%)
(762.6-1459)
38.8
(29%)
(24.5-51.7)
100
(capsules)
6
17.9
(18%)
(15.2-
23.7)
-
4.00
(40%)
(2.5-6.0)
133
(23%)
(94.7-164)
2492
(27%)
(1624-3301)
81.7
(30%)
(45.9-113)
200
(capsules)
6
-1
-
3.33
(45%)
(1.5-6.0)
240
(38%)
(127-368)
4389
(45%)
(2095-7161)
151
(46%)
(67.8-250)
Data are presented as mean (CV) (minimum-maximum).
1.
Concentration data were available up to 24 h after the Day 11 dose, and t½ values were not 
calculated.
2.2.2.3.
Overall Summary/Conclusions of PK data
The original formulation used in the first three studies with GSK2838232 (HMI116787, 
200207, and 200912) was SDD.  Data from Study 200912 demonstrated that a change to 
the API formulation of GSK2838232 was feasible for future clinical studies. Study 
204953 utilized micronized API powder in a bottle as well as in a capsule. The capsule 
was shown to be a viable solid dosage form for subsequent studies.  A more detailed 
summary of the data from Study 204953 is in Section 2.2.2.2.
 
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
GSK2838232 SDD did not overall demonstrate significant escalation in exposure 
from an increase in dose from 100 mg to 200 mg in a cross-study comparison.  The 
API PiB formulation showed a proportional increase in AUC and Cmax for a 2-fold 
dose escalation from 100 mg to 200 mg.

The observed tmax of the API form was significantly increased over the SDD 
formulation (the API formulation also increased tlag relative to SDD).

The bioavailability of the GSK2838232 API formulation was on average 30-50% of 
the bioavailability of SDD formulation, but there was a large observed range of 
relative intra-subject exposures (11-150%).

Both 10 mg SDD and 20 mg API showed a 10-fold or greater increase in AUC with 
steady-state RTV (100 mg QD for 10 days) with a smaller (≤4-fold) increase in 
observed Cmax.  The t½ of GSK2838232 increased from 15-18 hours to 34-42 
hours in the presence of steady-state RTV, regardless of formulation.

After single doses of 50 to 250 mg GSK2838232 with RTV, increases in Cmax and 
AUC(0-) values were broadly proportional to the increase in dose.  On Day 11 
after repeated daily 20 to 200 mg doses of GSK2838232 with RTV, increases in 
Cmax and AUC(0-) values appeared to be proportional to the increase in dose with 
the PiB and capsule formulations.  

The relative bioavailability of the micronized API powder blend in capsules with 
RTV was approximately 45%-60% higher than the bioavailability of the micronized 
API administered as oral suspension from PiB with RTV.

Co-administration of the micronized API powder blend in capsules with RTV and a 
normal fat meal resulted in an approximately 60% increase in geometric mean 
Cmax and AUC(0-) values compared to the fasted state with RTV (Study 
204953).

Variability remains fairly constant across formulations and boosted versus 
unboosted at around 30%-40% (moderate-high).

Projections of potential future efficacious boosted GSK2838232 API regimens 
suggest that doses of 20 to 200 mg GSK2838232 API co-administered with RTV 
will result in mean trough values of at least 3-fold above the derived 90% maximal 
inhibitory concentration (IC90) target value (5 ng/mL). Even if protein binding has 
more impact than envisaged and causes a 5-fold increase in IC90 as seen in some 
preclinical virology studies, the predicted troughs will still be significantly higher 
than the 5-fold shifted IC90 (25 ng/mL) at doses of 50 mg or higher with RTV. 

The average and maximum AUC/Cmax values observed at the maximum dose 
studied to date are below NOAEL values in preclinical chronic toxicology studies 
(6-month rat, 9-month dog).
 
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3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To evaluate antiviral activity of 
GSK2838232/cobi in HIV-1 infected patients 
during 10-days of monotherapy.

Maximum decline from baseline (Day 1) in 
plasma HIV-1 RNA 

To assess safety and tolerability of 
GSK2838232/cobi when administered as 
monotherapy over 10 days.

Safety and tolerability parameters, 
including adverse event, concurrent 
medication, clinical laboratory, 
electrocardiogram (ECG) and vital signs 
assessments.

To characterize pharmacokinetics (PK) of 
GSK2838232 in HIV-1 infected patients 
following GSK2838232/cobi dosing for 10 
days

GSK2838232 PK parameters following 
dose administration, as follows:
Day 1:  area under the plasma 
concentration time curve AUC(0-24), 
maximum observed concentration 
(Cmax), time to maximum observed 
concentration (tmax), concentration at 24 
hours post dose (C24), absorption lag 
time (tlag); 
Following last repeat administration on 
Day 10:  AUC(0-), pre-dose 
concentration (C0), concentration at end 
of dosing interval (C), Cmax, tmax, t½, 
and apparent oral clearance (CL/F), if 
data permit
Secondary

To explore the relationship between 
GSK2838232 exposure and change in 
plasma HIV-1 RNA

GSK2838232 PK parameters Day 10 
AUC(0-), Cmax, Cwith Day 11 HIV-1 
RNA change from baseline

To assess the immunologic effect of 
GSK2838232/cobi when administered over 
10 days in HIV-1 infected adults

Change from baseline in CD4+ cell count 
to Day 11

To explore the relationship between 
GSK2838232 exposure and safety or 
immunologic parameters, if appropriate.

GSK2838232 PK parameters on Day 10: 
AUC(0-), Cmax, C  with Day 11 change 
from baseline in CD4+ cell count

To assess the development of viral 
resistance (genotypic and phenotypic) over 
10 days and correlate with viral response, if 
appropriate.

Emergence of drug resistance mutations, 
if appropriate
 
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Objectives
Endpoints

To estimate GSK2838232 accumulation and 
to assess attainment of steady state 
following administration of 
GSK2838232/cobi for 10 days in HIV 
infected subjects.

Accumulation:
GSK2838232 PK accumulation ratios (R): 
Day 10 AUC(0-), Cmax, and C
compared to Day 1 AUC(0-24), Cmax, 
and C24, respectively

Steady State:
pre-morning dose concentrations (C0) on 
Day 2 through 11 

To examine dose proportionality of 
GSK2838232 PK parameters following 
GSK2838232/cobi dosing for 10 days in HIV 
infected subjects.

Day 1 AUC(0-24), Cmax, and C24, and 
Day 10 AUC(0-), Cmax and C  at 
different doses levels for the assessment 
of dose proportionality
Note: Other exploratory objectives and endpoints will be specified in the RAP
4.
STUDY DESIGN
4.1.
Overall Design
This is a Phase IIa, multicenter, open-label, adaptive dose ranging, study to evaluate the 
antiviral effect, safety, tolerability, and PK of GSK2838232/cobi monotherapy over 10 
days in HIV-1 infected adults who are not currently receiving ART therapy. Subjects who 
have received any  prior maturation ihibitor therapy will not be eligible for this study. To 
minimize the number of subjects exposed to suboptimal doses, an adaptive and dose 
ranging design is applied in this study.
This study consists of a screening visit, a 10-day treatment period, and follow-up 
evaluations for 2 weeks following last dose.
Screening will be performed as the patients are identified, within 30 days of the first dose 
of study drug.  Eligible HIV-1 infected subjects will receive study treatments for 10 days.
Table 7
Study Design for 200911
GSK2838232/cobi Once Daily for 10 days1,2
Part A
Part B 
Cohort 1
Dose
(mg)
Interim Analysis
Cohort
N
(mg)
N=10
100
2
8
200
3
8
50
4
8
20
 
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1.
Part A Cohort 1 safety/PK/virology data will be evaluated at interim, prior to initiating other cohorts in Part B.  All 
doses will be given with 150 mg cobicistat.
2.
Part B doses are an illustration of the projected doses per cohort. The actual doses for each cohort are subject to 
modification based upon safety, PK and antiviral activity data from Cohort 1 (Part A). More doses/cohorts 
(including potential removal of cobicistat co-dosing) may be added. (The maximum dose in Cohort B will likely not  
exceed 200 mg with cobicistat unless overall plasma exposure [as AUC and Cmax] is lower in HIV-infected 
subjects than in healthy subjects at the same dose level).
After successfully completing screening evaluations, the first cohort will enroll 10 
subjects to receive the 100 mg GSK2838232/cobi dose.  Following interim analysis of 
Cohort 1, if warranted, Cohorts 2-4 will each enroll 8 subjects to receive a range of 
GSK2838232/cobi doses.
Day 1 – Day 10: Dosing 
Subjects will report to the clinic for outpatient visits in the morning on Days 1 through 10 
during the treatment period, except for the weekend (Days 6 and 7).  Subjects will arrive 
each day prior to administration of the morning dose for safety and lab assessments, 
including HIV-1 RNA blood draws, as described in the Time and Events Table (Section 
7.1).  Subjects will begin receiving study drug in the morning of Day 1.  
Serial, intensive blood PK samples will be collected on Day 1 (up to 24 hours post-
morning dose) and Day 10 (up to 96 hours post-morning dose), and limited, single blood 
PK samples pre-morning doses on Days 3 through 9, except for the weekend. Subjects 
will be required to fast for 10 hours [overnight] prior to the morning check in on the 
intensive PK sampling days (Days 1 and 10).  All dosing days will require co-
administration of treatment with a light snack/meal per cobicistat labeling guidelines. All 
doses of study medication will be taken with 240 mL of water.  Subjects will be required 
to stay in the clinic on Days 1 and 10 until all specified assessments are completed (8-12 
hours post-dose). Following Day 10, subjects will be required to attend the clinic for 
follow up assessments including virological and PK blood sampling for up to 3 weeks.
Subjects will be given morning doses on Days 1 through 10 (except for the weekend) in 
the clinic.  Weekend morning doses (Days 6 and 7) will be packaged and sent home for 
self-administration.  After Day 11, the subjects will return frequently for assessments 
including blood draws for PK and HIV viral load. A diary card will be used to monitor 
dosing adherence.
Follow-up Visits:
Subjects will return to the clinic on Days 11, 12, 14 (1 day), and 21 (1 day) for PK and 
measurement of HIV-1 RNA levels, viral genotype/phenotype and safety assessments as 
shown in the Time and Events Table (Section 7.1). 
4.2.
Type and Number of Subjects
At least 34 subjects will be enrolled such that approximately 6-10 evaluable subjects 
complete a number of cohorts.  Additional subjects/cohorts may be enrolled to allow for 
evaluation of additional dose levels as appropriate. 
 
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If subjects prematurely discontinue the study, additional subjects may be randomized and 
assigned to the same treatment cohort at the discretion of the Sponsor in consultation with 
the Investigator.
4.3.
Design/Dose Justification
The fastest track to establishing antiviral potential of any novel HIV drug is to study a 
short course of monotherapy in HIV infected subjects. There is precedent for this across a 
number of classes of ART drugs. 
Uncertainties over the impact of protein binding on the activity of GSK2838232 and the 
inherent potency of inhibiting the HIV maturation process as a target remain key 
objectives for the GSK2838232 program. This two-part adaptive design will allow an 
early understanding of the potential of GSK2838232 in combination with cobicistat (and 
by implication, RTV), while not exposing HIV-infected subjects to longer courses of 
what may be suboptimal doses and possible development of resistance. 
Early clinical studies have indicated that in order to achieve reasonable IQ values likely 
to be associated with antiviral efficacy, GSK2838232 will need to be boosted with a 
pharmacoenhancer, such as RTV or cobicistat (in common with many CYP3A4 
substrates). 
There is no a priori intention to study GSK2838232 unboosted, unless: i) following the 
preliminary analysis of Part A Cohort 1, there is such pronounced antiviral activity that it 
would seem the estimates of projected IQ are low, in which case GSK2838232 may be 
evaluated in a subsequent cohort unboosted, or ii) the data from ongoing and planned 
healthy volunteer trials,Study 204953 (GSK2838232 200 mg BID unboosted) and Study 
205820 (GSK2838232 500mg QD unboosted) support it.
4.3.1.
GSK2838232 with Ritonavir
In Study HMI116787, a single dose of 10 mg GSK2838232 (SDD) given after 10 days of 
RTV 100 mg daily dosing (to steady state) demonstrated an increase in overall exposure 
(AUC) and Cmax by an average of 10.8- and 2.6-fold, respectively, compared to 10 mg 
GSK2838232 alone. Terminal phase half-life also increased from approximately 20 hours 
to 34 hours. This effect was presumably the result of an inhibition of a CYP3A4-
mediated pathway. Studies 200912 and 200207 also indicated the utility of RTV in 
boosting GSK2838232 concentrations.
These data indicate the viability of studying a number of GSK2838232+RTV regimens in 
this PoC study. Predicted exposures following different GSK2838232 doses with steady-
state RTV are presented in Table 8, based on the results of linear regression analyses of 
the preliminary Day 11 data in Study 204953 (dose levels of 20 to 200 mg) and assuming 
no significant differences in PK (ADME) between HIV-infected subjects and healthy 
subjects. 
 
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Table 8
Predicted Mean Steady-State GSK2838232 AUC(0-24), Cmax, and IQ, 
Following Repeated Dose Administration + RTV with Fold Cover to 
NOAEL
Dose 
(mg)
Projected AUC24 
(ng.h/mL)1
Fold cover to 
NOAEL Dog2
Projected 
Cmax 
(ng/mL)1
Fold cover to 
NOAEL Dog2
IQ3
20+RTV
451
36
24
35
3.1
50+ RTV
1127
14
61
14
7.7
100+ RTV
2253
7.2
122
6.9
15
150+RTV
3380
4.8
183
4.6
23
200+RTV
4506
3.6
244
3.5
31
1.
Predicted mean values based on linear regression analyses of preliminary Day 11 data in Study 204953.
2.
Lowest NOAEL, 20 mg/kg/day obtained from 9-month study in dogs (AUC24 16200 ng.h/mL and Cmax 847 
ng/mL)
3.
Mean IQs derived from predicted C/IC90 (with target of 5 ng/mL).
C= Pre-dose (trough) concentration at the end of the dosing interval, IQ= inhibitory quotient.
The IQ following 20 mg to 200 mg GSK2838232/r QD is predicted to be >3 to >30-fold 
above the minimal target value (5 ng/mL) which was derived from preclinical virological 
assessment as 4 × EC50. No protein binding adjustment has been made because there was 
a minimal (≤5 fold) shift in assays where the effect of protein was assessed. If protein 
binding has more impact than anticipated, it is possible that the target Cmin value is 
approximately 25 ng/mL. In that scenario, projected IQ values at 200 mg/r QD would still 
be >5.
4.3.2.
GSK2838232 with Cobicistat
There have been no preclinical or clinical studies with GSK2838232 and cobicistat to 
date; however, a review of the literature indicates that pharmacoenhancement of drugs 
that are known to have dominant CYP3A metabolic pathways is similar with either RTV 
or cobicistat [Kakuda, 2009; Elion, 2011; Gallant, 2013].  Thus, the use of cobicistat as 
the CYP3A4 inhibitor pharmacoenhancer in this Phase IIa study in place of ritonavir is 
expected to produce a similar profile of GSK2838232 ADME (and therefore systemic 
exposure).  The pharmacokinetic data available after Part A Cohort 1 will confirm this 
assumption.  
4.3.3.
Interim Analysis
An evaluation of GSK2838232 safety, efficacy and PK data will be done after Part A 
Cohort 1, if the exposure level of GSK2838232 is in the range of the maximum 
GSK2838232 exposure seen previously in healthy subjects and the Bayesian probability 
from Cohort 1 is less than 70%, the study will not move forward into Part B, otherwise 
doses will be selected for evaluation in Part B. If pharmacokinetic exposure after the 100 
mg GSK2838232/cobi dose is in the range of values observed after 100 mg 
GSK2838232/r in prior studies, the doses for Part B will be extended to both lower 
(20 mg and/or 50 mg) and higher (200 mg) doses. The highest dose tested in Part B will 
be selected to result in exposures similar to those seen with 200 mg/r in Study 204953.  
 
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4.4.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK2838232 can be found in the Investigator’s Brochure.  The following section 
outlines the risk assessment and mitigation strategy for this protocol:  
 
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4.4.1.
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) GSK2838232 
Cardiovascular
Pre-clinical studies have shown the following findings:  elevated heart rates, an 
isolated episode of non-sustained ventricular tachycardia and minimal to mild, 
sporadic troponin I elevations in dogs.  A subsequent investigative cardiovascular 
study in telemetered dogs treated for 4 weeks did not replicate these effects. 
Isolated microscopic cardiovascular changes were noted (focal extramural 
arteritis and localized epicardial inflammation), however these changes were 
considered of uncertain relationship to GSK2838232 because similar findings 
occur at low incidence in normal beagles and there were no GSK2838232-related 
functional changes by telemetry and echocardiography, or changes in cTpnI and 
NTproBNP.  In addition there was no correlation between histologic changes and 
plasma exposure or heart tissue concentrations of GSK2838232. 
3, 6 and 9 month toxicology studies in rat and dog did not demonstrate any 
evidence of cardiovascular injury or impact on cardiovascular function.
In the four GSK2838232 studies conducted so far there was no pattern of 
cardiovascular changes of clinical significance related to GSK2838232 and no 
clinically significant abnormality in electrocardiogram values other than the two 
SAEs documented and discussed.
Review of published bevirimat preclinical and clinical safety data indicates no 
significant toxicities or AEs of interest, other than a 30% incidence of 
gastrointestinal symptoms (including diarrhea). There were no significant 
cardiovascular AEs reported in published clinical studies.
Subjects will be clinically monitored for any signs 
of myocardial injury (chest pain, shortness of 
breath, pain with inspiration), elevated heart rate 
or arrhythmias. Samples for the assessment of 
troponin will be taken. Baseline EKG and Holter 
(to use for screening and for later comparisons if 
needed)
Exposures of GSK2838232 will be closely 
monitored in the clinical study so as to not 
exceed pharmacokinetic stopping criteria.  
 
 
 
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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Cobicistat (Tybost)
General
The cobicistat label includes the following information: 
TYBOST decreases estimated creatinine clearance due to inhibition of tubular 
secretion of creatinine without affecting actual renal glomerular function. This 
effect should be considered when interpreting changes in estimated creatinine 
clearance in patients initiating TYBOST
In one study investigating cobi+( atazanavir and tenofovir DF/emtricitabine) vs 
RTV+( atazanavir and tenofovir DF/emtricitabine), a higher frequency of reports 
of jaundice (6% and 3%) and ocular icterus (4% and 2%) were reported in the 
cobi group compared to the RTV group.  
Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, and 
triglycerides have been observed. The implications of these findings are 
unknown.
The vast majority of available safety data has been obtained in combination 
studies with other ART. There are no warnings of obvious cobicistat-related 
adverse events or safety concerns. 
Subjects will be closely monitored for any signs 
or symptoms potentially associated with 
cobicistat administration, in particularchanges in 
serum creatinine and liver chemistry.
HIV-1 Infection/Patient population
HIV Resistance
Propensity for co-meds and 
possible Drug-Drug
Interactions (DDIs)
HIV Drug Resistance to unique mechanism
Recognize HIV patients have a higher chance of comorbidities/diseases and a 
risk of taking a medicine or product contraindicated in the study
Closely monitor HIV viral load and genotypic 
resistance
Strict adherence to protocol criteria around 
concurrent meds 
 
 
 
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4.4.2.
Benefit Assessment
This study in HIV-1 infected but otherwise healthy subjects is a 10-day monotherapy 
design. It is anticipated that all subjects receiving GSK2838232 will experience anti-HIV 
effects whereby their (blood) HIV viral titres are reduced, until administration stops and 
the viral load returns to baseline levels. There is no expected longer term anti-HIV 
benefit to administration of GSK2838232.  Participation in this study contributes to the 
process of developing GSK2838232 and other new therapies for the treatment of HIV 
infection.
4.4.3.
Overall Benefit:Risk Conclusion
To date, 115 healthy subjects have received GSK2838232 in four completed studies.  
Subjects have received single doses up to 200 mg SDD alone (studies HMI116787 and 
200912), 250 mg API in combination with RTV (204953), and then in repeated daily 
doses of up to 50 mg SDD alone (200207) for 5 days or 200 mg in combination with 
RTV (204953) for 11 days.
There have been two cardiovascular SAEs reported from clinical studies where the 
subject was receiving GSK2838232 to date (one in 200207, one in 204953). Neither is 
thought likely to be due to GSK2838232.
There have been no other withdrawals due to drug-related AEs and no trends relative to 
laboratory toxicity.  One subject was withdrawn in Part 1A of 204953 because of low 
haemoglobin lab values, thought unrelated to study drug or study procedures.
With respect to CV effects, with the exceptions noted, there have been no clinically 
significant changes in troponin, heart rate, blood pressure, ECG, or telemetry monitoring.
Subjects will also be at risk for AEs from cobicistat use and will be monitored closely for 
such events.
Given the preclinical profile and the clinical profile to date, the overall risk to HIV-1 
infected but otherwise healthy subjects at the proposed GSK2838232 doses (with or 
without cobicistat) for 10 days is predicted to be low.  Mean exposures at the highest 
dose studied are not projected to exceed NOAEL values obtained in chronic toxicology 
studies, further reducing potential risk. 
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on the GSK investigational product or other study treatment that 
may impact subject eligibility is provided in the Investigator’s Brochure.
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
 
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Approximately 10-12 HIV-1 infected subjects will be enrolled into Part A. If warranted 
by an interim safety, virology and PK data analysis, approximately 8 subjects will be 
enrolled in each of Cohorts 2-4 in Part B. Eligible patients are those who are maturation 
inhibitor-naïve and who are not currently receiving ART therapy.
Additional subjects/cohorts may be enrolled to allow for evaluation of additional dose 
levels or configurations (e.g., GSK2838232 alone).
If subjects prematurely discontinue the study, additional subjects may be enrolled .
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
1.
Between 18 and 55 years of age inclusive, at the time of signing the informed 
consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2.
Healthy (other than HIV infection) male or female as determined by the investigator 
or medically qualified designee based on a medical evaluation including medical 
history, physical examination, laboratory tests and cardiac monitoring. Defined as no 
other chronic medical conditions and taking no chronic medications.
3.
A subject with a clinical abnormality or laboratory parameter(s) which is/are not 
specifically listed in the inclusion or exclusion criteria, outside the reference range 
for the population being studied may be included only if the investigator in 
consultation with the Medical Monitor agree and document that the finding is 
unlikely to introduce additional risk factors and will not interfere with the study 
procedures. 
4.
A creatinine clearance >80 mL/min as determined by Cockcroft-Gault equation 
[Cockcroft, 1976] CLcr (mL/min) = (140 – age) * Wt / (72 * Scr) (times 0.85 if 
female) where age is in years, weight (Wt) is in kg, and serum creatinine (Scr) is in 
units of mg/dL.
5.
Confirmed HIV positive; CD4+ cell count ≥350 cells/mm3 and plasma HIV-1 RNA 
≥5000 copies/mL at Screening. 
6.
Antiretroviral treatment naive or ART-experienced (maturation inhibitor naive). No 
current ART (last dose completed at least 6 weeks prior to the first dose of study 
drug). A previous course of pre- or post-exposure prophylaxis is allowed provided 
that it was completed at least 6 weeks prior to the first dose of study drug. NOTE: 
Subjects with limited therapeutic options, including but not limited to those who 
have failed ≥2 antiretroviral regimens for any reasons or have documented resistance 
to >2 classes of antiretrovirals or have interrupted their treatment due to resistance, 
will not be eligible.
 
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WEIGHT
7.
Body weight 50 kg (110 lbs.) for men and 45 kg (99 lbs) for women and body 
mass index (BMI) within the range 18.5-35.0 kg/m2 (inclusive)
SEX
8.
Male or Female
A female subject of reproductive or non-reproductive potential is eligible to 
participate if she is not pregnant (as confirmed by a negative serum or urine human 
chorionic gonadotrophin (hCG) test at screening and prior to first dose), not 
lactating, and at least one of the following conditions applies:
Reproductive potential:
Females of reproductive potential may only be enrolled if they are using two forms 
of complementary contraception, which must include one barrier method. They will 
be counselled on safer sex practices
There is no definitive DDI information with GSK2838232 and an interaction with 
oral contraceptives is possible, so other (barrier, inter-uterine device etc.) methods of 
contraception will be required.
Fertile females, who have an established, long-term lifestyle of sexual abstinence, or 
only same sex partners, require no other means of birth control.  
Non-reproductive potential:

Pre-menopausal females with one of the following:

Documented tubal ligation

Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion 

Hysterectomy

Documented Bilateral Oophorectomy

Postmenopausal defined as 12 months of spontaneous amenorrhea in 
questionable cases a blood sample with simultaneous follicle stimulating 
hormone (FSH) and estradiol levels consistent with menopause (refer to 
laboratory reference ranges for confirmatory levels).  Females on hormone 
replacement therapy (HRT) must discontinue HRT to allow confirmation of 
post-menopausal status prior to study enrolment.
Male subjects with female partners of child bearing potential must comply with the 
following contraception requirements from the time of first dose of study medication 
until one week after the last dose of study medication.
a. Vasectomy with documentation of azoospermia.  
b. Male condom plus partner use of one of the contraceptive options below:

Contraceptive subdermal implant that meets the SOP effectiveness criteria 
 
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including a <1% rate of failure per year, as stated in the product label

Intrauterine device or intrauterine system that meets the SOP effectiveness 
criteria including a <1% rate of failure per year, as stated in the product 
label

Oral contraceptive, either combined or progestogen alone or Injectable 
progestogen 

Contraceptive vaginal ring 

Percutaneous contraceptive patches
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label.  The investigator is responsible 
for ensuring that subjects understand how to properly use these methods of 
contraception.
INFORMED CONSENT
9.
Capable of giving signed informed consent as described in Section 10.2, which 
includes compliance with the requirements and restrictions listed in the consent form 
and in this protocol.
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
1.
Alanine aminotransferase (ALT) and BIL >1.5xupper limit of normal (ULN; isolated 
BIL >1.5xULN is acceptable if BIL is fractionated and direct BIL <35%). 
2.
Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones); HBV and/or 
HCV positive.
3.
Subjects who have any other chronic medical condition, including CV, respiratory, 
neurologic, psychiatric, renal, gastrointestinal (GI), oncologic, rheumatologic, or 
dermatologic
4.
Medical history of cardiac arrhythmias or cardiac disease or a family or personal 
history of long QT syndrome.
 
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CONTRAINDICATIONS 
5.
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.
RELEVANT HABITS 
6.
Chronic marijuana or use of other elicit medications (cocaine, heroin) is an exclusion 
criteria.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
7.
Presence of hepatitis B surface antigen (HBsAg), positive (confirmed by 
Recombinant Immuno-Blot Assay [RIBA]) hepatitis C antibody test result at 
screening or within 3 months prior to first dose of study treatment.
8.
Screening or baseline cardiac troponin I greater than the 99% cutoff (>0.045 ng/mL 
by the Dimension Vista CTNI assay).
9.
A positive pre-study drug/alcohol screen.  
10. Prior history of receiving an HIV maturation inhibitor
11. Where participation in the study would result in donation of blood or blood products 
in excess of 500 mL within 56 days.
12. The subject has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day in the current 
study: 30 days, 5 half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer).
13. Exposure to more than four new chemical entities within 12 months prior to the first 
dosing day.
14. Treatment with radiation therapy or cytotoxic chemotherapeutic agents within 
30 days of study drug administration or anticipated need for such treatment within 
the study.
15. Treatment with immunomodulating agents (such as systemic corticosteroids, 
interleukins, interferons) or any agent with known anti-HIV activity (such as 
hydroxyurea or foscarnet) within 30 days of study drug administration.
16. An active Center for Disease Control and Prevention (CDC) Category C disease 
except cutaneous Kaposi’s sarcoma not requiring systemic therapy during the trial.
17. Treatment with any vaccine within 30 days prior to receiving study medication.
18. Exclusion Criteria for 24-Hour Screening Holter:

Any symptomatic arrhythmia (except isolated extra systoles).

Sustained cardiac arrhythmias (such as atrial fibrillation,flutter or 
supraventricular tachycardia (10 seconds)

Non-sustained or sustained ventricular tachycardia (defined as 3 consecutive 
 
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ventricular ectopic beats).

Any conduction abnormality including but not specific to left or complete 
bundle branch block, atrioventricular [AV] block, high grade or complete heart 
block Wolff-Parkinson-White [WPW] syndrome etc.).

Sinus Pauses >3 seconds.
19. Exclusion criteria for screening ECG (a single repeat is allowed for eligibility 
determination):
Males
Females
Heart rate
<45 and >100 bpm
<50 and >100 bpm
PR Interval
<120 and >220 msec
QRS duration
<70 and >120 msec
*QTc interval
>450 msec
*The QTc is the QT interval corrected for heart rate according to Bazett’s formula 
(QTcB), Fridericia’s formula (QTcF), and/or another method. It is either machine-
read or manually over-read. The specific formula used to determine eligibility and 
discontinuation for an individual participant in 200911 will be Fridericia’s formula. 

Note: A heart rate from 100 to 110 beats per minute (bpm) can be rechecked by 
ECG or vitals within 30 minutes to verify eligibility.

Evidence of previous myocardial infarction (Does not include ST segment 
changes associated with repolarization).

Any conduction abnormality (including but not specific to left or right complete 
bundle branch block, AV block [2nd degree or higher], WPW syndrome).

Sinus Pauses >3 seconds.

Any significant arrhythmia which, in the opinion of the principal investigator 
OR GSK medical monitor, will interfere with the safety for the individual 
subject. 

Non-sustained or sustained ventricular tachycardia (3 consecutive ventricular 
ectopic beats).
5.3.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and any SAEs.
 
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5.4.
Withdrawal/Stopping Criteria
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as 
soon as possible. 

The site must counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or should 
continue in the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and if necessary a certified letter to the subject’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be considered 
to have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this request has 
occurred in the site study records. 
5.4.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
 
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Phase II Liver Chemistry Stopping and Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus
Bilirubin≥2x
ULN (>35% 
direct) 
or plus
INR>1.5, if 
measured*
Possible
Hy’s Law
ALT≥3xULN
ALT≥5xULN
ALT≥3xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
ALT≥3xULN
but able to 
monitor 
weekly for 
4 weeks
No
Yes
Yes
Yes
Yes
No
No
No
No
Yes
ALT≥3xULN
persist for
4 weeks or 
stopping 
criteria 
met
Yes
No
*INR value not applicable to subjects on anticoagulants
Yes
If subject to be monitored weekly must refer to Liver Safety Required  Actions and  Follow  up 
Assessments  section  in  the  Appendix
Must refer to Liver Safety Required Actions and Follow  up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 2, Section 12.2 and Section 12.3. 
5.4.1.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed.
5.4.2.
QTc Stopping Criteria

The same QT correction formula must be used for each individual subject to 
determine eligibility for and discontinuation from the study.  This formula may 
not be changed or substituted once the subject has been enrolled.

For example, if a subject is eligible for the protocol based on QTcB, then QTcB 
must be used for discontinuation of this individual subject as well.

Once the QT correction formula has been chosen for a subject’s eligibility, the 
same formula must continue to be used for that subject for all QTc data being 
collected for data analysis.  Safety ECGs and other non-protocol specified 
ECGs are an exception.  

The QTc should be based on single or averaged QTc values of triplicate ECGs 
obtained over a brief (e.g., 5-10 minutes) recording period.  
A subject who meets either of the bulleted criteria below will be withdrawn from the 
study:
 
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
QTc >500 msec OR Uncorrected QT >600 msec

Change from baseline of QTc >60 msec
5.5.
Stopping criteria based on Adverse Events
Any grade 3 or higher treatment-related adverse events that occur in ≥2 subjects will be 
carefully reviewed and if considered clinically significant, dosing will be halted pending 
further discussion with the FDA.  Any single treatment-related SAE will also trigger 
immediate evaluation and reporting processes in accordance with applicable regulations.
5.6.
Subject and Study Completion
A completed subject is one who has completed all phases of the study including the 
follow-up visit.
The end of the study is defined as the last subject’s last visit.
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.
Treatment
Product name:
GSK2838232 
Capsule (API)
Tybost 
(cobicistat, cobi) tablet
Formulation 
description:
GSK2838232 powder blend in a 
capsule
Tablet
Dosage form:
Swedish orange, unmarked 
capsules (50 mg), and white, 
unmarked capsules (10 mg)
Orange, round, biconvex, film-coated 
tablets debossed with “GSI” on one side 
and plain faced on the other side 
providing 150 mg of cobicistat.
Unit dose strength(s)/
Dosage level(s):
50 mg capsule for 200 mg, 100 mg, 
50 mg doses and 10 mg capsule for 
20 mg doses 
150 mg for 150 mg doses
Route/
Administration/
Duration:
Administered orally QD for 10 days
Administer orally, QD for 10 days
 
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Treatment
Product name:
GSK2838232 
Capsule (API)
Tybost 
(cobicistat, cobi) tablet
Dosing instructions:
Administer with light meal and 240 
mL of water. 
Administer with light meal and 240 mL 
water.
Manufacturer/
source of 
procurement:
GSK
Gilead
Method for 
individualizing dosage:
Capsules supplied in high-density 
polyethylene bottles for 
individualized dosing by the clinic
Tablets supplied in bulk containers for 
individualized dosing by the clinic
6.2.
Treatment Assignment
Subjects will be assigned to treatment (active) groups in accordance with the 
randomization schedule generated by Clinical Statistics, prior to the start of the study, 
using validated internal software.
6.3.
Planned Dose Adjustments
Following the interim analysis of safety, virology and PK data from the first cohort of 
subjects in Part A, the option to adjust dose levels from those described exists. No dose 
will be administered that has an associated projected mean AUC or Cmax value higher 
than the most conservative NOAEL obtained from the chronic toxicity studies (i.e., from 
the 9-month dog toxicity study described in Section 2.2.1).
6.4.
Blinding
This will be an open-label study. Treatment allocation and GSK2838232 dose levels in 
Part B will be determined after the analysis of Part A data.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.5.
Preparation/Handling/Storage/Accountability
A description of the methods and materials required for capsule/tablet storage and 
dispensing will be detailed in a Study Specific Technical Agreement/Memo or Pharmacy 
Manual, which will be accompanied by a Quality Agreement.
No special preparation of study treatment is required.

Only subjects enrolled in the study may receive study treatment and only
authorized site staff may supply or administer study treatment.  All study 
treatments must be stored in a secure environmentally controlled and monitored 
 
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(manual or automated) area in accordance with the labelled storage conditions 
with access limited to the investigator and authorized site staff. 

The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation and final disposition records).

Further guidance and information for final disposition of unused study treatment 
are provided in the study reference manual (SRM). 

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  

A Material Safety Data Sheet/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.
6.6.
Compliance with Study Treatment Administration
When subjects are dosed at the site, they will receive study treatment directly from the 
investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents.  The dose of study 
treatment and study subject identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study treatment.  
When subjects self-administer study treatment(s) at home, compliance with study 
treatment(s) will be assessed through querying the subject during the site visits and 
documented in the source documents and case report form (CRF).  A record of the 
number of study treatment(s) dispensed to and taken by each subject must be maintained 
and reconciled with study treatment and compliance records.  Treatment start and stop 
dates, including dates for treatment delays and/or dose reductions will also be recorded in 
the CRF.
6.7.
Treatment of Study Treatment Overdose
For this study, any dose of GSK2838232 >200 mg+cobicistat within a 28-hour time 
period will be considered an overdose.
GSK does not recommend specific treatment for an overdose; however, in the event of an 
overdose, the investigator or treating physician should:

Contact the Medical Monitor immediately

Closely monitor the subject for AEs/SAEs and laboratory abnormalities until 
GSK2838232 can no longer be detected systemically (at least 10 days for 
GSK2838232)

Obtain a plasma sample for PK analysis within 2 days from the date of the last dose 
of study treatment if requested by the Medical Monitor (determined on a case-by-case 
basis)
 
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
Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the subject.
6.8.
Treatment after the End of the Study
Subjects receiving GSK2838232 may opt to receive marketed antiretrovirals after the 
completion of 10 days of GSK2838232 dosing and study follow-up visits (through 
Day 21) eligible for sponsor company reimbursement up to a maximum of 90 days. The 
selection of antiretrovirals will be investigator-chosen.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing 
reimbursement for post-study treatment.
6.9.
Lifestyle and/or Dietary Restrictions
6.9.1.
Meals and Dietary Restrictions

Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit juice 
from 7 days prior to the first dose of study medication until after the final dose.

Doses will be given in the fed state (light breakfast), following overnight fasting 
(>10 hours). 
6.9.2.
Alcohol, Caffeine and Exercise

During  the study  alcohol consumption should be limited to the following:

An average weekly intake of <14 drinks for males or <7 drinks for females.  One 
drink is equivalent to 12 g of alcohol: 12 ounces (360 mL) of beer, 5 ounces 
(150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.

Subjects should abstain from strenuous exercise during the treatment period.
6.10.
Contraception
Female subjects can be of childbearing or non-child bearing potential.  
Females of reproductive potential may only be enrolled if they are using two forms of 
complementary contraception, which must include one barrier method.  Although use of 
oral contraceptives is permitted, there is no definitive DDI information with 
GSK2838232 and an interaction with oral contraceptives is possible, so other (barrier, 
inter-uterine device etc.) methods of contraception will be required.
Females of reproductive potential, who have an established, long-term lifestyle of sexual 
abstinence, or only same sex partners, require no other means of birth control.  
Male subjects with female partners of child bearing potential must comply with the 
following contraception requirements from the time of first dose of study medication 
until one week after the last dose of study medication:
 
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1. Vasectomy with documentation of azoospermia. The documentation on male 
sterility can come from the site personnel’s review of subject’s medical records, 
medical examination and/or semen analysis, or medical history interview.
OR
2. Male condom plus partner use of one of the contraceptive options below that 
meets the SOP effectiveness criteria including a <1% rate of failure per year, as 
stated in the product label:
- Contraceptive subdermal implant
- Intrauterine device or intrauterine system
- Combined estrogen and progestogen oral contraceptive 
- Injectable progestogen
-Contraceptive vaginal ring 
- Percutaneous contraceptive patches 
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
6.11.
Concomitant Medications and Non-Drug Therapies
6.11.1.
Permitted Medications and Non-Drug Therapies

Acetaminophen at doses of 2 grams/day or NSAIDs are permitted for use any time 
during the study and their use documented in the CRF.  Other concomitant 
medication may be considered on a case by case basis by the investigator in 
consultation with the Medical Monitor if required.

Concomitant medications (prescription and non-prescription) should be administered 
only as medically necessary during the study. Subjects must notify their Investigator 
of any current or proposed concomitant medication, whether prescribed or over-the-
counter, because of the potential for interactions between such treatments and the 
study medications.
6.11.2.
Prohibited Medications and Non-Drug Therapies

Subjects must refrain from all illicit drugs throughout the study (from Screening until 
discharge from the study).  Drug screening will occur at Screening and Day -1 and at 
additional timepoints throughout the study.  A positive result will lead to exclusion 
from the remainder of the study.
7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table (Section 7.1), are essential and required for study 
conduct.
 
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This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table Section 7.1. In 
overview, subjects will be screened, begin dosing and then continue assessments through 
and for up to 2 weeks after the completion of dosing.
The following points must be noted: 

If assessments are scheduled for the same nominal time, THEN the assessments 
should occur in the following order:
1. 12-lead ECG
2. vital signs
3. blood draws.  
Note: The timing of the assessments should allow the blood draw to occur at the 
exact nominal time.
 
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7.1.
Time and Events Table
Day:
Screen1
Random
1
2
3
4
5
62
7
8
9
10
11
12
141
211 
(FU)
ET
Informed Consent
X
Review inclusion/exclusion
X
X
Demography including height, weight 
and BMI
X
Brief physical
X
Medical/medication/
drug/alcohol history
X
X
CDC Classification
X
X
X
X
Prior antiretroviral therapy
X
12-lead ECG3
X
X
X
X
X
X
X
X
X
Holter (24 hr)
X
Vital signs4
X
X
X
X
X
X
X
X
X
Drug screen
X
X
X
X
X
Hepatitis B Surface antigen and 
hepatitis C antibody testing
X
Serum or urine -hCG (WoCBP only)
X
X
X
Clinical lab tests (inc troponin)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Fasting lipid panel
X
X
AE assessment5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Con Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HIV-1 RNA PCR6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lymphocyte subsets7
X
X
X
Plasma for genotype/phenotype8
X
X
X
X
X
X
X
HIV-associated conditions assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK blood sample9
X
X
X
X
X
X
X
X
X
X
X
X14
Plasma samples10
X
X
X
Dosing11
X
X
X
X
X
X
X
X
X
X
PGx12
X
 
 
 
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Day:
Screen1
Random
1
2
3
4
5
62
7
8
9
10
11
12
141
211 
(FU)
ET
Telephone call to IVRS13
X
X
X
Plasma for storage15
X
X
X
X
X
X
X
X
X
X
X
X
X
Outpatient visit
X
X
X
X
X
X
X
X
X
X
X
X
1.
Screening will occur within 14 - 30 days prior to the first dose of study drug.
2.
Table is set up for the weekend during dosing to occur on Days 6 and 7.  If the weekend occurs on Days 5 and 6, perform all “Day 5” assessments on Day 7.
3.
On Day 1, ECGs will be performed pre-dose , and then 1, 1.5, 2, 3, 4 and 6 hours post dose.  The ECGs should be performed at least 5 minutes apart and preferably within 1 
hour prior to dose.  On Days 4 and 8, ECGs will be obtained prior to morning dosing and at 2, 4 and 6 hours post-dose. To accommodate scheduling, serial ECGs collected on 
Days 4 and 8 may be performed 1 day. On Day 10, ECGs will be performed pre-dose, and then 1, 1.5, 2, 3, 4 and 6 hours post dose.  On Day 11, an ECG will be obtained 
prior to the 24-hour PK sample. ECGs will be performed in triplicate at all timepoints. 
4.
BP, RR, HR and temperature will be obtained at Screening (x1) and Day 1 pre-dose (x2).  BP and HR will be obtained on Day 1 at 2 hours post-morning dose and on Days 4, 5 
and 8 pre-dose.  BP and HR will be obtained on Day 10 at pre-dose and 2 hours post-morning dose, and at day 12 and Follow-up (Day 21).
5.
Only SAEs related to study participation will be collected between screening and Day 1. An AE enquiry will be made at each visit, subjects will be asked if they have 
experienced any neuropsychiatric adverse events, including psychosis or altered mental status.
6.
On Days 1-5 and 8-10 samples for HIV-1 RNA PCR collected before morning dose.  On Days 1, 10 and 11 two samples for HIV-1 RNA PCR will be collected 5-30 minutes 
apart.  HIV-1 RNA PCR samples will also be collected on days 12, 14 & Follow-up (Day 21).
7.
Lymphocyte subsets by flow cytometry (total lymphocyte counts, percentage, and absolute CD4+and CD8+counts).
8.
Blood samples for phenotype and genotype will be collected at pre-dose on Days 1, 4, 5 and 8 in the morning on Day 11 and at follow-up. 
9.
Serial plasma samples (2 mL) for determination of GSK2838232 will be collected on Day 1 and Day 10 at pre dose (within 15 minutes prior to dose) and 0.5, 1, 1.5, 2, 3, 4, 6, 
8, 12 (optional), and 24 hours (to occur on morning of Day 2 post-am dose and in the morning on Day 11) .  Pre-dose PK samples (within 15 minutes prior to dose) will be 
taken on the mornings of Days 3, 4, 5, 8 and 9 and a single sample will be taken on Days 12 and 14.
10. Samples (2 x 0.5mL) of plasma for assessment of immunological markers at screen, baseline (pre-dose) and day 11 
11. Subjects will receive a single dose of GSK2838232 and cobicistat each morning with a light breakfast meal and 240 mL of water from Day 1 to Day 10.  Doses taken in the 
clinic will be administered after an overnight fast of at least 10 hours .On Days 6 and 7, doses will be self administered but confirmed by phone 
12. PGx sample should be collected on Day 1.
13. A screening/registration call should be made to the IVRS to register the subject at screening.   An additional call will be made to document a screen failure.   A randomization 
call should be made to the IVRS system approximately one week prior to scheduled Day 1.  Note: The randomization call must be made in order to have study drug on site for 
Day 1. Additional calls will be made every day that the subject has a scheduled study visit to the clinic.  If a subject terminates the study prematurely a call should be made to 
the IVRS
14. Only if early termination visits occur during the treatment period.
15. Plasma samples for storage will be collected at each visit starting at Day 1, including unscheduled visits (e.g. for HIV-1 RNA levels and immunological parameters).  
Additionally these samples will be used when needed, such as when samples are lost or arrive at the laboratory unevaluable.
AE = Adverse event; CDC= Center for Disease Control and Prevention; ECG = Electrocardiogram; ET = Early termination; hCG = Human chorionic gonadotrophin; HIV = Human 
immunodeficiency virus;  IVRS= Interactive Voice Response System; PCR = Polymerase chain reaction; PK=Pharmacokinetic.
 
 
 
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7.2.
Visit Windows
Screening (baseline to pre-dose): All screening assessments should take place within 
14-21 days prior to the first dose. The screening visit window may be extended to 30 
days upon discussion with the Medical Monitor (i.e.; subject has scheduling conflicts or 
any screening assessment needs to be repeated).
Days 4 and 8: Based on subject and clinic schedule, Day 4 and Day 8 serial (up to 6h 
post-dose) ECG assessments may be conducted 1 day. 
Weekend(s): The T&E table is set up for study start (Day 1) to occur on a Monday and 
Days 6 and 7 to fall on the weekend. If the weekend occurs instead on Days 5 and 6, Day 
5 assessments should be performed on Day 7. The study start (Day 1) may also be 
adjusted to allow visits with assessments to be conducted over the weekend based on 
subject and clinic schedule.  
Assessments: The following applies to timing of procedures:
-
Window for assessments 4 h post-dose = 5 minutes 
-
Window for assessments >4 and < 12 h post-dose = 15 minutes
-
Window for assessments >12 h post-dose = 30 minutes
End of Treatment visit: should be within 14 days from last dose of study drug. If a 
subject is unable to return to the clinic for any reason site staff are encouraged to 
telephone the subject for assessment of adverse events.
7.3.
Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed at 
screening.
The following demographic parameters will be captured: year of birth, sex, race, and 
ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria.
Procedures conducted as part of the subject’s routine clinical management (e.g., blood 
count) and obtained prior to signing of informed consent may be utilized for Screening or 
baseline purposes provided the procedure meets the protocol-defined criteria and has 
been performed in the timeframe of the study.
7.3.1.
Holter Monitoring (Screening criteria)
The 24-hour Holter monitoring will be performed during the Screening period using a 
Holter monitoring device supplied by the Sponsor.
 
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Analysis of the Holter tapes will consider the following:

Heart rate (bradycardia and tachycardia)

Normal and aberrant beats

Number of supraventricular contractions, premature atrial contractions, premature 
ventricular contractions, couplets, triplets, and ventricular tachycardias

Atrio-ventricular conduction defects

Atrial fibrillation and flutter
7.4.
Efficacy
7.4.1.
HIV-1 RNA Sampling
Plasma for quantitative HIV-1 RNA will be collected at timepoints listed in the Time and 
Events Table in Section 7.1. To reduce sample variability, two plasma HIV-1 RNA 
samples will be collected on Days 1, 10, and 11.
An HIV-1 RNA PCR assay with a lower limit of detection (LLOD) of 50 copies/mL 
(ultrasensitive assay) will be used for post-baseline assessments. An HIV-1 RNA PCR 
assay with a LLOD of 400 copies/mL (standard assay) will be used for screening and 
baseline assessments and will include a re-test with and ultrasensitive assay for all 
baseline values below the LLOD. An HIV-1 RNA PCR assay with a LLOD of 2 
copies/mL (supersensitive assay) may be used for exploratory analysis.
7.4.2.
Lymphocyte Subsets by Flow Cytometry
Whole venous blood samples will be obtained from each subject for the analysis of 
lymphocyte subsets by flow cytometry at the timepoints listed in the Time and Events 
Table in Section 7.1.
Details concerning the handling, labeling and shipping of these samples will be supplied 
separately.
7.5.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).  Additional time points for safety tests (such as vital signs, physical exams 
and laboratory safety tests) may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring.
7.5.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 5, Section 12.5.
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
 
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7.5.1.1.
Time period and Frequency for collecting AE and SAE information

AEs and SAEs will be collected from the start of Study Treatment until the 
follow-up contact (see Section 7.5.1.3), at the timepoints specified in the Time 
and Events Table (Section 7.1). An AE enquiry will be made at each visit, where 
subjects will be specifically asked if they have experienced any neuropsychiatric 
adverse events, including psychosis or altered mental status  

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF.

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded from the time a subject consents to participate in the 
study up to and including any follow-up contact. 

All SAEs will be recorded and reported to Sponsor within 24 hours, as indicated 
in Appendix 5, Section 12.5.

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the 
investigator must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 5
7.5.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?”

“Have you experienced any alteration in personality, behaviour, mood or any 
altered mental status?”
7.5.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, and non-serious AEs of special interest 
(as defined in Section 12.5) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
 
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(as defined in Section 5.4). Further information on follow-up procedures is given in 
Appendix 5.
7.5.1.4.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 5 (Section 12.5.3) and all deaths, 
whether or not they are considered SAEs, specific CV and Death sections of the CRF will 
be required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed 
within one week of when the death is reported.
7.5.1.5.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
The following disease-related events (DREs) are common in subjects with HIV-1 
infection and can be serious/life threatening:

events or outcomes listed in the CDC Classification System for HIV-1 Infections 
(see Appendix 9; Section 12.8)

sign, symptom, diagnosis, illness, and/or clinical laboratory abnormality that can 
be linked to any of these events or outcomes
Because these events are typically associated with the disease under study, they will not 
be reported according to the standard process for expedited reporting of SAEs to GSK 
(even though the event may meet the definition of a serious adverse event). 
These events will be recorded on the DRE page in the subject’s CRF using the HIV 
Associated Conditions eCRF. These DREs will be monitored by the medical monitor and 
study team on routine basis.
However, if any of the following conditions apply, then the event should be reported as 
an SAE using the standard process:

The event is, in the Investigator’s opinion, of greater intensity, frequency, or 
duration than expected for the individual subject, 
or

The Investigator considers that there is a reasonable possibility that the event was 
related to treatment with the investigational product.
or
 
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
Death occurring for any reason during a study, including death due to a disease 
related event, will always be reported promptly. 
If either of the above conditions is met then record the DRE on the SAE page rather than 
the HIV Associated Conditions eCRF page and report promptly to GSK.
7.5.1.6.
Regulatory Reporting Requirements for SAE
Prompt notification by the investigator to GSK or designee of SAEs and non-serious AEs 
related to study treatment (even for non- interventional post-marketing studies) is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a product under clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.5.2.
Pregnancy

Details of all pregnancies in female subjects and if indicated female partners of 
male subjects will be collected after the start of dosing and until one week post 
study

If a pregnancy is reported then the investigator should inform GSK within 24hrs 
of learning of the pregnancy and should follow the procedures outlined in 
Appendix 7, Section 12.6.
7.5.3.
Physical Exams

A complete physical examination will include, at a minimum, assessment of the 
Cardiovascular, Respiratory, GI 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 should pay special attention to clinical signs related to previous 
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7.5.4.
Vital Signs

Vital signs will be measured in semi-supine position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure and pulse rate 

Three readings of blood pressure and pulse rate will be taken

First reading should be rejected

Second and third readings should be averaged to give the measurement to be 
recorded in the CRF. 
7.5.5.
Electrocardiogram (EGC)

Triplicate 12-lead ECGs will be obtained at each timepoint during the study using 
an ECG machine that automatically calculates the heart rate and measures PR, 
QRS, QT, and QTc intervals.  Refer to Section 5.4.2 for QTc withdrawal criteria 
and additional QTc readings that may be necessary.
7.5.6.
Clinical Safety Laboratory Assessments
All protocol-required laboratory assessments as defined in the Tables below must be 
conducted in accordance with the SRM and Protocol Time and Events Schedule (Section 
7.1). Laboratory requisition forms must be completed and samples must be clearly 
labelled with the subject number, protocol number, site/centre number, and visit date.
Details for the preparation and shipment of samples will be provided by the laboratory 
and are detailed in the SRM. Reference ranges for all safety parameters will be provided 
to the site by the laboratory responsible for the assessments.
If additional non-protocol-specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the CRF.
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
All study-required laboratory assessments will be performed by a central laboratory:
NOTE:  Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either a treatment and/or response evaluation to be 
performed. 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 treatment or response evaluation, the results must be entered in the CRF.
 
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Haematology, clinical chemistry, urinalysis, and additional parameters to be tested are 
listed below. 
Table 9
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
WBC count with Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes with T-cell 
subsets
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry 1
BUN
Potassium
AST (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose 
Bicarbonates
Alkaline phosphatise
Albumin
Troponin I
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

HIV

Hepatitis B (HBsAg)

Hepatitis C (Hep C antibody)

FSH and estradiol (as needed in women of non-child bearing 
potential only)

Alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines)

Urine hCG Pregnancy test (as needed for women of child bearing 
potential) 2
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 12.2 and Section 12.3
2.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or 
ethics committee.
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study or within 7 days after the last dose of study treatment 
should be repeated until the values return to normal or baseline.  If such values do not 
return to normal within a period judged reasonable by the investigator, the etiology
should be identified and the sponsor notified.
 
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7.6.
Pharmacokinetics
7.6.1.
Blood Sample Collection
Blood samples for analysis of GSK2838232 concentrations will be collected at the time 
points indicated in Time and Events Tables (Section 7.1).  
The actual date and time of each blood sample collection will be recorded.  The timing of 
PK samples may be altered and/or PK samples may be obtained at additional time points 
to ensure thorough PK monitoring.  
Details of PK blood sample collection (including volume to be collected), processing, 
storage and shipping procedures are provided in the Study Reference Manual (SRM).
7.6.2.
Sample Analysis
Plasma analysis will be performed by Covance, Madison under the control of 
Bioanalysis, Immunogenicity and Biomarkers (BIB), PTS, GlaxoSmithKline.
Concentrations of GSK2838232 will be determined in plasma using the currently 
approved bioanalytical methodology. 
Once the plasma has been analyzed for GSK2838232 any remaining plasma may be 
analyzed qualitatively for other circulating metabolites and these results would be 
reported under a separate PTS protocol.
Raw data will be archived at the Covance, Madison facility.
7.7.
Biomarker(s)/Pharmacodynamic Markers
7.7.1.
Viral Genotyping and Phenotyping
Whole venous blood samples will be obtained from each subject to provide plasma for 
viral genotype and phenotype analysis, at the times listed in the Time and Events Table in 
Section 7.1. Details concerning the handling, labeling and shipping of these samples will 
be supplied separately.
Genotypic and phenotypic analyses will be carried out by Monogram Biosciences using 
their GAG/PR and PR/RT formats, in which PCR amplification is used to generate HIV 
cDNA products including the Gag and the PR and RT coding regions, respectively. 
Phenotypic analyses of the GAG/PR region will include susceptibility to GSK2838232 . 
Analysis will be done on Day 1 and Day 11 samples.  In the case of rebound HIV-1 viral 
load, analysis will be completed on samples corresponding to time point of rebound 
occurrence. 
7.8.
Genetics
Information regarding genetic research is included in Appendix 4, Section 12.4.
 
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7.9.
Value Evidence and Outcomes
Not required.
8.
DATA MANAGEMENT

For this study subject data will be entered into GSK defined CRFs, transmitted 
electronically to GSK or designee and combined with data provided from other 
sources in a validated data system, 

Management of clinical data will be performed in accordance with applicable 
GSK standards and data cleaning procedures to ensure the integrity of the data 
(e.g., removing errors and inconsistencies in the data).

Adverse events and concomitant medications terms will be coded using MedDRA 
and an internal validated medication dictionary, GSKDrug.  

CRFs (including queries and audit trails) will be retained by GSK, and copies will 
be sent to the investigator to maintain as the investigator copy.  Subject initials
will not be collected or transmitted to GSK according to GSK policy.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
The primary objectives of this study are to investigate the safety, tolerability, and 
antiviral activity of GSK2838232 administered as monotherapy in combination with 
cobicistat in HIV-1 infected subjects, over a 10 day treatment period. The antiviral 
activity will be assessed by estimating plasma HIV-1 RNA max change from baseline 
during the study. 
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
The sample size for this study is based primarily on feasibility to provide adequate 
precision for the estimations.
Based on data from the short term monotherapy study of BMS-955176 PoC (AI468002) 
study and assuming viral load values for individual subjects follow a log-normal 
distribution, 1000 trial simulations in Fixed and Adaptive Clinical Trial Simulation 
(FACTS) software were conducted from the distribution with mean of change from 
baseline viral load drop on log scale at 1.0 to 1.5 copies and SD=0.4 and sample sizes=10 
for Part A.  Using Bayesian calculation with non-informative priors for the mean and 
weakly informative priors for the error parameters, Normal (0, 100) for mean and Inverse 
Gamma (0.35, 0.0875) for error parameters, the posterior probability to achieve a 
cutpoint 1.2 log was calculated for each simulated trial, and percentage of the trials with 
 
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posterior probability of viral load<-1.2log drop given true mean) ≥70% were calculated 
and are shown below in Table 10.
Table 10
Percentage of the trials with posterior probability>=70% for Part A
True Mean
Cutpoint
Posterior Prob>=70%
1.0
1.2
1.4%
1.1
1.2
9%
1.2
1.2
29%
1.3
1.2
59%
1.4
1.2
83%
1.5
1.2
96%
An Emax model with functional uniform priors [Bornkamp, 2014] was conducted using 
simulated data combining Part A and Part B with all doses. Success is defined as a 
posterior probability of the highest dose to achieve a cutpoint 1.2 log reduction in viral 
load.   This was calculated for each simulated trial and the percentage of the trials with 
posterior probability greater or equal to 70% were also calculated and are shown below 
(Table 11). The table lists different viral load drop scenarios. The last scenario assumes 
the flat drop for all doses are 0.5.  This scenario reflects the null hypothesis of no 
treatment effect. In this scenario 0% of the trials achieve the pre-specified decision rule 
for success.
Table 11
Percentage of the trials with posterior probability ≥70%
Cutpoint
Posterior Prob≥
Part A+ Part B 
mean VL drop for doses 200, 
100, 50, 20
Part A+ Part B
1.2
70%
1.5, 1.4, 1.2, 0
99%
1.5, 1.4, 1.2, 0.5
96%
1.5, 1.4, 1.0, 0.5
93%
1.5, 1.3, 1.2, 0.5
86%
0.5, 0.5, 0.5, 0.5
0%
9.2.2.
Sample Size Sensitivity
Similar simulations in FACTS were conducted from the distribution with mean of change 
from baseline viral load drop on log scale at 1.5 copies and SD=0.4 or 0.6 and sample 
sizes of 6-8 or 10 for Part A.  Using Bayesian calculation, the posterior probability to 
achieve a cutpoint 1.2 log (in Table 12) was calculated for each simulated trial, and 
percentage of the trials with posterior probability greater than or equal to 70% was 
calculated and are shown below.
 
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Table 12
Percentage of the trials with posterior probability ≥70% for Part A
True 
Mean
Cutpoint
Posterior 
Prob≥
Std for log10 
VL
N=6 
N=8
N=10
1.5
1.2
70%
0.4
90%
94%
96%
0.6
75%
81%
84%
9.2.3.
Sample Size Re-estimation or Adjustment
No sample size re-estimation will be performed.
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
Intent to Treat Exposed Population (ITT)
The ITT-Exposed Population is defined as all subjects who meet study criteria and are 
enrolled into the study with documented evidence of having received at least 1 dose of 
treatment and at least one post-baseline HIV-1 RNA measurement. This will be the
primary population for the final efficacy analysis for all active treatment groups.
Per Protocol Population (PP)
The Per Protocol Population is defined as all subjects who meet study criteria and are 
enrolled into the study with documented evidence of having received all doses and all 
post-baseline HIV-1 RNA measurement, with exceptions of major protocol deviation. 
Safety Population
The Safety Population is defined as all subjects who are enrolled into the study with 
documented evidence of having received at least 1 dose of randomized treatment.
Pharmacokinetic Population
The PK Population will include all subjects who receive GSK2838232 and undergo 
plasma PK sampling during the study. Subjects for whom a plasma PK sample is 
obtained and assayed will be included in the listing of plasma GSK2838232 
concentration-time data.  Results from samples collected from a subject with emesis 
occurring within 4 hours of the dose will not be considered as evaluable.
9.3.2.
Interim Analysis
An interim analysis of preliminary safety, tolerability, PK and antiviral activity will occur 
after subjects of Part A Cohort 1 complete their Day 13 visit. If the Cohort 1 dose is 
determined to be the highest dose based on this review (e.g., the exposure level of 
GSK2838232 is in the range of the maximum GSK2838232 exposure seen previously in 
healthy subjects), the Bayesian posterior probability that the log10 viral load decline from 
baseline is greater than a cut-point will be calculated. If the Bayesian probability from 
Cohort 1 is less than 70%, this will provide evidence to not move forward into Part B. 
Otherwise, the study team will review the data in order to make a dose selection decision 
for the subsequent Part B Cohorts.  If the pharmacokinetic exposures after the 100 mg 
GSK2838232/cobi dose look similar to those obtained with 100 mg GSK2838232/r in 
 
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prior studies, the doses for Part B will be extended to both lower (20 mg, 50 mg) and 
higher (200 mg) GSK2838232 doses.
Maximum change and change from baseline in plasma HIV-1 RNA will be summarized 
by treatment or by assessment day. The proportion of subjects with plasma HIV-1 RNA 
<400 and <50 copies/mL will be summarized by treatment and assessment day. The 
analyses will be done for both PP and ITT exposed population if the two populations are 
not the same. 
9.4.
Key Elements of Analysis Plan
9.4.1.
Primary Analyses
The final analysis will be performed after the completion of the study and final datasets 
authorization. Data will be listed and summarized according to GlaxoSmithKline 
reporting standards, where applicable. Listings will be sorted by subject, period, 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, geometric mean with 
associated 95% confidence interval (CI), and %CVb for continuous variables, whereas n 
and percent will be used as summary statistics for categorical variables. Baseline or pre-
dose 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 9.1 or higher 
of the SAS system will be used to analyze the data as well as to generate tables, figures, 
and listings. Complete details will be documented in the Reporting and Analysis Plan 
(RAP).
9.4.1.1.
Safety Analyses
Safety data will be presented in tabular format and summarized descriptively according to 
GSK’s Integrated Data Standards Library standards and data will be in CDISC format. 
No formal statistical analysis of the safety data will be conducted. 
9.4.1.2.
Efficacy Analyses
Both the PP and ITT Populations will be used for all efficacy analyses if there are 
dropouts.  Plasma HIV-1 RNA max change and change from baseline during the study 
will be calculated for each subject on each assessment day.
Plasma HIV-1 RNA will be listed by treatment, subject, and assessment day and 
summarized by treatment and assessment day along with change from baseline.
Plots of mean and median plasma HIV-1 RNA actual and change from baseline data will 
be generated by treatment and assessment day.

Plasma HIV-1 RNA change from baseline to the on-treatment nadir (maximum 
change) will be calculated for each subject and summarized by treatment.
 
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Together, the data from Parts A and B will investigate the complete dose-response curve 
and the impact of lower doses on potential development of resistance. A dose-response 
curve will be fit to the data from Parts A & B using functional uniform priors.  
9.4.1.3.
Pharmacokinetic Analyses
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacokinetics 
Modeling and Simulation Department, GlaxoSmithKline. Plasma GSK2838232 
concentration-time data will be analyzed by non-compartmental methods with 
WinNonlin Version 6.1 or higher. Calculations will be based on the actual sampling 
times recorded during the study. From the plasma concentration-time data, the following 
pharmacokinetic parameters will be determined, as data permit:
Plasma GSK2838232 Pharmacokinetic Parameters to be Estimated:
Study Day
Parameters
1
AUC(0-24), Cmax, tmax, tlag, C24
10
AUC(0-), Cmax, tmax, t½, C0, C, CL/F, R_AUC, R_Cmax, R_C
Results based on samples collected from a subject with emesis within 4 hours of the dose 
will not be considered as evaluable.
All PK data will be stored in the R&D archives, GlaxoSmithKline.
Statistical analyses of the pharmacokinetic parameter data will be the responsibility of 
Clinical Statistics, GlaxoSmithKline. Details of the statistical analyses will be provided in 
the RAP. An outline is provided below:
Pharmacokinetic data will be presented in graphical and tabular form and will be 
summarized descriptively. Plasma GSK2838232 PK parameters, with the exception of 
tmax and tlag, will be log-transformed prior to analysis.
Dose proportionality of plasma GSK2838232 PK parameters from Day 1 [AUC(0-24) 
and Cmax] and Day 10 [AUC(0-τ) and Cmax] will be assessed using a power model if 
multiple dose levels are assessed. The power model will be fitted by restricted maximum 
likelihood (REML) using SAS Proc Mixed. A fixed effects power model will be used. 
The mean slope will be estimated from the power model with the corresponding 90% CI. 
The accumulation ratio (R) and steady-state assessments will be performed, if quality of 
the data permits. Comparisons of Day 10 with Day 1 PK for each dose will be used for 
the accumulation ratio (R) evaluation. Pre-dose concentrations between Days 7-10 will be 
used for steady-state assessment. 
9.4.2.
Secondary Analyses
9.4.2.1.
Pharmacokinetic/Pharmacodynamic Analyses
Relationships between various PK parameters (e.g., AUC, Cmax, Cτ, etc.) and PD 
measures (e.g., log10 reduction from baseline in plasma HIV-1 RNA on Day 11 or safety 
 
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parameters) will be explored using various models including Emax. The relationship 
between dose and PD measures will also be explored. Details of the PK/PD exploratory 
analyses will be provided in the RAP.
9.4.2.2.
Viral Genotyping and Phenotyping Analyses
Viral genotypic/phenotypic data will be listed and descriptive summaries will be 
provided. Details of the analyses will be provided in the clinical virology report.
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

Obtaining signed informed consent

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, 
or both.

Signed informed consent must be obtained for each subject prior to participation 
in the study

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  
 
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
Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, 
written approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors or designee will contact the site prior to the start of the study to 
review with the site staff the protocol, study requirements, and their 
responsibilities to satisfy regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the CRF will 
serve as the source document.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
10.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and 
the regulatory agencies may conduct a regulatory inspection at any time during or 
after completion of the study. 

In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss 
the conduct of the study, any findings/relevant issues and to implement any 
corrective and/or preventative actions to address any findings/issues identified.
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor or 
designee will conduct site closure activities with the investigator or site staff, as 
appropriate, in accordance with applicable regulations including GCP, and GSK 
Standard Operating Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this 
study at any time for reasons including, but not limited to, safety or ethical issues 
or severe non-compliance. For multicenter studies, this can occur at one or more 
or at all sites.  
 
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
If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable).  When feasible, GSK will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.  

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical 
institution (where applicable) must maintain all site study records (except for 
those required by local regulations to be maintained elsewhere), in a safe and 
secure location.  

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review 
in conjunction with assessment of the facility, supporting systems, and relevant 
site staff.  

Where permitted by local laws/regulations or institutional policy, some or all of 
these records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.  

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, 
including re-generating a hard copy, if required.  Furthermore, the investigator 
must ensure there is an acceptable back-up of these reproductions and that an 
acceptable quality control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by 
any institutional requirements or local laws or regulations, GSK 
standards/procedures, and/or institutional requirements.  

The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of 
ownership of the records in the event the investigator is no longer associated with 
the site.
 
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10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.
10.8.
Review Committees
The Safety Review Team (SRT) is a GSK cross-functional team reviewing all available 
safety data related to the project, including in-stream data from this study, in an ongoing 
manner. The SRT is an internal GSK requirement put in place to ensure holistic 
evaluation of the safety profile of an investigational product with systematic, periodic and 
documented reviews of available safety data, with the appropriate communication and 
escalation of new findings that have the potential to impact patient safety
 
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11.
REFERENCES
Bloch M, Bodsworth N, Fidler M, Workman C, Balach A, Byakagwa H, et al. Efficacy, 
safety and pharmacokinetics of MPC-4326 (bevirimat dimeglumine) 200mg BID and 
300mg BID monotherapy administered for 14 days in subjects with HIV-1 infection. 
ICAAC. 2009; Abstract H-1230.
Bornkamp B, Practical considerations for using functional uniform prior distributions for 
dose-response estimation in clinical trials. Biometrical Journal 56 (2014) 6, 947-962
Cockcroft DW, Gault MH. Prediction of creatinine clearance form serum creatinine. 
Nephron. 1976;16:31-41.
Dang Z, Huang L, Chen C. HIV-1 maturation inhibitors:  An update. Drugs of the Future. 
2009;34 (10):797-802.
Elion R, Cohen C, Gathe J, Shalit P, Hawkins T, Liu HC, et al.  Phase 2 study of 
cobicistat versus ritonavir each with once-daily atazanavir and fixed-dose 
emtricitabine.tenofovir df in the initial treatment of HIV infection.  AIDS.  2011; 
25:1881-1886.
Food and Drug Administration (FDA). Guidance for industry: Estimating the maximum 
safe starting dose in initial clinical trials for therapeutics in adult healthy subjects. CDER, 
Rockville, MD; 2005. UCM078932.
Food and Drug Administration (FDA). Guidance for Industry: Human Immunodeficiency 
Virus-1 Infection: Developing Antiretroviral Drugs for Treatment. CDER, Rockville, 
MD; 2015. UCM355128.
Gallant JE, Koenig E, Andrade-Villaneuva J, Chetchotisakd P, deJesus E, Antunes F, 
Arastéh K,  et al.  Cobicistat versus ritonavir as a pharmacoenhancer of atazanavir plus 
emtricitabine/tenofovir disoproxil fumarate in treatment-naïve HIV type 1-infected 
patients:  week 48 results.  J. Infect. Dis.  2013; 208-:32-39.
GlaxoSmithKline Document Number 2012N151889_03 Compound GSK2838232. 
Investigator’s Brochure.  Effective November 2016.
GlaxoSmithKline Non-Clinical Research report. Document Number 2013N163221_00.
Hatcher RA, Trussel J, Nelson AL, Cates W, Stewart F, Kowal D, editors. Contraceptive 
Technology. 19th ed. New York:Ardent Media; 2007. 
Kakuda TN, Opsomer M, Timmers M, Iterbeke K, Van De Casteele T, Hillewaert V, et 
al.  Pharmacokinetics of darunavir in fixed-dose combination with cobicistat compared 
with coadministration of darunavir and ritonavir as single agents in healthy volunteers.  J. 
Clin. Pharmacol.  2009; 54:949-957.
 
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Lalezari J, McCallister S, Gigliotti M, Cohen C, Elion R, Brinson C, et al. Safety and 
efficacy study of bevirimat (BVM) in heavily treatment experienced HIV+ patients 
identifies the target phase 3 study profile. ICAAC. 2008; Abstract: H891. 
Mahmood I. Prediction of human drug clearance from animal data. Application of the 
rule of exponent and fu corrected intercept method (FCIM). J Pharm Sci. 
2006;95:1810-21. 
Martin D, Galbraith H, Ellis C, Schettler J and Doto J. Minimal effect of ritonavir (RTV) 
on the pharmacokinetics of bevirimat in healthy volunteers [abstract]. IAS Conference on 
HIV Pathogenesis, Treatment and Prevention. 2007; Abstract no. WEPEB015:Poster 
discussion.
Martin DE, Blum R, Doto J, Galbraith H, Ballow C. Multiple-dose pharmacokinetics and 
safety of bevirimat, a novel inhibitor of HIV maturation, in healthy volunteers. Clin 
Pharmacokinet. 2007(a);46(7):589-98.
Martin DE, Blum R, Wilton J, Doto J, Galbraith H, Burgess GL, et al. Safety and 
pharmacokinetics of bevirimat (PA-457), a novel inhibitor of human immunodeficiency 
virus maturation, in healthy volunteers. Antimicrobial Agents and Chemotherapy. 
2007(b);Sep:3063-6.
Martin DE, Galbraith H, Schettier J, Ellis C, Doto J. Pharmacokinetic properties and 
tolerability of bevirimat and atazanavir in healthy volunteers:  An open-label, parallel-
group study. Clinical Therapeutics. 2008;30(10):1794-1805.
NORVIR (ritonavir) Product Information. January, 2013.
Nowicka-Sans B, Protack T, Lin Z, Li Z, Zhang S, Meanwell N, et al. BMS-955176: 
Characterization of a second-generation HIV-1 maturation inhibitor. 8th IAS Conference 
on HIV Pathogenesis, Treatment and Prevention, July 19-22, 2015, Vancouver, Canada.
Qian K, Morris-Natschke SL, Lee KH. HIV entry inhibitors and their potential in HIV 
therapy. Medicinal Research Reviews. 2009;29(2):369-93.
Saxena SK, Gupta A, Bhagyashree K, Saxena R, Arora N, Banerjee AK, et al. Targeting 
strategies for human immunodeficiency virus: A combinatorial approach. Min Rev Med 
Chem. 2012;12(3):236-54.
TYBOST (cobicistat) Product Information. 2012
Wainburg MA, Albert J. Can the further clinical development of bevirimat be justified?. 
AIDS. 2010;24:773-4.
 
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
g/mL
Microgram per millilitre
ABC
Abacavir
AE
Adverse Event
AIDS
Acquired immunodeficiency syndrome
ALT
Alanine aminotransferase
API
Active Pharmaceutical Ingredient
ART
Antiretroviral therapy
AST
Aspartate aminotransferase
AUC
Area under the plasma concentration time curve
AUC(0-)
Area under the concentration-time curve from time zero 
(pre-dose) extrapolated to infinite time
AUC(0-)
Area under the concentration-time curve over the dosing 
interval 
AUC(0-24)
Area under the concentration-time curve from zero (pre-
dose) to 24 h
AUC(0-48)
Area under the concentration-time curve from zero (pre-
dose) to 48 h
AUC(0-t)
Area under the concentration-time curve from zero (pre-
dose) to time of last quantifiable concentration
BCRP
Breast cancer resistance protein
BID
Twice daily
Bpm
beats per minute
BVM
Bevirimat
BIL
Bilirubin
C
Pre-dose (trough) concentration at the end of the dosing 
interval
C24
24 hour trough concentration
CDC
Center for Disease Control and Prevention
CI
Confidence interval
CL/F
Oral Clearance
Cmax
Maximum plasma concentration
Cmin
Minimum plasma concentration
CPK
Creatine Phosphokinase
CRF
Case report form
cTnI
Cardiac troponin I
CV
Coefficient of variation
CVb
Between-subject variability
CYP
Cytochrome P450
DDI
Drug Drug Interaction
DNA
Deoxyribonucleic acid
EC50
50% protection against resistant mutant HIV infection 
 
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ECG
Electrocardiogram
FC
Fold Changes
FDA
Food and Drug Administration
FSH
Follicle stimulating hormone
FTIH
First time in Human Study
g
Gram
GI
Gastrointestinal
GSK
GlaxoSmithKline
h
Hour(s)
HBsAg
Hepatitis B surface antigen
hcG
Human chorionic gonadotrophin
HDPE
High density polyethylene
hERG
Human Ether-a-gogo Related Gene
HIV
Human Immunodeficiency Virus
IC50/90
50% or 90% maximal inhibitory concentration
IEC
International Ethics Committee
IQ
Inhibitory quotient
IRB
Institutional Review Board
ISR
Injection site reaction
IV
Intravenous
IVRS
Interactive voice response system
kg
Kilogram
L
Litre
LLOD
Lower limit of detection
MC
Melanocortin
MedDRA
Medical Dictionary for Regulatory Activities
mg/mL
Milligram per millilitre
MI
Maturation inhibitor
mL
Milliliter
mRNA
messenger Ribonucleic Acid
ND
Not done
ng/mL
Nanogram per millilitre 
nm
Nanometer
NO
Not observed
NOAEL
No Observed Adverse Effect Level
NTproBNP
N-terminal prohormone of brain natriuretic peptide
NSVT
Non-sustained ventricular tachycardia
OAT
Organic anion transporter
OATP
Organic anion transporting polypeptide
OCT
Organic cation transporter
PBL
Peripheral Blood Lymphocytes
PBMC
Peripheral Blood Mononuclear Cells
PD
Pharmacodynamics
PPD
Pharmaceutical Product Development
P-gp
P-glycoprotein
PHIV
Pseudo- HIV
 
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PiB
Powder-in-bottle
PK
Pharmacokinetic
PoC
Proof of Concept
PI
Protease Inhibitor
QD
Once daily
RAP
Reporting and analysis plan
RIBA
Recombinant Immuno-Blot Assay
RT
Reverse Transcriptase
SAE
Serious adverse event
SDD
Spray Dried Dispersion
SRM
Study reference manual
t½
Terminal elimination half-life
TEM
Transmission Electron Microscopy
tlag
Time of first quantifiable concentration
tmax
Time of occurrence of Cmax
U
Units
UGT
Uridine 5'-diphospho-glucuronosyltransferase
Vz/F
Mean apparent oral volume of distribution
WPW
Wolff-Parkinson-White
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Abbot, Roche HIV kit
Chiron RIBA 
Inform
Monogram
Phoenix WinNonlin 
SAS
Tybost (cobicistat)
 
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12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments
Phase II liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event etiology (in alignment with the 
FDA premarketing clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Phase II liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF and complete an 
SAE data collection tool if the event also meets 
the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries
resolve, stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge subject with study 
treatment unless allowed per protocol and GSK 
Medical Governance approval is granted 

If restart/rechallenge not allowed per protocol 
or not granted, permanently discontinue study 
treatment and may continue subject in the study 

Viral hepatitis serology4

Blood sample for pharmacokinetic (PK) 
analysis, obtained within 24hrs after 
last dose5

Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications 
on the concomitant medications report 
 
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for any protocol specified follow up assessments 
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 
24 hours

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to within 
baseline 

A specialist or hepatology consultation is 
recommended
For All other criteria: 

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24-
72 hours 

Monitor subjects weekly until liver chemistries 
resolve, stabilize or return to within baseline
form including acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG or gamma globulins).

Serum acetaminophen adduct high-
performance liquid chromatography
assay (quantifies potential 
acetaminophen contribution to liver 
injury in subjects with definite or likely 
acetaminophen use in the preceding 
week 

Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF 
forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN.. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
5.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.)  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.  
 
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Phase II liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 3xULN and <5xULN and bilirubin 
<2xULN, without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss subject safety. 

Subject can continue study treatment  

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to within 
baseline.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
 
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12.3.
Appendix 3: Liver Safety – Study Treatment Restart or 
Rechallenge Guidelines
Study treatment restart or re-challenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed.
 
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12.4.
Appendix 4: Genetic Research
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and: 

Response to medicine, including GSK2838232/RTV or any concomitant 
medicines;

HIV susceptibility, severity, and progression and related conditions
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic 
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research.  Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.  

A 6 ml blood or 2 ml saliva sample will be taken for Deoxyribonucleic acid 
(DNA) extraction. A sample is collected at the baseline visit, after the subject has 
been randomized and provided informed consent for genetic research. Instructions 
for collection and shipping of the genetic sample are described in the laboratory 
manual. The DNA from the blood/saliva sample may undergo quality control 
analyses to confirm the integrity of the sample. If there are concerns regarding the 
quality of the sample, then the sample may be destroyed. The blood/saliva sample 
is taken on a single occasion unless a duplicate sample is required due to an 
inability to utilize the original sample.  
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study.   This number can be traced or linked back to 
 
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the subject by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number). 
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study, or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form.  Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study.  Genetic informed consent must be obtained prior to any blood/saliva being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA 
sample is retained

Discontinue participation in the genetic research and destroy the genetic DNA 
sample 
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis. 

If a subject withdraws consent for genetic research and genotype data has not been 
analyzed, it will not be analyzed or used for future research.  

Genetic data that has been analyzed at the time of withdrawn consent will 
continue to be stored and used, as appropriate. 
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 
 
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reconciliation process.  In this instance a sample destruction form will not be available to 
include in the site files.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic 
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined.  Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care.
 
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12.5.
Appendix 5: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.5.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE.  However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition 
of an AE or SAE.

The signs and symptoms and/or clinical sequelae resulting from lack of efficacy will 
be reported if they fulfil the definition of an AE or SAE.  Also, "lack of efficacy" or 
"failure of expected pharmacological action" also constitutes an AE or SAE.
 
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Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
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.
12.5.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
c.
Results in death
d.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
e.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
 
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f.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption
g.
Is a congenital anomaly/birth defect
h.
Other situations:

Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.

Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse
i.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.

Refer to Appendix 2 for the required liver chemistry follow-up instructions
 
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12.5.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
12.5.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.

Subject-completed Value Evidence and Outcomes questionnaires and the collection 
of AE data are independent components of the study.

Responses to each question in the Value Evidence and Outcomes questionnaire will 
be treated in accordance with standard scoring and statistical procedures detailed by 
 
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the scale’s developer.

The use of a single question from a multidimensional health survey to designate a 
cause-effect relationship to an AE is inappropriate.
12.5.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important 
that the investigator always make an assessment of causality for every event 
prior to the initial transmission of the SAE data to GSK.
 
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
The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

By specific request, the investigator is obligated to report any grade 2 or higher 
“alteration in personality-behavior or in mood” or “altered mental status” adverse 
events that occur in subjects taking this drug, to GSK within 3 days.

The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.

If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any post-mortem findings, 
including histopathology. 

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
12.5.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the Medical Monitor

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data

If a site receives a report of a new SAE from a study subject or receives updated data 
 
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on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the Medical 
Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
SAE reporting to GSK via paper CRF

Facsim0ile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the Medical Monitor 

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable, with a copy of the SAE data collection tool sent by 
overnight mail

Initial notification via the 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 receipt can be found at this beginning of the protocol on the 
Sponsor/Medical Monitor Contact Information page.
SAE reporting to GSK via PIMS

Facsimile transmission of the following PIMS listings for the corresponding subject 
is the preferred method to transmit SAE information to the Medical Monitor or 
protocol contact:
SAE listing
Demographic listing
Study treatment listing

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable, with a copy of all required information sent by overnight 
mail.

If the PIMS system is unavailable when the SAE occurs, the site will use the paper 
SAE form and fax that to the Medical Monitor or protocol contact. The site will enter 
the SAE data into PIMS as soon as the system becomes available.
 
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12.6.
Appendix 6: Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 
24hrs of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, which will be 
forwarded to GSK.  Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in Appendix 5. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
Any female subject who becomes pregnant while participating 

will discontinue study medication and be withdrawn from the study

This will only be included if either of the following apply:

Investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study.  This 
applies only to subjects who are randomized to receive study medication. 

After obtaining the necessary signed informed consent from the female partner 
directly, the investigator will record pregnancy information on the appropriate form 
report the event and submit it to GSK within 24hrs 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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12.7.
Appendix 7: Country Specific Requirements
No country-specific requirements exist.
 
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12.8.
Appendix 8: Division Of AIDS Table For Grading The 
Severity Of Adult And Pediatric Adverse Events Version 1.0, 
December 2004; Clarification August 2009
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
ESTIMATING SEVERITY GRADE
Clinical adverse 
event NOT identified 
elsewhere in the 
grading table
Mild symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities with 
intervention not 
indicated
Moderate 
symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
with intervention not 
indicated
Severe symptoms 
causing inability to 
perform usual social 
& functional activities 
with intervention or 
hospitalization 
indicated
Potentially life-
threatening symptoms 
causing inability to 
perform basic self-care 
functions OR Medical or 
operative intervention 
indicated to prevent 
permanent impairment, 
persistent disability, or 
death 
CARDIOVASCULAR
Arrhythmia
(by ECG or physical 
examination)
Specify type, if
applicable
No symptoms 
AND No 
intervention 
indicated
No symptoms AND
non-urgent 
intervention 
indicated
Non-life-threatening 
symptoms AND Non-
urgent intervention 
indicated
Life-threatening 
arrhythmia OR Urgent 
intervention indicated
Blood Pressure 
Abnormalities1 
Hypertension (with 
the lowest reading 
taken after repeat 
testing during a visit) 
≥ 18 years of age 
140 to < 160 
mmHg systolic 
OR 90 to < 100 
mmHg diastolic 
≥ 160 to < 180 
mmHg systolic OR 
≥ 100 to < 110 
mmHg diastolic 
≥ 180 mmHg systolic 
OR ≥ 110 mmHg 
diastolic 
Life-threatening 
consequences in a 
participant not 
previously diagnosed
with hypertension (e.g., 
malignant hypertension) 
OR Hospitalization 
indicated 
< 18 years of age 
> 120/80 mmHg 
≥ 95th to < 99th 
percentile + 5 
mmHg adjusted for 
age, height, and 
gender (systolic 
and/or diastolic) 
≥ 99th percentile + 5 
mmHg adjusted for 
age, height, and 
gender (systolic 
and/or diastolic) 
Life-threatening 
consequences in a 
participant not 
previously diagnosed 
with hypertension (e.g., 
malignant hypertension) 
OR Hospitalization 
indicated 
Hypotension 
No symptoms 
Symptoms 
corrected with oral 
fluid replacement 
Symptoms AND IV 
fluids indicated 
Shock requiring use of 
vasopressors or 
mechanical assistance 
to maintain blood 
pressure 
Cardiac Ischemia or 
Infarction 
Report only one 
NA 
NA 
New symptoms with 
ischemia (stable 
angina) OR New 
testing consistent 
with ischemia 
Unstable angina OR 
Acute myocardial 
infarction 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Heart Failure 
No symptoms 
AND Laboratory 
or cardiac imaging 
abnormalities 
Symptoms with mild 
to moderate activity 
or exertion 
Symptoms at rest or 
with minimal activity 
or exertion (e.g., 
hypoxemia) OR 
Intervention indicated 
(e.g., oxygen) 
Life-threatening 
consequences OR 
Urgent intervention 
indicated (e.g., 
vasoactive medications, 
ventricular assist device, 
heart transplant) 
Hemorrhage (with 
significant acute 
blood loss) 
NA 
Symptoms AND No 
transfusion 
indicated 
Symptoms AND 
Transfusion of ≤ 2 
units packed RBCs 
indicated 
Life-threatening 
hypotension OR 
Transfusion of > 2 units 
packed RBCs (for 
children, packed RBCs 
> 10 cc/kg) indicated 
Prolonged PR 
Interval or AV Block 
Report only one 
> 16 years of age 
PR interval 0.21 
to < 0.25 seconds 
PR interval ≥ 0.25 
seconds OR Type I 
2nd degree AV 
block 
Type II 2nd degree 
AV block OR 
Ventricular pause ≥ 
3.0 seconds 
Complete AV block 
≤ 16 years of age 
1st degree AV 
block (PR interval 
> normal for age 
and rate) 
Type I 2nd degree 
AV block 
Type II 2nd degree 
AV block OR 
Ventricular pause ≥ 
3.0 seconds 
Complete AV block 
Prolonged QTc 
Interval2 
0.45 to 0.47 
seconds 
> 0.47 to 0.50 
seconds 
> 0.50 seconds OR ≥ 
0.06 seconds above 
baseline 
Life-threatening 
consequences (e.g., 
Torsade de pointes, 
other associated serious 
ventricular dysrhythmia) 
Thrombosis or 
Embolism 
Report only one 
NA 
Symptoms AND No 
intervention 
indicated 
Symptoms AND 
Intervention indicated 
Life-threatening embolic 
event (e.g., pulmonary 
embolism, thrombus) 
DERMATOLOGIC
Alopecia (scalp only) 
Detectable by 
study participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Obvious on visual 
inspection AND 
Causing greater 
than minimal 
interference with 
usual social & 
functional activities 
NA 
NA 
Bruising 
Localized to one 
area 
Localized to more 
than one area 
Generalized 
NA 
Cellulitis 
NA 
Non-parenteral 
treatment indicated 
(e.g., oral 
antibiotics, 
antifungals, 
antivirals) 
IV treatment 
indicated (e.g., IV 
antibiotics, 
antifungals, antivirals) 
Life-threatening 
consequences (e.g., 
sepsis, tissue necrosis) 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Hyperpigmentation 
Slight or localized 
causing no or 
minimal 
interference with
usual social & 
functional 
activities 
Marked or 
generalized causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
NA 
NA 
Hypopigmentation 
Slight or localized 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Marked or 
generalized causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
NA 
NA 
Petechiae 
Localized to one 
area 
Localized to more 
than one area 
Generalized 
NA 
Pruritus3 (without 
skin lesions) 
Itching causing no 
or minimal 
interference with 
usual social & 
functional 
activities 
Itching causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Itching causing 
inability to perform 
usual social & 
functional activities 
NA 
Rash 
Specify type, if 
applicable 
Localized rash 
Diffuse rash OR 
Target lesions 
Diffuse rash AND 
Vesicles or limited 
number of bullae or 
superficial ulcerations 
of mucous membrane 
limited to one site 
Extensive or generalized 
bullous lesions OR 
Ulceration of mucous 
membrane involving two 
or more distinct mucosal 
sites OR Stevens-
Johnson syndrome OR 
Toxic epidermal 
necrolysis 
ENDOCRINE AND METABOLIC
Diabetes Mellitus 
Controlled without 
medication 
Controlled with 
medication OR 
Modification of 
current medication 
regimen 
Uncontrolled despite 
treatment 
modification OR 
Hospitalization for 
immediate glucose 
control indicated 
Life-threatening 
consequences (e.g., 
ketoacidosis, 
hyperosmolar non-
ketotic coma, end organ 
failure) 
Gynecomastia 
Detectable by 
study participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Obvious on visual 
inspection AND 
Causing pain with 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Disfiguring changes 
AND Symptoms 
requiring intervention 
or causing inability to 
perform usual social 
& functional activities 
NA 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Hyperthyroidism 
No symptoms 
AND Abnormal 
laboratory value 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
OR Thyroid 
suppression 
therapy indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Uncontrolled 
despite treatment 
modification 
Life-threatening 
consequences (e.g., 
thyroid storm) 
Hypothyroidism 
No symptoms 
AND Abnormal 
laboratory value 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
OR Thyroid 
replacement 
therapy indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Uncontrolled 
despite treatment 
modification 
Life-threatening 
consequences (e.g., 
myxedema coma) 
Lipoatrophy4 
Detectable by 
study participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Obvious on visual 
inspection AND 
Causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Disfiguring changes 
NA 
Lipohypertrophy5
Detectable by 
study participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Obvious on visual 
inspection AND 
Causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Disfiguring changes 
NA 
GASTROINTESTINAL
Anorexia 
Loss of appetite 
without decreased 
oral intake 
Loss of appetite 
associated with 
decreased oral 
intake without 
significant weight 
loss 
Loss of appetite 
associated with 
significant weight loss 
Life-threatening 
consequences OR 
Aggressive intervention 
indicated (e.g., tube 
feeding, total parenteral 
nutrition) 
Ascites 
No symptoms 
Symptoms AND 
Intervention 
indicated (e.g., 
diuretics, 
therapeutic 
paracentesis) 
Symptoms recur or 
persist despite 
intervention 
Life-threatening 
consequences 
 
2018N360917_00


2015N227852_03
CONFIDENTIAL
200911
91
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Bloating or 
Distension 
Report only one 
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Cholecystitis
NA 
Symptoms AND 
Medical intervention 
indicated 
Radiologic, 
endoscopic, or 
operative intervention 
indicated 
Life-threatening 
consequences (e.g., 
sepsis, perforation) 
Constipation 
NA 
Persistent 
constipation 
requiring regular 
use of dietary 
modifications, 
laxatives, or 
enemas 
Obstipation with 
manual evacuation 
indicated 
Life-threatening 
consequences (e.g., 
obstruction) 
Diarrhea ≥ 1 year of 
age 
Transient or 
intermittent 
episodes of 
unformed stools 
OR Increase of ≤ 
3 stools over 
baseline per 24-
hour period 
Persistent episodes 
of unformed to 
watery stools OR 
Increase of 4 to 6 
stools over baseline 
per 24-hour period 
Increase of ≥7 stools 
per 24-hour period 
OR IV fluid 
replacement 
indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Dysphagia or 
Odynophagia 
Report only one 
and specify 
location 
Symptoms but 
able to eat usual 
diet 
Symptoms causing 
altered dietary 
intake with no 
intervention 
indicated 
Symptoms causing 
severely altered 
dietary intake with 
intervention indicated 
Life-threatening 
reduction in oral intake 
Gastrointestinal 
Bleeding 
Not requiring 
intervention other 
than iron 
supplement 
Endoscopic 
intervention 
indicated 
Transfusion indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Mucositis or 
Stomatitis 
Report only one and 
specify location 
Mucosal erythema 
Patchy 
pseudomembranes 
or ulcerations 
Confluent 
pseudomembranes 
or ulcerations OR 
Mucosal bleeding 
with minor trauma 
Life-threatening 
consequences (e.g., 
aspiration, choking) OR 
Tissue necrosis OR 
Diffuse spontaneous 
mucosal bleeding 
Nausea 
Transient (< 24 
hours) or 
intermittent AND 
No or minimal 
interference with 
oral intake 
Persistent nausea 
resulting in 
decreased oral 
intake for 24 to 48 
hours 
Persistent nausea 
resulting in minimal 
oral intake for > 48 
hours OR 
Rehydration indicated 
(e.g., IV fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Pancreatitis 
NA 
Symptoms with 
hospitalization not 
indicated 
Symptoms with 
hospitalization 
indicated 
Life-threatening 
consequences (e.g., 
circulatory failure, 
hemorrhage, sepsis) 
 
2018N360917_00


2015N227852_03
CONFIDENTIAL
200911
92
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Perforation 
(colon or rectum) 
NA 
NA 
Intervention indicated 
Life-threatening 
consequences 
Proctitis 
Rectal discomfort 
with no 
intervention 
indicated 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
OR Medical 
intervention 
indicated 
Symptoms causing 
inability to perform 
usual social &
functional activities 
OR Operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
perforation) 
Rectal Discharge 
Visible discharge 
Discharge requiring 
the use of pads 
NA 
NA 
Vomiting 
Transient or 
intermittent AND 
No or minimal 
interference with 
oral intake 
Frequent episodes 
with no or mild 
dehydration 
Persistent vomiting 
resulting in 
orthostatic 
hypotension OR 
Aggressive 
rehydration indicated 
(e.g., IV fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
MUSCULOSKELETAL
Arthralgia 
Joint pain causing 
no or minimal 
interference with 
usual social & 
functional 
activities 
Joint pain causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Joint pain causing 
inability to perform 
usual social & 
functional activities 
Disabling joint pain 
causing inability to 
perform basic self-care 
functions 
Arthritis 
Stiffness or joint 
swelling causing 
no or minimal 
interference with 
usual social & 
functional 
activities 
Stiffness or joint 
swelling causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Stiffness or joint 
swelling causing 
inability to perform 
usual social & 
functional activities 
Disabling joint stiffness 
or swelling causing 
inability to perform basic 
self-care functions 
Myalgia 
(generalized) 
Muscle pain 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Muscle pain 
causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Muscle pain causing 
inability to perform 
usual social & 
functional activities 
Disabling muscle pain 
causing inability to 
perform basic self-care 
functions 
Osteonecrosis 
NA 
No symptoms but 
with radiographic 
findings AND No 
operative 
intervention 
indicated 
Bone pain with 
radiographic findings 
OR Operative 
intervention indicated 
Disabling bone pain with 
radiographic findings 
causing inability to 
perform basic self-care 
functions 
Osteopenia6
≥ 30 years of age 
BMD t-score -2.5 
to -1 
NA 
NA 
NA 
 
2018N360917_00


2015N227852_03
CONFIDENTIAL
200911
93
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
< 30 years of age 
BMD z-score -2 to 
-1 
NA
NA 
NA 
Osteoporosis6
≥ 30 years of age 
NA 
BMD t-score < -2.5 
Pathologic fracture 
(e.g., compression 
fracture causing loss 
of vertebral height) 
Pathologic fracture 
causing life-threatening 
consequences 
< 30 years of age 
NA 
BMD z-score < -2 
Pathologic fracture 
(e.g., compression 
fracture causing loss 
of vertebral height) 
Pathologic fracture 
causing life-threatening 
consequences 
NEUROLOGIC
Acute Central 
nervous system 
(CNS) Ischemia 
NA 
NA 
Transient ischemic 
attack 
Cerebral vascular 
accident (e.g., stroke 
with neurological deficit) 
Altered Mental 
Status (for 
Dementia, see 
Cognitive, 
Behavioral, or 
Attentional 
Disturbance below) 
Changes causing 
no or minimal 
interference with 
usual social & 
functional 
activities 
Mild lethargy or 
somnolence 
causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Confusion, memory 
impairment, lethargy, 
or somnolence 
causing inability to 
perform usual social 
& functional activities 
Delirium OR 
Obtundation OR Coma 
Ataxia 
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities OR No 
symptoms with 
ataxia detected on 
examination 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Disabling symptoms 
causing inability to 
perform basic self-care 
functions 
Cognitive, 
Behavioral, or 
Attentional 
Disturbance 
(includes dementia 
and attention deficit 
disorder) 
Specify type, if 
applicable 
Disability causing 
no or minimal 
interference with 
usual social & 
functional 
activities OR 
Specialized 
resources not 
indicated 
Disability causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
OR Specialized 
resources on part-
time basis indicated 
Disability causing 
inability to perform 
usual social & 
functional activities 
OR Specialized 
resources on a full-
time basis indicated 
Disability causing 
inability to perform basic 
self-care functions OR 
Institutionalization 
indicated 
 
2018N360917_00


2015N227852_03
CONFIDENTIAL
200911
94
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Developmental 
Delay < 18 years of 
age 
Specify type, if 
applicable 
Mild 
developmental 
delay, either 
motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Moderate 
developmental 
delay, either motor
or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Severe 
developmental delay, 
either motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Developmental 
regression, either motor 
or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Headache 
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Symptoms causing 
inability to perform basic 
self-care functions OR 
Hospitalization indicated 
OR Headache with 
significant impairment of 
alertness or other 
neurologic function 
Neuromuscular 
Weakness (includes 
myopathy and 
neuropathy) 
Specify type, if 
applicable 
Minimal muscle 
weakness causing 
no or minimal 
interference with 
usual social & 
functional
activities OR No 
symptoms with 
decreased 
strength on 
examination 
Muscle weakness 
causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Muscle weakness 
causing inability to 
perform usual social 
& functional activities 
Disabling muscle 
weakness causing 
inability to perform basic 
self-care functions OR 
Respiratory muscle 
weakness impairing 
ventilation 
Neurosensory 
Alteration (includes 
paresthesia and 
painful neuropathy) 
Specify type, if 
applicable 
Minimal 
paresthesia 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities OR No 
symptoms with 
sensory alteration 
on examination 
Sensory alteration 
or paresthesia 
causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Sensory alteration or 
paresthesia causing 
inability to perform 
usual social & 
functional activities 
Disabling sensory 
alteration or paresthesia 
causing inability to 
perform basic self-care 
functions 
Seizures New Onset 
Seizure 
≥ 18 years of age 
NA 
NA 
1 to 3 seizures 
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR Difficult 
to control (e.g., 
refractory epilepsy) 
< 18 years of age 
(includes new or pre-
existing febrile 
seizures) 
Seizure lasting < 
5 minutes with < 
24 hours postictal 
state 
Seizure lasting 5 to 
< 20 minutes with < 
24 hours postictal 
state 
Seizure lasting ≥ 20 
minutes OR > 24 
hours postictal state 
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR Difficult 
to control (e.g., 
refractory epilepsy) 
 
2018N360917_00


2015N227852_03
CONFIDENTIAL
200911
95
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Pre-existing Seizure 
NA 
Increased 
frequency from 
previous level of 
control without 
change in seizure 
character 
Change in seizure 
character either in 
duration or quality 
(e.g., severity or 
focality) 
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR Difficult 
to control (e.g., 
refractory epilepsy) 
Syncope 
Near syncope 
without loss of 
consciousness 
(e.g., pre-
syncope) 
Loss of 
consciousness with 
no intervention 
indicated 
Loss of 
consciousness AND 
Hospitalization or 
intervention required 
NA 
PREGNANCY, PUERPERIUM, AND PERINATAL
Fetal Death or 
Stillbirth (report 
using mother’s 
participant ID) 
Report only one 
NA 
NA 
Fetal loss occurring 
at ≥ 20 weeks 
gestation 
NA 
Preterm Delivery7
(report using 
mother’s participant 
ID) 
Delivery at 34 to < 
37 weeks 
gestational age 
Delivery at 28 to < 
34 weeks 
gestational age 
Delivery at 24 to < 28 
weeks gestational 
age 
Delivery at < 24 weeks 
gestational age 
Spontaneous 
Abortion or 
Miscarriage8 (report 
using mother’s 
participant ID) 
Report only one 
Chemical 
pregnancy 
Uncomplicated 
spontaneous 
abortion or 
miscarriage 
Complicated 
spontaneous abortion 
or miscarriage 
NA 
PSYCHIATRIC
Insomnia 
Mild difficulty 
falling asleep, 
staying asleep, or 
waking up early 
Moderate difficulty 
falling asleep, 
staying asleep, or 
waking up early 
Severe difficulty 
falling asleep, staying 
asleep, or waking up 
early 
NA 
Psychiatric 
Disorders 
(includes anxiety, 
depression, mania, 
and 
psychosis) 
Specify disorder 
Symptoms with 
intervention not 
indicated OR 
Behavior causing 
no or minimal 
interference with 
usual social & 
functional 
activities 
Symptoms with 
intervention 
indicated OR 
Behavior causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms with 
hospitalization 
indicated OR 
Behavior causing 
inability to perform 
usual social & 
functional activities 
Threatens harm to self 
or others OR Acute 
psychosis OR Behavior 
causing inability to 
perform basic self-care 
functions 
 
2018N360917_00


2015N227852_03
CONFIDENTIAL
200911
96
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Suicidal Ideation or 
Attempt 
Report only one 
Preoccupied with 
thoughts of death 
AND No wish to 
kill oneself 
Preoccupied with 
thoughts of death 
AND Wish to kill 
oneself with no 
specific plan or 
intent 
Thoughts of killing 
oneself with partial or 
complete plans but 
no attempt to do so 
OR Hospitalization 
indicated 
Suicide attempted 
RESPIRATORY
Acute 
Bronchospasm 
Forced expiratory 
volume in 1 
second or peak 
flow reduced to ≥ 
70 to < 80% OR 
Mild symptoms 
with intervention 
not indicated 
Forced expiratory 
volume in 1 second 
or peak flow 50 to < 
70% OR Symptoms 
with intervention 
indicated OR 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Forced expiratory 
volume in 1 second 
or peak flow 25 to < 
50% OR Symptoms 
causing inability to 
perform usual social 
& functional activities 
Forced expiratory 
volume in 1 second or 
peak flow < 25% OR 
Life-threatening 
respiratory or 
hemodynamic 
compromise OR 
Intubation 
Dyspnea or 
Respiratory 
Distress 
Report only one 
Dyspnea on 
exertion with no or 
minimal 
interference with 
usual social & 
functional 
activities OR 
Wheezing OR 
Minimal increase 
in respiratory rate 
for age 
Dyspnea on 
exertion causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
OR Nasal flaring 
OR Intercostal 
retractions OR 
Pulse oximetry 90 
to < 95% 
Dyspnea at rest 
causing inability to 
perform usual social 
& functional activities 
OR Pulse oximetry < 
90% 
Respiratory failure with 
ventilator support 
indicated (e.g., 
Continuous positive 
airway pressure [CPAP], 
Bilevel positive airway 
pressure [BPAP], 
intubation) 
SENSORY
Hearing Loss 
≥ 12 years of age 
NA 
Hearing aid or 
intervention not 
indicated 
Hearing aid or 
intervention indicated 
Profound bilateral 
hearing loss (> 80 dB at 
2 kHz and above) OR 
Non-serviceable hearing 
(i.e., >50 dB audiogram 
and <50% speech 
discrimination) 
< 12 years of age 
(based on a 1, 2, 3, 
4, 6 and 8 kHz 
audiogram) 
> 20 dB hearing 
loss at ≤ 4 kHz 
> 20 dB hearing 
loss at > 4 kHz 
> 20 dB hearing loss 
at ≥ 3 kHz in one ear 
with additional 
speech language 
related services 
indicated (where 
available) OR 
Hearing loss 
sufficient to indicate 
therapeutic 
intervention, including 
hearing aids 
Audiologic indication for 
cochlear implant and 
additional speech-
language related 
services indicated 
(where available) 
 
2018N360917_00


2015N227852_03
CONFIDENTIAL
200911
97
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Tinnitus 
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities with 
intervention not 
indicated 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
with intervention 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Uveitis 
No symptoms 
AND Detectable 
on examination 
Anterior uveitis with 
symptoms OR 
Medicamylasal 
intervention 
indicated 
Posterior or pan-
uveitis OR Operative 
intervention indicated 
Disabling visual loss in 
affected eye(s) 
Vertigo 
Vertigo causing 
no or minimal 
interference with 
usual social & 
functional 
activities 
Vertigo causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Vertigo causing 
inability to perform 
usual social & 
functional activities 
Disabling vertigo 
causing inability to 
perform basic self-care 
functions 
Visual Changes 
(assessed from 
baseline) 
Visual changes 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Visual changes 
causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Visual changes 
causing inability to 
perform usual social 
& functional activities 
Disabling visual loss in 
affected eye(s) 
SYSTEMIC
Acute Allergic 
Reaction 
Localized urticaria 
(wheals) with no 
medical 
intervention 
indicated 
Localized urticaria 
with intervention 
indicated OR Mild 
angioedema with 
no intervention 
indicated 
Generalized urticaria 
OR Angioedema with 
intervention indicated
OR Symptoms of 
mild bronchospasm 
Acute anaphylaxis OR 
Life-threatening 
bronchospasm OR 
Laryngeal edema 
Chills 
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Cytokine Release 
Syndrome9
Mild signs and 
symptoms AND 
Therapy (i.e., 
antibody infusion) 
interruption not 
indicated 
Therapy (i.e., 
antibody infusion) 
interruption 
indicated AND 
Responds promptly 
to symptomatic 
treatment OR 
Prophylactic 
medications 
indicated for ≤ 24 
hours 
Prolonged severe 
signs and symptoms 
OR Recurrence of 
symptoms following 
initial improvement 
Life-threatening 
consequences (e.g., 
requiring pressor or 
ventilator support) 
 
2018N360917_00


2015N227852_03
CONFIDENTIAL
200911
98
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Fatigue or Malaise 
Report only one 
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Incapacitating 
symptoms of fatigue or 
malaise causing inability 
to perform basic self-
care functions 
Fever (non-axillary 
temperatures only) 
38.0 to < 38.6°C 
or 100.4 to < 
101.5°F 
≥ 38.6 to < 39.3°C 
or ≥ 101.5 to < 
102.7°F 
≥ 39.3 to < 40.0°C or 
≥ 102.7 to < 104.0°F 
≥ 40.0°C or ≥ 104.0°F 
Pain10 (not 
associated with study 
agent injections and 
not specified 
elsewhere) 
Specify location 
Pain causing no 
or minimal 
interference with 
usual social & 
functional 
activities 
Pain causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Pain causing inability 
to perform usual 
social & functional 
activities 
Disabling pain causing 
inability to perform basic 
self-care functions OR 
Hospitalization indicated 
Serum Sickness11 
Mild signs and 
symptoms 
Moderate signs and 
symptoms AND 
Intervention 
indicated (e.g., 
antihistamines) 
Severe signs and 
symptoms AND 
Higher level 
intervention indicated 
(e.g., steroids or IV 
fluids) 
Life-threatening 
consequences (e.g., 
requiring pressor or 
ventilator support) 
Underweight12
> 5 to 19 years of 
age 
NA 
World Health 
Organization 
(WHO) BMI z-score 
< -2 to ≤ -3 
WHO BMI z-score < -
3 
WHO BMI z-score < -3 
with life-threatening 
consequences 
2 to 5 years of age 
NA 
WHO Weight-for-
height z-score 
< -2 to ≤ -3 
WHO Weight-for-
height z-score < -3 
WHO Weight-for-height 
z-score < -3 with life-
threatening 
consequences 
< 2 years of age 
NA 
WHO Weight-for-
length z-score 
< -2 to ≤ -3 
WHO Weight-for-
length z-score < -3 
WHO Weight-for-length 
z-score < -3 with life-
threatening 
consequences 
Weight Loss 
(excludes postpartum 
weight loss) 
NA 
5 to < 9% loss in 
body weight from 
baseline 
≥ 9 to < 20% loss in 
body weight from 
baseline 
≥ 20% loss in body 
weight from baseline OR 
Aggressive intervention 
indicated (e.g., tube 
feeding, total parenteral 
nutrition) 
URINARY
Urinary Tract 
Obstruction 
NA 
Signs or symptoms 
of urinary tract 
obstruction without 
hydronephrosis or 
renal dysfunction 
Signs or symptoms of 
urinary tract 
obstruction with 
hydronephrosis or 
renal dysfunction 
Obstruction causing life-
threatening 
consequences 
 
2018N360917_00


2015N227852_03
CONFIDENTIAL
200911
99
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
SITE REACTIONS TO INJECTIONS AND INFUSIONS
Injection Site Pain 
or Tenderness 
Report only one 
Pain or 
tenderness 
causing no or 
minimal limitation 
of use of limb 
Pain or tenderness 
causing greater 
than minimal 
limitation of use of 
limb 
Pain or tenderness 
causing inability to 
perform usual social 
& functional activities 
Pain or tenderness 
causing inability to 
perform basic self-care 
function OR 
Hospitalization indicated 
Injection Site 
Erythema or 
Redness13 
Report only one 
> 15 years of age 
2.5 to < 5 cm in 
diameter OR 6.25 
to < 25 cm2 
surface area AND 
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
≥ 5 to < 10 cm in 
diameter OR ≥ 25 
to < 100 cm2 
surface area OR 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
≥ 10 cm in diameter 
OR ≥ 100 cm2 
surface area OR 
Ulceration OR 
Secondary infection 
OR Phlebitis OR
Sterile abscess OR 
Drainage OR 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Potentially life-
threatening 
consequences (e.g., 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue) 
≤ 15 years of age 
≤2.5 cm in 
diameter 
> 2.5 cm in 
diameter with < 
50% surface area 
of the extremity 
segment involved 
(e.g., upper arm or 
thigh) 
≥ 50% surface area 
of the extremity 
segment involved 
(e.g., upper arm or 
thigh) OR Ulceration 
OR Secondary 
infection OR Phlebitis 
OR Sterile abscess 
OR Drainage 
Potentially life-
threatening 
consequences (e.g., 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue) 
Injection Site 
Induration or 
Swelling 
Report only one 
> 15 years of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 
years of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 
years of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, > 15 years of 
age 
≤ 15 years of age 
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15 
years of age 
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15 
years of age 
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, ≤ 15 years of 
age 
Injection Site 
Pruritus 
Itching localized 
to the injection 
site that is 
relieved 
spontaneously or 
in < 48 hours of 
treatment 
Itching beyond the 
injection site that is 
not generalized OR 
Itching localized to 
the injection site 
requiring ≥ 48 
hours treatment 
Generalized itching 
causing inability to 
perform usual social 
& functional activities 
NA 
LABORATORY VALUES Chemistries
Acidosis 
NA 
pH ≥ 7.3 to < Lower 
limit of normal 
(LLN) 
pH < 7.3 without life-
threatening 
consequences 
pH < 7.3 with life-
threatening 
consequences 
Albumin, Low (g/dL; 
g/L) 
3.0 to < LLN 
30 to < LLN 
≥ 2.0 to < 3.0
≥ 20 to < 30 
< 2.0 
< 20 
NA 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Alkaline 
Phosphatase, High 
1.25 to < 2.5 x 
ULN 
2.5 to < 5.0 x ULN 
5.0 to < 10.0 x ULN 
≥ 10.0 x ULN 
Alkalosis 
NA 
pH > ULN to ≤ 7.5 
pH > 7.5 without life-
threatening 
consequences 
pH > 7.5 with life-
threatening 
consequences 
ALT or SGPT, High 
Report only one 
1.25 to < 2.5 x 
ULN 
2.5 to < 5.0 x ULN 
5.0 to < 10.0 x ULN 
≥ 10.0 x ULN 
Amylase 
(Pancreatic) or 
Amylase (Total), 
High 
Report only one 
1.1 to < 1.5 x ULN 
1.5 to < 3.0 x ULN 
3.0 to < 5.0 x ULN 
≥ 5.0 x ULN 
AST or SGOT, High 
Report only one 
1.25 to < 2.5 x 
ULN 
2.5 to < 5.0 x ULN 
5.0 to < 10.0 x ULN 
≥ 10.0 x ULN 
Bicarbonate, Low
(mEq/L; mmol/L) 
16.0 to < LLN 
16.0 to < LLN 
11.0 to < 16.0 
11.0 to < 16.0 
8.0 to < 11.0 
8.0 to < 11.0 
< 8.0 
< 8.0 
Bilirubin Direct 
Bilirubin14, High 
> 28 days of age 
NA 
NA 
> ULN 
> ULN with life-
threatening 
consequences (e.g., 
signs and symptoms of 
liver failure) 
≤ 28 days of age 
ULN to ≤ 1 mg/dL 
> 1 to ≤ 1.5 mg/dL 
> 1.5 to ≤ 2 mg/dL 
> 2 mg/dL 
Total Bilirubin, High 
> 28 days of age 
1.1 to < 1.6 x ULN 
1.6 to < 2.6 x ULN 
2.6 to < 5.0 x ULN 
≥ 5.0 x ULN 
≤ 28 days of age 
Total Bilirubin for 
Term and Preterm 
Neonates 
Total Bilirubin for 
Term and Preterm 
Neonates 
Total Bilirubin for 
Term and Preterm 
Neonates 
Total Bilirubin for Term 
and Preterm Neonates 
Calcium, High 
(mg/dL; mmol/L) 
≥ 7 days of age 
10.6 to < 11.5 
2.65 to < 2.88 
11.5 to < 12.5 
2.88 to < 3.13 
12.5 to < 13.5 
3.13 to < 3.38 
≥ 13.5 
≥ 3.38 
< 7 days of age 
11.5 to < 12.4 
2.88 to < 3.10 
12.4 to < 12.9 
3.10 to < 3.23 
12.9 to < 13.5 
3.23 to < 3.38 
≥ 13.5 
≥ 3.38 
Calcium (Ionized), 
High (mg/dL; 
mmol/L) 
> ULN to < 6.0
> ULN to < 1.5 
6.0 to < 6.4 
1.5 to < 1.6 
6.4 to < 7.2 
1.6 to < 1.8 
≥ 7.2 
≥ 1.8 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Calcium, Low 
(mg/dL; mmol/L) 
≥ 7 days of age 
7.8 to < 8.4 
1.95 to < 2.10 
7.0 to < 7.8 
1.75 to < 1.95 
6.1 to < 7.0 
1.53 to < 1.75 
< 6.1 
< 1.53 
< 7 days of age 
6.5 to < 7.5 
1.63 to < 1.88 
6.0 to < 6.5 
1.50 to < 1.63 
5.50 to < 6.0 
1.38 to < 1.50 
< 5.50 
< 1.38 
Calcium (Ionized), 
Low (mg/dL; mmol/L) 
< LLN to 4.0 
< LLN to 1.0 
3.6 to < 4.0 
0.9 to < 1.0 
3.2 to < 3.6 
0.8 to < 0.9 
< 3.2 
< 0.8 
Cardiac Troponin I, 
High 
NA 
NA 
NA 
Levels consistent with 
myocardial infarction or 
unstable angina as 
defined by the local 
laboratory 
Creatine Kinase, 
High 
3 to < 6 x ULN 
6 to < 10 x ULN 
10 to < 20 x ULN 
≥ 20 x ULN 
Creatinine, High 
1.1 to 1.3 x ULN 
> 1.3 to 1.8 x ULN 
OR Increase of > 
0.3 mg/dL above 
baseline 
> 1.8 to < 3.5 x ULN 
OR Increase of 1.5 to 
< 2.0 x above 
baseline 
≥ 3.5 x ULN OR 
Increase of ≥ 2.0 x 
above baseline 
Creatinine 
Clearance15 or
Estimated 
glomerular filtration 
rate (eGFR), Low 
Report only one 
NA 
< 90 to 60 mL/min 
or mL/min/1.73 m2 
OR 10 to < 30% 
decrease from 
baseline 
< 60 to 30 mL/min or 
mL/min/1.73 m2 OR 
≥ 30 to < 50% 
decrease from 
baseline 
< 30 mL/min or 
mL/min/1.73 m2 OR ≥ 
50% decrease from 
baseline or dialysis 
needed 
Glucose 
(mg/dL; mmol/L) 
Fasting, High 
110 to 125 
6.11 to < 6.95 
> 125 to 250 
6.95 to < 13.89 
> 250 to 500 
13.89 to < 27.75 
> 500 
≥ 27.75 
Nonfasting, High 
116 to 160 
6.44 to < 8.89 
> 160 to 250 
8.89 to < 13.89 
> 250 to 500 
13.89 to < 27.75 
> 500 
≥ 27.75 
Glucose, Low 
(mg/dL; mmol/L) 
≥ 1 month of age 
55 to 64 
3.05 to 3.55 
40 to < 55 
2.22 to < 3.05 
30 to < 40 
1.67 to < 2.22 
< 30 
< 1.67 
Lactate, High 
ULN to < 2.0 x 
ULN without 
acidosis 
≥ 2.0 x ULN without 
acidosis 
Increased lactate with 
pH < 7.3 without life-
threatening 
consequences 
Increased lactate with 
pH < 7.3 with life-
threatening 
consequences 
Lipase, High 
1.1 to < 1.5 x ULN 
1.5 to < 3.0 x ULN 
3.0 to < 5.0 x ULN 
≥ 5.0 x ULN 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Lipid Disorders 
(mg/dL; mmol/L) 
Cholesterol, 
Fasting, High 
≥ 18 years of age 
200 to < 240 
5.18 to < 6.19 
240 to < 300 
6.19 to < 7.77 
≥ 300 
≥ 7.77 
NA 
< 18 years of age 
170 to < 200 4.40 
to < 5.15 
200 to < 300 5.15 to 
< 7.77 
≥ 300 ≥7.77 
NA 
Low Density 
Lipoprotein (LDL),
Fasting, High 
≥ 18 years of age 
130 to < 160 3.37 
to < 4.12 
160 to < 190 4.12 to 
< 4.90 
≥ 190 ≥ 4.90 
NA 
> 2 to < 18 years of 
age 
110 to < 130 2.85 
to < 3.34 
130 to < 190 3.34 to 
< 4.90 
≥ 190 ≥ 4.90 
NA 
Triglycerides, 
Fasting, High 
150 to 300 
1.71 to 3.42 
>300 to 500 
>3.42 to 5.7 
>500 to < 1,000 
>5.7 to 11.4 
> 1,000 
> 11.4 
Magnesium16, Low 
(mEq/L; mmol/L) 
1.2 to < 1.4 
0.60 to < 0.70 
0.9 to < 1.2 
0.45 to < 0.60 
0.6 to < 0.9 
0.30 to < 0.45 
< 0.6 
< 0.30 
Phosphate, Low 
(mg/dL; mmol/L) 
> 14 years of age 
2.0 to < LLN 
0.81 to < LLN 
1.4 to < 2.0 
0.65 to < 0.81 
1.0 to < 1.4 
0.32 to < 0.65 
< 1.0 
< 0.32 
1 to 14 years of age 
3.0 to < 3.5 
0.97 to < 1.13 
2.5 to < 3.0 
0.81 to < 0.97 
1.5 to < 2.5 
0.48 to < 0.81 
< 1.5 
< 0.48 
< 1 year of age 
3.5 to < 4.5 
1.13 to < 1.45 
2.5 to < 3.5 
0.81 to < 1.13 
1.5 to < 2.5 
0.48 to < 0.81 
< 1.5 
< 0.48 
Potassium, High 
(mEq/L; mmol/L) 
5.6 to < 6.0 
5.6 to < 6.0 
6.0 to < 6.5 
6.0 to < 6.5 
6.5 to < 7.0 
6.5 to < 7.0 
≥ 7.0 
≥ 7.0 
Potassium, Low 
(mEq/L; mmol/L) 
3.0 to < 3.4 
3.0 to < 3.4 
2.5 to < 3.0 
2.5 to < 3.0 
2.0 to < 2.5 
2.0 to < 2.5 
< 2.0 
< 2.0 
Sodium, High 
(mEq/L; mmol/L) 
146 to < 150 
146 to < 150 
150 to < 154 
150 to < 154 
154 to < 160 
154 to < 160 
≥ 160 
≥ 160 
Sodium, Low 
(mEq/L; mmol/L) 
130 to < 135 
130 to < 135 
125 to < 130 
125 to < 135 
121 to < 125 
121 to < 125 
≤ 120 
≤ 120 
Uric Acid, High 
(mg/dL; mmol/L) 
7.5 to < 10.0 
0.45 to < 0.59 
10.0 to < 12.0 
0.59 to < 0.71 
12.0 to < 15.0 
0.71 to < 0.89 
≥ 15.0 
≥ 0.89 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
HEMATOLOGY
Absolute cluster of 
differentiation 4 
(CD4+) Count, Low 
(cell/mm3; cells/L) 
> 5 years of age (not 
HIV infected) 
300 to < 400 
300 to < 400 
200 to < 300 
200 to < 300 
100 to < 200 
100 to < 200 
< 100 
< 100 
Absolute 
Lymphocyte Count, 
Low 
(cell/mm3; cells/L) 
> 5 years of age 
(not HIV infected) 
600 to < 650 
0.600 x 109 to < 
0.650 x 109
500 to < 600 
0.500 x 109 to < 
0.600 x 109
350 to < 500 
0.350 x 109 to < 
0.500 x 109
< 350 
< 0.350 x 109
Absolute Neutrophil 
Count (ANC), Low 
(cells/mm3; cells/L) 
> 7 days of age 
800 to 1,000 
0.800 x 109 to 
1.000 x 109
600 to 799 
0.600 x 109 to 0.799 
x 109
400 to 599 
0.400 x 109 to 0.599 
x 109
< 400 
< 0.400 x 109
2 to 7 days of age 
1,250 to 1,500 
1.250 x 109 to 
1.500 x 109
1,000 to 1,249 
1.000 x 109 to 1.249 
x 109
750 to 999 
0.750 x 109 to 0.999 
x 109
< 750 
< 0.750 x 109
≤ 1 day of age 
4,000 to 5,000 
4.000 x 109 to 
5.000 x 109 
3,000 to 3,999 
3.000 x 109 to 3.999 
x 109
1,500 to 2,999 
1.500 x 109 to 2.999 
x 109
< 1,500 
< 1.500 x 109
Fibrinogen, 
Decreased (mg/dL; 
g/L) 
100 to < 200 
1.00 to < 2.00 OR 
0.75 to < 1.00 x 
LLN 
75 to < 100 
0.75 to < 1.00 OR ≥ 
0.50 to < 0.75 x 
LLN 
50 to < 75 
0.50 to < 0.75 OR 
0.25 to < 0.50 x LLN 
< 50 
< 0.50 OR < 0.25 x LLN 
OR Associated with 
gross bleeding 
Hemoglobin17, Low 
(g/dL; mmol/L)18 
≥ 13 years of age 
(male only) 
10.0 to 10.9 
6.19 to 6.76 
9.0 to < 10.0 
5.57 to < 6.19 
7.0 to < 9.0 
4.34 to < 5.57 
< 7.0 
< 4.34 
≥ 13 years of age 
(female only) 
9.5 to 10.4 
5.88 to 6.48 
8.5 to < 9.5 
5.25 to < 5.88 
6.5 to < 8.5 
4.03 to < 5.25 
< 6.5 
< 4.03 
57 days of age to < 
13 years of age 
(male and female) 
9.5 to 10.4 
5.88 to 6.48 
8.5 to < 9.5 
5.25 to < 5.88 
6.5 to < 8.5 
4.03 to < 5.25 
< 6.5 
< 4.03 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
36 to 56 days of age 
(male and female) 
8.5 to 9.6 
5.26 to 5.99 
7.0 to < 8.5 
4.32 to < 5.26 
6.0 to < 7.0 
3.72 to < 4.32 
< 6.0 
< 3.72 
22 to 35 days of age 
(male and female) 
9.5 to 11.0 
5.88 to 6.86 
8.0 to < 9.5 
4.94 to < 5.88 
6.7 to < 8.0 
4.15 to < 4.94 
< 6.7 
< 4.15 
8 to ≤ 21 days of age 
(male and female) 
11.0 to 13.0 
6.81 to 8.10 
9.0 to < 11.0 
5.57 to < 6.81 
8.0 to < 9.0 
4.96 to < 5.57 
< 8.0 
< 4.96 
≤ 7 days of age 
(male and female) 
13.0 to 14.0 
8.05 to 8.72 
10.0 to < 13.0 
6.19 to < 8.05 
9.0 to < 10.0 
5.59 to < 6.19 
< 9.0 
< 5.59 
INR, High 
(not on 
anticoagulation 
therapy) 
1.1 to < 1.5 x ULN 
1.5 to < 2.0 x ULN 
2.0 to < 3.0 x ULN 
≥ 3.0 x ULN 
Methemoglobin (% 
hemoglobin) 
5.0 to < 10.0% 
10.0 to < 15.0% 
15.0 to < 20.0% 
≥ 20.0% 
PTT, High 
(not on 
anticoagulation 
therapy) 
1.1 to < 1.66 x 
ULN 
1.66 to < 2.33 x 
ULN 
2.33 to < 3.00 x ULN 
≥ 3.00 x ULN 
Platelets, 
Decreased 
(cells/mm3; cells/L) 
100,000 to < 
124,999 100.000 
x 109 to < 124.999 
x 109
50,000 to < 100,000 
50.000 x 109 to < 
100.000 x 109 
25,000 to < 50,000 
25.000 x 109 to < 
50.000 x 109
< 25,000 < 25.000 x 109
PT, High 
(not on 
anticoagulation 
therapy 
1.1 to < 1.25 x 
ULN 
1.25 to < 1.50 x 
ULN 
1.50 to < 3.00 x ULN 
≥ 3.00 x ULN 
WBC, Decreased
(cells/mm3; cells/L) 
> 7 days of age 
2,000 to 2,499 
2.000 x 109 to 
2.499 x 109
1,500 to 1,999 
1.500 x 109 to 1.999 
x 109
1,000 to 1,499 
1.000 x 109 to 1.499 
x 109
< 1,000 
< 1.000 x 109
≤ 7 days of age 
5,500 to 6,999 
5.500 x 109 to 
6.999 x 109 
4,000 to 5,499 
4.000 x 109 to 5.499 
x 109
2,500 to 3,999 
2.500 x 109 to 3.999 
x 109
< 2,500 
< 2.500 x 109
URINALYSIS
Glycosuria (random 
collection tested by 
dipstick) 
Trace to 1+ or 
≤ 250 mg 
2+ or ˃ 250 to 
≤ 500 mg 
> 2+ or > 500 mg 
NA 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Hematuria (not to be 
reported based on 
dipstick findings or 
on blood believed to 
be of menstrual 
origin) 
6 to < 10 RBCs 
per high power 
field 
≥ 10 RBCs per high 
power field 
Gross, with or without 
clots OR With RBC 
casts OR Intervention 
indicated 
Life-threatening 
consequences 
Proteinuria (random 
collection tested by 
dipstick) 
1+ 
2+ 
3+ or higher 
NA 
1.
Blood pressure norms for children <18 years of age can be found in: Expert Panel on Integrated Guidelines for 
Cardiovascular Health and Risk Reduction in Children and Adolescents. Pediatrics 2011;128;S213; originally 
published online November 14, 2011; DOI: 10.1542/peds.2009-2107C.  
2.
As per Bazett’s formula.  
3.
For pruritus associated with injections or infusions, see the Site Reactions to Injections and Infusions section.  
4.
Definition: A disorder characterized by fat loss in the face, extremities, and buttocks. 
5.
Definition: A disorder characterized by abnormal fat accumulation on the back of the neck, breasts, and abdomen.  
6.
Bone mineral density (BMD) t and z scores can be found in: Kanis JA on behalf of the World Health Organization 
Scientific Group (2007). Assessment of osteoporosis at the primary health-care level. Technical Report. World 
Health Organization Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, UK. 2007: Printed 
by the University of Sheffield.  
7.
Definition: A delivery of a live-born neonate occurring at ≥20 to <37 weeks gestational age. 
8.
Definition: A clinically recognized pregnancy occurring at <20 weeks gestational age.  
9.
Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and/or shortness of 
breath. 
10. For pain associated with injections or infusions, see the Site Reactions to Injections and Infusions section.
11. Definition: A disorder characterized by fever, arthralgia, myalgia, skin eruptions, lymphadenopathy, marked 
discomfort, and/or dyspnea.
12. WHO reference tables may be accesed by clicking the desired age range or by accessing the following URLs: 
http://www.who.int/growthref/who2007_bmi_for_age/en/ for participants >5 to 19 years of age and 
http://www.who.int/childgrowth/standards/chart_catalogue/en/ for those ≤ 5 years of age.  
13. Injection Site Erythema or Redness should be evaluated and graded using the greatest single diameter or
measured surface area. 
14. Direct bilirubin >1.5 mg/dL in a participant <28 days of age should be graded as Grade 2, if <10% of the total 
bilirubin.  
15. Use the applicable formula (i.e., Cockroft-Gault in mL/min or Schwatrz in mL/min/1.73m2).  
16. To convert a magnesium value from mg/dL to mmol/L, laboratories should multiply by 0.4114.  
17. Male and female sexes are defined as sex at birth. 
18. The conversion factor used to convert g/dL to mmol/L is 0.6206 and is the most commonly used conversion factor. 
For grading hemoglobin results obtained by an analytic method with a conversion factor other than 0.6206, the 
result must be converted to g/dL using the appropriate conversion factor for the particular laboratory.  
 
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12.9.
Appendix 9: Toxicity Management
ANEMIA
Grade 1 (mild) hemoglobin decrease:
Any hemoglobin decrease meeting the definition of Grade 1 must be repeated with the 
following additional tests:
20. peripheral blood smear
21. indirect bilirubin
(abnormal if increased >50% from baseline)
22. haptoglobin
(abnormal if 25 mg/dL)
23. reticulocyte count
(abnormal if 4%) 
If the additional tests are within the normal range, subjects may continue study 
medication.  If one or more of the additional tests is abnormal or suggestive of hemolytic 
anemia as specified above, subjects will permanently discontinue study medication and 
be withdrawn from the trial.  Subjects should be followed up until resolution of anemia.
Grade 2 (moderate) hemoglobin decrease:
Any hemoglobin decrease meeting the definition of Grade 2 must be repeated with the 
following additional tests:
1.
peripheral blood smear
2.
indirect bilirubin
(abnormal if increased > 50% from baseline)
3.
haptoglobin
(abnormal if 25 mg/dL)
4.
reticulocyte count
(abnormal if 4%) 
If the additional tests are within the normal range, subjects may continue study 
medication.  If one or more of the additional tests is abnormal or suggestive of hemolytic 
anemia as specified above, subjects will permanently discontinue study medication and 
be withdrawn from the trial.  Consultation with a Hematologist should be considered.  
Subjects should be followed up until resolution of anemia.
Grade 3 (severe) or Grade 4 (potentially life threatening) hemoglobin decrease:
Any hemoglobin decrease meeting the definition of Grade 3 or 4 must be repeated with 
the following additional tests:
5.
peripheral blood smear
6.
indirect bilirubin
7.
haptoglobin
8.
reticulocyte count 
 
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Subjects will permanently discontinue study medication and be withdrawn from the trial.  
Consultation with a Hematologist should be considered.  Subjects should be followed up 
until resolution of anemia.
TOTAL BILIRUBIN ELEVATION
Grade 1 (mild) bilirubin elevation (1.1 - 1.5 times ULN) or Grade 2 (moderate 
- 1.6-2.5 times ULN):
Any bilirubin value above the upper limit of normal must be repeated and fractionated 
(direct and indirect bilirubin).  Subjects may continue study medication.  Subjects should 
be followed up until resolution (return to baseline) of elevation.
Grade 3 (severe – 2.6-5.0 times ULN) or 4 (life-threatening - > 5.0 times ULN) 
bilirubin elevation:
Any bilirubin value above the upper limit of normal must be repeated and fractionated 
(direct and indirect bilirubin).  Subjects will permanently discontinue study medication 
and be withdrawn from the trial.  Subjects should be followed up until resolution (return 
to baseline) of bilirubin elevation.
AST AND ALT ELEVATION
See Appendix 9.
RASH
Grade 1 rash (Localized macular rash):
Subjects with Grade 1 rash should be evaluated by the Investigator immediately.  A 
dermatologist may be consulted and a biopsy may be obtained if recommended by the 
dermatologist.  The study drug should be permanently discontinued if the following signs 
or symptoms are noted at any time:
9.
Temperature > 38.5°C
10. Lymphadenopathy
11. Pharyngitis
12. Any indication of internal organ involvement (hepatitis, nephritis)
In the absence of the above signs or symptoms, subjects with Grade 1 rash may continue 
the study drug at the discretion of the Investigator.  The subject should be advised to 
contact the Investigator immediately if there is any worsening of the rash, if any systemic 
signs or symptoms worsen, or if mucosal ulceration develops. If the rash is considered to 
be most likely due to concomitant illness or non-study medication, standard management, 
including discontinuation of the likely causative agent, should be undertaken. If no other 
causative factor is found after clinical evaluation, the subject may be treated 
symptomatically until the rash resolves. Antihistamines, topical corticosteroids or 
antipruritic agents may be prescribed.  The subject should remain on the study to be 
followed for safety and PK as outlined in Section 10.5.
 
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Grade 2 rash (Diffuse macular, maculopapular, or morbilliform rash OR Target
lesions):
Subjects with Grade 2 rash should be evaluated by the Investigator immediately.  Digital 
photographs should be obtained.  A dermatologist may be consulted and a biopsy may be 
obtained if recommended by the dermatologist.  The study drug should be permanently 
discontinued if the following signs or symptoms are noted at any time:
13. Temperature > 38.5°C
14. Lymphadenopathy
15. Pharyngitis
16. Any indication of internal organ involvement (hepatitis, nephritis)
In the absence of the above signs or symptoms, subjects with Grade 2 rash may continue 
the study drug at the discretion of the Investigator.  It should be noted that oral mucosal 
erosions may be part of a Grade 2 rash.  Any mucosal ulceration increases the severity 
of the rash to at least Grade 3.  The subject should be advised to contact the Investigator 
immediately if there is any worsening of the rash, if any systemic signs or symptoms 
worsen, or if mucosal ulceration develops. If the rash is considered to be most likely due 
to concomitant illness or non-study medication, standard management, including 
discontinuation of the likely causative agent, should be undertaken. If no other causative 
factor is found after clinical evaluation, the subject may be treated symptomatically until 
the rash resolves. Antihistamines, topical corticosteroids or antipruritic agents may be 
prescribed.  The subject should remain on the study to be followed for safety and PK as 
outlined in Section 10.5.
Grade 3 rash (Diffuse macular, maculopapular, or morbilliform rash with vesicles 
or limited number of bullae OR Superficial ulcerations of mucous membrane 
limited to one site):
Subjects with a Grade 3 rash will permanently discontinue the study medication.  The 
subject should be evaluated in the physician’s office immediately and should be seen in 
the physician’s office or contacted by phone every 2 days until the rash resolves.  A 
dermatologist should be consulted and digital photographs and a biopsy should be 
obtained.  Antihistamines, topical corticosteroids or antipruritic agents may be prescribed 
at the discretion of the Investigator.  The subject should be advised to contact the 
Investigator immediately if there is any worsening of the rash, if any systemic signs or 
symptoms appear, or if mucosal involvement develops.  The subject should remain on the 
study to be followed for safety and PK as outlined in Section 10.5.
Grade 4 rash (Extensive or generalized bullous lesions OR Stevens-Johnson 
syndrome OR Ulceration of mucous membrane involving two or more distinct 
mucosal sites OR Toxic epidermal necrolysis (TEN)):
Subjects with a Grade 4 rash will permanently discontinue the study medication.  A 
dermatologist should be consulted and digital photographs and a biopsy should be 
obtained.  Sponsor and GSK Medical Monitor should be notified of this serious adverse 
event within 24 hours via phone or fax.  The subject should be closely followed everyday 
until resolution of the reaction.  The subject should remain on the study to be followed 
for safety and PK as outlined in Section 10.5.
 
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ALLERGIC REACTION
Grade 1 allergic reaction (Pruritis without rash):
Subjects with Grade 1 allergic reaction should be evaluated by the Investigator 
immediately.  The study drug should be permanently discontinued if the following signs 
or symptoms are noted at any time:
17. Temperature > 38.5°C
18. Eosinophilia
19. Respiratory involvement including bronchospasm, laryngospasm, or 
angioedema
20. Any indication of internal organ involvement (hepatitis, nephritis)
In the absence of the above signs or symptoms, subjects with Grade 1 allergic reaction 
may continue the study drug at the discretion of the Investigator.  The subject should be 
advised to contact the Investigator immediately if there is any worsening of the allergic 
reaction and/or if any systemic signs or symptoms worsen.  If the allergic reaction is 
considered to be most likely due to concomitant illness or non-study medication, standard
management, including discontinuation of the likely causative agent, should be 
undertaken.  If no other causative factor is found after clinical evaluation, the subject may 
be treated symptomatically until the rash resolves. Antihistamines, topical corticosteroids 
or antipruritic agents may be prescribed.  The subject should remain on the study to be 
followed for safety and PK as outlined.
Grade 2 allergic reaction (Localized urticaria):
Subjects with Grade 2 allergic reaction should be evaluated by the Investigator 
immediately.  The study drug should be permanently discontinued if the following signs 
or symptoms are noted at any time:
21. Temperature > 38.5°C
22. Eosinophilia
23. Respiratory involvement including bronchospasm, laryngospasm, or 
angioedema
24. Any indication of internal organ involvement (hepatitis, nephritis)
In the absence of the above signs or symptoms, subjects with Grade 2 allergic reaction 
may continue the study drug at the discretion of the Investigator.  The subject should be 
advised to contact the Investigator immediately if there is any worsening of the allergic 
reaction and/or if any systemic signs or symptoms worsen.  If the allergic reaction is 
considered to be most likely due to concomitant illness or non-study medication, standard 
management, including discontinuation of the likely causative agent, should be 
undertaken.  If no other causative factor is found after clinical evaluation, the subject may 
be treated symptomatically until the rash resolves. Antihistamines, topical corticosteroids 
or antipruritic agents may be prescribed.  The subject should remain on the study to be 
followed for safety and PK as outlined in Section 7.
 
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Grade 3 allergic reaction (Generalized urticaria or angioedema):
Subjects will permanently discontinue the study medication and be withdrawn from the 
trial.  Subjects will be treated as clinically appropriate.  Subjects should be followed up 
until resolution of the adverse event and standard management should be undertaken.
Grade 4 allergic reaction (Anaphylaxis):
Subjects will permanently discontinue the study medication and be withdrawn from the 
trial.  Subjects will be treated as clinically appropriate.  Subjects should be followed up 
until resolution of the adverse event and standard management should be undertaken.
Revised ACTG Toxicity Grade
Definitions
Investigator Action
Grade 1
Pruritus without rash
May continue therapy
Grade 2
Localized urticaria
May continue therapy
Grade 3
Generalized urticaria
Angioedema
Discontinue Therapy
Grade 4
Anaphylaxis
Discontinue Therapy
 
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12.10.
Appendix 10: Protocol Amendment Changes
12.10.1.
AMENDMENT 1
Protocol Amendment 1 (26-Apr-2017) from the original protocol (09-Nov-2016)
Where the Amendment Applies
This amendment applies to all subjects who will participate in this study in all countries.
List of Specific Changes: (bold indicates text added and strikethrough indicates text 
removed)
Summary of Protocol Amendment Changes with Rationale
Amendment 1 includes minor updates to Inclusion criteria (IE) criteria, including 
clarification on use of pre- or post-exposure prophylaxis, and removal of exclusionary 
requirements related to concomitant medications and tobacco and alcohol use during the 
study. Guidance around relevant habits is included in the Lifestyle section of the protocol 
and adjustments were made to reduce restrictions on these requirements. Modifications 
were also made to the pharmacokinetics sampling, allowing for the 12 h PK collection 
timepoint on Day 1 and 10 to be optional. Minor alterations were made regarding the 
order of screening procedures, including the Holter monitoring requirements. 
Visit/procedure windows were included to allow more flexibility with scheduling of 
assessments. Furthermore, the serial ECG collection (up to 6h post-dose) was removed on 
Day 5. Finally, the post-study care guidance was updated to include an option for subjects 
to receive reimbursement for marketed ART for a limited period after completion of 
study treatment and follow up. Minor clarifications, reformatting of tables, re-numbering 
of sections and correction of typographical errors were also made throughout this 
amendment.
List of Authors
Rationale for change
The list of authors was updated based on internal GSK team personnel changes.
Revised Text
PTS, Ware, UK
GCSP, Stockley Park, UK
Infectious Diseases, Clinical, Upper Providence, PA, US
Clinical Statistics, GSK, Upper Providence, PA, US
HIV DPU, RTP, NC, US
Virology, HIV DPU, RTP, NC, US
 
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CPMS, GSK, RTP, NC, US
HIV DPU, RTP, NC, US
Clinical Pharmacology, ViiV Healthcare, RTP, NC, US
PCPS, GSK, Upper Providence, PA, US
PCPS, GSK, Collegeville, PA, US 
Clinical Statistics, PAREXEL, RTP, NC, US
Infectious Diseases, Clinical, Cambridge, MA, US
Medical Monitor/SAE Contact Information
Rationale for change
The sponsor and medical monitoring information was updated to reflect the current 
contact information for safety and medical monitoring. 
Revised Text
Role
Name
Day Time 
Phone Number 
and email 
address
After-hours 
Phone/Cell/
Pager Number
Fax Number
Site Address
Primary 
Medical 
Monitor/SAE 
contact 
information
 MD
Pharmaceutical 
Product 
Development
(PPD) Safety 
Hotline 
Boston, 
MAPPD, 929 
North Front 
Street, 
Wilmington, 
NC 28401
Secondary 
Medical 
Monitor
MD
GlaxoSmithKline
1250 St 
Collegeville Rd 
Collegeville, PA 
19426
SAE contact 
information
MD
Boston, MA
Synopsis:
Design, Treatment Arms and Duration
Rationale for change
Minor clarifications were made to this section to reflect current status of studies being 
referenced. As synopsis being a standalone document, cross-referenced has been 
removed.
 
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Revised Text
Fourth paragraph
The possibility that an additional, unboosted GSK2838232 monotherapy cohort will be 
assessed in Part B is dependent on analysis of the PK data from ongoing Study 204953 
where unboosted GSK2838232 at a dose of 200 mg twice daily (BID) is being was
assessed.
Sixth paragraph
HIV Drug Resistance: Following cessation of GSK2838232/cobi dosing for 10 days, 
there will be prolonged exposure to waning plasma concentrations of GSK2838232, 
because of the long t½ (i.e., in the “tail” of the PK profile). However, based on in vitro 
resistance passage data with GSK2838232 [and unlike with many other ARV therapies], 
there appears to be a limited likelihood of developing maturation resistance mutations in 
HIV-infected subjects due to its virologic profile [GSK Document Number 
2013N163221_00]. 
Section 2
Introduction
Rationale for change
Abbreviation used on first instance has been defined.
Revised Text
GSK2838232 is a novel human immunodeficiency virus (HIV)-1 maturation inhibitor 
(MI) that is being developed for the treatment of HIV-1 infection in combination with 
other antiretrovirals (ART).
Section 2.1 Study Rationale
Rationale for change
Abbreviation used on first instance has been defined.
Revised Text
This ‘proof of concept (PoC)’ open-label study is being conducted to characterize the 
acute antiviral activity, pharmacokinetics (PK), the relationship between PK and antiviral 
activity, and safety of GSK2838232 given with 150 mg once daily (QD) cobicistat 
(GSK283232/cobi), administered across a range of doses over 10 days in HIV-1 infected 
patients. A two part adaptive and dose ranging design is to be applied in this study. Data 
from this study will be utilized to select doses for further studies in Phase IIb.
 
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Section 2.2 Brief Background
Rationale for change
Abbreviation used on first instance has been defined.
Addition of abbreviation for AIDS in first paragraph
Combination antiviral therapy with inhibitors of HIV protease, integrase, entry and 
reverse transcriptase (RT) has demonstrated significant improvement in acquired 
immunodeficiency syndrome (AIDS)-related morbidity and mortality over the last 10-
15 years.
Addition of abbreviation for RNA in second paragraph
Prior validation of this target was demonstrated with the HIV maturation inhibitor known 
as bevirimat (BVM; [Martin, 2007a; Martin, 2007b; Martin, 2008; NORVIR, 2013]). 
BVM reached Phase II studies in HIV patients; however, only modest reductions in 
plasma HIV-1 ribonucleic acid (RNA) concentrations were observed in Phase IIa 
monotherapy studies [Mahmood, 2006; Martin, 2007] and a pattern of polymorphic 
(differential) antiviral activity [Wainburg, 2010] led to termination of BVM development. 
The average decrease from baseline to Day 14 plasma HIV-1 ribonucleic acid (RNA) 
was 0.54 and 0.70 log10 copies/mL for 200 mg and 300 mg twice daily regimens (Table 
2); all subjects achieved plasma BVM concentrations above the in vitro EC90. 
Responders, classified based on 5 polymorphisms in HIV-1 gag (at positions 369, 370, 
and 371), achieved an average 1.15 log10 copies/mL reduction in plasma HIV-1 RNA, 
while an average 0.17 log10 copies/mL reduction was achieved for non-responders.
Section 2.2.2
Clinical Summary of Safety and Pharmacokinetics
Rationale for change
Minor clarifications were made to this section to reflect current status of studies being 
referenced.
Revised Text
To date, GSK2838232 has been evaluated in three completed clinical studies with or 
without ritonavir (RTV) (GSK2838232/r). A fourth study (204953) is on-going as of 1st
November completed late 2016 and data analysis is ongoing. Full details of the clinical 
results can be found in the Investigator’s Brochure.
Section 2.2.2.1
Clinical Summary of Safety
Rationale for change
Minor clarifications were made to this section to reflect current status of studies being 
referenced.
 
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Revised Text
Fifty As of November 2016 fifty-three subjects have had been exposed to GSK2838232 
in 3 completed studies. One study (204953) is completed in late 2016 and the analysis 
of results are ongoing (52 subjects have been 63 subjects were exposed to 
GSK2838232/r or placebo so far in this study). Overall, drug-related adverse events have 
been few and mild, and included headache, dizziness, fatigue, nausea, and palpitations 
and anxiety.  Similarly, treatment-emergent laboratory abnormalities have also been few 
and mostly grade 1.  There have been no discernible patterns, thus far, in terms of AEs or 
laboratory abnormalities.
Section 2.2.2.2
Study 204953 (completed); Pharmacokinetic Data
Rationale for change
Minor clarifications were made to this section to reflect current status of studies being 
referenced.
Change in Heading
Section 2.2.2.2
Study 204953 (on-going completed); Pharmacokinetic Data
Section 4.4.1
Risk Assessment
Rationale for change
Abbreviation used on first instance has been defined.
Revised Text
 
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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
HIV-1 Infection/Patient population
HIV Resistance
Propensity for co-meds and 
possible Drug-Drug 
Interactions (DDIs)
HIV Drug Resistance to unique mechanism
Recognize HIV patients have a higher chance of comorbidities/diseases and a 
risk of taking a medicine or product contraindicated in the study
Closely monitor HIV viral load and genotypic 
resistance
Strict adherence to protocol criteria around 
concurrent meds 
 
 
 
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Section 5.1
Inclusion Criteria
Rationale for change
Changes were made to this inclusion criteria to clarify that prior  use of pre- or post-
exposure prophylaxis would not exclude a subject from participation as long as last dose 
was 6 weeks before starting study treatment.
Revised Text
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
5 . Confirmed HIV positive; CD4+ cell count ≥350 cells/mm3 and plasma HIV-1 RNA 
≥5000 copies/mL at Screening. No current and no prior ART. (A previous course of 
pre- or post-exposure prophylaxis is allowed provided that it was completed at least 
6 weeks prior to the first dose of study drug).
Section 5.2
Exclusion Criteria
Rationale for change
This exclusion criteria was removed and the guidance for use of concomitant medications 
was further addressed in Section 6.12, Concomitant Medications and Non-Drug 
Therapies. The Relevant Habits section of the Exclusionary criteria was also removed 
and addressed in Section 6.10, Lifestyle and/or Dietary Restrictions, with the exception 
of illicit drug use. Smoking and limited alcohol use are no longer exclusionary. 
Additional clarification added to note that positive Hepatitis C result would need to be 
confirmed by RIBA. Abbreviation used on first instance has been defined.  Additional 
minor typographical errors were corrected.
Revised Text
CONCOMITANT MEDICATIONS
5.
Unable to refrain from the use of prescription or non-prescription drugs, including 
vitamins, herbal and dietary supplements (including St John’s Wort) within 7 days 
(or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is 
longer) prior to the first dose of study medication, unless in the opinion of the 
Investigator and GSK Medical Monitor the medication will not interfere with the 
study procedures or compromise subject safety. 
RELEVANT HABITS
6.
History of regular alcohol consumption within 6 months of the study defined as: 

An average weekly intake of >14 drinks for males or >7 drinks for females.  One 
drink is equivalent to 12 g of alcohol: 12 ounces (360 mL) of beer, 5 ounces 
(150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.
7.
Smoking is an exclusion criteria for this study. Urinary cotinine levels indicative of 
 
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smoking at screening.
6.
Chronic marijuana or use of other elicit medications (cocaine, heroin) is an exclusion 
criteria.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
7 . Presence of hepatitis B surface antigen (HBsAg), positive (confirmed by 
Recombinant Immuno-Blot Assay [RIBA]) hepatitis C antibody test result at screening 
or within 3 months prior to first dose of study treatment.
19 . Exclusion criteria for screening ECG (a single repeat is allowed for eligibility 
determination):
Males
Females
Heart rate
<45 and >100 bpm
<50 and >100 bpm
PR Interval
<120 and >220 msec
QRS duration
<70 and >120 msec
*QTc interval
>450 msec
*The QTc is the QT interval corrected for heart rate according to Bazett’s formula 
(QTcB), Fridericia’s formula (QTcF), and/or another method. It is either machine-
read or manually over-read. The specific formula used to determine eligibility and 
discontinuation for an individual participant in 204953200911 will be Fridericia’s 
formula. 
Section 6.1
Investigational Product and Other Study Treatment
Rationale for change 
Minor typographical error corrected in this section. 
Revised Text
Treatment
Product name:
GSK2838232 
Capsule (API)
Tybost 
(cobicistat, cobi) tablet
Method for 
individualizing dosage:
Capsules supplied in high-density 
polyethylene bottles for 
individualized dosing by the clinic
Capsules Tablets supplied in bulk 
containers for individualized dosing by 
the clinic
Section 6.9
Treatment after the End of the Study
Rationale for change 
Additional language was included in this section to allow subjects to opt to receive 
reimbursement from GSK for up to 3 months for marketed antiretroviral therapy (as 
 
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directed and prescribed by physician) based on the CDC guideline recommendations that 
patients be put on ARTs when diagnosed with HIV (test and treat guidelines). 
Revised Text
Subjects will not receive any additional treatment from GSK.
Subjects receiving GSK2838232 may opt to receive marketed antiretrovirals after 
the completion of 10 days of GSK2838232 dosing and study follow-up visits 
(through Day 21) eligible for sponsor company reimbursement up to a maximum of 
90 days. The selection of antiretrovirals will be investigator-chosen.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
reimbursement for post-study treatment.
Section 6.10.1
Meals and Dietary Restrictions
Previous section number 6.12
Rationale for change
This section was updated to remove language around meal provisions (language 
consistent for an in-patient trial). As this is an out-patient trial, it will be up to trial site to 
arrange when/how meals are provided during a subject’s participation in the trial. The 
section ‘Lifestyle and/or Dietary Restrictions’ had no content described under it. The 
sections ‘Meals and Dietary Restrictions’ and ‘Alcohol, Caffeine and Exercise’ has been 
moved as sub-sections under the section ‘Lifestyle and/or Dietary Restrictions’, as the 
sub-sections are related to this section.   
Revised Text
Second Bullet
Doses will be given in the fed state (light breakfast), following overnight fasting (>10 
hours). Lunch will provided 4 hours after the dose; water will be allowed ad libitum 
throughout.
Section 6.10.2
Alcohol, Caffeine and Exercise
Previous section number 6.13
Rationale for change 
Adjustments were made to these lifestyle habits to eliminate restrictions on use of 
tobacco products, reduce restrictions on alcohol use and to allow occasional and light 
exercise during study treatment.  
 
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Revised Text
Alcohol, Caffeine, Tobacco and Exercise

Subjects should refrain from alcohol for 48 hours before screening and then for 48 
hours prior to admission and baseline assessments (on Day 1). Alcohol is then not 
permitted for the duration of the treatment period (through Day 10) and until the 
final follow-up visit.  

Use of tobacco products is not allowed from screening until after the final follow-up 
visit

Subjects will During  the study  alcohol consumption should be limited to the 
following:

An average weekly intake of <14 drinks for males or <7 drinks for females.  
One drink is equivalent to 12 g of alcohol: 12 ounces (360 mL) of beer, 5 
ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.

Subjects will should abstain from strenuous exercise for 72 hours prior to each blood 
collection for clinical laboratory tests.  Subjects may participate in light recreational 
activities during studies (e.g., watch television, read).the treatment period.
Section 6.11
Contraception
Rationale for change
This section was updated to clarify that use of oral contraceptives are permitted during 
the study.
Revised Text
Second paragraph
Females of reproductive potential may only be enrolled if they are using two forms of 
complementary contraception, which must include one barrier method.  There Although 
use of oral contraceptives is permitted, tThere is no definitive DDI information with 
GSK2838232 and an interaction with oral contraceptives is possible, so other (barrier, 
inter-uterine device etc.) methods of contraception will be required.
Section 6.12
Concomitant Medications and Non-Drug Therapies
Previous section number 6.14
Rationale for change
Adjustments were made to the concomitant medication section to clarify that certain 
(medically necessary) medications were allowed and that all medication use should be 
discussed with the investigator. As section on ‘Meals and Dietary Restrictions’ (previous 
section 6.12) and ‘Alcohol, Caffeine and Exercise’ (previous section 6.13) has been 
moved under Lifestyle and/or Dietary Restrictions’ (Section 6.10), the section has been 
re-numbered.
 
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Deleted Text

Subjects must refrain from all illicit drugs throughout the study (from Screening until 
discharge from the study).  Drug screening will occur at Screening and Day -1 for 
each treatment period.  A positive result will lead to exclusion from the remainder of 
the study.

The Principal Investigator must be informed as soon as possible about any 
medications taken from the time of screening until the subject is discharged from the 
study.  Over-the-counter medications will not be permitted during the treatment 
period except as needed to treat an AE. If medication is needed, use should be 
restricted to 4 hours after dosing if possible. 
Section 6.12.1
Permitted Medications and Non-Drug Therapies
Previous section number 6.14.1
Rationale for change
Adjustments were made to the concomitant medication section to clarify that certain 
(medically necessary) medications were allowed and that all medication use should be 
discussed with the investigator. As section on ‘Meals and Dietary Restrictions’ (previous 
Section 6.12) and ‘Alcohol, Caffeine and Exercise’ (previous Section 6.13) has been 
moved under Lifestyle and/or Dietary Restrictions’ (Section 10), the section has been re-
numbered.
Revised Text
Addition of Second bullet

Concomitant medications (prescription and non-prescription) should be 
administered only as medically necessary during the study. Subjects must 
notify their Investigator of any current or proposed concomitant medication, 
whether prescribed or over-the-counter, because of the potential for 
interactions between such treatments and the study medications.
Section 6.12.2
Prohibited Medications and Non-Drug Therapies
Rationale for change 
Adjustments were made to the concomitant medication section to clarify that certain 
(medically necessary) medications were allowed and that all medication use should be 
discussed with the investigator. As section on ‘Meals and Dietary Restrictions’ (previous 
Section 6.12) and ‘Alcohol, Caffeine and Exercise’ (previous Section 6.13) has been 
moved under Lifestyle and/or Dietary Restrictions’ (Section 10), the section has been re-
numbered.
 
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Previous section number 6.14.2
Revised Text

Subjects must abstain from taking prescription or non-prescription drugs (including 
vitamins and dietary or herbal supplements), within 7 days (or 14 days if the drug is 
a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first 
dose of study medication until completion of the follow-up visit, unless in the 
opinion of the Investigator and sponsor the medication will not interfere with the
study. 

Subjects must refrain from all illicit drugs throughout the study (from 
Screening until discharge from the study).  Drug screening will occur at 
Screening and Day -1 and at additional timepoints throughout the study.  A 
positive result will lead to exclusion from the remainder of the study.
Section 7.1
Time and Events Table
Rationale for change 
The Time and Events table was updated to remove the post-dose 12-lead ECG on Day 5, 
which remains in line with the FDA’s guidance regarding days on which to perform post-
dose (2 & 6 hours to capture near Tmax) ECGs. Modifications were also made to the 
pharmacokinetics sampling, allowing for the 12 h PK collection timepoint on Day 1 and 
10 to be optional. Visit/procedure windows were included to allow more flexibility with 
scheduling of assessments. Also minor clarifications were made and typographical errors 
were corrected.
Revised Text
 
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Day:
Screen1
Random
1
2
3
4
5
62
7
8
9
10
11
12
141
211 
(FU)
ET
Informed Consent
X
Review inclusion/exclusion
X
X
Demography including height, weight and 
BMI
X
Brief physical
X
Medical/medication/
drug/alcohol history
X
X
CDC Classification
X
X
X
X
Prior antiretroviral therapy
X
12-lead ECG3
X
X
X
X
X
X
X
X
X
X
Holter (24 hr)
X
Vital signs4
X
X
X
X
X
X
X
X
X
Drug screen
X
X
X
X
X
Hepatitis B Surface antigen and hepatitis 
C antibody testing
X
Serum or urine -hCG (WoCBP only)
X
X
X
Clinical lab tests (inc troponin)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Fasting lipid panel
X
X
AE assessment5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Con Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HIV-1 RNA PCR6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lymphocyte subsets7
X
X
X
Plasma for genotype/phenotype8
X
X
X
X
X
X
X
HIV-associated conditions assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK blood sample9
X
X
X
X
X
X
X
X
X
X
X
XX14
Plasma samples10
X
X
X
Dosing11
X
X
X
X
X
X
X
X
X
X
PGx12
X
AE enquiry13
X
X
X
X
X
X
X
X
X
X
X
X
X
Telephone call to IVRS1314
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
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Day:
Screen1
Random
1
2
3
4
5
62
7
8
9
10
11
12
141
211 
(FU)
ET
Plasma for storage15
X
X
X
X
X
X
X
X
X
X
X
X
X
Outpatient visit
X
X
X
X
X
X
X
X
X
X
X
X
1.
Screening will occur within 14-30 days prior to the first dose of study drug.
2.
Table is set up for the weekend during dosing to occur on Days 6 and 7.  If the weekend occurs on Days 5 and 6, perform all “Day 5” assessments on Day 7.
3.
On Day 1, ECGs (x2) will be performed pre-dose , and then 1, 1.5, 2, 3, 4 and 6 hours post dose.  The pre-dose ECGs should be performed at least 5 minutes apart and 
preferably within 1 hour prior to dose.  On Days 4, 5 and 8, ECGs will be obtained prior to morning dosing and at 2, 4 and 6 hours post-dose. To accommodate scheduling, 
serial ECGs collected on Days 4 and 8 may be performed 1 day.  On Day 10, ECGs (x2) will be performed pre-dose, and then 1, 1.5, 2, 3, 4 and 6 hours post dose.  On 
Day 11, an ECG will be obtained prior to the 24-hour PK sample. ECGs will be performed in triplicate at all timepoints.
4.
BP, RR, HR and temperature will be obtained at Screening (x1) and Day 1 pre-dose (x2).  BP and HR will be obtained on Day 1 at 2 hours post-morning dose and on Days 4, 5 
and 8 pre-dose.  BP and HR will be obtained on Day 10 at pre-dose and 2 hours post-morning dose, and at day 12 and Follow-up (Day 21).
5.
Only SAEs related to study participation will be collected between screening and Day 1. An AE enquiry will be made at each visit, subjects will be asked if they have 
experienced any neuropsychiatric adverse events, including psychosis or altered mental status.
6.
On Days 1-5 and 8-10 samples for HIV-1 RNA PCR collected before morning dose.  On Days 1, 10 and 11 two samples for HIV-1 RNA PCR will be collected 5-30 minutes 
apart. HIV-1 RNA PCR samples will also be collected on days 12, 14 & Follow-up (Day 21).
7.
Lymphocyte subsets by flow cytometry (total lymphocyte counts, percentage, and absolute CD4+and CD8+counts).
8.
Blood samples for phenotype and genotype will be collected at pre-dose on Days 1, 4, 5 and 8 in the morning on Day 11 and at follow-up. 
9.
Serial plasma samples (2 mL) for determination of GSK2838232 will be collected on Day 1 and Day 10 at pre dose (within 15 minutes prior to dose) and 0.5, 1, 1.5, 2, 3, 4, 6, 
8, 12 (optional), and 24 hours (to occur on morning of Day 2 post-am dose and in the morning on Day 11) .  Pre-dose PK samples (within 15 minutes prior to dose) will be 
taken on the mornings of Days 3, 4, 5, 8 and 9 and a single sample will be taken on Days 12 and 14.
10. Samples (2 x 0.5mL) of plasma for assessment of immunological markers at screen, baseline (pre-dose) and day 11 
11. Subjects will receive a single dose of GSK2838232 and cobicistat each morning with a light breakfast meal and 240 mL of water from Day 1 to Day 10.  Doses taken in the 
clinic will be administered after an overnight fast of at least 10 hours .On Days 6 and 7, doses will be self administered but confirmed by phone 
12. PGx sample should be collected on Day 1.
13. An AE enquiry will be made at each visit, subjects will be asked if they have experienced any neuropsychiatric adverse events, including psychosis or altered mental status
13. A screening/registration call should be made to the IVRS to register the subject at screening.   An additional call will be made to document a screen failure.   A randomization 
call should be made to the IVRS system approximately one week prior to scheduled Day 1.  Note: The randomization call must be made in order to have study drug on site for 
Day 1. Additional calls will be made every day that the subject has a scheduled study visit to the clinic.  If a subject terminates the study prematurely a call should be made to 
the IVRS
14. Only if early termination visits occur during the treatment period.
15. Plasma samples for storage will be collected at each visit starting at Day 1, including unscheduled visits (e.g. for HIV-1 RNA levels and immunological 
parameters).  Additionally these samples will be used when needed, such as when samples are lost or arrive at the laboratory unevaluable.
AE = Adverse event; CDC= Center for Disease Control and Prevention; ECG = Electrocardiogram; ET = Early termination; hCG = Human chorionic gonadotrophin; HIV = Human 
immunodeficiency virus;  IVRS= Interactive Voice Response System; PCR = Polymerase chain reaction; PK=Pharmacokinetic.
 
 
 
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Section 7.2
Visit Windows
Rationale for Addition
Visit/procedure windows were included to allow more flexibility with scheduling of 
assessments. 
New Section
Screening (baseline to pre-dose): All screening assessments should take place within 
14-21 days prior to the first dose. The screening visit window may be extended to 30 
days upon discussion with the Medical Monitor (i.e.; subject has scheduling conflicts 
or any screening assessment needs to be repeated).
Days 4 and 8: Based on subject and clinic schedule, Day 4 and Day 8 serial (up to 6h 
post-dose) ECG assessments may be conducted 1 day.  
Weekend(s): The T&E table is set up for study start (Day 1) to occur on a Monday 
and Days 6 and 7 to fall on the weekend. If the weekend occurs instead on Days 5 
and 6, Day 5 assessments should be performed on Day 7. The study start (Day 1) 
may also be adjusted to allow visits with assessments to be conducted over the 
weekend based on subject and clinic schedule.  
Assessments: The following applies to timing of procedures:
-
Window for assessments 4 h post-dose = 5 minutes 
-
Window for assessments >4 and < 12 h post-dose = 15 minutes
-
Window for assessments >12 h post-dose = 30 minutes
End of Treatment visit: should be within 14 days from last dose of study drug. If a 
subject is unable to return to the clinic for any reason site staff are encouraged to 
telephone the subject for assessment of adverse events.
Section 7.3.1
Holter Monitoring (Screening criteria)
After addition of new section before this section, the section numbers from this section 
until Sections under 7.0 are re-numbered using the next available section number.  
Rationale for Change 
Minor alterations were made regarding the order of screening procedures, including the 
Holter monitoring requirement to allow flexibility based on clinic and subject schedule.
Revised Text
The 24-hour Holter monitoring should only will be performed at during the Screening 
after the subject has met all other inclusion criteria. period using a Holter monitoring 
device supplied by the Sponsor.
Analysis of the Holter tapes will consider the following:

Heart rate (bradycardia and tachycardia)
 
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
Normal and aberrant beats

Number of supraventricular contractions, premature atrial contractions, premature 
ventricular contractions, couplets, triplets, and ventricular tachycardias

Atrio-ventricular conduction defects

Atrial fibrillation and flutter
Section 7.5.1.1
Time period and Frequency for collecting AE and      
SAE information
Rationale for Change 
Minor clarifications made regarding Sponsor (to include PPD). 
Revised Text
Bullet 4

All SAEs will be recorded and reported to GSK Sponsor within 24 hours, as 
indicated in Appendix 5, Section 12.5.
Section 9.3.2
Interim Analysis
Rationale for Change 
Minor corrections and clarifications were made to this section.
Revised Text
An interim analysis of preliminary safety, tolerability, PK and antiviral activity will occur 
after subjects of Part A Cohort 1 complete their Day 13 visit. If based on this review the 
Cohort 1 dose is determined to be the highest dose based on this review (e.g., the 
exposure level of GSK2838232 is in the range of the maximum GSK2838232 exposure 
seen previously in healthy subjects), the Bayesian posterior probability that the log10 
viral load decline from baseline is greater than a cut-point will be calculated. If the 
Bayesian probability from Cohort 1 is less than 70%, this will provide evidenceto 
evidence to not move forward into Part B. Otherwise, the study team will review the data 
in order to make a dose selection decision for the subsequent Part B Cohorts.  If the 
pharmacokinetic exposures after the 100 mg GSK2838232/cobi dose look similar to 
those obtained with 100 mg GSK2838232/r in prior studies, the doses for Part B will be 
extended to both lower (20 mg, 50 mg) and higher (200 mg) GSK2838232 doses.
Maximum change and change from baseline in plasma HIV-1 RNA will be summarized 
by treatment or by assessment day. The proportion of subjects with plasma HIV-1 RNA 
<400 and <50 copies/mL will be summarized by treatment and assessment day. The 
analyses will be done for both PP and ITT exposed population if the two populations are 
not the same.
Section 10.3
Quality Control (Study Monitoring)
Rationale for Change
Minor clarifications made regarding Sponsor (to include PPD). 
 
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Revised Text
First Bullet
In accordance with applicable regulations including GCP, and GSK procedures, GSK
monitors or designee will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy regulatory, 
ethical, and GSK requirements.
Section 10.5
Study and Site Closure
Rationale for Change 
Minor clarifications made regarding Sponsor (to include PPD). 
Revised Text
First Bullet
Upon completion or premature discontinuation of the study, the GSK monitor or 
designee will conduct site closure activities with the investigator or site staff, as 
appropriate, in accordance with applicable regulations including GCP, and GSK Standard 
Operating Procedures.
Section 11 References
Rationale for Change 
Have mentioned the references as per GSK style guide and template.
Revised Text
Elion R, Cohen C, Gathe J, Shalit P, Hawkins T, Liu HC, et al. Mathias AA, Chuck SL, 
Kearney BP, Warren DR.  Phase 2 study of cobicistat versus ritonavir each with once-
daily atazanavir and fixed-dose emtricitabine.tenofovir df in the initial treatment of HIV 
infection.  AIDS.  2011; 25:1881-1886.
Gallant JE, Koenig E, Andrade-Villaneuva J, Chetchotisakd P, deJesus E, Antunes F, 
Arastéh K, et al. Moyle G, Rizzardini G, Fehr J, Liu Y, Zhong L, Callebaut C, 
Scwarcberg J, Rhee MS, Cheng AK.  Cobicistat versus ritonavir as a pharmacoenhancer 
of atazanavir plus emtricitabine/tenofovir disoproxil fumarate in treatment-naïve HIV 
type 1-infected patients:  week 48 results.  J. Infect. Dis.  2013; 208-:32-39.
Kakuda TN, Opsomer M, Timmers M, Iterbeke K, Van De Casteele T, Hillewaert V, et 
al. Petrovic R, Hoetelmans RMW.  Pharmacokinetics of darunavir in fixed-dose 
combination with cobicistat compared with coadministration of darunavir and ritonavir as 
single agents in healthy volunteers.  J. Clin. Pharmacol.  2009; 54:949-957.
Lalezari J, McCallister S, Gigliotti M, Cohen C, Elion R, Brinson C, et al. Safety and 
efficacy study of bevirimat (BVM) in heavily treatment experienced HIV+ patients 
identifies the target phase 3 study profile. ICAAC. 2008; Abstract: H891. 
Martin DE, Blum R, Wilton J, Doto J, Galbraith H, Burgess GL, et al. Safety and 
pharmacokinetics of bevirimat (PA-457), a novel inhibitor of human immunodeficiency 
 
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virus maturation, in healthy volunteers. Antimicrobial Agents and Chemotherapy. 
2007(b);Sep:3063-6.
Appendix 1
Abbreviations
Rationale for Change 
The abbreviations used in the document are added to the list of abbreviations.
AIDS
Auto Acquired immunodeficiency syndrome
BID 
Twice daily
DDI
Drug-Drug Interaction
PPD
Pharmaceutical Product Development
QD
Once daily
RIBA
Recombinant Immuno-Blot Assay
t1/2t½
Terminal elimination half-life
 
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12.10.2.
AMENDMENT 2
Protocol Amendment 2 (24-MAY-2017) from the Protocol Amendment 1 (26-Apr-2017)
Where the Amendment Applies
This amendment applies to all subjects who will participate in this study in all countries.
List of Specific Changes: (bold indicates text added and strikethrough indicates text 
removed)
Summary of Protocol Amendment Changes with Rationale
Amendment 2 includes expansion of the eligible subject population to allow treatment 
experienced HIV-1 infected patients, in addition to treatment naive patients. Patients with 
a treatment history of a prior maturation inhibitor will still be ineligible. Slight 
modifications were made to include flexible language for enrolment into Part B to allow 
prioritization of one dose cohort or to open randomization into Part B cohorts in a parallel 
fashion. Also the upper limit of the BMI inclusion criteria was increased from 31 to 35 
kg/m2. 
Minor clarifications, re-numbering of sections and correction of typographical errors 
were also made throughout this amendment.
Author (s)
Rationale for change A minor correction was made to this section.
A minor correction was made to this section.
Revised Text
                PCPS, GSK, CollegevilleUpper Providence, PA, US
Title Page
Rationale for change
The protocol title was updated to reflect the new subject population, which is no longer 
limited to treatment naive patients.
Revised Text
A Phase 2a, Multicenter, Randomized, Adaptive, Open-label,  Dose Ranging Study to 
Evaluate the Antiviral Effect, Safety, Tolerability and Pharmacokinetics of Cobicistat-
boosted GSK2838232 Monotherapy Over 10 Days in HIV-1 Infected Treatment-Naive
Adults
 
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Synopsis
Rationale
Rationale for change
Minor clarifications were made to this section to provide clarification regarding Study 
204953 (which is now completed). The reference to a parallel enrolment design for Part 
B was also removed to allow for prioritizing enrolment into any one dose cohort based on 
emerging data from Part A.
Revised Text
Second paragraph
Three clinical studies of GSK2838232 (n=53 healthy subjects) have been completed thus 
far. One study (Study 204953) is on-goingcompleted at the end of 2016 and analysis of 
the data is ongoing. Healthy subjects have received GSK2838232 or placebo in single or 
repeated dose designs, to a maximum single dose of 250 mg or repeated dose (for 
11 days) of 200 mg QD, in combination with ritonavir (RTV).
Fifth paragraph
Study 204953 is an on-going study and continues theinvestigated the safety and PK of 
GSK2838232 in single and repeat-doses exploration of safety and PK of GSK2838232as 
well as the suitability of a new, capsule formulation. Doses of up to 250 mg
GSK2838232/100 mg RTV (as single doses) or 200 mg GSK2838232/100 mg RTV (QD 
for 11 days) were studied. As of 26 October 2016, the study is ongoing with a cohort of 
subjects due to receiveThe final cohort of the study assessed unboosted GSK2838232 
(200mg BID) for 11 days. The study completed at the end of 2016 and the data 
analysis is ongoing.
Seventh paragraph
The objective of Study 200911 is to understand the safety, PK and HIV antiviral profile 
of GSK2838232/cobicistat (GSK2838232/cobi) when given to HIV-infected, treatment 
naive, otherwise healthy adults. Approximately 10 HIV-1 infected subjects will be 
enrolled into Part A. If warranted by an interim safety, virology, and PK data analysis, 
approximately 8 subjects will be enrolled in each of between two and four Cohorts in Part 
B, which will be a parallel group design.
Design, Treatment Arms and Duration
Rationale for change 
This section was updated to reflect the new subject population, which is no longer limited 
to treatment naive patients.The reference to a parallel enrolment design for Part B was 
also removed to allow for prioritizing enrolment into any one dose cohort based on 
 
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emerging data from Part A. A reference to Study 205820 was also included as data from 
this planned study will provide additional information on unboosted GSK2838232.
Revised Text
First paragraph
Approximately 34 HIV-1 infected treatment-naive subjects will be enrolled overall.
Second paragraph
This study is a 10-day monotherapy, open-label, adaptive, dose ranging, repeat-dose 
study and will be conducted as two parts with an interim (go/no-go) analysis performed 
after Part A (Table 1). Part A, Cohort 1 will evaluate a safe and well-tolerated dose level 
of GSK2838232 that has been tested (with RTV) in prior Phase I studies and that targets 
a high inhibitory quotient (IQ) value. Following the completion of an interim analysis of 
those data and according to criteria defined later in the protocol, further cohorts of 8 
subjects will then be studied in Part B in a parallel design in two or more cohorts 
(depending upon the data obtained in Part A).
Table 1
Study Design for 200911
Part A: GSK2838232/cobi 
Once Daily x 10 days1
Part B: GSK2838232/cobi 
Once Daily x 10 days1,2
Cohort
N
232 Dose
(mg)
Cohort
N
232 Dose 
(mg)
1
10
100
2
8
200
3
8
50
4
8
20
1. 
Part A Cohort 1 safety/PK/virology data will be evaluated at interim, prior to initiating other cohorts in Part B, which 
are planned to run in a parallel, randomized fashion. All doses will be given with 150 mg cobicistat.
2. 
Part B GSK2838232 doses are an illustration of the projected doses per cohort. The actual doses for each cohort 
and number of cohorts are subject to modification based upon safety, PK and antiviral activity data from Cohort 
1 (Part A). More doses/cohorts (including potential removal of cobi co-dosing) may be added (the maximum dose 
in Part B would likely not exceed 200 mg with cobicistat unless overall plasma exposure [as AUC and Cmax] was 
lower in HIV infected subjects than in healthy subjects at the same dose level).
Fourth paragraph
The possibility that an additional, unboosted GSK2838232 monotherapy cohort will be 
assessed in Part B is dependent on analysis of the PK data from Study 204953 where 
unboosted GSK2838232 at a dose of 200 mg twice daily (BID) was assessed and Study 
205820, which plans to evaluate GSK2838232 at a dose of 500mg once daily (QD).
 
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Section 2.2.2.1
Clinical Summary of Safety
Rationale for change
Minor clarifications were made to this section to provide clarification regarding Study 
204953 (which is now completed).
Revised Text
Fifth paragraph
In ongoingStudy 204953, there have been a small number of CV-related events of any 
sort: There have  been no serious adverse drug reactions, and no clinically significant 
drug-related abnormal findings for 12-lead ECGs, vital signs, safety laboratory results 
(including cardiac troponin I), or telemetry.  The following cardiovascular AEs were 
observed during the course of the study but were not considered to be caused by 
GSK2838232 exposure
Section 2.2.2.2
Study 204953 (completed); Pharmacokinetic Data
Rationale for change
Minor clarifications were made to this section to provide clarification regarding Study 
204953 (which is now completed and analysis is ongoing).
Revised Text
Second paragraph
In addition, it evaluated the relative bioavailability of a single fasted dose of micronized 
API powder blend in capsules with RTV compared to powder-in-bottle for oral 
suspension with RTV and the effect of a normal fat meal on the bioavailability of a single 
dose of GSK2838232 in the capsule formulation with RTV.  It will evaluate 
GSK2838232 exposure after repeated doses of unboosted GSK2838232 in the capsule 
formulation. Noncompartmental PK analysis was performed using scheduled sample 
times.  ThisThe study isanaylsis of data from this study is ongoing; preliminary results 
are presented.
Section 4.1 Overall Design
Rationale for change 
This section was updated to reflect the new subject population, which is no longer limited 
to treatment naive patients.The reference to a parallel enrolment design for Part B was 
also removed to allow for prioritizing enrolment into any one dose cohort based on 
emerging data from Part A.
 
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Revised Text
First paragraph
This is a Phase IIa, multicenter, open-label, adaptive dose ranging, study to evaluate the 
antiviral effect, safety, tolerability, and PK of GSK2838232/cobi monotherapy over 10 
days in ART-naïve HIV-1 infected adults who are not currently receiving ART therapy. 
Subjects who have received any ART (including prior MI) prior maturation ihibitor
therapy will not be eligible for this study. To minimize the number of subjects exposed to 
suboptimal doses, an adaptive and dose ranging design is applied in this study.
Study Design for 200911
GSK2838232/cobi Once Daily for 10 days1,2
Part A
Part B 
Cohort 1
Dose
(mg)
Interim Analysis
Cohort
N
(mg)
N=10
100
2
8
200
3
8
50
4
8
20
Day 1 – Day 10: Dosing
Second paragraph
Serial, intensive blood PK samples will be collected on Day 1 (up to 24 hours post-
morning dose) and Day 10 (up to 96 hours post-morning dose), and limited, single blood 
PK samples pre-morning doses on Days 3 through 9, except for the weekend. Subjects 
will be required to fast for 10 hours [overnight] prior to the morning check in on the 
intensive PK sampling days (Days 1 and 10).  All dosing days will require co-
administration of treatment with a light snack/meal per cobicistat labeling guidelines. All 
doses of study medication will be taken with 240 mL of water.  Subjects will be required 
to stay in the clinic on Days 1 and 10 until all specified assessments are completed (8-12 
hours post-dose). Following Day 10, subjects will be required to attend the clinic for 
follow up assessments including virological and PK blood sampling for up to 3 weeks.
1 . Part A Cohort 1 safety/PK/virology data will be evaluated at interim, prior to initiating 
other cohorts in Part B, which are planned to run in a parallel, randomized fashion.  All 
doses will be given with 150 mg cobicistat.
2 . Part B doses are an illustration of the projected doses per cohort. The actual doses for 
each cohort are subject to modification based upon safety, PK and antiviral activity data 
from Cohort 1 (Part A). More doses/cohorts (including potential removal of cobicistat co-
dosing) may be added. (The maximum dose in Cohort B will likely not exceed 200 mg 
with cobicistat unless overall plasma exposure [as AUC and Cmax] is lower in HIV-
infected subjects than in healthy subjects at the same dose level).
 
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Section 4.2 Type and Number of Subjects
Rationale for change 
Minor clarifications were made to this section.
Revised Text
At least 34 subjects will be enrolled such that approximately 6-10 evaluable subjects 
complete a number of cohorts.  Additional subjects/cohorts may be enrolled to allow for 
evaluation of additional dose levels as appropriate. 
If subjects prematurely discontinue the study, additionalreplacement subjects may be 
randomisedrandomized and assigned to the same treatment cohort at the discretion of the 
Sponsor in consultation with the Investigator.
Section 4.3 Design/Dose Justification
Rationale for change
Minor clarifications were made to this section to provide clarification regarding Study 
204953 (which is now completed).
Revised Text
Last paragraph
There is no a priori intention to study GSK2838232 unboosted, unless: i) following the 
preliminary analysis of Part A Cohort 1, there is such pronounced antiviral activity that it 
would seem the estimates of projected IQ are low, in which case GSK2838232 may be 
evaluated in a subsequent cohort unboosted, or ii) the data from ongoing and planned 
healthy volunteer trials,Cohort 7 in Study 204953 (planned, GSK2838232 200 mg BID 
unboosted) and Study 205820 (GSK2838232 500mg QD unboosted) support it.
Section 4.3.3
Interim Analysis
Rationale for change 
Minor clarifications were made to this section to allow for flexibility around selecting 
dose cohorts for Part B based on emerging data from Part A.
Revised Text
An evaluation of GSK2838232 safety, efficacy and PK data will be done after Part A 
Cohort 1, if the exposure level of GSK2838232 is in the range of the maximum 
GSK2838232 exposure seen previously in healthy subjects and the Bayesian probability 
from Cohort 1 is less than 70%, the study will not move forward into Part B, otherwise 
doses will be selected for evaluation in Part B. If pharmacokinetic exposure after the 100 
mg GSK2838232/cobi dose is in the range of values observed after 100 mg 
GSK2838232/r in prior studies, the doses for Part B will be extended to both lower 
 
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(20 mg and/or, 50 mg) and higher (200 mg) doses. The highest dose tested in Part B will 
be selected to result in exposures similar to those seen with 200 mg/r in Study 204953.
Section 4.4.3
Overall Benefit:Risk Conclusion
Rationale for change 
Minor clarifications were made to this section to provide clarification regarding Study 
204953 (which is now completed).
Revised Text
To date, 11553 healthy subjects have received GSK2838232 in fourthree completed 
studies. One study (204953) is ongoing (52 healthy subjects have completed this study so 
far).
Section 5
SELECTION OF STUDY POPULATION AND WITHDRAWAL 
CRITERIA
Rationale for change 
This section was updated to reflect the new subject population, which is no longer limited 
to treatment naive patients.The reference to a parallel enrolment design for Part B was 
also removed to allow for prioritizing enrolment into any one dose cohort based on 
emerging data from Part A.
Revised Text
Second paragraph
Approximately 10-12 HIV-1 infected subjects will be enrolled into Part A. If warranted 
by an interim safety, virology and PK data analysis, approximately 8 subjects will be 
enrolled in each of Cohorts 2-4 in Part B, which will be a parallel group design. Eligible 
patients are those who are maturation inhibitorART-naïve and who are not currently 
receiving ART therapy.
Last paragraph
If subjects prematurely discontinue the study, additional subjects may be enrolled as 
replacement subjects and assigned to the same treatment at the discretion of the Sponsor.
Section 5.1 Inclusion Criteria
Rationale for change 
The inclusion criteria were updated to reflect the new subject population, which is no 
longer limited to treatment naive patients. Also the upper limit of the BMI inclusion 
criteria was increased from 31 to 35 kg/m2. 
 
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Revised Text
5. Confirmed HIV positive; CD4+ cell count ≥350 cells/mm3 and plasma HIV-1 RNA 
≥5000 copies/mL at Screening. No current and no prior ART. (A previous course of pre-
or post-exposure prophylaxis is allowed provided that it was completed at least 6 weeks 
prior to the first dose of study drug).
5 .6. Antiretroviral treatment naive or ART-experienced (maturation inhibitor 
naive). No current ART (last dose completed at least 6 weeks prior to the first dose 
of study drug). (A previous course of pre- or post-exposure prophylaxis is allowed 
provided that it was completed at least 6 weeks prior to the first dose of study drug).
6 .7. Body weight 50 kg (110 lbs.) for men and 45 kg (99 lbs) for women and body 
mass index (BMI) within the range 18.5-351.0 kg/m2 (inclusive)
Section 6.2 Treatment Assignment
Rationale for change
A minor clarification was made to this section.
Revised Text
Subjects will be assigned to treatment (active) groups in accordance with the 
randomization schedule generated by Clinical Statistics, prior to the start of the study, 
using validated internal software.
Section 6.4 Blinding
Rationale for change 
Minor clarifications were made to this section.
Revised Text
This will be an open-label study. Treatment allocation and GSK2838232 dose levels in 
Part B will be determined after the analysis of Part A data. randomised (to 
GSK2838232 dose level).
 
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12.10.3.
AMENDMENT 3
Protocol Amendment 3 (15-JUN-2017) from the Protocol Amendment 2 (24-MAY-2017)
Where the Amendment Applies
This amendment applies to all subjects who will participate in this study in all countries.
List of Specific Changes: (bold indicates text added and strikethrough indicates text 
removed)
Summary of Protocol Amendment Changes with Rationale
Amendment 3 includes modification to the protocol Inclusion Criteria (#6) to ensure 
exclusion of treatment-experienced patients with limited remaining treatment options.
Section 5.1 Inclusion Criteria
Rationale for change
Additional language was added to the protocol Inclusion Criteria (#6) to clarify that with 
the patient population being expanded to include treatment-experienced patients for 
enrolment, patients with limited or no treatment options would remain ineligible. 
Revised Text
6. Antiretroviral treatment naive or ART-experienced (maturation inhibitor naive). No 
current ART (last dose completed at least 6 weeks prior to the first dose of study drug). A 
previous course of pre- or post-exposure prophylaxis is allowed provided that it was 
completed at least 6 weeks prior to the first dose of study drug. NOTE: Subjects with 
limited therapeutic options, including but not limited to those who have failed ≥2 
antiretroviral regimens for any reasons or have documented resistance to >2 classes 
of antiretrovirals or have interrupted their treatment due to resistance, will not be 
eligible.
Section 7
Time and Events Table
Rationale for change
A modification was made to this section to clarify the days where site calls to IVRS 
would be made (Screen, Randomization, Early Termination and/or unscheduled visits 
only). 
Revised Text
 
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Day:
Screen1
Random
1
2
3
4
5
62
7
8
9
10
11
12
141
211 
(FU)
ET
Informed Consent
X
Review inclusion/exclusion
X
X
Demography including height, weight and 
BMI
X
Brief physical
X
Medical/medication/
drug/alcohol history
X
X
CDC Classification
X
X
X
X
Prior antiretroviral therapy
X
12-lead ECG3
X
X
X
X
X
X
X
X
X
Holter (24 hr)
X
Vital signs4
X
X
X
X
X
X
X
X
X
Drug screen
X
X
X
X
X
Hepatitis B Surface antigen and hepatitis 
C antibody testing
X
Serum or urine -hCG (WoCBP only)
X
X
X
Clinical lab tests (inc troponin)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Fasting lipid panel
X
X
AE assessment5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Con Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HIV-1 RNA PCR6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lymphocyte subsets7
X
X
X
Plasma for genotype/phenotype8
X
X
X
X
X
X
X
HIV-associated conditions assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK blood sample9
X
X
X
X
X
X
X
X
X
X
X
X14
Plasma samples10
X
X
X
Dosing11
X
X
X
X
X
X
X
X
X
X
PGx12
X
Telephone call to IVRS13
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
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139
Day:
Screen1
Random
1
2
3
4
5
62
7
8
9
10
11
12
141
211 
(FU)
ET
Plasma for storage15
X
X
X
X
X
X
X
X
X
X
X
X
X
Outpatient visit
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
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2015N227852_02
CONFIDENTIAL
The GlaxoSmithKline group of companies
200911
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A Phase 2a, Multicenter, Randomized, Adaptive, Open-label,  
Dose Ranging Study to Evaluate the Antiviral Effect, Safety, 
Tolerability and Pharmacokinetics of Cobicistat-boosted 
GSK2838232 Monotherapy Over 10 Days in HIV-1 Infected 
Adults
Compound Number:
GSK2838232
Development Phase:
IIA
Effective Date:
24-MAY-2017
Protocol Amendment Number:  02
Author (s):
           PTS, Ware, UK
           GCSP, Stockley Park, UK
           Infectious Diseases, Clinical, Upper Providence, PA, US
           Clinical Statistics, GSK, Upper Providence, PA, US
           HIV DPU, Clinical RTP, NC, US
           Virology, HIV DPU, RTP, NC, US
           CPMS, GSK, RTP, NC, US
           HIV DPU, RTP, NC, US
          Clinical Pharmacology, ViiV Healthcare, RTP, NC, US
           PCPS, GSK, Upper Providence, PA, US
          PCPS, GSK, Upper Providence, PA, US
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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2015N227852_02
CONFIDENTIAL
The GlaxoSmithKline group of companies
200911
2
Revision Chronology
GlaxoSmithKline 
Document Number
Date
Version
2015N227852_00
2016-NOV-09
Original
2015N227852_01
2017-APR-26
Amendment No. 1
Amendment 1 includes minor updates to Inclusion-Exclusion (IE) criteria, including 
clarification on use of pre- or post-exposure prophylaxis, and removal of exclusionary 
requirements related to concomitant medications and tobacco and alcohol use during the 
study. Guidance around relevant habits is included in the Lifestyle section of the protocol 
and adjustments were made to reduce restrictions on these requirements. Modifications 
were also made to the pharmacokinetics sampling, allowing for the 12 h PK collection 
timepoint on Day 1 and 10 to be optional. Minor alterations were made regarding the 
order of screening procedures, including the Holter monitoring requirements. 
Visit/procedure windows were included to allow more flexibility with scheduling of 
assessments. Furthermore, the serial ECG collection (up to 6h post-dose) was removed on 
Day 5. Finally, the post-study care guidance was updated to include an option for subjects 
to receive reimbursement for marketed ART for a limited period after completion of 
study treatment and follow up. Minor clarifications, reformatting of tables, re-numbering 
of sections and correction of typographical errors were also made throughout this 
amendment.
2015N227852_02
2017-MAY-24
Amendment No. 2
Amendment 2 includes expansion of the eligible subject population to allow treatment 
experienced HIV-1 infected patients, in addition to treatment naive patients. Patients with 
a treatment history of a prior maturation inhibitor will still be ineligible. Slight 
modifications were made to include flexible language for enrolment into Part B to allow 
prioritization of one dose cohort or to open randomization into Part B cohorts in a parallel 
fashion. Also the upper limit of the BMI inclusion criteria was increased from 31 to 35
kg/m2.
 
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2015N227852_02
CONFIDENTIAL
200911
4
MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time 
Phone Number 
and email 
address
After-hours 
Phone/Cell/
Pager Number
Fax Number
Site Address
Primary 
Medical 
Monitor/SAE 
contact 
information 
Pharmaceutical 
Product 
Development 
(PPD) Safety 
Hotline 
PPD, 929 North 
Front Street, 
Wilmington, NC 
28401
Secondary 
Medical Monitor
 MD
GlaxoSmithKline
1250 St 
Collegeville Rd 
Collegeville, PA 
19426
Sponsor Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.   
Regulatory Agency Identifying Number(s):  116,094
 
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2015N227852_02
CONFIDENTIAL
200911
5
INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 200911
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date
 
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2015N227852_02
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200911
6
TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 200911........................................................9
2.
INTRODUCTION....................................................................................................13
2.1.
Study Rationale ..........................................................................................13
2.2.
Brief Background ........................................................................................13
2.2.1.
Preclinical Summary....................................................................14
2.2.2.
Clinical Summary of Safety and Pharmacokinetics ......................19
2.2.2.1.
Clinical Summary of Safety.........................................19
2.2.2.2.
Study 204953 (completed); Pharmacokinetic 
Data ...........................................................................20
2.2.2.3.
Overall Summary/Conclusions of PK data..................23
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................25
4.
STUDY DESIGN ....................................................................................................26
4.1.
Overall Design ............................................................................................26
4.2.
Type and Number of Subjects.....................................................................27
4.3.
Design/Dose Justification............................................................................28
4.3.1.
GSK2838232 with Ritonavir.........................................................28
4.3.2.
GSK2838232 with Cobicistat .......................................................29
4.3.3.
Interim Analysis ...........................................................................29
4.4.
Benefit:Risk Assessment ............................................................................30
4.4.1.
Risk Assessment .........................................................................31
4.4.2.
Benefit Assessment.....................................................................33
4.4.3.
Overall Benefit:Risk Conclusion...................................................33
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............33
5.1.
Inclusion Criteria.........................................................................................34
5.2.
Exclusion Criteria........................................................................................36
5.3.
Screening/Baseline/Run-in Failures............................................................38
5.4.
Withdrawal/Stopping Criteria.......................................................................39
5.4.1.
Liver Chemistry Stopping Criteria ................................................39
5.4.1.1.
Study Treatment Restart or Rechallenge....................40
5.4.2.
QTc Stopping Criteria ..................................................................40
5.5.
Stopping criteria based on Adverse Events.................................................41
5.6.
Subject and Study Completion....................................................................41
6.
STUDY TREATMENT ............................................................................................41
6.1.
Investigational Product and Other Study Treatment....................................41
6.2.
Treatment Assignment................................................................................42
6.3.
Planned Dose Adjustments.........................................................................42
6.4.
Blinding.......................................................................................................42
6.5.
Preparation/Handling/Storage/Accountability..............................................42
6.6.
Compliance with Study Treatment Administration.......................................43
6.7.
Treatment of Study Treatment Overdose....................................................43
6.8.
Treatment after the End of the Study ..........................................................44
6.9.
Lifestyle and/or Dietary Restrictions............................................................44
6.9.1.
Meals and Dietary Restrictions ....................................................44
 
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7
6.9.2.
Alcohol, Caffeine and Exercise ....................................................44
6.10.
Contraception .............................................................................................44
6.11.
Concomitant Medications and Non-Drug Therapies....................................45
6.11.1.
Permitted Medications and Non-Drug Therapies..........................45
6.11.2.
Prohibited Medications and Non-Drug Therapies.........................45
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................45
7.1.
Time and Events Table...............................................................................47
7.2.
Visit Windows .............................................................................................49
7.3.
Screening and Critical Baseline Assessments ............................................49
7.3.1.
Holter Monitoring (Screening criteria)...........................................49
7.4.
Efficacy.......................................................................................................50
7.4.1.
HIV-1 RNA Sampling ...................................................................50
7.4.2.
Lymphocyte Subsets by Flow Cytometry .....................................50
7.5.
Safety .........................................................................................................50
7.5.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........50
7.5.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................51
7.5.1.2.
Method of Detecting AEs and SAEs ...........................51
7.5.1.3.
Follow-up of AEs and SAEs........................................51
7.5.1.4.
Cardiovascular and Death Events ..............................52
7.5.1.5.
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ................52
7.5.1.6.
Regulatory Reporting Requirements for SAE..............53
7.5.2.
Pregnancy ...................................................................................53
7.5.3.
Physical Exams ...........................................................................53
7.5.4.
Vital Signs....................................................................................54
7.5.5.
Electrocardiogram (EGC).............................................................54
7.5.6.
Clinical Safety Laboratory Assessments ......................................54
7.6.
Pharmacokinetics .......................................................................................56
7.6.1.
Blood Sample Collection..............................................................56
7.6.2.
Sample Analysis ..........................................................................56
7.7.
Biomarker(s)/Pharmacodynamic Markers ...................................................56
7.7.1.
Viral Genotyping and Phenotyping...............................................56
7.8.
Genetics .....................................................................................................56
7.9.
Value Evidence and Outcomes...................................................................57
8.
DATA MANAGEMENT ...........................................................................................57
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................57
9.1.
Hypotheses.................................................................................................57
9.2.
Sample Size Considerations.......................................................................57
9.2.1.
Sample Size Assumptions ...........................................................57
9.2.2.
Sample Size Sensitivity................................................................58
9.2.3.
Sample Size Re-estimation or Adjustment...................................59
9.3.
Data Analysis Considerations .....................................................................59
9.3.1.
Analysis Populations....................................................................59
9.3.2.
Interim Analysis ...........................................................................59
9.4.
Key Elements of Analysis Plan ...................................................................60
9.4.1.
Primary Analyses.........................................................................60
9.4.1.1.
Safety Analyses..........................................................60
9.4.1.2.
Efficacy Analyses .......................................................60
 
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8
9.4.1.3.
Pharmacokinetic Analyses..........................................61
9.4.2.
Secondary Analyses ....................................................................61
9.4.2.1.
Pharmacokinetic/Pharmacodynamic Analyses ...........61
9.4.2.2.
Viral Genotyping and Phenotyping Analyses ..............62
10. STUDY GOVERNANCE CONSIDERATIONS........................................................62
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............62
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................62
10.3.
Quality Control (Study Monitoring) ..............................................................63
10.4.
Quality Assurance.......................................................................................63
10.5.
Study and Site Closure ...............................................................................63
10.6.
Records Retention......................................................................................64
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................65
10.8.
Review Committees....................................................................................65
11. REFERENCES.......................................................................................................66
12. APPENDICES........................................................................................................68
12.1.
Appendix 1: Abbreviations and Trademarks................................................68
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................71
12.3.
Appendix 3: Liver Safety – Study Treatment Restart or Rechallenge 
Guidelines...................................................................................................74
12.4.
Appendix 4: Genetic Research ...................................................................75
12.5.
Appendix 5: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................78
12.5.1.
Definition of Adverse Events........................................................78
12.5.2.
Definition of Serious Adverse Events...........................................79
12.5.3.
Definition of Cardiovascular Events .............................................81
12.5.4.
Recording of AEs and SAEs ........................................................81
12.5.5.
Evaluating AEs and SAEs............................................................82
12.5.6.
Reporting of SAEs to GSK...........................................................83
12.6.
Appendix 6: Collection of Pregnancy Information........................................85
12.7.
Appendix 7: Country Specific Requirements...............................................86
12.8.
Appendix 8: Division Of AIDS Table For Grading The Severity Of 
Adult And Pediatric Adverse Events Version 1.0, December 2004; 
Clarification August 2009............................................................................87
12.9.
Appendix 9: Toxicity Management ............................................................106
12.10. Appendix 10: Protocol Amendment Changes............................................111
12.10.1. AMENDMENT 1.........................................................................111
12.10.2. AMENDMENT 2.........................................................................129
 
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2015N227852_02
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200911
9
1.
PROTOCOL SYNOPSIS FOR STUDY 200911
Rationale
GSK2838232 is a novel human immunodeficiency virus (HIV-1) maturation inhibitor 
that is being developed for the treatment of HIV-1 in combination with other 
antiretrovirals.
Three clinical studies of GSK2838232 (n=53 healthy subjects) have been completed thus 
far. One study (Study 204953) completed at the end of 2016 and analysis of the data is 
ongoing. Healthy subjects have received GSK2838232 or placebo in single or repeated 
dose designs, to a maximum single dose of 250 mg or repeated dose (for 11 days) of 
200 mg QD, in combination with ritonavir (RTV). 
Study HMI116787 (completed November 2013) was the First Time in Human study of 
GSK2838232 and assessed safety and tolerability of escalating doses (5 mg to 100 mg), 
food effect, and the impact of steady-state ritonavir on GSK2838232 pharmacokinetics 
(PK). Following successful completion of 3-month toxicology studies in rat and dog in 
2014, clinical studies 200912 and 200207 were initiated. These were double-blind, 
placebo-controlled, single (Study 200912) and repeat-dose (Study 200207) escalation 
studies to investigate the safety, tolerability, and PK of GSK2838232 alone and when co-
administered with ritonavir 100 mg once daily (QD) for 8-11 days. Further assessment of 
an alternative formulation was also an objective in Study 200912.
Both studies were prematurely terminated/completed in March/April 2015 because of 
concerns over cardiovascular (CV) toxicity, in particular a clinical CV serious adverse 
event (SAE) whereby the Food and Drug Administrating (FDA) imposed a clinical hold. 
Following submission of long-term (6-month rat, 9-month dog) chronic toxicology data 
and follow up to the clinical SAE in November 2015, the hold was released in January 
2016 and Study 204953 was initiated.
Study 204953 investigated the safety and PK of GSK2838232 in single and repeat-doses
as well as the suitability of a new, capsule formulation. Doses of up to 250 mg 
GSK2838232/100 mg RTV (as single doses) or 200 mg GSK2838232/100 mg RTV (QD 
for 11 days) were studied. The final cohort of the study assessed unboosted GSK2838232 
(200mg BID) for 11 days. The study completed at the end of 2016 and the data analys is 
ongoing.
These studies have shown GSK2838232 with or without RTV to be well tolerated and, 
together with daily RTV dosing (“boosting”), demonstrate a PK profile suitable for 
progression to HIV patients in this Phase IIa proof of concept 10-day, monotherapy study 
design.  However, potential concerns over protease resistance necessitate a change to a 
pharmacoenhancer without antiviral effects in this study of GSK2838232 monotherapy. 
Therefore, for Study 200911, cobicistat (Tybost,150 mg QD) will be substituted for RTV.  
The objective of Study 200911 is to understand the safety, PK and HIV antiviral profile 
of GSK2838232/cobicistat (GSK2838232/cobi) when given to HIV-infected, treatment 
naive, otherwise healthy adults. Approximately 10 HIV-1 infected subjects will be 
enrolled into Part A. If warranted by an interim safety, virology, and PK data analysis, 
 
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2015N227852_02
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10
approximately 8 subjects will be enrolled in each of between two and four Cohorts in Part 
B.
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

To evaluate antiviral activity of 
GSK2838232/cobi in HIV-1 infected 
patients during 10 days of 
monotherapy.

Change from baseline (Day 1) in plasma HIV-1 
RNA 

To assess safety and tolerability of 
GSK2838232/cobi when administered 
as monotherapy over 10 days.

Safety and tolerability parameters, including 
adverse event, concurrent medication, clinical 
laboratory, electrocardiogram (ECG) and vital 
signs assessments.

To characterize the pharmacokinetics 
of GSK2838232 in HIV-1 infected 
patients following GSK2838232/cobi 
dosing for 10 days.

GSK2838232 PK parameters following dose 
administration, as follows:
Day 1: area under the plasma concentration time 
curve AUC(0-24), maximum observed 
concentration (Cmax), time to maximum 
observed concentration (tmax), concentration at 
24 hours post dose (C24), absorption lag time 
(tlag); 
Following last repeat administration on Day 10:  
AUC(0-), pre-dose concentration (C0), 
concentration at end of dosing interval (C), 
Cmax, tmax, t½, and apparent oral clearance 
(CL/F), if data permit
Secondary

To explore the relationship between 
GSK2838232 exposure and change 
in plasma HIV-1 RNA

GSK2838232 PK parameters Day 10 AUC(0-), 
Cmax, Cwith Day 11 HIV-1 RNA change from 
baseline

To assess the immunologic effect of 
GSK2838232/cobi when 
administered over 10 days in HIV-1 
infected adults

Change from baseline in CD4+ cell count to Day 
11

To explore the relationship between 
GSK2838232 exposure and safety or 
immunologic parameters, if 
appropriate.

GSK2838232 PK parameters on Day 10: 
AUC(0-), Cmax, Cwith Day 11 change from 
baseline in CD4+ cell count
 
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11
Objectives
Endpoints

To assess the development of viral 
resistance (genotypic and 
phenotypic) over 10 days and 
correlate with viral response, if 
appropriate.

Emergence of drug resistance mutations, if 
appropriate

To estimate GSK2838232 
accumulation and to assess 
attainment of steady state following 
administration of GSK2838232/cobi 
for 10 days in HIV infected subjects.

Accumulation:
GSK2838232 PK accumulation ratios (R): Day 
10 AUC(0-), Cmax, and Ccompared to Day 1 
AUC(0-24), Cmax, and C24, respectively

Steady State:
pre-morning dose concentrations (C0) on Days 2 
through 11 

To examine dose proportionality of 
GSK2838232 pharmacokinetic 
parameters following 
GSK2838232/cobi dosing for 10 days
in HIV infected subjects.

Day 1 AUC(0-24), Cmax, and C24, and Day 10 
AUC(0-), Cmax, and Cat different dose levels 
for the assessment of dose proportionality
Note: Other exploratory objectives and endpoints will be specified in the RAP
Design, Treatment Arms and Duration
Approximately 34 HIV-1 infected subjects will be enrolled overall. 
This study is a 10-day monotherapy, open-label, adaptive, dose ranging, repeat-dose 
study and will be conducted as two parts with an interim (go/no-go) analysis performed 
after Part A (Table 1). Part A, Cohort 1 will evaluate a safe and well-tolerated dose level 
of GSK2838232 that has been tested (with RTV) in prior Phase I studies and that targets 
a high inhibitory quotient (IQ) value. Following the completion of an interim analysis of 
those data and according to criteria defined later in the protocol, further cohorts of 8 
subjects will then be studied in Part B in two or more cohorts (depending upon the data 
obtained in Part A). 
The totality of this data will provide a full dose-response of GSK2838232 over a wide 
dose range to explore the safety and PK/pharmacodynamics (PD) relationship of 
GSK2838232 in HIV-1 infected subjects and facilitate choice of doses for Phase IIb 
studies.
 
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Table 1
Study Design for 200911
Part A: GSK2838232/cobi 
Once Daily x 10 days1
Part B: GSK2838232/cobi 
Once Daily x 10 days1,2
Cohort
N
232 Dose
(mg)
Cohort
N
232 Dose 
(mg)
1
10
100
2
8
200
3
8
50
4
8
20
1. 
Part A Cohort 1 safety/PK/virology data will be evaluated at interim, prior to initiating other cohorts in Part B. All 
doses will be given with 150 mg cobicistat.
2. 
Part B GSK2838232 doses are an illustration of the projected doses per cohort. The actual doses for each cohort 
and number of cohorts are subject to modification based upon safety, PK and antiviral activity data from Cohort 1 
(Part A). More doses/cohorts (including potential removal of cobi co-dosing) may be added (the maximum dose in 
Part B would likely not exceed 200 mg with cobicistat unless overall plasma exposure [as AUC and Cmax] was 
lower in HIV infected subjects than in healthy subjects at the same dose level).
The possibility that an additional, unboosted GSK2838232 monotherapy cohort will be 
assessed in Part B is dependent on analysis of the PK data from Study 204953 where 
unboosted GSK2838232 at a dose of 200 mg twice daily (BID) was assessed and Study 
205820, which plans to evaluate GSK2838232 at a dose of 500mg once daily (QD). 
Subjects in both parts 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 6 weeks.
HIV Drug Resistance: Following cessation of GSK2838232/cobi dosing for 10 days, 
there will be prolonged exposure to waning plasma concentrations of GSK2838232, 
because of the long t½ (i.e., in the “tail” of the PK profile). However, based on in vitro 
resistance passage data with GSK2838232 [and unlike with many other ARV therapies], 
there appears to be a limited likelihood of developing maturation resistance mutations in 
HIV-infected subjects due to its virologic profile. 
Analysis
The primary objectives of this study are to investigate the safety, tolerability, PK and 
antiviral activity of 10 days repeated doses of GSK2838232/cobi in HIV-1 infected 
otherwise healthy subjects. Descriptive summaries will be provided for safety, PK, and 
HIV viral load data.
 
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2.
INTRODUCTION
GSK2838232 is a novel human immunodeficiency virus (HIV)-1 maturation inhibitor 
(MI) that is being developed for the treatment of HIV-1 infection in combination with 
other antiretrovirals (ART).
2.1.
Study Rationale
This ‘proof of concept (PoC)’ open-label study is being conducted to characterize the 
acute antiviral activity, pharmacokinetics (PK), the relationship between PK and antiviral 
activity, and safety of GSK2838232 given with 150 mg once daily (QD) cobicistat 
(GSK283232/cobi), administered across a range of doses over 10 days in HIV-1 infected 
patients. A two-part adaptive and dose ranging design is to be applied in this study. Data 
from this study will be utilized to select doses for further studies in Phase IIb.
2.2.
Brief Background
Combination antiviral therapy with inhibitors of HIV protease, integrase, entry and 
reverse transcriptase (RT) has demonstrated significant improvement in acquired 
immunodeficiency syndrome (AIDS)-related morbidity and mortality over the last 10-15 
years. Emerging multi-class drug resistant viral strains and long-term toxicities warrant 
development of new classes of antiretroviral therapies targeting various parts of the HIV-
1 viral life cycle [Wainburg, 2010]. The inhibition of maturation of HIV-1 is a novel 
target for drug development, distinct from viral protease RT or integrase [Saxena, 2012; 
Qian, 2009]. HIV maturation is the final cleavage step of the capsidSp1 (transcription 
factor) polyprotein that generates the functional capsid p24 protein. This mechanism of 
action results in accumulation of the uncleaved p25 protein with subsequent improper 
assembly of the HIV core, resulting in a non-infectious virion. Gel-based mechanism of 
action studies suggest that compound GSK2838232 acts as a maturation inhibitor. 
Western Blot analysis shows inhibition of capsid-Sp1 cleavage and accumulation of p25 
in the presence of GSK2838232.
Prior validation of this target was demonstrated with the HIV maturation inhibitor known 
as bevirimat (BVM; [Martin, 2007a; Martin, 2007b; Martin, 2008; NORVIR, 2013]). 
BVM reached Phase II studies in HIV patients; however, only modest reductions in 
plasma HIV-1 ribonucleic acid (RNA) concentrations were observed in Phase IIa 
monotherapy studies [Mahmood, 2006; Martin, 2007] and a pattern of polymorphic 
(differential) antiviral activity [Wainburg, 2010] led to termination of BVM development. 
The average decrease from baseline to Day 14 plasma HIV-1 ribonucleic acid (RNA) was 
0.54 and 0.70 log10 copies/mL for 200 mg and 300 mg twice daily regimens (Table 2); 
all subjects achieved plasma BVM concentrations above the in vitro EC90. Responders, 
classified based on 5 polymorphisms in HIV-1 gag (at positions 369, 370, and 371), 
achieved an average 1.15 log10 copies/mL reduction in plasma HIV-1 RNA, while an 
average 0.17 log10 copies/mL reduction was achieved for non-responders.
 
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Table 2
Summary of Bevirimat Antiviral Response and PK in a 14-day 
Monotherapy Study in HIV-infected Adults
BVM dosage 
regimen
Mean (SD) viral load 
change from 
baseline to Day 14
2IQ
Plasma BVM 
1Cmin (g/mL)
Plasma BVM 
1Cmax 
(g/mL)
Plasma BVM 
1AUC(0-) 
(g.h/mL)
200 mg BID
(N=14)
-0.54 (0.64)
1.70
46
(41, 51)
58
(53, 64)
632
(571, 699)
300 mg BID
(N=18)
-0.70 (0.77)
2.67
72
(65, 80)
91
(84, 99)
973
(890, 1064)
1.
Cmin, Cmax, and AUC reported as geometric mean (95% CI).
2.
IQ=geometric mean Cmin/in vitro EC90; reported EC90=27 g/mL; all subjects achieved IQ 1.
        AUC(0-) = Area under the concentration-time curve over the dosing interval; BVM = Bevirimat; CI = Confidence 
interval; Cmax = Maximum plasma concentration; Cmin = Minimum plasma concentration; EC90 = 50% protection 
against resistant mutant HIV infection; IQ = Inhibitory quotient; SD = Standard deviation.
Early clinical data for BMS955176, a second generation maturation inhibitor, have been 
recently presented [Nowicka-Sans, 2015]. In a 10-day monotherapy trial in HIV-infected 
patients, plasma HIV-1 RNA was reduced at doses of between 40 mg and 120 mg QD. 
All doses were well tolerated. The maximum change, seen between 10 and 12 days after 
starting dosing, was about 1.5 log10, which is substantially better than the effect 
demonstrated with BVM and may indicate the maximum expected clinical effect of 
inhibiting this viral target.
Although BMS955176 is currently in Phase II studies in HIV-infected patients, there are 
no maturation inhibitors approved for the treatment of HIV infection.  The uncertainties 
of early drug development and continuing need for novel ART, especially for heavily 
treated/experienced HIV-infected persons, support continued compound development. 
GSK2838232’s low nanomolar in vitro potency against multiple HIV-1 gag 
polymorphisms and broader spectrum across multiple HIV-1 subtypes indicates it has 
utility in this setting.
2.2.1.
Preclinical Summary
Nonclinical pharmacology
Virology
GSK2838232, in vitro, is an inhibitor of HIV maturation by preventing the cleavage of 
the HIV gag structural subunit p25 to p24. GSK2838232 is a potent antiviral agent with a 
mean 50% maximal inhibitory concentration (50% maximal inhibitory concentration 
[IC50]) value of 1.6 nM (range: 0.8 to 4.3 nM) when tested in a panel of 26 HIV-1 
isolates with various polymorphic gag genotypes in peripheral blood mononuclear cells 
(PBMCs), suggesting that GSK2838232 can inhibit a broad spectrum of HIV isolates. In 
another PBMC assay, GSK2838232 showed potent antiviral activity in 59 of 60 isolates 
with IC50 values ranging from 0.22 to 5.1 nM. GSK2838232 also inhibited HIV-1 strains 
containing the consensus Sp1 QVT region or the V370A polymorphism in MT4 cells
(IC50 = 0.73 to 0.81 nM). 
 
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In an MT2 cell-based assay utilizing recombinant viruses harboring gag and protease 
from subjects before and after a protease inhibitor (PI) based regimen, GSK2838232 
inhibited 12 of 15 viruses with a mean IC50 value of 1.7 nM (range = 0.4 to 3 nM). The 
remaining 3 viruses were not inhibited by GSK2838232 up to the top concentrations 
tested at 400 nM. There was no correlation of PI sensitivity and susceptibility to 
GSK2838232. GSK2838232 resistance mutations were selected for by serial passage of 
virus in a SupT1 cell-based assay with increasing concentrations of GSK2838232. In the 
lab strain NL4-3 and gag/protease recombinant viruses, the resistance mutation A364V 
arose and resistance confirmed by site-directed mutagenesis. This resistance mutation 
maintains susceptibility to other classes of anti-retrovirals including PIs and non-
nucleoside RT inhibitors.
GSK2838232 was tested in vitro in combination with two marketed PIs, atazanavir and 
darunavir. Using a dose-wise additivity model, GSK2838232A showed additive anti-viral 
activity with both PIs.
Secondary Pharmacology
In a secondary pharmacology study, GSK2838232 was tested against a panel of 
receptors, ion channels and transporters and demonstrated no significant effect (IC50 of 
1 M). It is important to note that the selectivity for antiviral activity of GSK2828232 
compared to all tested off-target activities was >100-fold, and the potential for organ 
toxicity was characterized in the nonclinical toxicology studies (see below).
In safety pharmacology studies in male rats, there were no hemodynamic changes or 
neurobehavioral effects following single oral doses up to 300 mg/kg. A single oral dose 
of GSK2838232 at 30 mg/kg or 300 mg/kg produced reversible increases in respiratory 
tidal volume (32% and 36%, respectively) and derived minute volume (17% and 26%, 
respectively) at 6 hours after dosing. These doses did not produce any effect on 
respiratory rate, airway resistance or body temperature. There were no respiratory effects 
in rats given 5 mg/kg (mean maximum plasma concentration [Cmax] 0.12 g/mL; AUC0-24
1.0 g.h/mL based on Day 1 of the 4-week repeat dose study). These findings were not 
considered to suggest a safety concern in humans.
GSK2838232 at the maximum feasible concentration, limited by solubility, of 4.09 M 
(3.31 g/mL) caused no inhibition of human ether-a-gogo related gene (hERG) tail 
current in Human Embryonic Kidney 293 cells stably transfected with hERG cDNA, 
indicating a low probability for interaction at the hERG channel.
In conscious telemetered male dogs (n=4), a single oral dose of GSK2838232 at 
60 mg/kg (Cmax 0.59 g/mL; AUC0-24 8.7 g.h/mL based on Day 1 exposure data from 
the 4-week oral repeat dose toxicity study) was associated with one episode of 
non-sustained ventricular tachycardia in one dog lasting ~1.2 seconds. There were no 
effects on arterial pressures, heart rate, or electrocardiogram (ECG) interval durations. An 
investigative safety pharmacology cardiovascular study was conducted in telemetered 
dogs given 60 mg/kg/day for 4 weeks with serial monitoring by echocardiography, 
cardiac biomarkers, qualitative and quantitative electrocardiology, microscopy, and 
transmission electron microscopy (TEM) of the heart. 
 
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There were no changes in echocardiography endpoints, ECG intervals, ECG waveforms, 
arterial pressures, heart rates, serum cTpnI, N-terminal prohormone of brain natriuretic 
peptide (NTproBNP), or in heart tissue as assessed by TEM. With routine microscopy, 
one treated dog had a single focus of degeneration/necrosis of the tunica media 
(moderate) in an extramural artery and another treated dog had localised, mixed-cell 
inflammation (mild) along the epicardium of the coronary groove. Both changes have 
been reported in normal beagles and were considered of uncertain relationship to 
treatment in the absence of changes in any other structural or functional cardiovascular 
endpoints. The 28-day exposures were similar to the previous 4-week toxicity study in 
dogs: the Cmax range at 60 mg/kg/day in this investigative safety pharmacology study was 
0.542 to 2.00 g/mL and range of AUC0-24 was 6.04 to 35.7 g.h/mL. In subsequent 
repeat-dose studies in dogs treated for up to 9 months with up to 70 mg/kg/day, no 
changes were evident in cardiac biomarkers (including cTpnI and NTproBNP), functional 
(including ECG waveform) or structural (including microscopic evaluation) 
cardiovascular endpoints at slightly higher exposures than those achieved than in 
previous studies. The end of the 9-month study, gender averaged Cmax at 70 mg/kg/day 
was 1.95 g/mL and AUC0-24 was 38.8 g.h/mL. These studies support an absence of 
GSK2838232-related functional or structural effects on the heart in preclinical testing. 
The No Observed Adverse Effect Level (NOAEL) was established at 20 mg/kg/day (on 
the basis of mild hepatic findings) with an associated area under the curve at 24 hours 
(AUC24) of 16.2 g.hr/mL and Cmax 0.847 g/mL.
Pharmacokinetics and product metabolism in animals
The PK of GSK2838232 were investigated in the mouse, rat, and dog. The oral 
bioavailability of GSK2838232 was low to moderate (~6% to 40%) depending on the 
species and formulation. Plasma and blood clearance were low and the volume of 
distribution at steady state was high relative to total body water. The half-life of 
GSK2838232 was short in the mouse and rat, but moderate in the dog. Systemic exposure 
of GSK2838232 generally increased in a less than dose-proportional manner.  In rats, 
there were no differences in systemic exposure between single and repeat-dose 
administration, or between males and females.  In a 7-day study in dogs, systemic 
exposures were generally similar between males and females and after single and repeat 
dosing; however, in a 4-week study, systemic exposures were higher in females than in 
males in the high-dose group (60 mg/kg/day) and higher after repeat dosing than after a 
single dose. The distribution of radioactivity in male pigmented rats following a single 
oral administration of [14C] GSK2838232 at a target dose level of 20 mg/kg showed 
radioactivity was rapidly absorbed and widely distributed throughout the body with all 
tissues, except the brain and spinal cord. There were no tissues that retained detectable 
levels of radioactivity at 28 days post dose. In a bile duct canulated rat study, 30% of the 
administered dose was excreted in the bile as an acylglucuronide. In the same study, 
unchanged drug and metabolites were eliminated primarily in the bile and feces, while a 
mean of <1% of the dose was eliminated in urine.
In vitro, GSK2838232 is highly protein bound (>99.9%) and has low passive 
permeability. In vivo evidence suggests active uptake of GSK2838232 by transporters in 
the rat liver. 
 
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After single oral doses of 5, 100, or 300 mg/kg, the average liver to plasma ratio was 51, 
17, and 10, respectively. After 7 days of dosing at 30, 100, or 300 mg/kg/day, liver to 
blood ratios ranged from 10 to 16.
In the 13-week repeat dose studies in dogs given 35 mg/kg BID (70 mg/kg/day), heart 
tissue collected at necropsy had GSK2838232 concentrations 2.5 to 5-times higher than 
the 24-hour post-dose plasma concentrations, similar to the previous 4-week CV 
investigative findings.  In the 13-week repeat dose studies in rats given 300 mg/kg/day, 
heart tissue collected at necropsy had GSK2838232 concentrations approximately 3 times 
higher than the 24-hour post-dose plasma concentrations, similar to the previous 7-day 
findings.  Overall GSK2838232 did not appear to be highly concentrated in heart tissue 
after repeat dosing and suggests that accumulation upon chronic dosing is unlikely.
Routes of metabolism identified in liver microsomal incubations and rat, dog, and human 
hepatocytes were N-dealkylation, oxidation, oxidative deamination, and glucuronidation, 
alone or in combination, with no human-specific metabolites detected.  N-dealkylated 
products and glucuronidation were observed in rat plasma and the bile. In general, in 
vitro metabolite profiles of the nonclinical species and human were qualitatively similar, 
such that all metabolites of [14C] GSK2838232 observed in human hepatocyte 
incubations were observed in rat and/or dog. Minor to trace levels of potential aldehydes 
metabolites formed as a result of N-dealkylation and oxidative deamination were 
observed in rat, dog and humans.  
GSK2838232 did not show evidence for glutathione adduct formation in rat or human 
liver microsomes.  Data from pooled human liver microsomes along with recombinant 
cytochrome P450 (CYP) enzymes suggest that in vitro the oxidative metabolism of 
GSK2838232 was primarily mediated by CYP3A4.  Preliminary in vitro investigations 
showed GSK2838232 did not inhibit CYP1A2, 2C9, 2C19, 2D6, 3A4 and was not a 
metabolism-dependent inhibitor of CYP3A4. No drug interaction risk was identified for 
co-administrated substrates of UGT1A1, 1A3, 1A6, 1A9, 2B7, and 2B15, OAT1, OAT3, 
OATP1B1, OATP1B3 or OCT2 at a clinical dose of 200 mg GSK2838232/ritonavir 
(predicted Cmax 0.32 µM). Extrapolation of the clinical risk (using FDA and EMA 
regulatory guidance) did indicate a risk for GSK2838232-mediated inhibition of 
UGT1A4 and of gut contributions of CYP3A4, P-gp, and BCRP at the same clinical 
exposure; however, the potential for clinically significant interactions via these 
mechanisms is predicted to be low (<2 fold change in AUC). GSK2838232 did show 
weak induction of CYP3A4 enzyme activity. However, based on the maximum predicted 
plasma concentrations and high protein binding, the potential for clinically significant 
drug interactions through CYP3A4 induction by GSK2838232 appears to be low.
The inclusion of cobicistat as a CYP3A4 inhibitor pharmacoenhancer in this Phase IIa 
study in place of ritonavir is unlikely to produce a significantly different profile of 
GSK2838232 ADME (and therefore systemic exposure); however, there have been no 
preclinical studies conducted with GSK2838232 and cobicistat to date.  
Toxicology
GSK2838232 administered by oral gavage in repeat dose studies up to 6 months duration 
resulted in no adverse treatment-related effects in rats given up to 300 mg/kg/day QD. 
 
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In dogs given up to 70 mg/kg/day (35 mg/kg/day BID), adverse liver effects were noted 
at this dose in the 9-month repeat dose study.  Though isolated, low grade changes in 
heart rate and cardiac troponin I (cTnI) had been noted in 4-week toxicity studies in rats 
and dogs; however, there were no treatment-related structural or functional 
cardiovascular changes in studies of 3 months and greater duration as assessed by 
echocardiography, ECG, microscopy, and cardiac biomarkers, indicating an absence of 
GSK2838232-related functional or structural effects on the heart in preclinical testing. 
Only non-adverse treatment-related changes were noted in the definitive 6-month rat 
study, which included occasional salivation in animals given 300mg/kg/day and minimal 
clinical pathology changes without histologic correlates (transient clinical chemistry 
changes at 5 mg/kg/day and reversible urine chemistry changes at 300 mg/kg/day). The 
NOAEL in this study was considered to be 300 mg/kg/day (mean AUC[0-t] 
21.3 g.h/mL, mean Cmax 1.77 g/mL [Week 26 values for males and females 
combined]).  
As noted above, dogs given GSK2838232 at 70 mg/kg/day for 9 months had minimal to 
moderate pigmentation (consistent with bile) with minimal to mild mixed cell infiltration 
in the liver and isolated mild increases in alanine aminotransferase (ALT) activity.  These 
findings were considered adverse, but were reversible after the 6-week off-dose period.  
The NOAEL for this dog study was considered to be the mid-dose level of 20 mg/kg/day 
(mean AUC[0-t] 16.2 g.h/mL, mean Cmax 0.847 g/mL [Week 39 values for males and 
females combined]).
Data from genotoxicity assessments suggest that GSK2838232 does not present a 
genotoxic hazard to humans.
During discussions with the FDA regarding the resolution of the clinical hold, the 
Agency recommended that the sporadic cardiovascular changes observed in the early (1-
month) rat GLP study at the highest dose level (300 mg/kg/day) should be considered 
when defining the NOAEL and establishing a safe dose of GlaxoSmithKline (GSK) for 
the initiation of this study protocol.  Accordingly, for the initial PK studies, the reference 
dose level of 30 mg/kg/day in the 1-month rat study was initially used to define the 
NOAEL and therefore the values for fold cover at maximum projected mean exposure 
and Cmax in human subjects were lower, at >2.5-fold.  However, based on the 
cumulative clinical safety data through Cohort 5 of Study 204953, the designated 
NOAEL for the most sensitive species (i.e., 20 mg/kg/day in the 9-month dog study 
based on liver endpoints) is currently used for assessing fold-cover for projected clinical 
dosing in this study.
The inclusion of cobicistat as a CYP3A4 inhibitor pharmacoenhancer in this Phase IIa 
study in place of ritonavir is unlikely to produce a significantly different profile of 
GSK2838232 ADME (and therefore systemic exposure and toxicity); however, there 
have been no preclinical studies conducted with GSK2838232 and cobicistat to date.  
Full details of non-clinical and clinical data may be found in the current Investigator’s 
Brochure (IB) [GSK Document Number 2012N151889_03].
 
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2.2.2.
Clinical Summary of Safety and Pharmacokinetics
To date, GSK2838232 has been evaluated in three completed clinical studies with or 
without ritonavir (RTV) (GSK2838232/r). A fourth study (204953) completed late 2016 
and data analysis is ongoing. Full details of the clinical results can be found in the 
Investigator’s Brochure.
2.2.2.1.
Clinical Summary of Safety
As of November 2016 fifty-three subjects had been exposed to GSK2838232 in 3 
completed studies. One study (204953) completed in late 2016 and the analysis of results 
are ongoing (63 subjects were exposed to GSK2838232/r or placebo so far in this study).  
Overall, drug-related adverse events have been few and mild, and included headache, 
dizziness, fatigue, nausea, and palpitations and anxiety.  Similarly, treatment-emergent 
laboratory abnormalities have also been few and mostly grade 1.  There have been no 
discernible patterns, thus far, in terms of AEs or laboratory abnormalities.
One subject in study 200912 discontinued treatment with RTV due to an AE.  A 47-year-
old female who developed right upper quadrant abdominal pain, nausea and flatulence 
associated with grade 4 elevations in ALT and aspartate aminotransferase, and grade 2 
elevations in total bilirubin (BIL). She was diagnosed with a common bile duct 
obstruction due to gallstones that spontaneously resolved. The Investigator assessed this 
AE as unrelated to study treatment.
Due to sporadic CV-related safety signals in the early animal studies (see Section 2.2.2), 
intense CV monitoring was in place for all four studies.  
One AE occurred in HMI116787 that was initially considered a CV AE but after further 
evaluation was considered not to be of cardiac etiology.  Two CV AEs occurred in 
200207 that were initially considered possibly related to GSK2838232 exposure.  
However, further evaluation confirmed that there is a low likelihood that these events 
were due to GSK2838232 exposure.  A summary of each event is provided in the IB.
In Study 204953, there have been a small number of CV-related events of any sort: There 
have  been no serious adverse drug reactions, and no clinically significant drug-related 
abnormal findings for 12-lead ECGs, vital signs, safety laboratory results (including 
cardiac troponin I), or telemetry.  The following cardiovascular AEs were observed 
during the course of the study but were not considered to be caused by GSK2838232 
exposure:

In Part 1A (Cohort 1), Period 2, a subject was withdrawn due to an AE (low 
hemoglobin) prior to GSK2838232 exposure Day -2.  A replacement subject 
was brought in, but was not dosed with GSK2838232 or placebo because during 
the 2-day RTV run-in, on Day -1, the replacement subject met the stopping 
criteria for telemetry due to as brief occurrence of asymptomatic, NSVT prior to 
the first dose of GSK2838232 or placebo.  Because the subject was excluded 
from the study prior to the first dose of investigational drug, the NSVT was not 
considered to be a serious and unexpected adverse drug reaction that would 
qualify for IND safety reporting.  
 
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
In Part 1A (Cohort 1), Period 3 (Period “3A” for the purpose of differentiating 
between 100 mg GSK2838232/r vs. 200 mg GSK2838232/r), one subject was 
discontinued prior to the first dose of study drug due to a series of 
cardiovascular findings (pre-ventricular contractions on telemetry).  None of the 
findings were abnormal or atypical, but the investigator determined that this 
would not be a good etiology to have in a subject about to receive 
investigational drug.  Because the event occurred prior to first dose of 
investigational drug, the finding was not considered to be due to GSK2838232 
exposure.  

In Part 1A (Cohort 1), Period 3 (Period “3A” for the purpose of differentiating 
between 100 mg GSK2838232/r vs. 200 mg GSK2838232/r), one subject who 
had already been dosed on 2 previous occasions (with either GSK2838232 or
placebo) was dosed for 2 days with RTV, and then on 05 May 2016 was dosed 
with either GSK2838232/r or placebo/r as scheduled. On the following day (06 
May 2016), the subject experienced an asymptomatic, 6-beat run of NSVT, 
which was classified at the time as an SAE. Further monitoring, including 
continuous Holter monitoring revealed no further events. The subject had no 
troponin elevation throughout the study. After additional investigation it was 
determined that the NSVT had occurred after the subject had received placebo 
the previous day. Although the subject had received active on the two prior 
visits, the protocol allowed for sufficient washout between each dose.  
Therefore, because the subject had received placebo prior to experiencing the 
NSVT, the event was not considered to be due to GSK2838232 exposure or a 
serious and unexpected suspected adverse reaction that would qualify for IND 
safety reporting.

In Part 2 (Cohort 6, 200mg/r), a 40 year old male enrolled in the study with no 
significant medical history experienced an asymptomatic ventricular triplet 
(NSVT) while asleep at 5:33am on Day 8 (of 11 days worth of dosing) 
approximately 21 hours after receiving 200 mg GSK2838232/r on the previous 
day at 8.25am. This event was noted by the site staff and the subject was 
assessed and found to have no associated clinical symptoms or complaints. The 
GSK medical monitor was notified.  Because the subject was not symptomatic 
and this did not meet protocol-defined stopping criteria, the study was not 
unblinded at the time, and the subject was allowed to continue dosing. Dosing 
in the study is now complete and no further events have been noted. It was the 
assessment of the site PI and the GSK safety/monitoring team that a ventricular 
triplet can be seen in healthy volunteers on continuous Holter monitoring.
Therefore neither the PI nor GSK considered this event to be a serious and 
unexpected suspected adverse reaction.
2.2.2.2.
Study 204953 (completed); Pharmacokinetic Data
Study 204953 investigated the safety, tolerability, and PK of escalating doses of 
GSK2838232 as micronized API, with 100 mg RTV, initially as single doses and then as 
repeated doses for 11 days.  
 
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In addition, it evaluated the relative bioavailability of a single fasted dose of micronized 
API powder blend in capsules with RTV compared to powder-in-bottle for oral 
suspension with RTV and the effect of a normal fat meal on the bioavailability of a single 
dose of GSK2838232 in the capsule formulation with RTV.  It will evaluate 
GSK2838232 exposure after repeated doses of unboosted GSK2838232 in the capsule 
formulation. Noncompartmental PK analysis was performed using scheduled sample 
times.  The anaylsis of data from this study is ongoing; preliminary results are presented.
Pharmacokinetic analysis was performed on GSK2838232 plasma concentration-time 
data using nominal time following single doses of 50, 100, and 250 mg in combination 
with RTV in Part 1A of Study 204953 (Table 3).  On average, GSK2838232 Cmax 
values were reached 4-6 hours after dosing.  Terminal half-life values ranged from 15 to 
28 hours across the three dose levels.  Overall, broad dose proportionality was observed 
for Cmax and AUC(0-) values with ascending single doses of GSK2838232 (50, 100, 
and 250 mg with 100 mg RTV).
Table 3
Summary of Preliminary Pharmacokinetic Parameter Values after 
Single Doses of GSK2838232 in Combination with 100 mg Ritonavir 
(Study 204953, Part 1A)
Dose (mg)
n
t½ 
(h)
tlag 
(h)
tmax 
(h)
Cmax 
(ng/mL)
AUC(0-) 
(ng.h/mL)
50
8
22.7
(17%)
(17.2-28.5)
0.188
(138%)
(0-0.5)
3.63
(41%)
(2.5-6.0)
17.2
(43%)
(8.7-27.9)
458.6
(33%)
(210.6-662.0)
100
6
18.0
(14%)
(15.8-22.3)
0.167
(155%)
(0-0.5)
6.00
(59%)
(2.5-12.0)
25.2
(20%)
(17.5-31.5)
890.5
(20%)
(619.1-1053)
250
5
17.3
(6.4%)
(15.5-18.6)
0
(-)
(0-0)
5.50
(71%)
(2.0-12.0)
60.7
(23%)
(40.8-73.1)
1731
(29%)
(1222-2505)
Data are presented as mean (CV) (minimum-maximum).
Study 204953 Part 1B was an open label, 2x2+1 three-period, crossover design, 
evaluating the relative bioavailability of the micronized API GSK2838232 powder blend 
in capsules compared to the PiB reference formulation for the first two periods, with the 
assessment of food effect on the capsule formulation in Period 3.  
The relative bioavailability of the micronized powder blend in 50 mg hand-filled capsules 
compared to the micronized API as PiB for oral suspension was assessed as 100 mg 
GSK2838232 single doses with 100 mg RTV after two pre-doses (48 h) in the fasted state 
in a randomized crossover design in 12 subjects in the first two periods of Part 1B of 
Study 204953. Preliminary geometric mean AUC(0-) and Cmax values were 
approximately 45% and 60% higher, respectively, after administration in the capsule 
formulation compared to oral suspension from PiB (Table 4).
 
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Table 4
Preliminary Assessment of Relative Bioavailability of Capsule 
Formulation vs. Powder-in-Bottle Formulation of GSK2838232 (Study 
204953, Part 1B)
Parameter
Test
Reference
n
Ratio of Geometric 
Least Square Means
90% CIof Ratio
AUC(0-) 
Capsule
PiB
12
1.43
(1.194,1.702)
Cmax 
Capsule
PiB
12
1.58
(1.312,1.900)
PiB = powder-in-bottle.
The potential food effect with the capsule formulation was assessed as 100 mg 
GSK2838232 single doses with 100 mg RTV after two pre-doses (48 h) in the fasted state 
and with a normal fat meal in a non-randomized crossover design (fasted in either Period 
1 or 2, fed in Period 3).  Eleven subjects provided data for both dietary conditions.   
Preliminary geometric mean AUC(0-) and Cmax values were approximately 60% 
higher after administration in the capsule formulation with a normal fat meal compared to 
the fasted state (Table 5).
Table 5
Preliminary Assessment of the Effect of a Normal Fat Meal on 
GSK2838232 Exposure when Administered as a Capsule 
Formulation with Ritonavir (Study 204953, Part 1B)
Parameter
n
Capsule – food
Geometric mean
Capsule –
fasted
Geometric 
mean
Ratio of geometric 
means 
(food/fasted)
AUC(0-) (ng.h/mL)
11
2414
1539
1.57
Cmax (ng/mL)
11
76.9
47.2
1.63
Repeat dose PK parameter values in Study 204953 Part 2 were determined on Day 1 and 
Day 11 using nominal time in Part 2 of Study 204953 (Table 6). After the Day 11 dose of 
GSK2838232 with RTV, exposure (Cmax, AUC[0-]) appeared to increase 
proportionally with the increase in dose level with the PiB and capsule formulations. 
 
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Table 6
Summary of Preliminary Pharmacokinetic Parameter Values on 
Day 1 and Day 11 during Repeated Dosing of GSK2838232 in 
Combination with 100 mg Ritonavir (Study 204953, Part 2)
Dose 
(mg)
n
t½ 
(h)
tlag 
(h)
tmax 
(h)
Cmax 
(ng/mL)
AUC(0-) 
(ng.h/mL)
C
(ng/mL)
Study Day 1
20
(PiB)
6
-
0.417
(49%)
(0-0.5)
3.67
(11%)
(3.0-4.0)
12.2
(47%)
(5.8-20.8)
189.4
(40%)
(83.7-284.4)
6.1
(39%)
(2.5-8.9)
50
(PiB)
6
-
0.167
(155%)
(0-0.5)
3.00
(51%)
(2.0-6.0)
18.7
(40%)
(9.0-25.9)
288.7
(39%)
(138.6-380.2)
9.5
(35%)
(5.1-12.6)
100
(capsules)
6
-
0.167
(155%)
(0-0.5)
2.25
(23%)
(1.5-3.0)
48.4
(32%)
(28.1-69.6)
664.1
(31%)
(422.5-932.7)
21.6
(33%)
(12.8-29.3)
200
(capsules)
6
-
0.083
(245%)
(0-0.5)
2.50
(25%)
(2.0-3.5)
79.4
(38%)
(50.8-125)
1124
(39%)
(636.7-1794)
38.9
(36%)
(21.7-58.6)
Study Day 11
20
(PiB)
6
19.2
(16%)
(15.1-
24.2)
-
5.00
(32%)
(2.5-6.0)
27.4
(38%)
(11.3-40.4)
474.3
(31%)
(214.3-613.2)
15.3
(30%)
(7.1-19.2)
50
(PiB)
6
27.3
(52%)
(15.2-
50.4)
-
3.50
(46%)
(1.5-6.0)
58.0
(24%)
(40.9-78.0)
1113
(23%)
(762.6-1459)
38.8
(29%)
(24.5-51.7)
100
(capsules)
6
17.9
(18%)
(15.2-
23.7)
-
4.00
(40%)
(2.5-6.0)
133
(23%)
(94.7-164)
2492
(27%)
(1624-3301)
81.7
(30%)
(45.9-113)
200
(capsules)
6
-1
-
3.33
(45%)
(1.5-6.0)
240
(38%)
(127-368)
4389
(45%)
(2095-7161)
151
(46%)
(67.8-250)
Data are presented as mean (CV) (minimum-maximum).
1.
Concentration data were available up to 24 h after the Day 11 dose, and t½ values were not 
calculated.
2.2.2.3.
Overall Summary/Conclusions of PK data
The original formulation used in the first three studies with GSK2838232 (HMI116787, 
200207, and 200912) was SDD.  Data from Study 200912 demonstrated that a change to 
the API formulation of GSK2838232 was feasible for future clinical studies. Study 
204953 utilized micronized API powder in a bottle as well as in a capsule. The capsule 
was shown to be a viable solid dosage form for subsequent studies.  A more detailed 
summary of the data from Study 204953 is in Section 2.2.2.2.
 
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
GSK2838232 SDD did not overall demonstrate significant escalation in exposure 
from an increase in dose from 100 mg to 200 mg in a cross-study comparison.  The 
API PiB formulation showed a proportional increase in AUC and Cmax for a 2-fold 
dose escalation from 100 mg to 200 mg.

The observed tmax of the API form was significantly increased over the SDD 
formulation (the API formulation also increased tlag relative to SDD).

The bioavailability of the GSK2838232 API formulation was on average 30-50% of 
the bioavailability of SDD formulation, but there was a large observed range of 
relative intra-subject exposures (11-150%).

Both 10 mg SDD and 20 mg API showed a 10-fold or greater increase in AUC with 
steady-state RTV (100 mg QD for 10 days) with a smaller (≤4-fold) increase in 
observed Cmax.  The t½ of GSK2838232 increased from 15-18 hours to 34-42 
hours in the presence of steady-state RTV, regardless of formulation.

After single doses of 50 to 250 mg GSK2838232 with RTV, increases in Cmax and 
AUC(0-) values were broadly proportional to the increase in dose.  On Day 11 
after repeated daily 20 to 200 mg doses of GSK2838232 with RTV, increases in 
Cmax and AUC(0-) values appeared to be proportional to the increase in dose with 
the PiB and capsule formulations.  

The relative bioavailability of the micronized API powder blend in capsules with 
RTV was approximately 45%-60% higher than the bioavailability of the micronized 
API administered as oral suspension from PiB with RTV.

Co-administration of the micronized API powder blend in capsules with RTV and a 
normal fat meal resulted in an approximately 60% increase in geometric mean 
Cmax and AUC(0-) values compared to the fasted state with RTV (Study 
204953).

Variability remains fairly constant across formulations and boosted versus 
unboosted at around 30%-40% (moderate-high).

Projections of potential future efficacious boosted GSK2838232 API regimens 
suggest that doses of 20 to 200 mg GSK2838232 API co-administered with RTV 
will result in mean trough values of at least 3-fold above the derived 90% maximal 
inhibitory concentration (IC90) target value (5 ng/mL). Even if protein binding has 
more impact than envisaged and causes a 5-fold increase in IC90 as seen in some 
preclinical virology studies, the predicted troughs will still be significantly higher 
than the 5-fold shifted IC90 (25 ng/mL) at doses of 50 mg or higher with RTV. 

The average and maximum AUC/Cmax values observed at the maximum dose 
studied to date are below NOAEL values in preclinical chronic toxicology studies 
(6-month rat, 9-month dog).
 
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3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To evaluate antiviral activity of 
GSK2838232/cobi in HIV-1 infected patients 
during 10-days of monotherapy.

Maximum decline from baseline (Day 1) in 
plasma HIV-1 RNA 

To assess safety and tolerability of 
GSK2838232/cobi when administered as 
monotherapy over 10 days.

Safety and tolerability parameters, 
including adverse event, concurrent 
medication, clinical laboratory, 
electrocardiogram (ECG) and vital signs 
assessments.

To characterize pharmacokinetics (PK) of 
GSK2838232 in HIV-1 infected patients 
following GSK2838232/cobi dosing for 10 
days

GSK2838232 PK parameters following 
dose administration, as follows:
Day 1:  area under the plasma 
concentration time curve AUC(0-24), 
maximum observed concentration 
(Cmax), time to maximum observed 
concentration (tmax), concentration at 24 
hours post dose (C24), absorption lag 
time (tlag); 
Following last repeat administration on 
Day 10:  AUC(0-), pre-dose 
concentration (C0), concentration at end 
of dosing interval (C), Cmax, tmax, t½, 
and apparent oral clearance (CL/F), if 
data permit
Secondary

To explore the relationship between 
GSK2838232 exposure and change in 
plasma HIV-1 RNA

GSK2838232 PK parameters Day 10 
AUC(0-), Cmax, Cwith Day 11 HIV-1 
RNA change from baseline

To assess the immunologic effect of 
GSK2838232/cobi when administered over 
10 days in HIV-1 infected adults

Change from baseline in CD4+ cell count 
to Day 11

To explore the relationship between 
GSK2838232 exposure and safety or 
immunologic parameters, if appropriate.

GSK2838232 PK parameters on Day 10: 
AUC(0-), Cmax, C  with Day 11 change 
from baseline in CD4+ cell count

To assess the development of viral 
resistance (genotypic and phenotypic) over 
10 days and correlate with viral response, if 
appropriate.

Emergence of drug resistance mutations, 
if appropriate
 
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Objectives
Endpoints

To estimate GSK2838232 accumulation and 
to assess attainment of steady state 
following administration of 
GSK2838232/cobi for 10 days in HIV 
infected subjects.

Accumulation:
GSK2838232 PK accumulation ratios (R): 
Day 10 AUC(0-), Cmax, and C
compared to Day 1 AUC(0-24), Cmax, 
and C24, respectively

Steady State:
pre-morning dose concentrations (C0) on 
Day 2 through 11 

To examine dose proportionality of 
GSK2838232 PK parameters following 
GSK2838232/cobi dosing for 10 days in HIV 
infected subjects.

Day 1 AUC(0-24), Cmax, and C24, and 
Day 10 AUC(0-), Cmax and C  at 
different doses levels for the assessment 
of dose proportionality
Note: Other exploratory objectives and endpoints will be specified in the RAP
4.
STUDY DESIGN
4.1.
Overall Design
This is a Phase IIa, multicenter, open-label, adaptive dose ranging, study to evaluate the 
antiviral effect, safety, tolerability, and PK of GSK2838232/cobi monotherapy over 10 
days in HIV-1 infected adults who are not currently receiving ART therapy. Subjects who 
have received any prior maturation ihibitor therapy will not be eligible for this study. To 
minimize the number of subjects exposed to suboptimal doses, an adaptive and dose 
ranging design is applied in this study.
This study consists of a screening visit, a 10-day treatment period, and follow-up 
evaluations for 2 weeks following last dose.
Screening will be performed as the patients are identified, within 30 days of the first dose 
of study drug.  Eligible HIV-1 infected subjects will receive study treatments for 10 days.
Table 7
Study Design for 200911
GSK2838232/cobi Once Daily for 10 days1,2
Part A
Part B 
Cohort 1
Dose
(mg)
Interim Analysis
Cohort
N
(mg)
N=10
100
2
8
200
3
8
50
4
8
20
 
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1.
Part A Cohort 1 safety/PK/virology data will be evaluated at interim, prior to initiating other cohorts in Part B.  All 
doses will be given with 150 mg cobicistat.
2.
Part B doses are an illustration of the projected doses per cohort. The actual doses for each cohort are subject to 
modification based upon safety, PK and antiviral activity data from Cohort 1 (Part A). More doses/cohorts 
(including potential removal of cobicistat co-dosing) may be added. (The maximum dose in Cohort B will likely not  
exceed 200 mg with cobicistat unless overall plasma exposure [as AUC and Cmax] is lower in HIV-infected 
subjects than in healthy subjects at the same dose level).
After successfully completing screening evaluations, the first cohort will enroll 10 
subjects to receive the 100 mg GSK2838232/cobi dose.  Following interim analysis of 
Cohort 1, if warranted, Cohorts 2-4 will each enroll 8 subjects to receive a range of 
GSK2838232/cobi doses.
Day 1 – Day 10: Dosing 
Subjects will report to the clinic for outpatient visits in the morning on Days 1 through 10 
during the treatment period, except for the weekend (Days 6 and 7).  Subjects will arrive 
each day prior to administration of the morning dose for safety and lab assessments, 
including HIV-1 RNA blood draws, as described in the Time and Events Table (Section 
7.1).  Subjects will begin receiving study drug in the morning of Day 1.  
Serial, intensive blood PK samples will be collected on Day 1 (up to 24 hours post-
morning dose) and Day 10 (up to 96 hours post-morning dose), and limited, single blood 
PK samples pre-morning doses on Days 3 through 9, except for the weekend. Subjects 
will be required to fast for 10 hours [overnight] prior to the morning check in on the 
intensive PK sampling days (Days 1 and 10).  All dosing days will require co-
administration of treatment with a light snack/meal per cobicistat labeling guidelines. All 
doses of study medication will be taken with 240 mL of water.  Subjects will be required 
to stay in the clinic on Days 1 and 10 until all specified assessments are completed (8-12 
hours post-dose). Following Day 10, subjects will be required to attend the clinic for 
follow up assessments including virological and PK blood sampling for up to 3 weeks.
Subjects will be given morning doses on Days 1 through 10 (except for the weekend) in 
the clinic.  Weekend morning doses (Days 6 and 7) will be packaged and sent home for 
self-administration.  After Day 11, the subjects will return frequently for assessments 
including blood draws for PK and HIV viral load. A diary card will be used to monitor 
dosing adherence.
Follow-up Visits:
Subjects will return to the clinic on Days 11, 12, 14 (1 day), and 21 (1 day) for PK and 
measurement of HIV-1 RNA levels, viral genotype/phenotype and safety assessments as 
shown in the Time and Events Table (Section 7.1). 
4.2.
Type and Number of Subjects
At least 34 subjects will be enrolled such that approximately 6-10 evaluable subjects 
complete a number of cohorts.  Additional subjects/cohorts may be enrolled to allow for 
evaluation of additional dose levels as appropriate. 
 
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If subjects prematurely discontinue the study, additional subjects may be randomized and 
assigned to the same treatment cohort at the discretion of the Sponsor in consultation with 
the Investigator.
4.3.
Design/Dose Justification
The fastest track to establishing antiviral potential of any novel HIV drug is to study a 
short course of monotherapy in HIV infected subjects. There is precedent for this across a 
number of classes of ART drugs. 
Uncertainties over the impact of protein binding on the activity of GSK2838232 and the 
inherent potency of inhibiting the HIV maturation process as a target remain key 
objectives for the GSK2838232 program. This two-part adaptive design will allow an 
early understanding of the potential of GSK2838232 in combination with cobicistat (and 
by implication, RTV), while not exposing HIV-infected subjects to longer courses of 
what may be suboptimal doses and possible development of resistance. 
Early clinical studies have indicated that in order to achieve reasonable IQ values likely 
to be associated with antiviral efficacy, GSK2838232 will need to be boosted with a 
pharmacoenhancer, such as RTV or cobicistat (in common with many CYP3A4 
substrates). 
There is no a priori intention to study GSK2838232 unboosted, unless: i) following the 
preliminary analysis of Part A Cohort 1, there is such pronounced antiviral activity that it 
would seem the estimates of projected IQ are low, in which case GSK2838232 may be 
evaluated in a subsequent cohort unboosted, or ii) the data from ongoing and planned
healthy volunteer trials,Study 204953 (GSK2838232 200 mg BID unboosted) and Study 
205820 (GSK2838232 500mg QD unboosted) support it.
4.3.1.
GSK2838232 with Ritonavir
In Study HMI116787, a single dose of 10 mg GSK2838232 (SDD) given after 10 days of 
RTV 100 mg daily dosing (to steady state) demonstrated an increase in overall exposure 
(AUC) and Cmax by an average of 10.8- and 2.6-fold, respectively, compared to 10 mg 
GSK2838232 alone. Terminal phase half-life also increased from approximately 20 hours 
to 34 hours. This effect was presumably the result of an inhibition of a CYP3A4-
mediated pathway. Studies 200912 and 200207 also indicated the utility of RTV in 
boosting GSK2838232 concentrations.
These data indicate the viability of studying a number of GSK2838232+RTV regimens in 
this PoC study. Predicted exposures following different GSK2838232 doses with steady-
state RTV are presented in Table 8, based on the results of linear regression analyses of 
the preliminary Day 11 data in Study 204953 (dose levels of 20 to 200 mg) and assuming 
no significant differences in PK (ADME) between HIV-infected subjects and healthy 
subjects. 
 
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Table 8
Predicted Mean Steady-State GSK2838232 AUC(0-24), Cmax, and IQ, 
Following Repeated Dose Administration + RTV with Fold Cover to 
NOAEL
Dose 
(mg)
Projected AUC24 
(ng.h/mL)1
Fold cover to 
NOAEL Dog2
Projected 
Cmax 
(ng/mL)1
Fold cover to 
NOAEL Dog2
IQ3
20+RTV
451
36
24
35
3.1
50+ RTV
1127
14
61
14
7.7
100+ RTV
2253
7.2
122
6.9
15
150+RTV
3380
4.8
183
4.6
23
200+RTV
4506
3.6
244
3.5
31
1.
Predicted mean values based on linear regression analyses of preliminary Day 11 data in Study 204953.
2.
Lowest NOAEL, 20 mg/kg/day obtained from 9-month study in dogs (AUC24 16200 ng.h/mL and Cmax 847 
ng/mL)
3.
Mean IQs derived from predicted C/IC90 (with target of 5 ng/mL).
C= Pre-dose (trough) concentration at the end of the dosing interval, IQ= inhibitory quotient.
The IQ following 20 mg to 200 mg GSK2838232/r QD is predicted to be >3 to >30-fold 
above the minimal target value (5 ng/mL) which was derived from preclinical virological 
assessment as 4 × EC50. No protein binding adjustment has been made because there was 
a minimal (≤5 fold) shift in assays where the effect of protein was assessed. If protein 
binding has more impact than anticipated, it is possible that the target Cmin value is 
approximately 25 ng/mL. In that scenario, projected IQ values at 200 mg/r QD would still 
be >5.
4.3.2.
GSK2838232 with Cobicistat
There have been no preclinical or clinical studies with GSK2838232 and cobicistat to 
date; however, a review of the literature indicates that pharmacoenhancement of drugs 
that are known to have dominant CYP3A metabolic pathways is similar with either RTV 
or cobicistat [Kakuda, 2009; Elion, 2011; Gallant, 2013].  Thus, the use of cobicistat as 
the CYP3A4 inhibitor pharmacoenhancer in this Phase IIa study in place of ritonavir is 
expected to produce a similar profile of GSK2838232 ADME (and therefore systemic 
exposure).  The pharmacokinetic data available after Part A Cohort 1 will confirm this 
assumption.  
4.3.3.
Interim Analysis
An evaluation of GSK2838232 safety, efficacy and PK data will be done after Part A 
Cohort 1, if the exposure level of GSK2838232 is in the range of the maximum 
GSK2838232 exposure seen previously in healthy subjects and the Bayesian probability
from Cohort 1 is less than 70%, the study will not move forward into Part B, otherwise 
doses will be selected for evaluation in Part B. If pharmacokinetic exposure after the 100 
mg GSK2838232/cobi dose is in the range of values observed after 100 mg 
GSK2838232/r in prior studies, the doses for Part B will be extended to both lower 
(20 mg and/or 50 mg) and higher (200 mg) doses. The highest dose tested in Part B will 
be selected to result in exposures similar to those seen with 200 mg/r in Study 204953.  
 
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4.4.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK2838232 can be found in the Investigator’s Brochure.  The following section 
outlines the risk assessment and mitigation strategy for this protocol:  
 
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4.4.1.
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) GSK2838232 
Cardiovascular
Pre-clinical studies have shown the following findings:  elevated heart rates, an 
isolated episode of non-sustained ventricular tachycardia and minimal to mild, 
sporadic troponin I elevations in dogs.  A subsequent investigative cardiovascular 
study in telemetered dogs treated for 4 weeks did not replicate these effects. 
Isolated microscopic cardiovascular changes were noted (focal extramural 
arteritis and localized epicardial inflammation), however these changes were 
considered of uncertain relationship to GSK2838232 because similar findings 
occur at low incidence in normal beagles and there were no GSK2838232-related 
functional changes by telemetry and echocardiography, or changes in cTpnI and 
NTproBNP.  In addition there was no correlation between histologic changes and 
plasma exposure or heart tissue concentrations of GSK2838232. 
3, 6 and 9 month toxicology studies in rat and dog did not demonstrate any 
evidence of cardiovascular injury or impact on cardiovascular function.
In the four GSK2838232 studies conducted so far there was no pattern of 
cardiovascular changes of clinical significance related to GSK2838232 and no 
clinically significant abnormality in electrocardiogram values other than the two 
SAEs documented and discussed.
Review of published bevirimat preclinical and clinical safety data indicates no 
significant toxicities or AEs of interest, other than a 30% incidence of 
gastrointestinal symptoms (including diarrhea). There were no significant 
cardiovascular AEs reported in published clinical studies.
Subjects will be clinically monitored for any signs 
of myocardial injury (chest pain, shortness of 
breath, pain with inspiration), elevated heart rate 
or arrhythmias. Samples for the assessment of 
troponin will be taken. Baseline EKG and Holter 
(to use for screening and for later comparisons if 
needed)
Exposures of GSK2838232 will be closely 
monitored in the clinical study so as to not 
exceed pharmacokinetic stopping criteria.  
 
 
 
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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Cobicistat (Tybost)
General
The cobicistat label includes the following information: 
TYBOST decreases estimated creatinine clearance due to inhibition of tubular 
secretion of creatinine without affecting actual renal glomerular function. This 
effect should be considered when interpreting changes in estimated creatinine 
clearance in patients initiating TYBOST
In one study investigating cobi+( atazanavir and tenofovir DF/emtricitabine) vs 
RTV+( atazanavir and tenofovir DF/emtricitabine), a higher frequency of reports 
of jaundice (6% and 3%) and ocular icterus (4% and 2%) were reported in the 
cobi group compared to the RTV group.  
Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, and 
triglycerides have been observed. The implications of these findings are 
unknown.
The vast majority of available safety data has been obtained in combination 
studies with other ART. There are no warnings of obvious cobicistat-related 
adverse events or safety concerns. 
Subjects will be closely monitored for any signs 
or symptoms potentially associated with 
cobicistat administration, in particularchanges in 
serum creatinine and liver chemistry.
HIV-1 Infection/Patient population
HIV Resistance
Propensity for co-meds and 
possible Drug-Drug 
Interactions (DDIs)
HIV Drug Resistance to unique mechanism
Recognize HIV patients have a higher chance of comorbidities/diseases and a 
risk of taking a medicine or product contraindicated in the study
Closely monitor HIV viral load and genotypic 
resistance
Strict adherence to protocol criteria around 
concurrent meds 
 
 
 
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4.4.2.
Benefit Assessment
This study in HIV-1 infected but otherwise healthy subjects is a 10-day monotherapy 
design. It is anticipated that all subjects receiving GSK2838232 will experience anti-HIV 
effects whereby their (blood) HIV viral titres are reduced, until administration stops and 
the viral load returns to baseline levels. There is no expected longer term anti-HIV 
benefit to administration of GSK2838232.  Participation in this study contributes to the 
process of developing GSK2838232 and other new therapies for the treatment of HIV 
infection.
4.4.3.
Overall Benefit:Risk Conclusion
To date, 115 healthy subjects have received GSK2838232 in four completed studies.  
Subjects have received single doses up to 200 mg SDD alone (studies HMI116787 and 
200912), 250 mg API in combination with RTV (204953), and then in repeated daily 
doses of up to 50 mg SDD alone (200207) for 5 days or 200 mg in combination with 
RTV (204953) for 11 days.
There have been two cardiovascular SAEs reported from clinical studies where the 
subject was receiving GSK2838232 to date (one in 200207, one in 204953). Neither is 
thought likely to be due to GSK2838232.
There have been no other withdrawals due to drug-related AEs and no trends relative to 
laboratory toxicity.  One subject was withdrawn in Part 1A of 204953 because of low 
haemoglobin lab values, thought unrelated to study drug or study procedures.
With respect to CV effects, with the exceptions noted, there have been no clinically 
significant changes in troponin, heart rate, blood pressure, ECG, or telemetry monitoring.
Subjects will also be at risk for AEs from cobicistat use and will be monitored closely for 
such events.
Given the preclinical profile and the clinical profile to date, the overall risk to HIV-1 
infected but otherwise healthy subjects at the proposed GSK2838232 doses (with or 
without cobicistat) for 10 days is predicted to be low.  Mean exposures at the highest 
dose studied are not projected to exceed NOAEL values obtained in chronic toxicology 
studies, further reducing potential risk. 
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on the GSK investigational product or other study treatment that 
may impact subject eligibility is provided in the Investigator’s Brochure.
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
 
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Approximately 10-12 HIV-1 infected subjects will be enrolled into Part A. If warranted 
by an interim safety, virology and PK data analysis, approximately 8 subjects will be 
enrolled in each of Cohorts 2-4 in Part B. Eligible patients are those who are maturation 
inhibitor-naïve and who are not currently receiving ART therapy.
Additional subjects/cohorts may be enrolled to allow for evaluation of additional dose 
levels or configurations (e.g., GSK2838232 alone).
If subjects prematurely discontinue the study, additional subjects may be enrolled .
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
1.
Between 18 and 55 years of age inclusive, at the time of signing the informed 
consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2.
Healthy (other than HIV infection) male or female as determined by the investigator 
or medically qualified designee based on a medical evaluation including medical 
history, physical examination, laboratory tests and cardiac monitoring. Defined as no 
other chronic medical conditions and taking no chronic medications.
3.
A subject with a clinical abnormality or laboratory parameter(s) which is/are not 
specifically listed in the inclusion or exclusion criteria, outside the reference range 
for the population being studied may be included only if the investigator in 
consultation with the Medical Monitor agree and document that the finding is 
unlikely to introduce additional risk factors and will not interfere with the study 
procedures. 
4.
A creatinine clearance >80 mL/min as determined by Cockcroft-Gault equation 
[Cockcroft, 1976] CLcr (mL/min) = (140 – age) * Wt / (72 * Scr) (times 0.85 if 
female) where age is in years, weight (Wt) is in kg, and serum creatinine (Scr) is in 
units of mg/dL.
5.
Confirmed HIV positive; CD4+ cell count ≥350 cells/mm3 and plasma HIV-1 RNA 
≥5000 copies/mL at Screening. 
6.
Antiretroviral treatment naive or ART-experienced (maturation inhibitor naive). No 
current ART (last dose completed at least 6 weeks prior to the first dose of study 
drug). A previous course of pre- or post-exposure prophylaxis is allowed provided 
that it was completed at least 6 weeks prior to the first dose of study drug.
 
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WEIGHT
7.
Body weight 50 kg (110 lbs.) for men and 45 kg (99 lbs) for women and body 
mass index (BMI) within the range 18.5-35.0 kg/m2 (inclusive)
SEX
8.
Male or Female
A female subject of reproductive or non-reproductive potential is eligible to 
participate if she is not pregnant (as confirmed by a negative serum or urine human 
chorionic gonadotrophin (hCG) test at screening and prior to first dose), not 
lactating, and at least one of the following conditions applies:
Reproductive potential:
Females of reproductive potential may only be enrolled if they are using two forms 
of complementary contraception, which must include one barrier method. They will 
be counselled on safer sex practices
There is no definitive DDI information with GSK2838232 and an interaction with 
oral contraceptives is possible, so other (barrier, inter-uterine device etc.) methods of 
contraception will be required.
Fertile females, who have an established, long-term lifestyle of sexual abstinence, or 
only same sex partners, require no other means of birth control.  
Non-reproductive potential:

Pre-menopausal females with one of the following:

Documented tubal ligation

Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion 

Hysterectomy

Documented Bilateral Oophorectomy

Postmenopausal defined as 12 months of spontaneous amenorrhea in 
questionable cases a blood sample with simultaneous follicle stimulating 
hormone (FSH) and estradiol levels consistent with menopause (refer to 
laboratory reference ranges for confirmatory levels).  Females on hormone 
replacement therapy (HRT) must discontinue HRT to allow confirmation of 
post-menopausal status prior to study enrolment.
Male subjects with female partners of child bearing potential must comply with the 
following contraception requirements from the time of first dose of study medication 
until one week after the last dose of study medication.
a. Vasectomy with documentation of azoospermia.  
b. Male condom plus partner use of one of the contraceptive options below:

Contraceptive subdermal implant that meets the SOP effectiveness criteria 
 
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including a <1% rate of failure per year, as stated in the product label

Intrauterine device or intrauterine system that meets the SOP effectiveness 
criteria including a <1% rate of failure per year, as stated in the product 
label

Oral contraceptive, either combined or progestogen alone or Injectable 
progestogen 

Contraceptive vaginal ring 

Percutaneous contraceptive patches
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label.  The investigator is responsible 
for ensuring that subjects understand how to properly use these methods of 
contraception.
INFORMED CONSENT
9.
Capable of giving signed informed consent as described in Section 10.2, which 
includes compliance with the requirements and restrictions listed in the consent form 
and in this protocol.
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
1.
Alanine aminotransferase (ALT) and BIL >1.5xupper limit of normal (ULN; isolated 
BIL >1.5xULN is acceptable if BIL is fractionated and direct BIL <35%). 
2.
Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones); HBV and/or 
HCV positive.
3.
Subjects who have any other chronic medical condition, including CV, respiratory, 
neurologic, psychiatric, renal, gastrointestinal (GI), oncologic, rheumatologic, or 
dermatologic
4.
Medical history of cardiac arrhythmias or cardiac disease or a family or personal 
history of long QT syndrome.
 
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CONTRAINDICATIONS 
5.
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.
RELEVANT HABITS 
6.
Chronic marijuana or use of other elicit medications (cocaine, heroin) is an exclusion 
criteria.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
7.
Presence of hepatitis B surface antigen (HBsAg), positive (confirmed by 
Recombinant Immuno-Blot Assay [RIBA]) hepatitis C antibody test result at 
screening or within 3 months prior to first dose of study treatment.
8.
Screening or baseline cardiac troponin I greater than the 99% cutoff (>0.045 ng/mL 
by the Dimension Vista CTNI assay).
9.
A positive pre-study drug/alcohol screen.  
10. Prior history of receiving an HIV maturation inhibitor
11. Where participation in the study would result in donation of blood or blood products 
in excess of 500 mL within 56 days.
12. The subject has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day in the current 
study: 30 days, 5 half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer).
13. Exposure to more than four new chemical entities within 12 months prior to the first 
dosing day.
14. Treatment with radiation therapy or cytotoxic chemotherapeutic agents within 
30 days of study drug administration or anticipated need for such treatment within 
the study.
15. Treatment with immunomodulating agents (such as systemic corticosteroids, 
interleukins, interferons) or any agent with known anti-HIV activity (such as 
hydroxyurea or foscarnet) within 30 days of study drug administration.
16. An active Center for Disease Control and Prevention (CDC) Category C disease 
except cutaneous Kaposi’s sarcoma not requiring systemic therapy during the trial.
17. Treatment with any vaccine within 30 days prior to receiving study medication.
18. Exclusion Criteria for 24-Hour Screening Holter:

Any symptomatic arrhythmia (except isolated extra systoles).

Sustained cardiac arrhythmias (such as atrial fibrillation,flutter or 
supraventricular tachycardia (10 seconds)

Non-sustained or sustained ventricular tachycardia (defined as 3 consecutive 
 
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ventricular ectopic beats).

Any conduction abnormality including but not specific to left or complete 
bundle branch block, atrioventricular [AV] block, high grade or complete heart 
block Wolff-Parkinson-White [WPW] syndrome etc.).

Sinus Pauses >3 seconds.
19. Exclusion criteria for screening ECG (a single repeat is allowed for eligibility 
determination):
Males
Females
Heart rate
<45 and >100 bpm
<50 and >100 bpm
PR Interval
<120 and >220 msec
QRS duration
<70 and >120 msec
*QTc interval
>450 msec
*The QTc is the QT interval corrected for heart rate according to Bazett’s formula 
(QTcB), Fridericia’s formula (QTcF), and/or another method. It is either machine-
read or manually over-read. The specific formula used to determine eligibility and 
discontinuation for an individual participant in 200911 will be Fridericia’s formula. 

Note: A heart rate from 100 to 110 beats per minute (bpm) can be rechecked by 
ECG or vitals within 30 minutes to verify eligibility.

Evidence of previous myocardial infarction (Does not include ST segment 
changes associated with repolarization).

Any conduction abnormality (including but not specific to left or right complete 
bundle branch block, AV block [2nd degree or higher], WPW syndrome).

Sinus Pauses >3 seconds.

Any significant arrhythmia which, in the opinion of the principal investigator 
OR GSK medical monitor, will interfere with the safety for the individual 
subject. 

Non-sustained or sustained ventricular tachycardia (3 consecutive ventricular 
ectopic beats).
5.3.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and any SAEs.
 
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5.4.
Withdrawal/Stopping Criteria
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as 
soon as possible. 

The site must counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or should 
continue in the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and if necessary a certified letter to the subject’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be considered 
to have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this request has 
occurred in the site study records. 
5.4.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
 
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Phase II Liver Chemistry Stopping and Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus
Bilirubin≥2x
ULN (>35% 
direct) 
or plus
INR>1.5, if 
measured*
Possible
Hy’s Law
ALT≥3xULN
ALT≥5xULN
ALT≥3xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
ALT≥3xULN
but able to 
monitor 
weekly for 
4 weeks
No
Yes
Yes
Yes
Yes
No
No
No
No
Yes
ALT≥3xULN
persist for
4 weeks or 
stopping 
criteria 
met
Yes
No
*INR value not applicable to subjects on anticoagulants
Yes
If subject to be monitored weekly must refer to Liver Safety Required  Actions and  Follow  up 
Assessments  section  in  the  Appendix
Must refer to Liver Safety Required Actions and Follow  up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 2, Section 12.2 and Section 12.3. 
5.4.1.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed.
5.4.2.
QTc Stopping Criteria

The same QT correction formula must be used for each individual subject to 
determine eligibility for and discontinuation from the study.  This formula may 
not be changed or substituted once the subject has been enrolled.

For example, if a subject is eligible for the protocol based on QTcB, then QTcB 
must be used for discontinuation of this individual subject as well.

Once the QT correction formula has been chosen for a subject’s eligibility, the 
same formula must continue to be used for that subject for all QTc data being 
collected for data analysis.  Safety ECGs and other non-protocol specified 
ECGs are an exception.  

The QTc should be based on single or averaged QTc values of triplicate ECGs 
obtained over a brief (e.g., 5-10 minutes) recording period.  
A subject who meets either of the bulleted criteria below will be withdrawn from the 
study:
 
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
QTc >500 msec OR Uncorrected QT >600 msec

Change from baseline of QTc >60 msec
5.5.
Stopping criteria based on Adverse Events
Any grade 3 or higher treatment-related adverse events that occur in ≥2 subjects will be 
carefully reviewed and if considered clinically significant, dosing will be halted pending 
further discussion with the FDA.  Any single treatment-related SAE will also trigger 
immediate evaluation and reporting processes in accordance with applicable regulations.
5.6.
Subject and Study Completion
A completed subject is one who has completed all phases of the study including the 
follow-up visit.
The end of the study is defined as the last subject’s last visit.
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.
Treatment
Product name:
GSK2838232 
Capsule (API)
Tybost 
(cobicistat, cobi) tablet
Formulation 
description:
GSK2838232 powder blend in a 
capsule
Tablet
Dosage form:
Swedish orange, unmarked 
capsules (50 mg), and white, 
unmarked capsules (10 mg)
Orange, round, biconvex, film-coated 
tablets debossed with “GSI” on one side 
and plain faced on the other side 
providing 150 mg of cobicistat.
Unit dose strength(s)/
Dosage level(s):
50 mg capsule for 200 mg, 100 mg, 
50 mg doses and 10 mg capsule for 
20 mg doses 
150 mg for 150 mg doses
Route/
Administration/
Duration:
Administered orally QD for 10 days
Administer orally, QD for 10 days
 
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Treatment
Product name:
GSK2838232 
Capsule (API)
Tybost 
(cobicistat, cobi) tablet
Dosing instructions:
Administer with light meal and 240 
mL of water. 
Administer with light meal and 240 mL 
water.
Manufacturer/
source of 
procurement:
GSK
Gilead
Method for 
individualizing dosage:
Capsules supplied in high-density 
polyethylene bottles for 
individualized dosing by the clinic
Tablets supplied in bulk containers for 
individualized dosing by the clinic
6.2.
Treatment Assignment
Subjects will be assigned to treatment (active) groups in accordance with the 
randomization schedule generated by Clinical Statistics, prior to the start of the study, 
using validated internal software.
6.3.
Planned Dose Adjustments
Following the interim analysis of safety, virology and PK data from the first cohort of 
subjects in Part A, the option to adjust dose levels from those described exists. No dose 
will be administered that has an associated projected mean AUC or Cmax value higher 
than the most conservative NOAEL obtained from the chronic toxicity studies (i.e., from 
the 9-month dog toxicity study described in Section 2.2.1).
6.4.
Blinding
This will be an open-label study. Treatment allocation and GSK2838232 dose levels in 
Part B will be determined after the analysis of Part A data.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.5.
Preparation/Handling/Storage/Accountability
A description of the methods and materials required for capsule/tablet storage and 
dispensing will be detailed in a Study Specific Technical Agreement/Memo or Pharmacy 
Manual, which will be accompanied by a Quality Agreement.
No special preparation of study treatment is required.

Only subjects enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment.  All study 
treatments must be stored in a secure environmentally controlled and monitored 
 
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(manual or automated) area in accordance with the labelled storage conditions 
with access limited to the investigator and authorized site staff. 

The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation and final disposition records).

Further guidance and information for final disposition of unused study treatment 
are provided in the study reference manual (SRM). 

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  

A Material Safety Data Sheet/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.
6.6.
Compliance with Study Treatment Administration
When subjects are dosed at the site, they will receive study treatment directly from the 
investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents.  The dose of study 
treatment and study subject identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study treatment.  
When subjects self-administer study treatment(s) at home, compliance with study 
treatment(s) will be assessed through querying the subject during the site visits and 
documented in the source documents and case report form (CRF).  A record of the 
number of study treatment(s) dispensed to and taken by each subject must be maintained 
and reconciled with study treatment and compliance records.  Treatment start and stop 
dates, including dates for treatment delays and/or dose reductions will also be recorded in 
the CRF.
6.7.
Treatment of Study Treatment Overdose
For this study, any dose of GSK2838232 >200 mg+cobicistat within a 28-hour time 
period will be considered an overdose.
GSK does not recommend specific treatment for an overdose; however, in the event of an 
overdose, the investigator or treating physician should:

Contact the Medical Monitor immediately

Closely monitor the subject for AEs/SAEs and laboratory abnormalities until 
GSK2838232 can no longer be detected systemically (at least 10 days for 
GSK2838232)

Obtain a plasma sample for PK analysis within 2 days from the date of the last dose 
of study treatment if requested by the Medical Monitor (determined on a case-by-case 
basis)
 
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
Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the subject.
6.8.
Treatment after the End of the Study
Subjects receiving GSK2838232 may opt to receive marketed antiretrovirals after the 
completion of 10 days of GSK2838232 dosing and study follow-up visits (through 
Day 21) eligible for sponsor company reimbursement up to a maximum of 90 days. The 
selection of antiretrovirals will be investigator-chosen.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing 
reimbursement for post-study treatment.
6.9.
Lifestyle and/or Dietary Restrictions
6.9.1.
Meals and Dietary Restrictions

Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit juice 
from 7 days prior to the first dose of study medication until after the final dose.

Doses will be given in the fed state (light breakfast), following overnight fasting 
(>10 hours). 
6.9.2.
Alcohol, Caffeine and Exercise

During  the study  alcohol consumption should be limited to the following:

An average weekly intake of <14 drinks for males or <7 drinks for females.  One 
drink is equivalent to 12 g of alcohol: 12 ounces (360 mL) of beer, 5 ounces 
(150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.

Subjects should abstain from strenuous exercise during the treatment period.
6.10.
Contraception
Female subjects can be of childbearing or non-child bearing potential.  
Females of reproductive potential may only be enrolled if they are using two forms of 
complementary contraception, which must include one barrier method.  Although use of 
oral contraceptives is permitted, there is no definitive DDI information with 
GSK2838232 and an interaction with oral contraceptives is possible, so other (barrier, 
inter-uterine device etc.) methods of contraception will be required.
Females of reproductive potential, who have an established, long-term lifestyle of sexual 
abstinence, or only same sex partners, require no other means of birth control.  
Male subjects with female partners of child bearing potential must comply with the 
following contraception requirements from the time of first dose of study medication 
until one week after the last dose of study medication:
 
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1. Vasectomy with documentation of azoospermia. The documentation on male 
sterility can come from the site personnel’s review of subject’s medical records, 
medical examination and/or semen analysis, or medical history interview.
OR
2. Male condom plus partner use of one of the contraceptive options below that 
meets the SOP effectiveness criteria including a <1% rate of failure per year, as 
stated in the product label:
- Contraceptive subdermal implant
- Intrauterine device or intrauterine system
- Combined estrogen and progestogen oral contraceptive 
- Injectable progestogen
-Contraceptive vaginal ring 
- Percutaneous contraceptive patches 
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
6.11.
Concomitant Medications and Non-Drug Therapies
6.11.1.
Permitted Medications and Non-Drug Therapies

Acetaminophen at doses of 2 grams/day or NSAIDs are permitted for use any time 
during the study and their use documented in the CRF.  Other concomitant 
medication may be considered on a case by case basis by the investigator in 
consultation with the Medical Monitor if required.

Concomitant medications (prescription and non-prescription) should be administered 
only as medically necessary during the study. Subjects must notify their Investigator 
of any current or proposed concomitant medication, whether prescribed or over-the-
counter, because of the potential for interactions between such treatments and the 
study medications.
6.11.2.
Prohibited Medications and Non-Drug Therapies

Subjects must refrain from all illicit drugs throughout the study (from Screening until 
discharge from the study).  Drug screening will occur at Screening and Day -1 and at 
additional timepoints throughout the study.  A positive result will lead to exclusion 
from the remainder of the study.
7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table (Section 7.1), are essential and required for study 
conduct.
 
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This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table Section 7.1. In 
overview, subjects will be screened, begin dosing and then continue assessments through 
and for up to 2 weeks after the completion of dosing.
The following points must be noted: 

If assessments are scheduled for the same nominal time, THEN the assessments 
should occur in the following order:
1.12-lead ECG
2. vital signs
3. blood draws.  
Note: The timing of the assessments should allow the blood draw to occur at the 
exact nominal time.
 
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7.1.
Time and Events Table
Day:
Screen1
Random
1
2
3
4
5
62
7
8
9
10
11
12
141
211 
(FU)
ET
Informed Consent
X
Review inclusion/exclusion
X
X
Demography including height, weight 
and BMI
X
Brief physical
X
Medical/medication/
drug/alcohol history
X
X
CDC Classification
X
X
X
X
Prior antiretroviral therapy
X
12-lead ECG3
X
X
X
X
X
X
X
X
X
Holter (24 hr)
X
Vital signs4
X
X
X
X
X
X
X
X
X
Drug screen
X
X
X
X
X
Hepatitis B Surface antigen and 
hepatitis C antibody testing
X
Serum or urine -hCG (WoCBP only)
X
X
X
Clinical lab tests (inc troponin)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Fasting lipid panel
X
X
AE assessment5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Con Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HIV-1 RNA PCR6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lymphocyte subsets7
X
X
X
Plasma for genotype/phenotype8
X
X
X
X
X
X
X
HIV-associated conditions assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK blood sample9
X
X
X
X
X
X
X
X
X
X
X
X14
Plasma samples10
X
X
X
Dosing11
X
X
X
X
X
X
X
X
X
X
PGx12
X
 
 
 
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Day:
Screen1
Random
1
2
3
4
5
62
7
8
9
10
11
12
141
211 
(FU)
ET
Telephone call to IVRS13
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Plasma for storage15
X
X
X
X
X
X
X
X
X
X
X
X
X
Outpatient visit
X
X
X
X
X
X
X
X
X
X
X
X
1.
Screening will occur within 14 - 30 days prior to the first dose of study drug.
2.
Table is set up for the weekend during dosing to occur on Days 6 and 7.  If the weekend occurs on Days 5 and 6, perform all “Day 5” assessments on Day 7.
3.
On Day 1, ECGs will be performed pre-dose , and then 1, 1.5, 2, 3, 4 and 6 hours post dose.  The ECGs should be performed at least 5 minutes apart and preferably within 1 
hour prior to dose.  On Days 4 and 8, ECGs will be obtained prior to morning dosing and at 2, 4 and 6 hours post-dose. To accommodate scheduling, serial ECGs collected on 
Days 4 and 8 may be performed 1 day. On Day 10, ECGs will be performed pre-dose, and then 1, 1.5, 2, 3, 4 and 6 hours post dose.  On Day 11, an ECG will be obtained 
prior to the 24-hour PK sample. ECGs will be performed in triplicate at all timepoints. 
4.
BP, RR, HR and temperature will be obtained at Screening (x1) and Day 1 pre-dose (x2).  BP and HR will be obtained on Day 1 at 2 hours post-morning dose and on Days 4, 5 
and 8 pre-dose.  BP and HR will be obtained on Day 10 at pre-dose and 2 hours post-morning dose, and at day 12 and Follow-up (Day 21).
5.
Only SAEs related to study participation will be collected between screening and Day 1. An AE enquiry will be made at each visit, subjects will be asked if they have 
experienced any neuropsychiatric adverse events, including psychosis or altered mental status.
6.
On Days 1-5 and 8-10 samples for HIV-1 RNA PCR collected before morning dose.  On Days 1, 10 and 11 two samples for HIV-1 RNA PCR will be collected 5-30 minutes 
apart.  HIV-1 RNA PCR samples will also be collected on days 12, 14 & Follow-up (Day 21).
7.
Lymphocyte subsets by flow cytometry (total lymphocyte counts, percentage, and absolute CD4+and CD8+counts).
8.
Blood samples for phenotype and genotype will be collected at pre-dose on Days 1, 4, 5 and 8 in the morning on Day 11 and at follow-up. 
9.
Serial plasma samples (2 mL) for determination of GSK2838232 will be collected on Day 1 and Day 10 at pre dose (within 15 minutes prior to dose) and 0.5, 1, 1.5, 2, 3, 4, 6, 
8, 12 (optional), and 24 hours (to occur on morning of Day 2 post-am dose and in the morning on Day 11) .  Pre-dose PK samples (within 15 minutes prior to dose) will be 
taken on the mornings of Days 3, 4, 5, 8 and 9 and a single sample will be taken on Days 12 and 14.
10. Samples (2 x 0.5mL) of plasma for assessment of immunological markers at screen, baseline (pre-dose) and day 11 
11. Subjects will receive a single dose of GSK2838232 and cobicistat each morning with a light breakfast meal and 240 mL of water from Day 1 to Day 10.  Doses taken in the 
clinic will be administered after an overnight fast of at least 10 hours .On Days 6 and 7, doses will be self administered but confirmed by phone 
12. PGx sample should be collected on Day 1.
13. A screening/registration call should be made to the IVRS to register the subject at screening.   An additional call will be made to document a screen failure.   A randomization 
call should be made to the IVRS system approximately one week prior to scheduled Day 1.  Note: The randomization call must be made in order to have study drug on site for 
Day 1. Additional calls will be made every day that the subject has a scheduled study visit to the clinic.  If a subject terminates the study prematurely a call should be made to 
the IVRS
14. Only if early termination visits occur during the treatment period.
15. Plasma samples for storage will be collected at each visit starting at Day 1, including unscheduled visits (e.g. for HIV-1 RNA levels and immunological parameters).  
Additionally these samples will be used when needed, such as when samples are lost or arrive at the laboratory unevaluable.
AE = Adverse event; CDC= Center for Disease Control and Prevention; ECG = Electrocardiogram; ET = Early termination; hCG = Human chorionic gonadotrophin; HIV = Human 
immunodeficiency virus;  IVRS= Interactive Voice Response System; PCR = Polymerase chain reaction; PK=Pharmacokinetic.
 
 
 
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7.2.
Visit Windows
Screening (baseline to pre-dose): All screening assessments should take place within 
14-21 days prior to the first dose. The screening visit window may be extended to 30 
days upon discussion with the Medical Monitor (i.e.; subject has scheduling conflicts or 
any screening assessment needs to be repeated).
Days 4 and 8: Based on subject and clinic schedule, Day 4 and Day 8 serial (up to 6h 
post-dose) ECG assessments may be conducted 1 day. 
Weekend(s): The T&E table is set up for study start (Day 1) to occur on a Monday and 
Days 6 and 7 to fall on the weekend. If the weekend occurs instead on Days 5 and 6, Day 
5 assessments should be performed on Day 7. The study start (Day 1) may also be 
adjusted to allow visits with assessments to be conducted over the weekend based on 
subject and clinic schedule.  
Assessments: The following applies to timing of procedures:
-
Window for assessments 4 h post-dose = 5 minutes 
-
Window for assessments >4 and < 12 h post-dose = 15 minutes
-
Window for assessments >12 h post-dose = 30 minutes
End of Treatment visit: should be within 14 days from last dose of study drug. If a 
subject is unable to return to the clinic for any reason site staff are encouraged to 
telephone the subject for assessment of adverse events.
7.3.
Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed at 
screening.
The following demographic parameters will be captured: year of birth, sex, race, and 
ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria.
Procedures conducted as part of the subject’s routine clinical management (e.g., blood 
count) and obtained prior to signing of informed consent may be utilized for Screening or 
baseline purposes provided the procedure meets the protocol-defined criteria and has 
been performed in the timeframe of the study.
7.3.1.
Holter Monitoring (Screening criteria)
The 24-hour Holter monitoring will be performed during the Screening period using a 
Holter monitoring device supplied by the Sponsor.
 
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Analysis of the Holter tapes will consider the following:

Heart rate (bradycardia and tachycardia)

Normal and aberrant beats

Number of supraventricular contractions, premature atrial contractions, premature 
ventricular contractions, couplets, triplets, and ventricular tachycardias

Atrio-ventricular conduction defects

Atrial fibrillation and flutter
7.4.
Efficacy
7.4.1.
HIV-1 RNA Sampling
Plasma for quantitative HIV-1 RNA will be collected at timepoints listed in the Time and 
Events Table in Section 7.1. To reduce sample variability, two plasma HIV-1 RNA 
samples will be collected on Days 1, 10, and 11.
An HIV-1 RNA PCR assay with a lower limit of detection (LLOD) of 50 copies/mL 
(ultrasensitive assay) will be used for post-baseline assessments. An HIV-1 RNA PCR 
assay with a LLOD of 400 copies/mL (standard assay) will be used for screening and 
baseline assessments and will include a re-test with and ultrasensitive assay for all 
baseline values below the LLOD. An HIV-1 RNA PCR assay with a LLOD of 2 
copies/mL (supersensitive assay) may be used for exploratory analysis.
7.4.2.
Lymphocyte Subsets by Flow Cytometry
Whole venous blood samples will be obtained from each subject for the analysis of 
lymphocyte subsets by flow cytometry at the timepoints listed in the Time and Events 
Table in Section 7.1.
Details concerning the handling, labeling and shipping of these samples will be supplied 
separately.
7.5.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).  Additional time points for safety tests (such as vital signs, physical exams 
and laboratory safety tests) may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring.
7.5.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 5, Section 12.5.
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
 
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7.5.1.1.
Time period and Frequency for collecting AE and SAE information

AEs and SAEs will be collected from the start of Study Treatment until the 
follow-up contact (see Section 7.5.1.3), at the timepoints specified in the Time 
and Events Table (Section 7.1). An AE enquiry will be made at each visit, where 
subjects will be specifically asked if they have experienced any neuropsychiatric 
adverse events, including psychosis or altered mental status  

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF.

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded from the time a subject consents to participate in the 
study up to and including any follow-up contact. 

All SAEs will be recorded and reported to Sponsor within 24 hours, as indicated 
in Appendix 5, Section 12.5.

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the 
investigator must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 5
7.5.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?”

“Have you experienced any alteration in personality, behaviour, mood or any 
altered mental status?”
7.5.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, and non-serious AEs of special interest 
(as defined in Section 12.5) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
 
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(as defined in Section 5.4). Further information on follow-up procedures is given in 
Appendix 5.
7.5.1.4.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 5 (Section 12.5.3) and all deaths, 
whether or not they are considered SAEs, specific CV and Death sections of the CRF will 
be required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed 
within one week of when the death is reported.
7.5.1.5.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
The following disease-related events (DREs) are common in subjects with HIV-1 
infection and can be serious/life threatening:

events or outcomes listed in the CDC Classification System for HIV-1 Infections 
(see Appendix 9; Section 12.8)

sign, symptom, diagnosis, illness, and/or clinical laboratory abnormality that can 
be linked to any of these events or outcomes
Because these events are typically associated with the disease under study, they will not 
be reported according to the standard process for expedited reporting of SAEs to GSK 
(even though the event may meet the definition of a serious adverse event). 
These events will be recorded on the DRE page in the subject’s CRF using the HIV 
Associated Conditions eCRF. These DREs will be monitored by the medical monitor and 
study team on routine basis.
However, if any of the following conditions apply, then the event should be reported as 
an SAE using the standard process:

The event is, in the Investigator’s opinion, of greater intensity, frequency, or 
duration than expected for the individual subject, 
or

The Investigator considers that there is a reasonable possibility that the event was 
related to treatment with the investigational product.
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
Death occurring for any reason during a study, including death due to a disease 
related event, will always be reported promptly. 
If either of the above conditions is met then record the DRE on the SAE page rather than 
the HIV Associated Conditions eCRF page and report promptly to GSK.
7.5.1.6.
Regulatory Reporting Requirements for SAE
Prompt notification by the investigator to GSK or designee of SAEs and non-serious AEs 
related to study treatment (even for non- interventional post-marketing studies) is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a product under clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.5.2.
Pregnancy

Details of all pregnancies in female subjects and if indicated female partners of 
male subjects will be collected after the start of dosing and until one week post 
study

If a pregnancy is reported then the investigator should inform GSK within 24hrs 
of learning of the pregnancy and should follow the procedures outlined in 
Appendix 7, Section 12.6.
7.5.3.
Physical Exams

A complete physical examination will include, at a minimum, assessment of the 
Cardiovascular, Respiratory, GI 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 should pay special attention to clinical signs related to previous 
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7.5.4.
Vital Signs

Vital signs will be measured in semi-supine position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure and pulse rate 

Three readings of blood pressure and pulse rate will be taken

First reading should be rejected

Second and third readings should be averaged to give the measurement to be 
recorded in the CRF. 
7.5.5.
Electrocardiogram (EGC)

Triplicate 12-lead ECGs will be obtained at each timepoint during the study using 
an ECG machine that automatically calculates the heart rate and measures PR, 
QRS, QT, and QTc intervals.  Refer to Section 5.4.2 for QTc withdrawal criteria 
and additional QTc readings that may be necessary.
7.5.6.
Clinical Safety Laboratory Assessments
All protocol-required laboratory assessments as defined in the Tables below must be 
conducted in accordance with the SRM and Protocol Time and Events Schedule (Section 
7.1). Laboratory requisition forms must be completed and samples must be clearly 
labelled with the subject number, protocol number, site/centre number, and visit date.
Details for the preparation and shipment of samples will be provided by the laboratory 
and are detailed in the SRM. Reference ranges for all safety parameters will be provided 
to the site by the laboratory responsible for the assessments.
If additional non-protocol-specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the CRF.
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
All study-required laboratory assessments will be performed by a central laboratory:
NOTE:  Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either a treatment and/or response evaluation to be 
performed. 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 treatment or response evaluation, the results must be entered in the CRF.
 
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Haematology, clinical chemistry, urinalysis, and additional parameters to be tested are 
listed below. 
Table 9
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
WBC count with Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes with T-cell 
subsets
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry 1
BUN
Potassium
AST (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose 
Bicarbonates
Alkaline phosphatise
Albumin
Troponin I
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

HIV

Hepatitis B (HBsAg)

Hepatitis C (Hep C antibody)

FSH and estradiol (as needed in women of non-child bearing 
potential only)

Alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines)

Urine hCG Pregnancy test (as needed for women of child bearing 
potential) 2
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 12.2 and Section 12.3
2.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or 
ethics committee.
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study or within 7 days after the last dose of study treatment 
should be repeated until the values return to normal or baseline.  If such values do not 
return to normal within a period judged reasonable by the investigator, the etiology
should be identified and the sponsor notified.
 
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7.6.
Pharmacokinetics
7.6.1.
Blood Sample Collection
Blood samples for analysis of GSK2838232 concentrations will be collected at the time 
points indicated in Time and Events Tables (Section 7.1).  
The actual date and time of each blood sample collection will be recorded.  The timing of 
PK samples may be altered and/or PK samples may be obtained at additional time points 
to ensure thorough PK monitoring.  
Details of PK blood sample collection (including volume to be collected), processing, 
storage and shipping procedures are provided in the Study Reference Manual (SRM).
7.6.2.
Sample Analysis
Plasma analysis will be performed by Covance, Madison under the control of 
Bioanalysis, Immunogenicity and Biomarkers (BIB), PTS, GlaxoSmithKline.
Concentrations of GSK2838232 will be determined in plasma using the currently 
approved bioanalytical methodology. 
Once the plasma has been analyzed for GSK2838232 any remaining plasma may be 
analyzed qualitatively for other circulating metabolites and these results would be 
reported under a separate PTS protocol.
Raw data will be archived at the Covance, Madison facility.
7.7.
Biomarker(s)/Pharmacodynamic Markers
7.7.1.
Viral Genotyping and Phenotyping
Whole venous blood samples will be obtained from each subject to provide plasma for 
viral genotype and phenotype analysis, at the times listed in the Time and Events Table in 
Section 7.1. Details concerning the handling, labeling and shipping of these samples will 
be supplied separately.
Genotypic and phenotypic analyses will be carried out by Monogram Biosciences using 
their GAG/PR and PR/RT formats, in which PCR amplification is used to generate HIV 
cDNA products including the Gag and the PR and RT coding regions, respectively. 
Phenotypic analyses of the GAG/PR region will include susceptibility to GSK2838232 . 
Analysis will be done on Day 1 and Day 11 samples.  In the case of rebound HIV-1 viral 
load, analysis will be completed on samples corresponding to time point of rebound 
occurrence. 
7.8.
Genetics
Information regarding genetic research is included in Appendix 4, Section 12.4.
 
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7.9.
Value Evidence and Outcomes
Not required.
8.
DATA MANAGEMENT

For this study subject data will be entered into GSK defined CRFs, transmitted 
electronically to GSK or designee and combined with data provided from other 
sources in a validated data system, 

Management of clinical data will be performed in accordance with applicable 
GSK standards and data cleaning procedures to ensure the integrity of the data 
(e.g., removing errors and inconsistencies in the data).

Adverse events and concomitant medications terms will be coded using MedDRA 
and an internal validated medication dictionary, GSKDrug.  

CRFs (including queries and audit trails) will be retained by GSK, and copies will 
be sent to the investigator to maintain as the investigator copy.  Subject initials 
will not be collected or transmitted to GSK according to GSK policy.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
The primary objectives of this study are to investigate the safety, tolerability, and 
antiviral activity of GSK2838232 administered as monotherapy in combination with 
cobicistat in HIV-1 infected subjects, over a 10 day treatment period. The antiviral 
activity will be assessed by estimating plasma HIV-1 RNA max change from baseline 
during the study. 
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
The sample size for this study is based primarily on feasibility to provide adequate 
precision for the estimations.
Based on data from the short term monotherapy study of BMS-955176 PoC (AI468002) 
study and assuming viral load values for individual subjects follow a log-normal 
distribution, 1000 trial simulations in Fixed and Adaptive Clinical Trial Simulation 
(FACTS) software were conducted from the distribution with mean of change from 
baseline viral load drop on log scale at 1.0 to 1.5 copies and SD=0.4 and sample sizes=10 
for Part A.  Using Bayesian calculation with non-informative priors for the mean and 
weakly informative priors for the error parameters, Normal (0, 100) for mean and Inverse 
Gamma (0.35, 0.0875) for error parameters, the posterior probability to achieve a 
cutpoint 1.2 log was calculated for each simulated trial, and percentage of the trials with 
 
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posterior probability of viral load<-1.2log drop given true mean) ≥70% were calculated 
and are shown below in Table 10.
Table 10
Percentage of the trials with posterior probability>=70% for Part A
True Mean
Cutpoint
Posterior Prob>=70%
1.0
1.2
1.4%
1.1
1.2
9%
1.2
1.2
29%
1.3
1.2
59%
1.4
1.2
83%
1.5
1.2
96%
An Emax model with functional uniform priors [Bornkamp, 2014] was conducted using 
simulated data combining Part A and Part B with all doses. Success is defined as a 
posterior probability of the highest dose to achieve a cutpoint 1.2 log reduction in viral 
load.   This was calculated for each simulated trial and the percentage of the trials with 
posterior probability greater or equal to 70% were also calculated and are shown below 
(Table 11). The table lists different viral load drop scenarios. The last scenario assumes 
the flat drop for all doses are 0.5.  This scenario reflects the null hypothesis of no 
treatment effect. In this scenario 0% of the trials achieve the pre-specified decision rule 
for success.
Table 11
Percentage of the trials with posterior probability ≥70%
Cutpoint
Posterior Prob≥
Part A+ Part B 
mean VL drop for doses 200, 
100, 50, 20
Part A+ Part B
1.2
70%
1.5, 1.4, 1.2, 0
99%
1.5, 1.4, 1.2, 0.5
96%
1.5, 1.4, 1.0, 0.5
93%
1.5, 1.3, 1.2, 0.5
86%
0.5, 0.5, 0.5, 0.5
0%
9.2.2.
Sample Size Sensitivity
Similar simulations in FACTS were conducted from the distribution with mean of change 
from baseline viral load drop on log scale at 1.5 copies and SD=0.4 or 0.6 and sample 
sizes of 6-8 or 10 for Part A.  Using Bayesian calculation, the posterior probability to 
achieve a cutpoint 1.2 log (in Table 12) was calculated for each simulated trial, and 
percentage of the trials with posterior probability greater than or equal to 70% was 
calculated and are shown below.
 
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Table 12
Percentage of the trials with posterior probability ≥70% for Part A
True 
Mean
Cutpoint
Posterior 
Prob≥
Std for log10 
VL
N=6 
N=8
N=10
1.5
1.2
70%
0.4
90%
94%
96%
0.6
75%
81%
84%
9.2.3.
Sample Size Re-estimation or Adjustment
No sample size re-estimation will be performed.
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
Intent to Treat Exposed Population (ITT)
The ITT-Exposed Population is defined as all subjects who meet study criteria and are 
enrolled into the study with documented evidence of having received at least 1 dose of 
treatment and at least one post-baseline HIV-1 RNA measurement. This will be the 
primary population for the final efficacy analysis for all active treatment groups.
Per Protocol Population (PP)
The Per Protocol Population is defined as all subjects who meet study criteria and are 
enrolled into the study with documented evidence of having received all doses and all 
post-baseline HIV-1 RNA measurement, with exceptions of major protocol deviation. 
Safety Population
The Safety Population is defined as all subjects who are enrolled into the study with 
documented evidence of having received at least 1 dose of randomized treatment.
Pharmacokinetic Population
The PK Population will include all subjects who receive GSK2838232 and undergo 
plasma PK sampling during the study. Subjects for whom a plasma PK sample is 
obtained and assayed will be included in the listing of plasma GSK2838232 
concentration-time data.  Results from samples collected from a subject with emesis 
occurring within 4 hours of the dose will not be considered as evaluable.
9.3.2.
Interim Analysis
An interim analysis of preliminary safety, tolerability, PK and antiviral activity will occur 
after subjects of Part A Cohort 1 complete their Day 13 visit. If the Cohort 1 dose is 
determined to be the highest dose based on this review (e.g., the exposure level of 
GSK2838232 is in the range of the maximum GSK2838232 exposure seen previously in 
healthy subjects), the Bayesian posterior probability that the log10 viral load decline from 
baseline is greater than a cut-point will be calculated. If the Bayesian probability from 
Cohort 1 is less than 70%, this will provide evidence to not move forward into Part B. 
Otherwise, the study team will review the data in order to make a dose selection decision 
for the subsequent Part B Cohorts.  If the pharmacokinetic exposures after the 100 mg 
GSK2838232/cobi dose look similar to those obtained with 100 mg GSK2838232/r in 
 
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prior studies, the doses for Part B will be extended to both lower (20 mg, 50 mg) and 
higher (200 mg) GSK2838232 doses.
Maximum change and change from baseline in plasma HIV-1 RNA will be summarized 
by treatment or by assessment day. The proportion of subjects with plasma HIV-1 RNA 
<400 and <50 copies/mL will be summarized by treatment and assessment day. The 
analyses will be done for both PP and ITT exposed population if the two populations are 
not the same. 
9.4.
Key Elements of Analysis Plan
9.4.1.
Primary Analyses
The final analysis will be performed after the completion of the study and final datasets 
authorization. Data will be listed and summarized according to GlaxoSmithKline 
reporting standards, where applicable. Listings will be sorted by subject, period, 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, geometric mean with 
associated 95% confidence interval (CI), and %CVb for continuous variables, whereas n 
and percent will be used as summary statistics for categorical variables. Baseline or pre-
dose 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 9.1 or higher 
of the SAS system will be used to analyze the data as well as to generate tables, figures, 
and listings. Complete details will be documented in the Reporting and Analysis Plan 
(RAP).
9.4.1.1.
Safety Analyses
Safety data will be presented in tabular format and summarized descriptively according to 
GSK’s Integrated Data Standards Library standards and data will be in CDISC format. 
No formal statistical analysis of the safety data will be conducted. 
9.4.1.2.
Efficacy Analyses
Both the PP and ITT Populations will be used for all efficacy analyses if there are 
dropouts.  Plasma HIV-1 RNA max change and change from baseline during the study 
will be calculated for each subject on each assessment day.
Plasma HIV-1 RNA will be listed by treatment, subject, and assessment day and 
summarized by treatment and assessment day along with change from baseline.
Plots of mean and median plasma HIV-1 RNA actual and change from baseline data will 
be generated by treatment and assessment day.

Plasma HIV-1 RNA change from baseline to the on-treatment nadir (maximum 
change) will be calculated for each subject and summarized by treatment.
 
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Together, the data from Parts A and B will investigate the complete dose-response curve 
and the impact of lower doses on potential development of resistance. A dose-response 
curve will be fit to the data from Parts A & B using functional uniform priors.  
9.4.1.3.
Pharmacokinetic Analyses
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacokinetics 
Modeling and Simulation Department, GlaxoSmithKline. Plasma GSK2838232 
concentration-time data will be analyzed by non-compartmental methods with 
WinNonlin Version 6.1 or higher. Calculations will be based on the actual sampling 
times recorded during the study. From the plasma concentration-time data, the following 
pharmacokinetic parameters will be determined, as data permit:
Plasma GSK2838232 Pharmacokinetic Parameters to be Estimated:
Study Day
Parameters
1
AUC(0-24), Cmax, tmax, tlag, C24
10
AUC(0-), Cmax, tmax, t½, C0, C, CL/F, R_AUC, R_Cmax, R_C
Results based on samples collected from a subject with emesis within 4 hours of the dose 
will not be considered as evaluable.
All PK data will be stored in the R&D archives, GlaxoSmithKline.
Statistical analyses of the pharmacokinetic parameter data will be the responsibility of 
Clinical Statistics, GlaxoSmithKline. Details of the statistical analyses will be provided in 
the RAP. An outline is provided below:
Pharmacokinetic data will be presented in graphical and tabular form and will be 
summarized descriptively. Plasma GSK2838232 PK parameters, with the exception of 
tmax and tlag, will be log-transformed prior to analysis.
Dose proportionality of plasma GSK2838232 PK parameters from Day 1 [AUC(0-24) 
and Cmax] and Day 10 [AUC(0-τ) and Cmax] will be assessed using a power model if 
multiple dose levels are assessed. The power model will be fitted by restricted maximum 
likelihood (REML) using SAS Proc Mixed. A fixed effects power model will be used. 
The mean slope will be estimated from the power model with the corresponding 90% CI. 
The accumulation ratio (R) and steady-state assessments will be performed, if quality of 
the data permits. Comparisons of Day 10 with Day 1 PK for each dose will be used for 
the accumulation ratio (R) evaluation. Pre-dose concentrations between Days 7-10 will be 
used for steady-state assessment. 
9.4.2.
Secondary Analyses
9.4.2.1.
Pharmacokinetic/Pharmacodynamic Analyses
Relationships between various PK parameters (e.g., AUC, Cmax, Cτ, etc.) and PD 
measures (e.g., log10 reduction from baseline in plasma HIV-1 RNA on Day 11 or safety 
 
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parameters) will be explored using various models including Emax. The relationship 
between dose and PD measures will also be explored. Details of the PK/PD exploratory 
analyses will be provided in the RAP.
9.4.2.2.
Viral Genotyping and Phenotyping Analyses
Viral genotypic/phenotypic data will be listed and descriptive summaries will be 
provided. Details of the analyses will be provided in the clinical virology report.
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

Obtaining signed informed consent

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, 
or both.

Signed informed consent must be obtained for each subject prior to participation 
in the study

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  
 
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
Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, 
written approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors or designee will contact the site prior to the start of the study to 
review with the site staff the protocol, study requirements, and their 
responsibilities to satisfy regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the CRF will 
serve as the source document.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
10.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and 
the regulatory agencies may conduct a regulatory inspection at any time during or 
after completion of the study. 

In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss 
the conduct of the study, any findings/relevant issues and to implement any 
corrective and/or preventative actions to address any findings/issues identified.
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor or 
designee will conduct site closure activities with the investigator or site staff, as 
appropriate, in accordance with applicable regulations including GCP, and GSK 
Standard Operating Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this 
study at any time for reasons including, but not limited to, safety or ethical issues 
or severe non-compliance. For multicenter studies, this can occur at one or more 
or at all sites.  
 
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
If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable).  When feasible, GSK will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.  

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical 
institution (where applicable) must maintain all site study records (except for 
those required by local regulations to be maintained elsewhere), in a safe and 
secure location.  

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review 
in conjunction with assessment of the facility, supporting systems, and relevant 
site staff.  

Where permitted by local laws/regulations or institutional policy, some or all of 
these records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.  

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, 
including re-generating a hard copy, if required.  Furthermore, the investigator 
must ensure there is an acceptable back-up of these reproductions and that an 
acceptable quality control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by 
any institutional requirements or local laws or regulations, GSK 
standards/procedures, and/or institutional requirements.  

The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of 
ownership of the records in the event the investigator is no longer associated with 
the site.
 
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10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.
10.8.
Review Committees
The Safety Review Team (SRT) is a GSK cross-functional team reviewing all available 
safety data related to the project, including in-stream data from this study, in an ongoing 
manner. The SRT is an internal GSK requirement put in place to ensure holistic 
evaluation of the safety profile of an investigational product with systematic, periodic and 
documented reviews of available safety data, with the appropriate communication and 
escalation of new findings that have the potential to impact patient safety
 
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11.
REFERENCES
Bloch M, Bodsworth N, Fidler M, Workman C, Balach A, Byakagwa H, et al. Efficacy, 
safety and pharmacokinetics of MPC-4326 (bevirimat dimeglumine) 200mg BID and 
300mg BID monotherapy administered for 14 days in subjects with HIV-1 infection. 
ICAAC. 2009; Abstract H-1230.
Bornkamp B, Practical considerations for using functional uniform prior distributions for 
dose-response estimation in clinical trials. Biometrical Journal 56 (2014) 6, 947-962
Cockcroft DW, Gault MH. Prediction of creatinine clearance form serum creatinine. 
Nephron. 1976;16:31-41.
Dang Z, Huang L, Chen C. HIV-1 maturation inhibitors:  An update. Drugs of the Future. 
2009;34 (10):797-802.
Elion R, Cohen C, Gathe J, Shalit P, Hawkins T, Liu HC, et al.  Phase 2 study of 
cobicistat versus ritonavir each with once-daily atazanavir and fixed-dose 
emtricitabine.tenofovir df in the initial treatment of HIV infection.  AIDS.  2011; 
25:1881-1886.
Food and Drug Administration (FDA). Guidance for industry: Estimating the maximum 
safe starting dose in initial clinical trials for therapeutics in adult healthy subjects. CDER, 
Rockville, MD; 2005. UCM078932.
Food and Drug Administration (FDA). Guidance for Industry: Human Immunodeficiency 
Virus-1 Infection: Developing Antiretroviral Drugs for Treatment. CDER, Rockville, 
MD; 2015. UCM355128.
Gallant JE, Koenig E, Andrade-Villaneuva J, Chetchotisakd P, deJesus E, Antunes F, 
Arastéh K,  et al.  Cobicistat versus ritonavir as a pharmacoenhancer of atazanavir plus 
emtricitabine/tenofovir disoproxil fumarate in treatment-naïve HIV type 1-infected 
patients:  week 48 results.  J. Infect. Dis.  2013; 208-:32-39.
GlaxoSmithKline Document Number 2012N151889_03 Compound GSK2838232. 
Investigator’s Brochure.  Effective November 2016.
GlaxoSmithKline Non-Clinical Research report. Document Number 2013N163221_00.
Hatcher RA, Trussel J, Nelson AL, Cates W, Stewart F, Kowal D, editors. Contraceptive 
Technology. 19th ed. New York:Ardent Media; 2007. 
Kakuda TN, Opsomer M, Timmers M, Iterbeke K, Van De Casteele T, Hillewaert V, et 
al.  Pharmacokinetics of darunavir in fixed-dose combination with cobicistat compared 
with coadministration of darunavir and ritonavir as single agents in healthy volunteers.  J. 
Clin. Pharmacol.  2009; 54:949-957.
 
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Lalezari J, McCallister S, Gigliotti M, Cohen C, Elion R, Brinson C, et al. Safety and 
efficacy study of bevirimat (BVM) in heavily treatment experienced HIV+ patients 
identifies the target phase 3 study profile. ICAAC. 2008; Abstract: H891. 
Mahmood I. Prediction of human drug clearance from animal data. Application of the 
rule of exponent and fu corrected intercept method (FCIM). J Pharm Sci. 
2006;95:1810-21. 
Martin D, Galbraith H, Ellis C, Schettler J and Doto J. Minimal effect of ritonavir (RTV) 
on the pharmacokinetics of bevirimat in healthy volunteers [abstract]. IAS Conference on 
HIV Pathogenesis, Treatment and Prevention. 2007; Abstract no. WEPEB015:Poster 
discussion.
Martin DE, Blum R, Doto J, Galbraith H, Ballow C. Multiple-dose pharmacokinetics and 
safety of bevirimat, a novel inhibitor of HIV maturation, in healthy volunteers. Clin 
Pharmacokinet. 2007(a);46(7):589-98.
Martin DE, Blum R, Wilton J, Doto J, Galbraith H, Burgess GL, et al. Safety and 
pharmacokinetics of bevirimat (PA-457), a novel inhibitor of human immunodeficiency 
virus maturation, in healthy volunteers. Antimicrobial Agents and Chemotherapy. 
2007(b);Sep:3063-6.
Martin DE, Galbraith H, Schettier J, Ellis C, Doto J. Pharmacokinetic properties and 
tolerability of bevirimat and atazanavir in healthy volunteers:  An open-label, parallel-
group study. Clinical Therapeutics. 2008;30(10):1794-1805.
NORVIR (ritonavir) Product Information. January, 2013.
Nowicka-Sans B, Protack T, Lin Z, Li Z, Zhang S, Meanwell N, et al. BMS-955176: 
Characterization of a second-generation HIV-1 maturation inhibitor. 8th IAS Conference 
on HIV Pathogenesis, Treatment and Prevention, July 19-22, 2015, Vancouver, Canada.
Qian K, Morris-Natschke SL, Lee KH. HIV entry inhibitors and their potential in HIV 
therapy. Medicinal Research Reviews. 2009;29(2):369-93.
Saxena SK, Gupta A, Bhagyashree K, Saxena R, Arora N, Banerjee AK, et al. Targeting 
strategies for human immunodeficiency virus: A combinatorial approach. Min Rev Med 
Chem. 2012;12(3):236-54.
TYBOST (cobicistat) Product Information. 2012
Wainburg MA, Albert J. Can the further clinical development of bevirimat be justified?. 
AIDS. 2010;24:773-4.
 
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
g/mL
Microgram per millilitre
ABC
Abacavir
AE
Adverse Event
AIDS
Acquired immunodeficiency syndrome
ALT
Alanine aminotransferase
API
Active Pharmaceutical Ingredient
ART
Antiretroviral therapy
AST
Aspartate aminotransferase
AUC
Area under the plasma concentration time curve
AUC(0-)
Area under the concentration-time curve from time zero 
(pre-dose) extrapolated to infinite time
AUC(0-)
Area under the concentration-time curve over the dosing 
interval 
AUC(0-24)
Area under the concentration-time curve from zero (pre-
dose) to 24 h
AUC(0-48)
Area under the concentration-time curve from zero (pre-
dose) to 48 h
AUC(0-t)
Area under the concentration-time curve from zero (pre-
dose) to time of last quantifiable concentration
BCRP
Breast cancer resistance protein
BID
Twice daily
Bpm
beats per minute
BVM
Bevirimat
BIL
Bilirubin
C
Pre-dose (trough) concentration at the end of the dosing 
interval
C24
24 hour trough concentration
CDC
Center for Disease Control and Prevention
CI
Confidence interval
CL/F
Oral Clearance
Cmax
Maximum plasma concentration
Cmin
Minimum plasma concentration
CPK
Creatine Phosphokinase
CRF
Case report form
cTnI
Cardiac troponin I
CV
Coefficient of variation
CVb
Between-subject variability
CYP
Cytochrome P450
DDI
Drug Drug Interaction
DNA
Deoxyribonucleic acid
EC50
50% protection against resistant mutant HIV infection 
 
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ECG
Electrocardiogram
FC
Fold Changes
FDA
Food and Drug Administration
FSH
Follicle stimulating hormone
FTIH
First time in Human Study
g
Gram
GI
Gastrointestinal
GSK
GlaxoSmithKline
h
Hour(s)
HBsAg
Hepatitis B surface antigen
hcG
Human chorionic gonadotrophin
HDPE
High density polyethylene
hERG
Human Ether-a-gogo Related Gene
HIV
Human Immunodeficiency Virus
IC50/90
50% or 90% maximal inhibitory concentration
IEC
International Ethics Committee
IQ
Inhibitory quotient
IRB
Institutional Review Board
ISR
Injection site reaction
IV
Intravenous
IVRS
Interactive voice response system
kg
Kilogram
L
Litre
LLOD
Lower limit of detection
MC
Melanocortin
MedDRA
Medical Dictionary for Regulatory Activities
mg/mL
Milligram per millilitre
MI
Maturation inhibitor
mL
Milliliter
mRNA
messenger Ribonucleic Acid
ND
Not done
ng/mL
Nanogram per millilitre 
nm
Nanometer
NO
Not observed
NOAEL
No Observed Adverse Effect Level
NTproBNP
N-terminal prohormone of brain natriuretic peptide
NSVT
Non-sustained ventricular tachycardia
OAT
Organic anion transporter
OATP
Organic anion transporting polypeptide
OCT
Organic cation transporter
PBL
Peripheral Blood Lymphocytes
PBMC
Peripheral Blood Mononuclear Cells
PD
Pharmacodynamics
PPD
Pharmaceutical Product Development
P-gp
P-glycoprotein
PHIV
Pseudo- HIV
 
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PiB
Powder-in-bottle
PK
Pharmacokinetic
PoC
Proof of Concept
PI
Protease Inhibitor
QD
Once daily
RAP
Reporting and analysis plan
RIBA
Recombinant Immuno-Blot Assay
RT
Reverse Transcriptase
SAE
Serious adverse event
SDD
Spray Dried Dispersion
SRM
Study reference manual
t½
Terminal elimination half-life
TEM
Transmission Electron Microscopy
tlag
Time of first quantifiable concentration
tmax
Time of occurrence of Cmax
U
Units
UGT
Uridine 5'-diphospho-glucuronosyltransferase
Vz/F
Mean apparent oral volume of distribution
WPW
Wolff-Parkinson-White
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Abbot, Roche HIV kit
Chiron RIBA 
Inform
Monogram
Phoenix WinNonlin 
SAS
Tybost (cobicistat)
 
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12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments
Phase II liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event etiology (in alignment with the 
FDA premarketing clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Phase II liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF and complete an 
SAE data collection tool if the event also meets 
the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries
resolve, stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge subject with study 
treatment unless allowed per protocol and GSK 
Medical Governance approval is granted 

If restart/rechallenge not allowed per protocol 
or not granted, permanently discontinue study 
treatment and may continue subject in the study 

Viral hepatitis serology4

Blood sample for pharmacokinetic (PK) 
analysis, obtained within 24hrs after 
last dose5

Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications 
on the concomitant medications report 
 
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for any protocol specified follow up assessments 
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 
24 hours

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to within 
baseline 

A specialist or hepatology consultation is 
recommended
For All other criteria: 

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24-
72 hours 

Monitor subjects weekly until liver chemistries 
resolve, stabilize or return to within baseline
form including acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG or gamma globulins).

Serum acetaminophen adduct high-
performance liquid chromatography
assay (quantifies potential 
acetaminophen contribution to liver 
injury in subjects with definite or likely 
acetaminophen use in the preceding 
week 

Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF 
forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN.. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
5.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.)  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.  
 
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Phase II liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 3xULN and <5xULN and bilirubin 
<2xULN, without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss subject safety. 

Subject can continue study treatment  

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to within 
baseline.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
 
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12.3.
Appendix 3: Liver Safety – Study Treatment Restart or 
Rechallenge Guidelines
Study treatment restart or re-challenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed.
 
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12.4.
Appendix 4: Genetic Research
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and: 

Response to medicine, including GSK2838232/RTV or any concomitant 
medicines;

HIV susceptibility, severity, and progression and related conditions
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic 
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research.  Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.  

A 6 ml blood or 2 ml saliva sample will be taken for Deoxyribonucleic acid 
(DNA) extraction. A sample is collected at the baseline visit, after the subject has 
been randomized and provided informed consent for genetic research. Instructions 
for collection and shipping of the genetic sample are described in the laboratory 
manual. The DNA from the blood/saliva sample may undergo quality control 
analyses to confirm the integrity of the sample. If there are concerns regarding the 
quality of the sample, then the sample may be destroyed. The blood/saliva sample 
is taken on a single occasion unless a duplicate sample is required due to an 
inability to utilize the original sample.  
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study.   This number can be traced or linked back to 
 
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the subject by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number). 
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study, or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form.  Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study.  Genetic informed consent must be obtained prior to any blood/saliva being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA 
sample is retained

Discontinue participation in the genetic research and destroy the genetic DNA 
sample 
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis. 

If a subject withdraws consent for genetic research and genotype data has not been 
analyzed, it will not be analyzed or used for future research.  

Genetic data that has been analyzed at the time of withdrawn consent will 
continue to be stored and used, as appropriate. 
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 
 
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reconciliation process.  In this instance a sample destruction form will not be available to 
include in the site files.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic 
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined.  Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care.
 
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12.5.
Appendix 5: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.5.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE.  However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition 
of an AE or SAE.

The signs and symptoms and/or clinical sequelae resulting from lack of efficacy will 
be reported if they fulfil the definition of an AE or SAE.  Also, "lack of efficacy" or 
"failure of expected pharmacological action" also constitutes an AE or SAE.
 
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Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
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.
12.5.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
c.
Results in death
d.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
e.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
 
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f.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption
g.
Is a congenital anomaly/birth defect
h.
Other situations:

Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.

Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse
i.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.

Refer to Appendix 2 for the required liver chemistry follow-up instructions
 
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12.5.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
12.5.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.

Subject-completed Value Evidence and Outcomes questionnaires and the collection 
of AE data are independent components of the study.

Responses to each question in the Value Evidence and Outcomes questionnaire will 
be treated in accordance with standard scoring and statistical procedures detailed by 
 
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the scale’s developer.

The use of a single question from a multidimensional health survey to designate a 
cause-effect relationship to an AE is inappropriate.
12.5.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important 
that the investigator always make an assessment of causality for every event 
prior to the initial transmission of the SAE data to GSK.
 
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
The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

By specific request, the investigator is obligated to report any grade 2 or higher 
“alteration in personality-behavior or in mood” or “altered mental status” adverse 
events that occur in subjects taking this drug, to GSK within 3 days.

The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.

If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any post-mortem findings, 
including histopathology. 

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
12.5.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the Medical Monitor

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data

If a site receives a report of a new SAE from a study subject or receives updated data 
 
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on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the Medical 
Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
SAE reporting to GSK via paper CRF

Facsim0ile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the Medical Monitor 

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable, with a copy of the SAE data collection tool sent by 
overnight mail

Initial notification via the 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 receipt can be found at this beginning of the protocol on the 
Sponsor/Medical Monitor Contact Information page.
SAE reporting to GSK via PIMS

Facsimile transmission of the following PIMS listings for the corresponding subject 
is the preferred method to transmit SAE information to the Medical Monitor or 
protocol contact:
SAE listing
Demographic listing
Study treatment listing

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable, with a copy of all required information sent by overnight 
mail.

If the PIMS system is unavailable when the SAE occurs, the site will use the paper 
SAE form and fax that to the Medical Monitor or protocol contact. The site will enter 
the SAE data into PIMS as soon as the system becomes available.
 
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12.6.
Appendix 6: Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 
24hrs of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, which will be 
forwarded to GSK.  Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in Appendix 5. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
Any female subject who becomes pregnant while participating 

will discontinue study medication and be withdrawn from the study

This will only be included if either of the following apply:

Investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study.  This 
applies only to subjects who are randomized to receive study medication. 

After obtaining the necessary signed informed consent from the female partner 
directly, the investigator will record pregnancy information on the appropriate form 
report the event and submit it to GSK within 24hrs 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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12.7.
Appendix 7: Country Specific Requirements
No country-specific requirements exist.
 
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12.8.
Appendix 8: Division Of AIDS Table For Grading The 
Severity Of Adult And Pediatric Adverse Events Version 1.0, 
December 2004; Clarification August 2009
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
ESTIMATING SEVERITY GRADE
Clinical adverse 
event NOT identified 
elsewhere in the 
grading table
Mild symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities with 
intervention not 
indicated
Moderate 
symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
with intervention not 
indicated
Severe symptoms 
causing inability to 
perform usual social 
& functional activities 
with intervention or 
hospitalization 
indicated
Potentially life-
threatening symptoms 
causing inability to 
perform basic self-care 
functions OR Medical or 
operative intervention 
indicated to prevent 
permanent impairment, 
persistent disability, or 
death 
CARDIOVASCULAR
Arrhythmia
(by ECG or physical 
examination)
Specify type, if
applicable
No symptoms 
AND No 
intervention 
indicated
No symptoms AND
non-urgent 
intervention 
indicated
Non-life-threatening 
symptoms AND Non-
urgent intervention 
indicated
Life-threatening 
arrhythmia OR Urgent 
intervention indicated
Blood Pressure 
Abnormalities1 
Hypertension (with 
the lowest reading 
taken after repeat 
testing during a visit) 
≥ 18 years of age 
140 to < 160 
mmHg systolic 
OR 90 to < 100 
mmHg diastolic 
≥ 160 to < 180 
mmHg systolic OR 
≥ 100 to < 110 
mmHg diastolic 
≥ 180 mmHg systolic 
OR ≥ 110 mmHg 
diastolic 
Life-threatening 
consequences in a 
participant not 
previously diagnosed
with hypertension (e.g., 
malignant hypertension) 
OR Hospitalization 
indicated 
< 18 years of age 
> 120/80 mmHg 
≥ 95th to < 99th 
percentile + 5 
mmHg adjusted for 
age, height, and 
gender (systolic 
and/or diastolic) 
≥ 99th percentile + 5 
mmHg adjusted for 
age, height, and 
gender (systolic 
and/or diastolic) 
Life-threatening 
consequences in a 
participant not 
previously diagnosed 
with hypertension (e.g., 
malignant hypertension) 
OR Hospitalization 
indicated 
Hypotension 
No symptoms 
Symptoms 
corrected with oral 
fluid replacement 
Symptoms AND IV 
fluids indicated 
Shock requiring use of 
vasopressors or 
mechanical assistance 
to maintain blood 
pressure 
Cardiac Ischemia or 
Infarction 
Report only one 
NA 
NA 
New symptoms with 
ischemia (stable 
angina) OR New 
testing consistent 
with ischemia 
Unstable angina OR 
Acute myocardial 
infarction 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Heart Failure 
No symptoms 
AND Laboratory 
or cardiac imaging 
abnormalities 
Symptoms with mild 
to moderate activity 
or exertion 
Symptoms at rest or 
with minimal activity 
or exertion (e.g., 
hypoxemia) OR 
Intervention indicated 
(e.g., oxygen) 
Life-threatening 
consequences OR 
Urgent intervention 
indicated (e.g., 
vasoactive medications, 
ventricular assist device, 
heart transplant) 
Hemorrhage (with 
significant acute 
blood loss) 
NA 
Symptoms AND No 
transfusion 
indicated 
Symptoms AND 
Transfusion of ≤ 2 
units packed RBCs 
indicated 
Life-threatening 
hypotension OR 
Transfusion of > 2 units 
packed RBCs (for 
children, packed RBCs 
> 10 cc/kg) indicated 
Prolonged PR 
Interval or AV Block 
Report only one 
> 16 years of age 
PR interval 0.21 
to < 0.25 seconds 
PR interval ≥ 0.25 
seconds OR Type I 
2nd degree AV 
block 
Type II 2nd degree 
AV block OR 
Ventricular pause ≥ 
3.0 seconds 
Complete AV block 
≤ 16 years of age 
1st degree AV 
block (PR interval 
> normal for age 
and rate) 
Type I 2nd degree 
AV block 
Type II 2nd degree 
AV block OR 
Ventricular pause ≥ 
3.0 seconds 
Complete AV block 
Prolonged QTc 
Interval2 
0.45 to 0.47 
seconds 
> 0.47 to 0.50 
seconds 
> 0.50 seconds OR ≥ 
0.06 seconds above 
baseline 
Life-threatening 
consequences (e.g., 
Torsade de pointes, 
other associated serious 
ventricular dysrhythmia) 
Thrombosis or 
Embolism 
Report only one 
NA 
Symptoms AND No 
intervention 
indicated 
Symptoms AND 
Intervention indicated 
Life-threatening embolic 
event (e.g., pulmonary 
embolism, thrombus) 
DERMATOLOGIC
Alopecia (scalp only) 
Detectable by 
study participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Obvious on visual 
inspection AND 
Causing greater 
than minimal 
interference with 
usual social & 
functional activities 
NA 
NA 
Bruising 
Localized to one 
area 
Localized to more 
than one area 
Generalized 
NA 
Cellulitis 
NA 
Non-parenteral 
treatment indicated 
(e.g., oral 
antibiotics, 
antifungals, 
antivirals) 
IV treatment 
indicated (e.g., IV 
antibiotics, 
antifungals, antivirals) 
Life-threatening 
consequences (e.g., 
sepsis, tissue necrosis) 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Hyperpigmentation 
Slight or localized 
causing no or 
minimal 
interference with
usual social & 
functional 
activities 
Marked or 
generalized causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
NA 
NA 
Hypopigmentation 
Slight or localized 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Marked or 
generalized causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
NA 
NA 
Petechiae 
Localized to one 
area 
Localized to more 
than one area 
Generalized 
NA 
Pruritus3 (without 
skin lesions) 
Itching causing no 
or minimal 
interference with 
usual social & 
functional 
activities 
Itching causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Itching causing 
inability to perform 
usual social & 
functional activities 
NA 
Rash 
Specify type, if 
applicable 
Localized rash 
Diffuse rash OR 
Target lesions 
Diffuse rash AND 
Vesicles or limited 
number of bullae or 
superficial ulcerations 
of mucous membrane 
limited to one site 
Extensive or generalized 
bullous lesions OR 
Ulceration of mucous 
membrane involving two 
or more distinct mucosal 
sites OR Stevens-
Johnson syndrome OR 
Toxic epidermal 
necrolysis 
ENDOCRINE AND METABOLIC
Diabetes Mellitus 
Controlled without 
medication 
Controlled with 
medication OR 
Modification of 
current medication 
regimen 
Uncontrolled despite 
treatment 
modification OR 
Hospitalization for 
immediate glucose 
control indicated 
Life-threatening 
consequences (e.g., 
ketoacidosis, 
hyperosmolar non-
ketotic coma, end organ 
failure) 
Gynecomastia 
Detectable by 
study participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Obvious on visual 
inspection AND 
Causing pain with 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Disfiguring changes 
AND Symptoms 
requiring intervention 
or causing inability to 
perform usual social 
& functional activities 
NA 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Hyperthyroidism 
No symptoms 
AND Abnormal 
laboratory value 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
OR Thyroid 
suppression 
therapy indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Uncontrolled 
despite treatment 
modification 
Life-threatening 
consequences (e.g., 
thyroid storm) 
Hypothyroidism 
No symptoms 
AND Abnormal 
laboratory value 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
OR Thyroid 
replacement 
therapy indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Uncontrolled 
despite treatment 
modification 
Life-threatening 
consequences (e.g., 
myxedema coma) 
Lipoatrophy4 
Detectable by 
study participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Obvious on visual 
inspection AND 
Causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Disfiguring changes 
NA 
Lipohypertrophy5
Detectable by 
study participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Obvious on visual 
inspection AND 
Causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Disfiguring changes 
NA 
GASTROINTESTINAL
Anorexia 
Loss of appetite 
without decreased 
oral intake 
Loss of appetite 
associated with 
decreased oral 
intake without 
significant weight 
loss 
Loss of appetite 
associated with 
significant weight loss 
Life-threatening 
consequences OR 
Aggressive intervention 
indicated (e.g., tube 
feeding, total parenteral 
nutrition) 
Ascites 
No symptoms 
Symptoms AND 
Intervention 
indicated (e.g., 
diuretics, 
therapeutic 
paracentesis) 
Symptoms recur or 
persist despite 
intervention 
Life-threatening 
consequences 
 
2018N360917_00


2015N227852_02
CONFIDENTIAL
200911
91
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Bloating or 
Distension 
Report only one 
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Cholecystitis
NA 
Symptoms AND 
Medical intervention 
indicated 
Radiologic, 
endoscopic, or 
operative intervention 
indicated 
Life-threatening 
consequences (e.g., 
sepsis, perforation) 
Constipation 
NA 
Persistent 
constipation 
requiring regular 
use of dietary 
modifications, 
laxatives, or 
enemas 
Obstipation with 
manual evacuation 
indicated 
Life-threatening 
consequences (e.g., 
obstruction) 
Diarrhea ≥ 1 year of 
age 
Transient or 
intermittent 
episodes of 
unformed stools 
OR Increase of ≤ 
3 stools over 
baseline per 24-
hour period 
Persistent episodes 
of unformed to 
watery stools OR 
Increase of 4 to 6 
stools over baseline 
per 24-hour period 
Increase of ≥ 7 stools 
per 24-hour period 
OR IV fluid 
replacement 
indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Dysphagia or 
Odynophagia 
Report only one 
and specify 
location 
Symptoms but 
able to eat usual 
diet 
Symptoms causing 
altered dietary 
intake with no 
intervention 
indicated 
Symptoms causing 
severely altered 
dietary intake with 
intervention indicated 
Life-threatening 
reduction in oral intake 
Gastrointestinal 
Bleeding 
Not requiring 
intervention other 
than iron 
supplement 
Endoscopic 
intervention 
indicated 
Transfusion indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Mucositis or 
Stomatitis 
Report only one and 
specify location 
Mucosal erythema 
Patchy 
pseudomembranes 
or ulcerations 
Confluent 
pseudomembranes 
or ulcerations OR 
Mucosal bleeding 
with minor trauma 
Life-threatening 
consequences (e.g., 
aspiration, choking) OR 
Tissue necrosis OR 
Diffuse spontaneous 
mucosal bleeding 
Nausea 
Transient (< 24 
hours) or 
intermittent AND 
No or minimal 
interference with 
oral intake 
Persistent nausea 
resulting in 
decreased oral 
intake for 24 to 48 
hours 
Persistent nausea 
resulting in minimal 
oral intake for > 48 
hours OR 
Rehydration indicated 
(e.g., IV fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Pancreatitis 
NA 
Symptoms with 
hospitalization not 
indicated 
Symptoms with 
hospitalization 
indicated 
Life-threatening 
consequences (e.g., 
circulatory failure, 
hemorrhage, sepsis) 
 
2018N360917_00


2015N227852_02
CONFIDENTIAL
200911
92
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Perforation 
(colon or rectum) 
NA 
NA 
Intervention indicated 
Life-threatening 
consequences 
Proctitis 
Rectal discomfort 
with no 
intervention 
indicated 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
OR Medical 
intervention 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
perforation) 
Rectal Discharge 
Visible discharge 
Discharge requiring 
the use of pads 
NA 
NA 
Vomiting 
Transient or 
intermittent AND 
No or minimal 
interference with 
oral intake 
Frequent episodes 
with no or mild 
dehydration 
Persistent vomiting 
resulting in 
orthostatic 
hypotension OR 
Aggressive 
rehydration indicated 
(e.g., IV fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
MUSCULOSKELETAL
Arthralgia 
Joint pain causing 
no or minimal 
interference with 
usual social & 
functional 
activities 
Joint pain causing
greater than 
minimal 
interference with 
usual social & 
functional activities 
Joint pain causing 
inability to perform 
usual social & 
functional activities 
Disabling joint pain 
causing inability to 
perform basic self-care 
functions 
Arthritis 
Stiffness or joint 
swelling causing 
no or minimal 
interference with 
usual social & 
functional 
activities 
Stiffness or joint 
swelling causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Stiffness or joint 
swelling causing 
inability to perform 
usual social & 
functional activities 
Disabling joint stiffness 
or swelling causing 
inability to perform basic 
self-care functions 
Myalgia 
(generalized) 
Muscle pain 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Muscle pain 
causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Muscle pain causing 
inability to perform 
usual social & 
functional activities 
Disabling muscle pain 
causing inability to 
perform basic self-care 
functions 
Osteonecrosis 
NA 
No symptoms but 
with radiographic 
findings AND No 
operative 
intervention 
indicated 
Bone pain with 
radiographic findings 
OR Operative 
intervention indicated 
Disabling bone pain with 
radiographic findings 
causing inability to 
perform basic self-care 
functions 
Osteopenia6
≥ 30 years of age 
BMD t-score -2.5 
to -1 
NA 
NA 
NA 
 
2018N360917_00


2015N227852_02
CONFIDENTIAL
200911
93
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
< 30 years of age 
BMD z-score -2 to 
-1 
NA 
NA 
NA 
Osteoporosis6
≥ 30 years of age 
NA 
BMD t-score < -2.5 
Pathologic fracture 
(e.g., compression 
fracture causing loss 
of vertebral height) 
Pathologic fracture 
causing life-threatening 
consequences 
< 30 years of age 
NA 
BMD z-score < -2 
Pathologic fracture 
(e.g., compression 
fracture causing loss 
of vertebral height) 
Pathologic fracture 
causing life-threatening 
consequences 
NEUROLOGIC
Acute Central 
nervous system 
(CNS) Ischemia 
NA 
NA 
Transient ischemic 
attack 
Cerebral vascular 
accident (e.g., stroke 
with neurological deficit) 
Altered Mental 
Status (for 
Dementia, see 
Cognitive, 
Behavioral, or 
Attentional 
Disturbance below) 
Changes causing 
no or minimal 
interference with 
usual social & 
functional 
activities 
Mild lethargy or 
somnolence 
causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Confusion, memory 
impairment, lethargy, 
or somnolence 
causing inability to 
perform usual social 
& functional activities 
Delirium OR 
Obtundation OR Coma 
Ataxia 
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities OR No 
symptoms with 
ataxia detected on 
examination 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Disabling symptoms 
causing inability to 
perform basic self-care 
functions 
Cognitive, 
Behavioral, or 
Attentional 
Disturbance 
(includes dementia 
and attention deficit 
disorder) 
Specify type, if 
applicable 
Disability causing 
no or minimal 
interference with 
usual social & 
functional 
activities OR 
Specialized 
resources not 
indicated 
Disability causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
OR Specialized 
resources on part-
time basis indicated 
Disability causing 
inability to perform 
usual social & 
functional activities 
OR Specialized 
resources on a full-
time basis indicated 
Disability causing 
inability to perform basic 
self-care functions OR 
Institutionalization 
indicated 
 
2018N360917_00


2015N227852_02
CONFIDENTIAL
200911
94
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Developmental 
Delay < 18 years of 
age 
Specify type, if 
applicable 
Mild 
developmental 
delay, either 
motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Moderate 
developmental 
delay, either motor 
or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Severe 
developmental delay, 
either motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Developmental 
regression, either motor 
or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Headache 
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Symptoms causing 
inability to perform basic 
self-care functions OR 
Hospitalization indicated 
OR Headache with 
significant impairment of 
alertness or other 
neurologic function 
Neuromuscular 
Weakness (includes 
myopathy and 
neuropathy) 
Specify type, if 
applicable 
Minimal muscle 
weakness causing 
no or minimal 
interference with 
usual social & 
functional 
activities OR No 
symptoms with 
decreased 
strength on 
examination 
Muscle weakness 
causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Muscle weakness 
causing inability to 
perform usual social 
& functional activities 
Disabling muscle 
weakness causing 
inability to perform basic 
self-care functions OR 
Respiratory muscle 
weakness impairing 
ventilation 
Neurosensory 
Alteration (includes 
paresthesia and 
painful neuropathy) 
Specify type, if 
applicable 
Minimal 
paresthesia 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities OR No 
symptoms with 
sensory alteration 
on examination 
Sensory alteration 
or paresthesia 
causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Sensory alteration or 
paresthesia causing 
inability to perform 
usual social & 
functional activities 
Disabling sensory 
alteration or paresthesia 
causing inability to 
perform basic self-care 
functions 
Seizures New Onset 
Seizure 
≥ 18 years of age 
NA 
NA 
1 to 3 seizures 
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR Difficult 
to control (e.g., 
refractory epilepsy) 
< 18 years of age 
(includes new or pre-
existing febrile 
seizures) 
Seizure lasting < 
5 minutes with < 
24 hours postictal 
state 
Seizure lasting 5 to 
< 20 minutes with < 
24 hours postictal 
state 
Seizure lasting ≥ 20 
minutes OR > 24 
hours postictal state
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR Difficult 
to control (e.g., 
refractory epilepsy) 
 
2018N360917_00


2015N227852_02
CONFIDENTIAL
200911
95
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Pre-existing Seizure 
NA 
Increased 
frequency from 
previous level of 
control without 
change in seizure 
character 
Change in seizure 
character either in 
duration or quality 
(e.g., severity or 
focality) 
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR Difficult 
to control (e.g., 
refractory epilepsy) 
Syncope 
Near syncope 
without loss of 
consciousness 
(e.g., pre-
syncope) 
Loss of 
consciousness with 
no intervention 
indicated 
Loss of 
consciousness AND 
Hospitalization or 
intervention required 
NA 
PREGNANCY, PUERPERIUM, AND PERINATAL
Fetal Death or 
Stillbirth (report 
using mother’s 
participant ID) 
Report only one 
NA 
NA 
Fetal loss occurring 
at ≥ 20 weeks 
gestation 
NA 
Preterm Delivery7
(report using 
mother’s participant 
ID) 
Delivery at 34 to < 
37 weeks 
gestational age 
Delivery at 28 to < 
34 weeks 
gestational age 
Delivery at 24 to < 28 
weeks gestational 
age 
Delivery at < 24 weeks 
gestational age 
Spontaneous 
Abortion or 
Miscarriage8 (report 
using mother’s 
participant ID) 
Report only one 
Chemical 
pregnancy 
Uncomplicated 
spontaneous 
abortion or 
miscarriage 
Complicated 
spontaneous abortion 
or miscarriage 
NA 
PSYCHIATRIC
Insomnia 
Mild difficulty 
falling asleep, 
staying asleep, or 
waking up early 
Moderate difficulty 
falling asleep, 
staying asleep, or 
waking up early 
Severe difficulty 
falling asleep, staying 
asleep, or waking up 
early 
NA 
Psychiatric 
Disorders 
(includes anxiety, 
depression, mania, 
and 
psychosis) 
Specify disorder 
Symptoms with 
intervention not 
indicated OR 
Behavior causing 
no or minimal 
interference with 
usual social & 
functional 
activities 
Symptoms with 
intervention 
indicated OR 
Behavior causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms with 
hospitalization 
indicated OR 
Behavior causing 
inability to perform 
usual social & 
functional activities 
Threatens harm to self 
or others OR Acute 
psychosis OR Behavior 
causing inability to 
perform basic self-care 
functions 
 
2018N360917_00


2015N227852_02
CONFIDENTIAL
200911
96
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Suicidal Ideation or 
Attempt 
Report only one 
Preoccupied with 
thoughts of death 
AND No wish to 
kill oneself 
Preoccupied with 
thoughts of death 
AND Wish to kill 
oneself with no 
specific plan or 
intent 
Thoughts of killing 
oneself with partial or 
complete plans but 
no attempt to do so 
OR Hospitalization 
indicated 
Suicide attempted 
RESPIRATORY
Acute 
Bronchospasm 
Forced expiratory 
volume in 1 
second or peak 
flow reduced to ≥ 
70 to < 80% OR 
Mild symptoms 
with intervention 
not indicated 
Forced expiratory 
volume in 1 second 
or peak flow 50 to < 
70% OR Symptoms 
with intervention 
indicated OR 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Forced expiratory 
volume in 1 second 
or peak flow 25 to < 
50% OR Symptoms 
causing inability to 
perform usual social 
& functional activities 
Forced expiratory 
volume in 1 second or 
peak flow < 25% OR 
Life-threatening 
respiratory or 
hemodynamic 
compromise OR 
Intubation 
Dyspnea or 
Respiratory 
Distress 
Report only one 
Dyspnea on 
exertion with no or 
minimal 
interference with 
usual social & 
functional 
activities OR 
Wheezing OR 
Minimal increase 
in respiratory rate 
for age 
Dyspnea on 
exertion causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
OR Nasal flaring 
OR Intercostal 
retractions OR 
Pulse oximetry 90 
to < 95% 
Dyspnea at rest 
causing inability to 
perform usual social 
& functional activities 
OR Pulse oximetry < 
90% 
Respiratory failure with 
ventilator support 
indicated (e.g., 
Continuous positive 
airway pressure [CPAP], 
Bilevel positive airway 
pressure [BPAP], 
intubation) 
SENSORY
Hearing Loss 
≥ 12 years of age 
NA 
Hearing aid or 
intervention not 
indicated 
Hearing aid or 
intervention indicated 
Profound bilateral 
hearing loss (> 80 dB at 
2 kHz and above) OR 
Non-serviceable hearing 
(i.e., >50 dB audiogram 
and <50% speech 
discrimination) 
< 12 years of age 
(based on a 1, 2, 3, 
4, 6 and 8 kHz 
audiogram) 
> 20 dB hearing 
loss at ≤ 4 kHz 
> 20 dB hearing 
loss at > 4 kHz 
> 20 dB hearing loss 
at ≥ 3 kHz in one ear 
with additional 
speech language 
related services 
indicated (where 
available) OR 
Hearing loss 
sufficient to indicate 
therapeutic 
intervention, including 
hearing aids 
Audiologic indication for 
cochlear implant and 
additional speech-
language related 
services indicated 
(where available) 
 
2018N360917_00


2015N227852_02
CONFIDENTIAL
200911
97
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Tinnitus 
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities with 
intervention not 
indicated 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
with intervention 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Uveitis 
No symptoms 
AND Detectable 
on examination 
Anterior uveitis with 
symptoms OR 
Medicamylasal 
intervention 
indicated 
Posterior or pan-
uveitis OR Operative 
intervention indicated 
Disabling visual loss in 
affected eye(s) 
Vertigo 
Vertigo causing 
no or minimal 
interference with 
usual social & 
functional 
activities 
Vertigo causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Vertigo causing 
inability to perform 
usual social & 
functional activities 
Disabling vertigo 
causing inability to 
perform basic self-care 
functions 
Visual Changes 
(assessed from 
baseline) 
Visual changes 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Visual changes 
causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Visual changes 
causing inability to 
perform usual social 
& functional activities 
Disabling visual loss in 
affected eye(s) 
SYSTEMIC
Acute Allergic 
Reaction 
Localized urticaria 
(wheals) with no 
medical 
intervention 
indicated 
Localized urticaria 
with intervention 
indicated OR Mild 
angioedema with 
no intervention 
indicated 
Generalized urticaria 
OR Angioedema with 
intervention indicated 
OR Symptoms of 
mild bronchospasm 
Acute anaphylaxis OR 
Life-threatening 
bronchospasm OR 
Laryngeal edema 
Chills 
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Cytokine Release 
Syndrome9
Mild signs and 
symptoms AND 
Therapy (i.e., 
antibody infusion) 
interruption not 
indicated 
Therapy (i.e., 
antibody infusion) 
interruption 
indicated AND 
Responds promptly 
to symptomatic 
treatment OR 
Prophylactic 
medications 
indicated for ≤ 24 
hours 
Prolonged severe 
signs and symptoms 
OR Recurrence of 
symptoms following 
initial improvement 
Life-threatening 
consequences (e.g., 
requiring pressor or 
ventilator support) 
 
2018N360917_00


2015N227852_02
CONFIDENTIAL
200911
98
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Fatigue or Malaise 
Report only one 
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Incapacitating 
symptoms of fatigue or 
malaise causing inability 
to perform basic self-
care functions 
Fever (non-axillary 
temperatures only) 
38.0 to < 38.6°C 
or 100.4 to < 
101.5°F 
≥ 38.6 to < 39.3°C 
or ≥ 101.5 to < 
102.7°F 
≥ 39.3 to < 40.0°C or 
≥ 102.7 to < 104.0°F 
≥ 40.0°C or ≥ 104.0°F 
Pain10 (not 
associated with study 
agent injections and 
not specified 
elsewhere) 
Specify location 
Pain causing no 
or minimal 
interference with 
usual social & 
functional 
activities 
Pain causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Pain causing inability 
to perform usual 
social & functional 
activities 
Disabling pain causing 
inability to perform basic 
self-care functions OR 
Hospitalization indicated 
Serum Sickness11 
Mild signs and 
symptoms 
Moderate signs and 
symptoms AND 
Intervention 
indicated (e.g., 
antihistamines) 
Severe signs and 
symptoms AND 
Higher level 
intervention indicated 
(e.g., steroids or IV 
fluids) 
Life-threatening 
consequences (e.g., 
requiring pressor or 
ventilator support) 
Underweight12
> 5 to 19 years of 
age 
NA 
World Health 
Organization 
(WHO) BMI z-score 
< -2 to ≤ -3 
WHO BMI z-score < -
3 
WHO BMI z-score < -3 
with life-threatening 
consequences 
2 to 5 years of age 
NA 
WHO Weight-for-
height z-score 
< -2 to ≤ -3 
WHO Weight-for-
height z-score < -3 
WHO Weight-for-height 
z-score < -3 with life-
threatening 
consequences 
< 2 years of age 
NA 
WHO Weight-for-
length z-score 
< -2 to ≤ -3
WHO Weight-for-
length z-score < -3 
WHO Weight-for-length 
z-score < -3 with life-
threatening 
consequences 
Weight Loss 
(excludes postpartum 
weight loss) 
NA 
5 to < 9% loss in 
body weight from 
baseline 
≥ 9 to < 20% loss in 
body weight from 
baseline 
≥ 20% loss in body 
weight from baseline OR 
Aggressive intervention 
indicated (e.g., tube 
feeding, total parenteral 
nutrition) 
URINARY
Urinary Tract 
Obstruction 
NA 
Signs or symptoms 
of urinary tract 
obstruction without 
hydronephrosis or 
renal dysfunction
Signs or symptoms of 
urinary tract 
obstruction with 
hydronephrosis or 
renal dysfunction 
Obstruction causing life-
threatening 
consequences 
 
2018N360917_00


2015N227852_02
CONFIDENTIAL
200911
99
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
SITE REACTIONS TO INJECTIONS AND INFUSIONS
Injection Site Pain 
or Tenderness 
Report only one 
Pain or 
tenderness 
causing no or 
minimal limitation 
of use of limb 
Pain or tenderness 
causing greater 
than minimal 
limitation of use of 
limb 
Pain or tenderness 
causing inability to 
perform usual social 
& functional activities 
Pain or tenderness 
causing inability to 
perform basic self-care 
function OR 
Hospitalization indicated 
Injection Site 
Erythema or 
Redness13 
Report only one 
> 15 years of age 
2.5 to < 5 cm in 
diameter OR 6.25 
to < 25 cm2 
surface area AND 
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
≥ 5 to < 10 cm in 
diameter OR ≥ 25 
to < 100 cm2 
surface area OR 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
≥ 10 cm in diameter 
OR ≥ 100 cm2 
surface area OR 
Ulceration OR 
Secondary infection 
OR Phlebitis OR 
Sterile abscess OR 
Drainage OR 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Potentially life-
threatening 
consequences (e.g., 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue) 
≤ 15 years of age 
≤ 2.5 cm in 
diameter 
> 2.5 cm in 
diameter with < 
50% surface area 
of the extremity 
segment involved 
(e.g., upper arm or 
thigh) 
≥ 50% surface area 
of the extremity 
segment involved 
(e.g., upper arm or 
thigh) OR Ulceration 
OR Secondary 
infection OR Phlebitis 
OR Sterile abscess 
OR Drainage 
Potentially life-
threatening 
consequences (e.g., 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue) 
Injection Site 
Induration or 
Swelling 
Report only one 
> 15 years of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 
years of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 
years of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, > 15 years of 
age 
≤ 15 years of age 
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15 
years of age 
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15 
years of age 
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, ≤ 15 years of 
age 
Injection Site 
Pruritus 
Itching localized 
to the injection 
site that is 
relieved 
spontaneously or 
in < 48 hours of 
treatment 
Itching beyond the 
injection site that is 
not generalized OR 
Itching localized to 
the injection site 
requiring ≥ 48 
hours treatment 
Generalized itching 
causing inability to 
perform usual social 
& functional activities 
NA 
LABORATORY VALUES Chemistries
Acidosis 
NA 
pH ≥ 7.3 to < Lower 
limit of normal 
(LLN) 
pH < 7.3 without life-
threatening 
consequences 
pH < 7.3 with life-
threatening 
consequences 
Albumin, Low (g/dL; 
g/L) 
3.0 to < LLN 
30 to < LLN 
≥ 2.0 to < 3.0
≥ 20 to < 30 
< 2.0 
< 20 
NA 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Alkaline 
Phosphatase, High 
1.25 to < 2.5 x 
ULN 
2.5 to < 5.0 x ULN 
5.0 to < 10.0 x ULN 
≥ 10.0 x ULN 
Alkalosis 
NA 
pH > ULN to ≤ 7.5 
pH > 7.5 without life-
threatening 
consequences 
pH > 7.5 with life-
threatening 
consequences 
ALT or SGPT, High 
Report only one 
1.25 to < 2.5 x 
ULN 
2.5 to < 5.0 x ULN 
5.0 to < 10.0 x ULN 
≥ 10.0 x ULN
Amylase 
(Pancreatic) or 
Amylase (Total), 
High 
Report only one 
1.1 to < 1.5 x ULN 
1.5 to < 3.0 x ULN 
3.0 to < 5.0 x ULN 
≥ 5.0 x ULN 
AST or SGOT, High 
Report only one 
1.25 to < 2.5 x 
ULN 
2.5 to < 5.0 x ULN 
5.0 to < 10.0 x ULN 
≥ 10.0 x ULN 
Bicarbonate, Low 
(mEq/L; mmol/L) 
16.0 to < LLN 
16.0 to < LLN 
11.0 to < 16.0 
11.0 to < 16.0 
8.0 to < 11.0 
8.0 to < 11.0 
< 8.0 
< 8.0 
Bilirubin Direct 
Bilirubin14, High 
> 28 days of age 
NA 
NA 
> ULN 
> ULN with life-
threatening 
consequences (e.g., 
signs and symptoms of 
liver failure) 
≤ 28 days of age 
ULN to ≤ 1 mg/dL 
> 1 to ≤ 1.5 mg/dL 
> 1.5 to ≤ 2 mg/dL 
> 2 mg/dL 
Total Bilirubin, High 
> 28 days of age 
1.1 to < 1.6 x ULN 
1.6 to < 2.6 x ULN 
2.6 to < 5.0 x ULN 
≥ 5.0 x ULN 
≤ 28 days of age 
Total Bilirubin for 
Term and Preterm 
Neonates 
Total Bilirubin for 
Term and Preterm 
Neonates 
Total Bilirubin for 
Term and Preterm 
Neonates 
Total Bilirubin for Term 
and Preterm Neonates 
Calcium, High 
(mg/dL; mmol/L) 
≥ 7 days of age 
10.6 to < 11.5 
2.65 to < 2.88 
11.5 to < 12.5 
2.88 to < 3.13 
12.5 to < 13.5 
3.13 to < 3.38 
≥ 13.5 
≥ 3.38 
< 7 days of age 
11.5 to < 12.4 
2.88 to < 3.10 
12.4 to < 12.9 
3.10 to < 3.23 
12.9 to < 13.5 
3.23 to < 3.38 
≥ 13.5 
≥ 3.38 
Calcium (Ionized), 
High (mg/dL; 
mmol/L) 
> ULN to < 6.0
> ULN to < 1.5 
6.0 to < 6.4 
1.5 to < 1.6 
6.4 to < 7.2 
1.6 to < 1.8 
≥ 7.2 
≥ 1.8 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Calcium, Low 
(mg/dL; mmol/L) 
≥ 7 days of age 
7.8 to < 8.4 
1.95 to < 2.10 
7.0 to < 7.8 
1.75 to < 1.95 
6.1 to < 7.0 
1.53 to < 1.75 
< 6.1 
< 1.53 
< 7 days of age 
6.5 to < 7.5 
1.63 to < 1.88 
6.0 to < 6.5 
1.50 to < 1.63 
5.50 to < 6.0 
1.38 to < 1.50 
< 5.50 
< 1.38 
Calcium (Ionized), 
Low (mg/dL; mmol/L) 
< LLN to 4.0 
< LLN to 1.0 
3.6 to < 4.0 
0.9 to < 1.0 
3.2 to < 3.6 
0.8 to < 0.9 
< 3.2 
< 0.8 
Cardiac Troponin I, 
High 
NA 
NA 
NA 
Levels consistent with 
myocardial infarction or 
unstable angina as 
defined by the local 
laboratory 
Creatine Kinase, 
High 
3 to < 6 x ULN 
6 to < 10 x ULN 
10 to < 20 x ULN 
≥ 20 x ULN 
Creatinine, High 
1.1 to 1.3 x ULN 
> 1.3 to 1.8 x ULN 
OR Increase of > 
0.3 mg/dL above 
baseline 
> 1.8 to < 3.5 x ULN 
OR Increase of 1.5 to 
< 2.0 x above 
baseline 
≥ 3.5 x ULN OR 
Increase of ≥ 2.0 x 
above baseline 
Creatinine 
Clearance15 or
Estimated 
glomerular filtration 
rate (eGFR), Low 
Report only one 
NA 
< 90 to 60 mL/min 
or mL/min/1.73 m2 
OR 10 to < 30% 
decrease from 
baseline 
< 60 to 30 mL/min or 
mL/min/1.73 m2 OR 
≥ 30 to < 50% 
decrease from 
baseline 
< 30 mL/min or 
mL/min/1.73 m2 OR ≥ 
50% decrease from 
baseline or dialysis 
needed 
Glucose 
(mg/dL; mmol/L) 
Fasting, High 
110 to 125 
6.11 to < 6.95 
> 125 to 250 
6.95 to < 13.89 
> 250 to 500 
13.89 to < 27.75 
> 500 
≥ 27.75 
Nonfasting, High 
116 to 160 
6.44 to < 8.89 
> 160 to 250 
8.89 to < 13.89 
> 250 to 500 
13.89 to < 27.75 
> 500 
≥ 27.75 
Glucose, Low 
(mg/dL; mmol/L) 
≥ 1 month of age 
55 to 64 
3.05 to 3.55 
40 to < 55 
2.22 to < 3.05 
30 to < 40 
1.67 to < 2.22 
< 30 
< 1.67 
Lactate, High 
ULN to < 2.0 x 
ULN without 
acidosis 
≥ 2.0 x ULN without 
acidosis 
Increased lactate with 
pH < 7.3 without life-
threatening 
consequences 
Increased lactate with 
pH < 7.3 with life-
threatening 
consequences 
Lipase, High 
1.1 to < 1.5 x ULN 
1.5 to < 3.0 x ULN 
3.0 to < 5.0 x ULN 
≥ 5.0 x ULN 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Lipid Disorders 
(mg/dL; mmol/L) 
Cholesterol, 
Fasting, High 
≥ 18 years of age 
200 to < 240 
5.18 to < 6.19 
240 to < 300 
6.19 to < 7.77 
≥ 300 
≥ 7.77 
NA 
< 18 years of age 
170 to < 200 4.40 
to < 5.15 
200 to < 300 5.15 to 
< 7.77 
≥ 300 ≥7.77 
NA 
Low Density 
Lipoprotein (LDL),
Fasting, High 
≥ 18 years of age 
130 to < 160 3.37 
to < 4.12 
160 to < 190 4.12 to 
< 4.90 
≥ 190 ≥ 4.90 
NA 
> 2 to < 18 years of 
age 
110 to < 130 2.85 
to < 3.34 
130 to < 190 3.34 to 
< 4.90 
≥ 190 ≥ 4.90 
NA 
Triglycerides, 
Fasting, High 
150 to 300 
1.71 to 3.42 
>300 to 500 
>3.42 to 5.7 
>500 to < 1,000 
>5.7 to 11.4 
> 1,000 
> 11.4 
Magnesium16, Low 
(mEq/L; mmol/L) 
1.2 to < 1.4 
0.60 to < 0.70 
0.9 to < 1.2 
0.45 to < 0.60 
0.6 to < 0.9 
0.30 to < 0.45 
< 0.6 
< 0.30 
Phosphate, Low 
(mg/dL; mmol/L) 
> 14 years of age 
2.0 to < LLN 
0.81 to < LLN 
1.4 to < 2.0 
0.65 to < 0.81 
1.0 to < 1.4 
0.32 to < 0.65 
< 1.0 
< 0.32 
1 to 14 years of age 
3.0 to < 3.5 
0.97 to < 1.13 
2.5 to < 3.0 
0.81 to < 0.97 
1.5 to < 2.5 
0.48 to < 0.81 
< 1.5 
< 0.48 
< 1 year of age 
3.5 to < 4.5 
1.13 to < 1.45 
2.5 to < 3.5 
0.81 to < 1.13 
1.5 to < 2.5 
0.48 to < 0.81 
< 1.5 
< 0.48 
Potassium, High 
(mEq/L; mmol/L) 
5.6 to < 6.0 
5.6 to < 6.0 
6.0 to < 6.5 
6.0 to < 6.5 
6.5 to < 7.0 
6.5 to < 7.0 
≥ 7.0 
≥ 7.0 
Potassium, Low 
(mEq/L; mmol/L) 
3.0 to < 3.4 
3.0 to < 3.4 
2.5 to < 3.0 
2.5 to < 3.0 
2.0 to < 2.5 
2.0 to < 2.5 
< 2.0 
< 2.0 
Sodium, High 
(mEq/L; mmol/L) 
146 to < 150 
146 to < 150 
150 to < 154 
150 to < 154 
154 to < 160 
154 to < 160 
≥ 160 
≥ 160 
Sodium, Low 
(mEq/L; mmol/L) 
130 to < 135 
130 to < 135 
125 to < 130 
125 to < 135 
121 to < 125 
121 to < 125 
≤ 120 
≤ 120 
Uric Acid, High 
(mg/dL; mmol/L) 
7.5 to < 10.0 
0.45 to < 0.59 
10.0 to < 12.0 
0.59 to < 0.71 
12.0 to < 15.0 
0.71 to < 0.89 
≥ 15.0 
≥ 0.89 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
HEMATOLOGY
Absolute cluster of 
differentiation 4 
(CD4+) Count, Low 
(cell/mm3; cells/L) 
> 5 years of age (not 
HIV infected) 
300 to < 400 
300 to < 400 
200 to < 300 
200 to < 300 
100 to < 200 
100 to < 200 
< 100 
< 100 
Absolute 
Lymphocyte Count, 
Low 
(cell/mm3; cells/L) 
> 5 years of age 
(not HIV infected) 
600 to < 650 
0.600 x 109 to < 
0.650 x 109
500 to < 600 
0.500 x 109 to < 
0.600 x 109
350 to < 500 
0.350 x 109 to < 
0.500 x 109
< 350 
< 0.350 x 109
Absolute Neutrophil 
Count (ANC), Low 
(cells/mm3; cells/L) 
> 7 days of age 
800 to 1,000 
0.800 x 109 to 
1.000 x 109
600 to 799 
0.600 x 109 to 0.799 
x 109
400 to 599 
0.400 x 109 to 0.599 
x 109
< 400 
< 0.400 x 109
2 to 7 days of age 
1,250 to 1,500 
1.250 x 109 to 
1.500 x 109
1,000 to 1,249 
1.000 x 109 to 1.249 
x 109
750 to 999 
0.750 x 109 to 0.999 
x 109
< 750 
< 0.750 x 109
≤ 1 day of age 
4,000 to 5,000 
4.000 x 109 to 
5.000 x 109 
3,000 to 3,999 
3.000 x 109 to 3.999 
x 109
1,500 to 2,999 
1.500 x 109 to 2.999 
x 109
< 1,500 
< 1.500 x 109
Fibrinogen, 
Decreased (mg/dL; 
g/L) 
100 to < 200 
1.00 to < 2.00 OR 
0.75 to < 1.00 x 
LLN 
75 to < 100 
0.75 to < 1.00 OR ≥ 
0.50 to < 0.75 x 
LLN 
50 to < 75 
0.50 to < 0.75 OR 
0.25 to < 0.50 x LLN 
< 50 
< 0.50 OR < 0.25 x LLN 
OR Associated with 
gross bleeding 
Hemoglobin17, Low 
(g/dL; mmol/L)18 
≥ 13 years of age 
(male only) 
10.0 to 10.9 
6.19 to 6.76 
9.0 to < 10.0 
5.57 to < 6.19 
7.0 to < 9.0 
4.34 to < 5.57 
< 7.0 
< 4.34 
≥ 13 years of age 
(female only) 
9.5 to 10.4 
5.88 to 6.48 
8.5 to < 9.5 
5.25 to < 5.88 
6.5 to < 8.5 
4.03 to < 5.25 
< 6.5 
< 4.03 
57 days of age to < 
13 years of age 
(male and female) 
9.5 to 10.4 
5.88 to 6.48 
8.5 to < 9.5 
5.25 to < 5.88 
6.5 to < 8.5 
4.03 to < 5.25 
< 6.5 
< 4.03 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
36 to 56 days of age 
(male and female) 
8.5 to 9.6 
5.26 to 5.99 
7.0 to < 8.5 
4.32 to < 5.26 
6.0 to < 7.0 
3.72 to < 4.32 
< 6.0 
< 3.72 
22 to 35 days of age 
(male and female) 
9.5 to 11.0 
5.88 to 6.86 
8.0 to < 9.5 
4.94 to < 5.88 
6.7 to < 8.0 
4.15 to < 4.94 
< 6.7 
< 4.15 
8 to ≤ 21 days of age 
(male and female) 
11.0 to 13.0 
6.81 to 8.10 
9.0 to < 11.0 
5.57 to < 6.81 
8.0 to < 9.0 
4.96 to < 5.57 
< 8.0 
< 4.96 
≤ 7 days of age 
(male and female) 
13.0 to 14.0 
8.05 to 8.72 
10.0 to < 13.0 
6.19 to < 8.05 
9.0 to < 10.0 
5.59 to < 6.19 
< 9.0 
< 5.59 
INR, High 
(not on 
anticoagulation 
therapy) 
1.1 to < 1.5 x ULN 
1.5 to < 2.0 x ULN 
2.0 to < 3.0 x ULN 
≥ 3.0 x ULN 
Methemoglobin (% 
hemoglobin) 
5.0 to < 10.0% 
10.0 to < 15.0% 
15.0 to < 20.0% 
≥ 20.0% 
PTT, High 
(not on 
anticoagulation 
therapy) 
1.1 to < 1.66 x 
ULN 
1.66 to < 2.33 x 
ULN 
2.33 to < 3.00 x ULN 
≥ 3.00 x ULN 
Platelets, 
Decreased 
(cells/mm3; cells/L) 
100,000 to < 
124,999 100.000 
x 109 to < 124.999 
x 109
50,000 to < 100,000 
50.000 x 109 to < 
100.000 x 109 
25,000 to < 50,000 
25.000 x 109 to < 
50.000 x 109
< 25,000 < 25.000 x 109
PT, High 
(not on 
anticoagulation 
therapy 
1.1 to < 1.25 x 
ULN 
1.25 to < 1.50 x 
ULN 
1.50 to < 3.00 x ULN 
≥ 3.00 x ULN 
WBC, Decreased
(cells/mm3; cells/L) 
> 7 days of age 
2,000 to 2,499 
2.000 x 109 to 
2.499 x 109
1,500 to 1,999 
1.500 x 109 to 1.999 
x 109
1,000 to 1,499 
1.000 x 109 to 1.499 
x 109
< 1,000 
< 1.000 x 109
≤ 7 days of age 
5,500 to 6,999 
5.500 x 109 to 
6.999 x 109 
4,000 to 5,499 
4.000 x 109 to 5.499 
x 109
2,500 to 3,999 
2.500 x 109 to 3.999 
x 109
< 2,500 
< 2.500 x 109
URINALYSIS
Glycosuria (random 
collection tested by 
dipstick) 
Trace to 1+ or 
≤ 250 mg 
2+ or ˃ 250 to 
≤ 500 mg 
> 2+ or > 500 mg 
NA 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Hematuria (not to be 
reported based on 
dipstick findings or 
on blood believed to 
be of menstrual 
origin) 
6 to < 10 RBCs 
per high power 
field 
≥ 10 RBCs per high 
power field 
Gross, with or without 
clots OR With RBC 
casts OR Intervention 
indicated 
Life-threatening 
consequences 
Proteinuria (random 
collection tested by 
dipstick) 
1+ 
2+ 
3+ or higher 
NA 
1.
Blood pressure norms for children <18 years of age can be found in: Expert Panel on Integrated Guidelines for 
Cardiovascular Health and Risk Reduction in Children and Adolescents. Pediatrics 2011;128;S213; originally 
published online November 14, 2011; DOI: 10.1542/peds.2009-2107C.  
2.
As per Bazett’s formula.  
3.
For pruritus associated with injections or infusions, see the Site Reactions to Injections and Infusions section.  
4.
Definition: A disorder characterized by fat loss in the face, extremities, and buttocks. 
5.
Definition: A disorder characterized by abnormal fat accumulation on the back of the neck, breasts, and abdomen.  
6.
Bone mineral density (BMD) t and z scores can be found in: Kanis JA on behalf of the World Health Organization 
Scientific Group (2007). Assessment of osteoporosis at the primary health-care level. Technical Report. World 
Health Organization Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, UK. 2007: Printed 
by the University of Sheffield.  
7.
Definition: A delivery of a live-born neonate occurring at ≥20 to <37 weeks gestational age. 
8.
Definition: A clinically recognized pregnancy occurring at <20 weeks gestational age.  
9.
Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and/or shortness of 
breath. 
10. For pain associated with injections or infusions, see the Site Reactions to Injections and Infusions section.
11. Definition: A disorder characterized by fever, arthralgia, myalgia, skin eruptions, lymphadenopathy, marked 
discomfort, and/or dyspnea.
12. WHO reference tables may be accesed by clicking the desired age range or by accessing the following URLs: 
http://www.who.int/growthref/who2007_bmi_for_age/en/ for participants >5 to 19 years of age and 
http://www.who.int/childgrowth/standards/chart_catalogue/en/ for those ≤ 5 years of age.  
13. Injection Site Erythema or Redness should be evaluated and graded using the greatest single diameter or
measured surface area. 
14. Direct bilirubin >1.5 mg/dL in a participant <28 days of age should be graded as Grade 2, if <10% of the total 
bilirubin.  
15. Use the applicable formula (i.e., Cockroft-Gault in mL/min or Schwatrz in mL/min/1.73m2).  
16. To convert a magnesium value from mg/dL to mmol/L, laboratories should multiply by 0.4114.  
17. Male and female sexes are defined as sex at birth. 
18. The conversion factor used to convert g/dL to mmol/L is 0.6206 and is the most commonly used conversion factor. 
For grading hemoglobin results obtained by an analytic method with a conversion factor other than 0.6206, the 
result must be converted to g/dL using the appropriate conversion factor for the particular laboratory.  
 
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12.9.
Appendix 9: Toxicity Management
ANEMIA
Grade 1 (mild) hemoglobin decrease:
Any hemoglobin decrease meeting the definition of Grade 1 must be repeated with the 
following additional tests:
20. peripheral blood smear
21. indirect bilirubin
(abnormal if increased >50% from baseline)
22. haptoglobin
(abnormal if 25 mg/dL)
23. reticulocyte count
(abnormal if 4%) 
If the additional tests are within the normal range, subjects may continue study 
medication.  If one or more of the additional tests is abnormal or suggestive of hemolytic 
anemia as specified above, subjects will permanently discontinue study medication and 
be withdrawn from the trial.  Subjects should be followed up until resolution of anemia.
Grade 2 (moderate) hemoglobin decrease:
Any hemoglobin decrease meeting the definition of Grade 2 must be repeated with the 
following additional tests:
1.
peripheral blood smear
2.
indirect bilirubin
(abnormal if increased > 50% from baseline)
3.
haptoglobin
(abnormal if 25 mg/dL)
4.
reticulocyte count
(abnormal if 4%) 
If the additional tests are within the normal range, subjects may continue study 
medication.  If one or more of the additional tests is abnormal or suggestive of hemolytic 
anemia as specified above, subjects will permanently discontinue study medication and 
be withdrawn from the trial.  Consultation with a Hematologist should be considered.  
Subjects should be followed up until resolution of anemia.
Grade 3 (severe) or Grade 4 (potentially life threatening) hemoglobin decrease:
Any hemoglobin decrease meeting the definition of Grade 3 or 4 must be repeated with 
the following additional tests:
5.
peripheral blood smear
6.
indirect bilirubin
7.
haptoglobin
8.
reticulocyte count 
 
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Subjects will permanently discontinue study medication and be withdrawn from the trial.  
Consultation with a Hematologist should be considered.  Subjects should be followed up 
until resolution of anemia.
TOTAL BILIRUBIN ELEVATION
Grade 1 (mild) bilirubin elevation (1.1 - 1.5 times ULN) or Grade 2 (moderate 
- 1.6-2.5 times ULN):
Any bilirubin value above the upper limit of normal must be repeated and fractionated 
(direct and indirect bilirubin).  Subjects may continue study medication.  Subjects should 
be followed up until resolution (return to baseline) of elevation.
Grade 3 (severe – 2.6-5.0 times ULN) or 4 (life-threatening - > 5.0 times ULN) 
bilirubin elevation:
Any bilirubin value above the upper limit of normal must be repeated and fractionated 
(direct and indirect bilirubin).  Subjects will permanently discontinue study medication 
and be withdrawn from the trial.  Subjects should be followed up until resolution (return 
to baseline) of bilirubin elevation.
AST AND ALT ELEVATION
See Appendix 9.
RASH
Grade 1 rash (Localized macular rash):
Subjects with Grade 1 rash should be evaluated by the Investigator immediately.  A 
dermatologist may be consulted and a biopsy may be obtained if recommended by the 
dermatologist.  The study drug should be permanently discontinued if the following signs 
or symptoms are noted at any time:
9.
Temperature > 38.5°C
10. Lymphadenopathy
11. Pharyngitis
12. Any indication of internal organ involvement (hepatitis, nephritis)
In the absence of the above signs or symptoms, subjects with Grade 1 rash may continue 
the study drug at the discretion of the Investigator.  The subject should be advised to 
contact the Investigator immediately if there is any worsening of the rash, if any systemic 
signs or symptoms worsen, or if mucosal ulceration develops. If the rash is considered to 
be most likely due to concomitant illness or non-study medication, standard management, 
including discontinuation of the likely causative agent, should be undertaken. If no other 
causative factor is found after clinical evaluation, the subject may be treated 
symptomatically until the rash resolves. Antihistamines, topical corticosteroids or 
antipruritic agents may be prescribed.  The subject should remain on the study to be 
followed for safety and PK as outlined in Section 10.5.
 
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Grade 2 rash (Diffuse macular, maculopapular, or morbilliform rash OR Target
lesions):
Subjects with Grade 2 rash should be evaluated by the Investigator immediately.  Digital 
photographs should be obtained.  A dermatologist may be consulted and a biopsy may be 
obtained if recommended by the dermatologist.  The study drug should be permanently 
discontinued if the following signs or symptoms are noted at any time:
13. Temperature > 38.5°C
14. Lymphadenopathy
15. Pharyngitis
16. Any indication of internal organ involvement (hepatitis, nephritis)
In the absence of the above signs or symptoms, subjects with Grade 2 rash may continue 
the study drug at the discretion of the Investigator.  It should be noted that oral mucosal 
erosions may be part of a Grade 2 rash.  Any mucosal ulceration increases the severity 
of the rash to at least Grade 3.  The subject should be advised to contact the Investigator 
immediately if there is any worsening of the rash, if any systemic signs or symptoms 
worsen, or if mucosal ulceration develops. If the rash is considered to be most likely due 
to concomitant illness or non-study medication, standard management, including 
discontinuation of the likely causative agent, should be undertaken. If no other causative 
factor is found after clinical evaluation, the subject may be treated symptomatically until 
the rash resolves. Antihistamines, topical corticosteroids or antipruritic agents may be 
prescribed.  The subject should remain on the study to be followed for safety and PK as 
outlined in Section 10.5.
Grade 3 rash (Diffuse macular, maculopapular, or morbilliform rash with vesicles 
or limited number of bullae OR Superficial ulcerations of mucous membrane 
limited to one site):
Subjects with a Grade 3 rash will permanently discontinue the study medication.  The 
subject should be evaluated in the physician’s office immediately and should be seen in 
the physician’s office or contacted by phone every 2 days until the rash resolves.  A 
dermatologist should be consulted and digital photographs and a biopsy should be 
obtained.  Antihistamines, topical corticosteroids or antipruritic agents may be prescribed 
at the discretion of the Investigator.  The subject should be advised to contact the 
Investigator immediately if there is any worsening of the rash, if any systemic signs or 
symptoms appear, or if mucosal involvement develops.  The subject should remain on the 
study to be followed for safety and PK as outlined in Section 10.5.
Grade 4 rash (Extensive or generalized bullous lesions OR Stevens-Johnson 
syndrome OR Ulceration of mucous membrane involving two or more distinct 
mucosal sites OR Toxic epidermal necrolysis (TEN)):
Subjects with a Grade 4 rash will permanently discontinue the study medication.  A 
dermatologist should be consulted and digital photographs and a biopsy should be 
obtained.  Sponsor and GSK Medical Monitor should be notified of this serious adverse 
event within 24 hours via phone or fax.  The subject should be closely followed everyday 
until resolution of the reaction.  The subject should remain on the study to be followed 
for safety and PK as outlined in Section 10.5.
 
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ALLERGIC REACTION
Grade 1 allergic reaction (Pruritis without rash):
Subjects with Grade 1 allergic reaction should be evaluated by the Investigator 
immediately.  The study drug should be permanently discontinued if the following signs 
or symptoms are noted at any time:
17. Temperature > 38.5°C
18. Eosinophilia
19. Respiratory involvement including bronchospasm, laryngospasm, or 
angioedema
20. Any indication of internal organ involvement (hepatitis, nephritis)
In the absence of the above signs or symptoms, subjects with Grade 1 allergic reaction 
may continue the study drug at the discretion of the Investigator.  The subject should be 
advised to contact the Investigator immediately if there is any worsening of the allergic 
reaction and/or if any systemic signs or symptoms worsen.  If the allergic reaction is 
considered to be most likely due to concomitant illness or non-study medication, standard
management, including discontinuation of the likely causative agent, should be 
undertaken.  If no other causative factor is found after clinical evaluation, the subject may 
be treated symptomatically until the rash resolves. Antihistamines, topical corticosteroids 
or antipruritic agents may be prescribed.  The subject should remain on the study to be 
followed for safety and PK as outlined.
Grade 2 allergic reaction (Localized urticaria):
Subjects with Grade 2 allergic reaction should be evaluated by the Investigator 
immediately.  The study drug should be permanently discontinued if the following signs 
or symptoms are noted at any time:
21. Temperature > 38.5°C
22. Eosinophilia
23. Respiratory involvement including bronchospasm, laryngospasm, or 
angioedema
24. Any indication of internal organ involvement (hepatitis, nephritis)
In the absence of the above signs or symptoms, subjects with Grade 2 allergic reaction 
may continue the study drug at the discretion of the Investigator.  The subject should be 
advised to contact the Investigator immediately if there is any worsening of the allergic 
reaction and/or if any systemic signs or symptoms worsen.  If the allergic reaction is 
considered to be most likely due to concomitant illness or non-study medication, standard 
management, including discontinuation of the likely causative agent, should be 
undertaken.  If no other causative factor is found after clinical evaluation, the subject may 
be treated symptomatically until the rash resolves. Antihistamines, topical corticosteroids 
or antipruritic agents may be prescribed.  The subject should remain on the study to be 
followed for safety and PK as outlined in Section 7.
 
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Grade 3 allergic reaction (Generalized urticaria or angioedema):
Subjects will permanently discontinue the study medication and be withdrawn from the 
trial.  Subjects will be treated as clinically appropriate.  Subjects should be followed up 
until resolution of the adverse event and standard management should be undertaken.
Grade 4 allergic reaction (Anaphylaxis):
Subjects will permanently discontinue the study medication and be withdrawn from the 
trial.  Subjects will be treated as clinically appropriate.  Subjects should be followed up 
until resolution of the adverse event and standard management should be undertaken.
Revised ACTG Toxicity Grade
Definitions
Investigator Action
Grade 1
Pruritus without rash
May continue therapy
Grade 2
Localized urticaria
May continue therapy
Grade 3
Generalized urticaria
Angioedema
Discontinue Therapy
Grade 4
Anaphylaxis
Discontinue Therapy
 
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12.10.
Appendix 10: Protocol Amendment Changes
12.10.1.
AMENDMENT 1
Protocol Amendment 1 (26-Apr-2017) from the original protocol (09-Nov-2016)
Where the Amendment Applies
This amendment applies to all subjects who will participate in this study in all countries.
List of Specific Changes: (bold indicates text added and strikethrough indicates text 
removed)
Summary of Protocol Amendment Changes with Rationale
Amendment 1 includes minor updates to Inclusion criteria (IE) criteria, including 
clarification on use of pre- or post-exposure prophylaxis, and removal of exclusionary 
requirements related to concomitant medications and tobacco and alcohol use during the 
study. Guidance around relevant habits is included in the Lifestyle section of the protocol 
and adjustments were made to reduce restrictions on these requirements. Modifications 
were also made to the pharmacokinetics sampling, allowing for the 12 h PK collection 
timepoint on Day 1 and 10 to be optional. Minor alterations were made regarding the 
order of screening procedures, including the Holter monitoring requirements. 
Visit/procedure windows were included to allow more flexibility with scheduling of 
assessments. Furthermore, the serial ECG collection (up to 6h post-dose) was removed on 
Day 5. Finally, the post-study care guidance was updated to include an option for subjects 
to receive reimbursement for marketed ART for a limited period after completion of 
study treatment and follow up. Minor clarifications, reformatting of tables, re-numbering 
of sections and correction of typographical errors were also made throughout this 
amendment.
List of Authors
Rationale for change
The list of authors was updated based on internal GSK team personnel changes.
Revised Text
PTS, Ware, UK
GCSP, Stockley Park, UK
Infectious Diseases, Clinical, Upper Providence, PA, US
Clinical Statistics, GSK, Upper Providence, PA, US
HIV DPU, RTP, NC, US
Virology, HIV DPU, RTP, NC, US
 
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CPMS, GSK, RTP, NC, US
HIV DPU, RTP, NC, US
Clinical Pharmacology, ViiV Healthcare, RTP, NC, US
PCPS, GSK, Upper Providence, PA, US
PCPS, GSK, Collegeville, PA, US 
Clinical Statistics, PAREXEL, RTP, NC, US
Infectious Diseases, Clinical, Cambridge, MA, US
Medical Monitor/SAE Contact Information
Rationale for change
The sponsor and medical monitoring information was updated to reflect the current 
contact information for safety and medical monitoring. 
Revised Text
Role
Name
Day Time 
Phone Number 
and email 
address
After-hours 
Phone/Cell/
Pager Number
Fax Number
Site Address
Primary 
Medical 
Monitor/SAE 
contact 
information
MD
Pharmaceutical 
Product 
Development
(PPD) Safety 
Hotline 
Boston, 
MAPPD, 929 
North Front 
Street, 
Wilmington, 
NC 28401
Secondary 
Medical 
Monitor
MD
GlaxoSmithKline
1250 St 
Collegeville Rd 
Collegeville, PA 
19426
SAE contact 
information
MD
Boston, MA
Synopsis:
Design, Treatment Arms and Duration
Rationale for change
Minor clarifications were made to this section to reflect current status of studies being 
referenced. As synopsis being a standalone document, cross-referenced has been 
removed.
 
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Revised Text
Fourth paragraph
The possibility that an additional, unboosted GSK2838232 monotherapy cohort will be 
assessed in Part B is dependent on analysis of the PK data from ongoing Study 204953 
where unboosted GSK2838232 at a dose of 200 mg twice daily (BID) is being was
assessed.
Sixth paragraph
HIV Drug Resistance: Following cessation of GSK2838232/cobi dosing for 10 days, 
there will be prolonged exposure to waning plasma concentrations of GSK2838232, 
because of the long t½ (i.e., in the “tail” of the PK profile). However, based on in vitro 
resistance passage data with GSK2838232 [and unlike with many other ARV therapies], 
there appears to be a limited likelihood of developing maturation resistance mutations in 
HIV-infected subjects due to its virologic profile [GSK Document Number 
2013N163221_00]. 
Section 2
Introduction
Rationale for change
Abbreviation used on first instance has been defined.
Revised Text
GSK2838232 is a novel human immunodeficiency virus (HIV)-1 maturation inhibitor 
(MI) that is being developed for the treatment of HIV-1 infection in combination with 
other antiretrovirals (ART).
Section 2.1 Study Rationale
Rationale for change
Abbreviation used on first instance has been defined.
Revised Text
This ‘proof of concept (PoC)’ open-label study is being conducted to characterize the 
acute antiviral activity, pharmacokinetics (PK), the relationship between PK and antiviral 
activity, and safety of GSK2838232 given with 150 mg once daily (QD) cobicistat 
(GSK283232/cobi), administered across a range of doses over 10 days in HIV-1 infected 
patients. A two part adaptive and dose ranging design is to be applied in this study. Data 
from this study will be utilized to select doses for further studies in Phase IIb.
 
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Section 2.2 Brief Background
Rationale for change
Abbreviation used on first instance has been defined.
Addition of abbreviation for AIDS in first paragraph
Combination antiviral therapy with inhibitors of HIV protease, integrase, entry and 
reverse transcriptase (RT) has demonstrated significant improvement in acquired 
immunodeficiency syndrome (AIDS)-related morbidity and mortality over the last 10-
15 years.
Addition of abbreviation for RNA in second paragraph
Prior validation of this target was demonstrated with the HIV maturation inhibitor known 
as bevirimat (BVM; [Martin, 2007a; Martin, 2007b; Martin, 2008; NORVIR, 2013]). 
BVM reached Phase II studies in HIV patients; however, only modest reductions in 
plasma HIV-1 ribonucleic acid (RNA) concentrations were observed in Phase IIa 
monotherapy studies [Mahmood, 2006; Martin, 2007] and a pattern of polymorphic 
(differential) antiviral activity [Wainburg, 2010] led to termination of BVM development. 
The average decrease from baseline to Day 14 plasma HIV-1 ribonucleic acid (RNA) 
was 0.54 and 0.70 log10 copies/mL for 200 mg and 300 mg twice daily regimens (Table 
2); all subjects achieved plasma BVM concentrations above the in vitro EC90. 
Responders, classified based on 5 polymorphisms in HIV-1 gag (at positions 369, 370, 
and 371), achieved an average 1.15 log10 copies/mL reduction in plasma HIV-1 RNA, 
while an average 0.17 log10 copies/mL reduction was achieved for non-responders.
Section 2.2.2
Clinical Summary of Safety and Pharmacokinetics
Rationale for change
Minor clarifications were made to this section to reflect current status of studies being 
referenced.
Revised Text
To date, GSK2838232 has been evaluated in three completed clinical studies with or 
without ritonavir (RTV) (GSK2838232/r). A fourth study (204953) is on-going as of 1st
November completed late 2016 and data analysis is ongoing. Full details of the clinical 
results can be found in the Investigator’s Brochure.
Section 2.2.2.1
Clinical Summary of Safety
Rationale for change
Minor clarifications were made to this section to reflect current status of studies being 
referenced.
 
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Revised Text
Fifty As of November 2016 fifty-three subjects have had been exposed to GSK2838232 
in 3 completed studies. One study (204953) is completed in late 2016 and the analysis 
of results are ongoing (52 subjects have been 63 subjects were exposed to 
GSK2838232/r or placebo so far in this study). Overall, drug-related adverse events have 
been few and mild, and included headache, dizziness, fatigue, nausea, and palpitations 
and anxiety.  Similarly, treatment-emergent laboratory abnormalities have also been few 
and mostly grade 1.  There have been no discernible patterns, thus far, in terms of AEs or 
laboratory abnormalities.
Section 2.2.2.2
Study 204953 (completed); Pharmacokinetic Data
Rationale for change
Minor clarifications were made to this section to reflect current status of studies being 
referenced.
Change in Heading
Section 2.2.2.2
Study 204953 (on-going completed); Pharmacokinetic Data
Section 4.4.1
Risk Assessment
Rationale for change
Abbreviation used on first instance has been defined.
Revised Text
 
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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
HIV-1 Infection/Patient population
HIV Resistance
Propensity for co-meds and 
possible Drug-Drug 
Interactions (DDIs)
HIV Drug Resistance to unique mechanism
Recognize HIV patients have a higher chance of comorbidities/diseases and a 
risk of taking a medicine or product contraindicated in the study
Closely monitor HIV viral load and genotypic 
resistance
Strict adherence to protocol criteria around 
concurrent meds 
 
 
 
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Section 5.1
Inclusion Criteria
Rationale for change
Changes were made to this inclusion criteria to clarify that prior  use of pre- or post-
exposure prophylaxis would not exclude a subject from participation as long as last dose 
was 6 weeks before starting study treatment.
Revised Text
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
5 . Confirmed HIV positive; CD4+ cell count ≥350 cells/mm3 and plasma HIV-1 RNA 
≥5000 copies/mL at Screening. No current and no prior ART. (A previous course of 
pre- or post-exposure prophylaxis is allowed provided that it was completed at least 
6 weeks prior to the first dose of study drug).
Section 5.2
Exclusion Criteria
Rationale for change
This exclusion criteria was removed and the guidance for use of concomitant medications 
was further addressed in Section 6.12, Concomitant Medications and Non-Drug 
Therapies. The Relevant Habits section of the Exclusionary criteria was also removed 
and addressed in Section 6.10, Lifestyle and/or Dietary Restrictions, with the exception 
of illicit drug use. Smoking and limited alcohol use are no longer exclusionary. 
Additional clarification added to note that positive Hepatitis C result would need to be 
confirmed by RIBA. Abbreviation used on first instance has been defined.  Additional 
minor typographical errors were corrected.
Revised Text
CONCOMITANT MEDICATIONS
5.
Unable to refrain from the use of prescription or non-prescription drugs, including 
vitamins, herbal and dietary supplements (including St John’s Wort) within 7 days 
(or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is 
longer) prior to the first dose of study medication, unless in the opinion of the 
Investigator and GSK Medical Monitor the medication will not interfere with the 
study procedures or compromise subject safety. 
RELEVANT HABITS
6.
History of regular alcohol consumption within 6 months of the study defined as: 

An average weekly intake of >14 drinks for males or >7 drinks for females.  One 
drink is equivalent to 12 g of alcohol: 12 ounces (360 mL) of beer, 5 ounces 
(150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.
7.
Smoking is an exclusion criteria for this study. Urinary cotinine levels indicative of 
 
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smoking at screening.
6.
Chronic marijuana or use of other elicit medications (cocaine, heroin) is an exclusion 
criteria.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
7 . Presence of hepatitis B surface antigen (HBsAg), positive (confirmed by 
Recombinant Immuno-Blot Assay [RIBA]) hepatitis C antibody test result at screening 
or within 3 months prior to first dose of study treatment.
19 . Exclusion criteria for screening ECG (a single repeat is allowed for eligibility 
determination):
Males
Females
Heart rate
<45 and >100 bpm
<50 and >100 bpm
PR Interval
<120 and >220 msec
QRS duration
<70 and >120 msec
*QTc interval
>450 msec
*The QTc is the QT interval corrected for heart rate according to Bazett’s formula 
(QTcB), Fridericia’s formula (QTcF), and/or another method. It is either machine-
read or manually over-read. The specific formula used to determine eligibility and 
discontinuation for an individual participant in 204953200911 will be Fridericia’s 
formula. 
Section 6.1
Investigational Product and Other Study Treatment
Rationale for change 
Minor typographical error corrected in this section. 
Revised Text
Treatment
Product name:
GSK2838232 
Capsule (API)
Tybost 
(cobicistat, cobi) tablet
Method for 
individualizing dosage:
Capsules supplied in high-density 
polyethylene bottles for 
individualized dosing by the clinic
Capsules Tablets supplied in bulk 
containers for individualized dosing by 
the clinic
Section 6.9
Treatment after the End of the Study
Rationale for change 
Additional language was included in this section to allow subjects to opt to receive 
reimbursement from GSK for up to 3 months for marketed antiretroviral therapy (as 
 
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directed and prescribed by physician) based on the CDC guideline recommendations that 
patients be put on ARTs when diagnosed with HIV (test and treat guidelines). 
Revised Text
Subjects will not receive any additional treatment from GSK.
Subjects receiving GSK2838232 may opt to receive marketed antiretrovirals after 
the completion of 10 days of GSK2838232 dosing and study follow-up visits 
(through Day 21) eligible for sponsor company reimbursement up to a maximum of 
90 days. The selection of antiretrovirals will be investigator-chosen.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
reimbursement for post-study treatment.
Section 6.10.1
Meals and Dietary Restrictions
Previous section number 6.12
Rationale for change
This section was updated to remove language around meal provisions (language 
consistent for an in-patient trial). As this is an out-patient trial, it will be up to trial site to 
arrange when/how meals are provided during a subject’s participation in the trial. The 
section ‘Lifestyle and/or Dietary Restrictions’ had no content described under it. The 
sections ‘Meals and Dietary Restrictions’ and ‘Alcohol, Caffeine and Exercise’ has been 
moved as sub-sections under the section ‘Lifestyle and/or Dietary Restrictions’, as the 
sub-sections are related to this section.   
Revised Text
Second Bullet
Doses will be given in the fed state (light breakfast), following overnight fasting (>10 
hours). Lunch will provided 4 hours after the dose; water will be allowed ad libitum 
throughout.
Section 6.10.2
Alcohol, Caffeine and Exercise
Previous section number 6.13
Rationale for change 
Adjustments were made to these lifestyle habits to eliminate restrictions on use of 
tobacco products, reduce restrictions on alcohol use and to allow occasional and light 
exercise during study treatment.  
 
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Revised Text
Alcohol, Caffeine, Tobacco and Exercise

Subjects should refrain from alcohol for 48 hours before screening and then for 48 
hours prior to admission and baseline assessments (on Day 1). Alcohol is then not 
permitted for the duration of the treatment period (through Day 10) and until the 
final follow-up visit.  

Use of tobacco products is not allowed from screening until after the final follow-up 
visit

Subjects will During  the study  alcohol consumption should be limited to the 
following:

An average weekly intake of <14 drinks for males or <7 drinks for females.  
One drink is equivalent to 12 g of alcohol: 12 ounces (360 mL) of beer, 5 
ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.

Subjects will should abstain from strenuous exercise for 72 hours prior to each blood 
collection for clinical laboratory tests.  Subjects may participate in light recreational 
activities during studies (e.g., watch television, read).the treatment period.
Section 6.11
Contraception
Rationale for change
This section was updated to clarify that use of oral contraceptives are permitted during 
the study.
Revised Text
Second paragraph
Females of reproductive potential may only be enrolled if they are using two forms of 
complementary contraception, which must include one barrier method.  There Although 
use of oral contraceptives is permitted, tThere is no definitive DDI information with 
GSK2838232 and an interaction with oral contraceptives is possible, so other (barrier, 
inter-uterine device etc.) methods of contraception will be required.
Section 6.12
Concomitant Medications and Non-Drug Therapies
Previous section number 6.14
Rationale for change
Adjustments were made to the concomitant medication section to clarify that certain 
(medically necessary) medications were allowed and that all medication use should be 
discussed with the investigator. As section on ‘Meals and Dietary Restrictions’ (previous 
section 6.12) and ‘Alcohol, Caffeine and Exercise’ (previous section 6.13) has been 
moved under Lifestyle and/or Dietary Restrictions’ (Section 6.10), the section has been 
re-numbered.
 
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Deleted Text

Subjects must refrain from all illicit drugs throughout the study (from Screening until 
discharge from the study).  Drug screening will occur at Screening and Day -1 for 
each treatment period.  A positive result will lead to exclusion from the remainder of 
the study.

The Principal Investigator must be informed as soon as possible about any 
medications taken from the time of screening until the subject is discharged from the 
study.  Over-the-counter medications will not be permitted during the treatment 
period except as needed to treat an AE. If medication is needed, use should be 
restricted to 4 hours after dosing if possible. 
Section 6.12.1
Permitted Medications and Non-Drug Therapies
Previous section number 6.14.1
Rationale for change
Adjustments were made to the concomitant medication section to clarify that certain 
(medically necessary) medications were allowed and that all medication use should be 
discussed with the investigator. As section on ‘Meals and Dietary Restrictions’ (previous 
Section 6.12) and ‘Alcohol, Caffeine and Exercise’ (previous Section 6.13) has been 
moved under Lifestyle and/or Dietary Restrictions’ (Section 10), the section has been re-
numbered.
Revised Text
Addition of Second bullet

Concomitant medications (prescription and non-prescription) should be 
administered only as medically necessary during the study. Subjects must 
notify their Investigator of any current or proposed concomitant medication, 
whether prescribed or over-the-counter, because of the potential for 
interactions between such treatments and the study medications.
Section 6.12.2
Prohibited Medications and Non-Drug Therapies
Rationale for change 
Adjustments were made to the concomitant medication section to clarify that certain 
(medically necessary) medications were allowed and that all medication use should be 
discussed with the investigator. As section on ‘Meals and Dietary Restrictions’ (previous 
Section 6.12) and ‘Alcohol, Caffeine and Exercise’ (previous Section 6.13) has been 
moved under Lifestyle and/or Dietary Restrictions’ (Section 10), the section has been re-
numbered.
 
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Previous section number 6.14.2
Revised Text

Subjects must abstain from taking prescription or non-prescription drugs (including 
vitamins and dietary or herbal supplements), within 7 days (or 14 days if the drug is 
a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first 
dose of study medication until completion of the follow-up visit, unless in the 
opinion of the Investigator and sponsor the medication will not interfere with the
study. 

Subjects must refrain from all illicit drugs throughout the study (from 
Screening until discharge from the study).  Drug screening will occur at 
Screening and Day -1 and at additional timepoints throughout the study.  A 
positive result will lead to exclusion from the remainder of the study.
Section 7.1
Time and Events Table
Rationale for change 
The Time and Events table was updated to remove the post-dose 12-lead ECG on Day 5, 
which remains in line with the FDA’s guidance regarding days on which to perform post-
dose (2 & 6 hours to capture near Tmax) ECGs. Modifications were also made to the 
pharmacokinetics sampling, allowing for the 12 h PK collection timepoint on Day 1 and 
10 to be optional. Visit/procedure windows were included to allow more flexibility with 
scheduling of assessments. Also minor clarifications were made and typographical errors 
were corrected.
Revised Text
 
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Day:
Screen1
Random
1
2
3
4
5
62
7
8
9
10
11
12
141
211 
(FU)
ET
Informed Consent
X
Review inclusion/exclusion
X
X
Demography including height, weight and 
BMI
X
Brief physical
X
Medical/medication/
drug/alcohol history
X
X
CDC Classification
X
X
X
X
Prior antiretroviral therapy
X
12-lead ECG3
X
X
X
X
X
X
X
X
X
X
Holter (24 hr)
X
Vital signs4
X
X
X
X
X
X
X
X
X
Drug screen
X
X
X
X
X
Hepatitis B Surface antigen and hepatitis 
C antibody testing
X
Serum or urine -hCG (WoCBP only)
X
X
X
Clinical lab tests (inc troponin)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Fasting lipid panel
X
X
AE assessment5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Con Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HIV-1 RNA PCR6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lymphocyte subsets7
X
X
X
Plasma for genotype/phenotype8
X
X
X
X
X
X
X
HIV-associated conditions assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK blood sample9
X
X
X
X
X
X
X
X
X
X
X
XX14
Plasma samples10
X
X
X
Dosing11
X
X
X
X
X
X
X
X
X
X
PGx12
X
AE enquiry13
X
X
X
X
X
X
X
X
X
X
X
X
X
Telephone call to IVRS1314
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
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Day:
Screen1
Random
1
2
3
4
5
62
7
8
9
10
11
12
141
211 
(FU)
ET
Plasma for storage15
X
X
X
X
X
X
X
X
X
X
X
X
X
Outpatient visit
X
X
X
X
X
X
X
X
X
X
X
X
1.
Screening will occur within 14-30 days prior to the first dose of study drug.
2.
Table is set up for the weekend during dosing to occur on Days 6 and 7.  If the weekend occurs on Days 5 and 6, perform all “Day 5” assessments on Day 7.
3.
On Day 1, ECGs (x2) will be performed pre-dose , and then 1, 1.5, 2, 3, 4 and 6 hours post dose.  The pre-dose ECGs should be performed at least 5 minutes apart and 
preferably within 1 hour prior to dose.  On Days 4, 5 and 8, ECGs will be obtained prior to morning dosing and at 2, 4 and 6 hours post-dose. To accommodate scheduling, 
serial ECGs collected on Days 4 and 8 may be performed 1 day.  On Day 10, ECGs (x2) will be performed pre-dose, and then 1, 1.5, 2, 3, 4 and 6 hours post dose.  On 
Day 11, an ECG will be obtained prior to the 24-hour PK sample. ECGs will be performed in triplicate at all timepoints.
4.
BP, RR, HR and temperature will be obtained at Screening (x1) and Day 1 pre-dose (x2).  BP and HR will be obtained on Day 1 at 2 hours post-morning dose and on Days 4, 5 
and 8 pre-dose.  BP and HR will be obtained on Day 10 at pre-dose and 2 hours post-morning dose, and at day 12 and Follow-up (Day 21).
5.
Only SAEs related to study participation will be collected between screening and Day 1. An AE enquiry will be made at each visit, subjects will be asked if they have 
experienced any neuropsychiatric adverse events, including psychosis or altered mental status.
6.
On Days 1-5 and 8-10 samples for HIV-1 RNA PCR collected before morning dose.  On Days 1, 10 and 11 two samples for HIV-1 RNA PCR will be collected 5-30 minutes 
apart. HIV-1 RNA PCR samples will also be collected on days 12, 14 & Follow-up (Day 21).
7.
Lymphocyte subsets by flow cytometry (total lymphocyte counts, percentage, and absolute CD4+and CD8+counts).
8.
Blood samples for phenotype and genotype will be collected at pre-dose on Days 1, 4, 5 and 8 in the morning on Day 11 and at follow-up. 
9.
Serial plasma samples (2 mL) for determination of GSK2838232 will be collected on Day 1 and Day 10 at pre dose (within 15 minutes prior to dose) and 0.5, 1, 1.5, 2, 3, 4, 6, 
8, 12 (optional), and 24 hours (to occur on morning of Day 2 post-am dose and in the morning on Day 11) .  Pre-dose PK samples (within 15 minutes prior to dose) will be 
taken on the mornings of Days 3, 4, 5, 8 and 9 and a single sample will be taken on Days 12 and 14.
10. Samples (2 x 0.5mL) of plasma for assessment of immunological markers at screen, baseline (pre-dose) and day 11 
11. Subjects will receive a single dose of GSK2838232 and cobicistat each morning with a light breakfast meal and 240 mL of water from Day 1 to Day 10.  Doses taken in the 
clinic will be administered after an overnight fast of at least 10 hours .On Days 6 and 7, doses will be self administered but confirmed by phone 
12. PGx sample should be collected on Day 1.
13. An AE enquiry will be made at each visit, subjects will be asked if they have experienced any neuropsychiatric adverse events, including psychosis or altered mental status
13. A screening/registration call should be made to the IVRS to register the subject at screening.   An additional call will be made to document a screen failure.   A randomization 
call should be made to the IVRS system approximately one week prior to scheduled Day 1.  Note: The randomization call must be made in order to have study drug on site for 
Day 1. Additional calls will be made every day that the subject has a scheduled study visit to the clinic.  If a subject terminates the study prematurely a call should be made to 
the IVRS
14. Only if early termination visits occur during the treatment period.
15. Plasma samples for storage will be collected at each visit starting at Day 1, including unscheduled visits (e.g. for HIV-1 RNA levels and immunological 
parameters).  Additionally these samples will be used when needed, such as when samples are lost or arrive at the laboratory unevaluable.
AE = Adverse event; CDC= Center for Disease Control and Prevention; ECG = Electrocardiogram; ET = Early termination; hCG = Human chorionic gonadotrophin; HIV = Human 
immunodeficiency virus;  IVRS= Interactive Voice Response System; PCR = Polymerase chain reaction; PK=Pharmacokinetic.
 
 
 
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Section 7.2
Visit Windows
Rationale for Addition
Visit/procedure windows were included to allow more flexibility with scheduling of 
assessments. 
New Section
Screening (baseline to pre-dose): All screening assessments should take place within 
14-21 days prior to the first dose. The screening visit window may be extended to 30 
days upon discussion with the Medical Monitor (i.e.; subject has scheduling conflicts 
or any screening assessment needs to be repeated).
Days 4 and 8: Based on subject and clinic schedule, Day 4 and Day 8 serial (up to 6h 
post-dose) ECG assessments may be conducted 1 day.  
Weekend(s): The T&E table is set up for study start (Day 1) to occur on a Monday 
and Days 6 and 7 to fall on the weekend. If the weekend occurs instead on Days 5 
and 6, Day 5 assessments should be performed on Day 7. The study start (Day 1) 
may also be adjusted to allow visits with assessments to be conducted over the 
weekend based on subject and clinic schedule.  
Assessments: The following applies to timing of procedures:
-
Window for assessments 4 h post-dose = 5 minutes 
-
Window for assessments >4 and < 12 h post-dose = 15 minutes
-
Window for assessments >12 h post-dose = 30 minutes
End of Treatment visit: should be within 14 days from last dose of study drug. If a 
subject is unable to return to the clinic for any reason site staff are encouraged to 
telephone the subject for assessment of adverse events.
Section 7.3.1
Holter Monitoring (Screening criteria)
After addition of new section before this section, the section numbers from this section 
until Sections under 7.0 are re-numbered using the next available section number.  
Rationale for Change 
Minor alterations were made regarding the order of screening procedures, including the 
Holter monitoring requirement to allow flexibility based on clinic and subject schedule.
Revised Text
The 24-hour Holter monitoring should only will be performed at during the Screening 
after the subject has met all other inclusion criteria. period using a Holter monitoring 
device supplied by the Sponsor.
Analysis of the Holter tapes will consider the following:

Heart rate (bradycardia and tachycardia)
 
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
Normal and aberrant beats

Number of supraventricular contractions, premature atrial contractions, premature 
ventricular contractions, couplets, triplets, and ventricular tachycardias

Atrio-ventricular conduction defects

Atrial fibrillation and flutter
Section 7.5.1.1
Time period and Frequency for collecting AE and      
SAE information
Rationale for Change 
Minor clarifications made regarding Sponsor (to include PPD). 
Revised Text
Bullet 4

All SAEs will be recorded and reported to GSK Sponsor within 24 hours, as 
indicated in Appendix 5, Section 12.5.
Section 9.3.2
Interim Analysis
Rationale for Change 
Minor corrections and clarifications were made to this section.
Revised Text
An interim analysis of preliminary safety, tolerability, PK and antiviral activity will occur 
after subjects of Part A Cohort 1 complete their Day 13 visit. If based on this review the 
Cohort 1 dose is determined to be the highest dose based on this review (e.g., the 
exposure level of GSK2838232 is in the range of the maximum GSK2838232 exposure 
seen previously in healthy subjects), the Bayesian posterior probability that the log10 
viral load decline from baseline is greater than a cut-point will be calculated. If the 
Bayesian probability from Cohort 1 is less than 70%, this will provide evidenceto 
evidence to not move forward into Part B. Otherwise, the study team will review the data 
in order to make a dose selection decision for the subsequent Part B Cohorts.  If the 
pharmacokinetic exposures after the 100 mg GSK2838232/cobi dose look similar to 
those obtained with 100 mg GSK2838232/r in prior studies, the doses for Part B will be 
extended to both lower (20 mg, 50 mg) and higher (200 mg) GSK2838232 doses.
Maximum change and change from baseline in plasma HIV-1 RNA will be summarized 
by treatment or by assessment day. The proportion of subjects with plasma HIV-1 RNA 
<400 and <50 copies/mL will be summarized by treatment and assessment day. The 
analyses will be done for both PP and ITT exposed population if the two populations are 
not the same.
Section 10.3
Quality Control (Study Monitoring)
Rationale for Change
Minor clarifications made regarding Sponsor (to include PPD). 
 
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Revised Text
First Bullet
In accordance with applicable regulations including GCP, and GSK procedures, GSK
monitors or designee will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy regulatory, 
ethical, and GSK requirements.
Section 10.5
Study and Site Closure
Rationale for Change 
Minor clarifications made regarding Sponsor (to include PPD). 
Revised Text
First Bullet
Upon completion or premature discontinuation of the study, the GSK monitor or 
designee will conduct site closure activities with the investigator or site staff, as 
appropriate, in accordance with applicable regulations including GCP, and GSK Standard 
Operating Procedures.
Section 11 References
Rationale for Change 
Have mentioned the references as per GSK style guide and template.
Revised Text
Elion R, Cohen C, Gathe J, Shalit P, Hawkins T, Liu HC, et al. Mathias AA, Chuck SL, 
Kearney BP, Warren DR.  Phase 2 study of cobicistat versus ritonavir each with once-
daily atazanavir and fixed-dose emtricitabine.tenofovir df in the initial treatment of HIV 
infection.  AIDS.  2011; 25:1881-1886.
Gallant JE, Koenig E, Andrade-Villaneuva J, Chetchotisakd P, deJesus E, Antunes F, 
Arastéh K, et al. Moyle G, Rizzardini G, Fehr J, Liu Y, Zhong L, Callebaut C, 
Scwarcberg J, Rhee MS, Cheng AK.  Cobicistat versus ritonavir as a pharmacoenhancer 
of atazanavir plus emtricitabine/tenofovir disoproxil fumarate in treatment-naïve HIV 
type 1-infected patients:  week 48 results.  J. Infect. Dis.  2013; 208-:32-39.
Kakuda TN, Opsomer M, Timmers M, Iterbeke K, Van De Casteele T, Hillewaert V, et 
al. Petrovic R, Hoetelmans RMW.  Pharmacokinetics of darunavir in fixed-dose 
combination with cobicistat compared with coadministration of darunavir and ritonavir as 
single agents in healthy volunteers.  J. Clin. Pharmacol.  2009; 54:949-957.
Lalezari J, McCallister S, Gigliotti M, Cohen C, Elion R, Brinson C, et al. Safety and 
efficacy study of bevirimat (BVM) in heavily treatment experienced HIV+ patients 
identifies the target phase 3 study profile. ICAAC. 2008; Abstract: H891. 
Martin DE, Blum R, Wilton J, Doto J, Galbraith H, Burgess GL, et al. Safety and 
pharmacokinetics of bevirimat (PA-457), a novel inhibitor of human immunodeficiency 
 
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virus maturation, in healthy volunteers. Antimicrobial Agents and Chemotherapy. 
2007(b);Sep:3063-6.
Appendix 1
Abbreviations
Rationale for Change 
The abbreviations used in the document are added to the list of abbreviations.
AIDS
Auto Acquired immunodeficiency syndrome
BID 
Twice daily
DDI
Drug-Drug Interaction
PPD
Pharmaceutical Product Development
QD
Once daily
RIBA
Recombinant Immuno-Blot Assay
t1/2t½
Terminal elimination half-life
 
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12.10.2.
AMENDMENT 2
Protocol Amendment 2 (24-MAY-2017) from the Protocol Amendment 1 (26-Apr-2017)
Where the Amendment Applies
This amendment applies to all subjects who will participate in this study in all countries.
List of Specific Changes: (bold indicates text added and strikethrough indicates text 
removed)
Summary of Protocol Amendment Changes with Rationale
Amendment 2 includes expansion of the eligible subject population to allow treatment 
experienced HIV-1 infected patients, in addition to treatment naive patients. Patients with 
a treatment history of a prior maturation inhibitor will still be ineligible. Slight 
modifications were made to include flexible language for enrolment into Part B to allow 
prioritization of one dose cohort or to open randomization into Part B cohorts in a parallel 
fashion. Also the upper limit of the BMI inclusion criteria was increased from 31 to 35 
kg/m2.
Minor clarifications, re-numbering of sections and correction of typographical errors 
were also made throughout this amendment.
Author (s)
Rationale for change A minor correction was made to this section.
A minor correction was made to this section.
Revised Text
                PCPS, GSK, CollegevilleUpper Providence, PA, US
Title Page
Rationale for change
The protocol title was updated to reflect the new subject population, which is no longer 
limited to treatment naive patients.
Revised Text
A Phase 2a, Multicenter, Randomized, Adaptive, Open-label,  Dose Ranging Study to 
Evaluate the Antiviral Effect, Safety, Tolerability and Pharmacokinetics of Cobicistat-
boosted GSK2838232 Monotherapy Over 10 Days in HIV-1 Infected Treatment-Naive
Adults
 
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Synopsis
Rationale
Rationale for change
Minor clarifications were made to this section to provide clarification regarding Study 
204953 (which is now completed). The reference to a parallel enrolment design for Part 
B was also removed to allow for prioritizing enrolment into any one dose cohort based on 
emerging data from Part A.
Revised Text
Second paragraph
Three clinical studies of GSK2838232 (n=53 healthy subjects) have been completed thus 
far. One study (Study 204953) is on-goingcompleted at the end of 2016 and analysis of 
the data is ongoing. Healthy subjects have received GSK2838232 or placebo in single or 
repeated dose designs, to a maximum single dose of 250 mg or repeated dose (for 
11 days) of 200 mg QD, in combination with ritonavir (RTV).
Fifth paragraph
Study 204953 is an on-going study and continues theinvestigated the safety and PK of 
GSK2838232 in single and repeat-doses exploration of safety and PK of GSK2838232as 
well as the suitability of a new, capsule formulation. Doses of up to 250 mg 
GSK2838232/100 mg RTV (as single doses) or 200 mg GSK2838232/100 mg RTV (QD 
for 11 days) were studied. As of 26 October 2016, the study is ongoing with a cohort of 
subjects due to receiveThe final cohort of the study assessed unboosted GSK2838232 
(200mg BID) for 11 days. The study completed at the end of 2016 and the data 
analysis is ongoing.
Seventh paragraph
The objective of Study 200911 is to understand the safety, PK and HIV antiviral profile 
of GSK2838232/cobicistat (GSK2838232/cobi) when given to HIV-infected, treatment 
naive, otherwise healthy adults. Approximately 10 HIV-1 infected subjects will be 
enrolled into Part A. If warranted by an interim safety, virology, and PK data analysis, 
approximately 8 subjects will be enrolled in each of between two and four Cohorts in Part 
B, which will be a parallel group design.
Design, Treatment Arms and Duration
Rationale for change
This section was updated to reflect the new subject population, which is no longer limited 
to treatment naive patients.The reference to a parallel enrolment design for Part B was 
also removed to allow for prioritizing enrolment into any one dose cohort based on 
 
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emerging data from Part A. A reference to Study 205820 was also included as data from 
this planned study will provide additional information on unboosted GSK2838232.
Revised Text
First paragraph
Approximately 34 HIV-1 infected treatment-naive subjects will be enrolled overall.
Second paragraph
This study is a 10-day monotherapy, open-label, adaptive, dose ranging, repeat-dose 
study and will be conducted as two parts with an interim (go/no-go) analysis performed 
after Part A (Table 1). Part A, Cohort 1 will evaluate a safe and well-tolerated dose level 
of GSK2838232 that has been tested (with RTV) in prior Phase I studies and that targets 
a high inhibitory quotient (IQ) value. Following the completion of an interim analysis of 
those data and according to criteria defined later in the protocol, further cohorts of 8 
subjects will then be studied in Part B in a parallel design in two or more cohorts 
(depending upon the data obtained in Part A).
Table 1
Study Design for 200911
Part A: GSK2838232/cobi 
Once Daily x 10 days1
Part B: GSK2838232/cobi 
Once Daily x 10 days1,2
Cohort
N
232 Dose
(mg)
Cohort
N
232 Dose 
(mg)
1
10
100
2
8
200
3
8
50
4
8
20
1. 
Part A Cohort 1 safety/PK/virology data will be evaluated at interim, prior to initiating other cohorts in Part B, which 
are planned to run in a parallel, randomized fashion. All doses will be given with 150 mg cobicistat.
2. 
Part B GSK2838232 doses are an illustration of the projected doses per cohort. The actual doses for each cohort 
and number of cohorts are subject to modification based upon safety, PK and antiviral activity data from Cohort 
1 (Part A). More doses/cohorts (including potential removal of cobi co-dosing) may be added (the maximum dose 
in Part B would likely not exceed 200 mg with cobicistat unless overall plasma exposure [as AUC and Cmax] was 
lower in HIV infected subjects than in healthy subjects at the same dose level).
Fourth paragraph
The possibility that an additional, unboosted GSK2838232 monotherapy cohort will be 
assessed in Part B is dependent on analysis of the PK data from Study 204953 where 
unboosted GSK2838232 at a dose of 200 mg twice daily (BID) was assessed and Study 
205820, which plans to evaluate GSK2838232 at a dose of 500mg once daily (QD).
 
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Section 2.2.2.1
Clinical Summary of Safety
Rationale for change
Minor clarifications were made to this section to provide clarification regarding Study 
204953 (which is now completed).
Revised Text
Fifth paragraph
In ongoingStudy 204953, there have been a small number of CV-related events of any 
sort: There have  been no serious adverse drug reactions, and no clinically significant 
drug-related abnormal findings for 12-lead ECGs, vital signs, safety laboratory results 
(including cardiac troponin I), or telemetry.  The following cardiovascular AEs were 
observed during the course of the study but were not considered to be caused by 
GSK2838232 exposure
Section 2.2.2.2
Study 204953 (completed); Pharmacokinetic Data
Rationale for change
Minor clarifications were made to this section to provide clarification regarding Study 
204953 (which is now completed and analysis is ongoing).
Revised Text
Second paragraph
In addition, it evaluated the relative bioavailability of a single fasted dose of micronized 
API powder blend in capsules with RTV compared to powder-in-bottle for oral 
suspension with RTV and the effect of a normal fat meal on the bioavailability of a single 
dose of GSK2838232 in the capsule formulation with RTV.  It will evaluate 
GSK2838232 exposure after repeated doses of unboosted GSK2838232 in the capsule 
formulation. Noncompartmental PK analysis was performed using scheduled sample 
times.  ThisThe study isanaylsis of data from this study is ongoing; preliminary results 
are presented.
Section 4.1 Overall Design
Rationale for change
This section was updated to reflect the new subject population, which is no longer limited 
to treatment naive patients.The reference to a parallel enrolment design for Part B was 
also removed to allow for prioritizing enrolment into any one dose cohort based on 
emerging data from Part A.
 
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Revised Text
First paragraph
This is a Phase IIa, multicenter, open-label, adaptive dose ranging, study to evaluate the 
antiviral effect, safety, tolerability, and PK of GSK2838232/cobi monotherapy over 10 
days in ART-naïve HIV-1 infected adults who are not currently receiving ART therapy. 
Subjects who have received any ART (including prior MI) prior maturation ihibitor
therapy will not be eligible for this study. To minimize the number of subjects exposed to 
suboptimal doses, an adaptive and dose ranging design is applied in this study.
Study Design for 200911
GSK2838232/cobi Once Daily for 10 days1,2
Part A
Part B 
Cohort 1
Dose
(mg)
Interim Analysis
Cohort
N
(mg)
N=10
100
2
8
200
3
8
50
4
8
20
Day 1 – Day 10: Dosing
Second paragraph
Serial, intensive blood PK samples will be collected on Day 1 (up to 24 hours post-
morning dose) and Day 10 (up to 96 hours post-morning dose), and limited, single blood 
PK samples pre-morning doses on Days 3 through 9, except for the weekend. Subjects 
will be required to fast for 10 hours [overnight] prior to the morning check in on the 
intensive PK sampling days (Days 1 and 10).  All dosing days will require co-
administration of treatment with a light snack/meal per cobicistat labeling guidelines. All 
doses of study medication will be taken with 240 mL of water.  Subjects will be required 
to stay in the clinic on Days 1 and 10 until all specified assessments are completed (8-12 
hours post-dose). Following Day 10, subjects will be required to attend the clinic for 
follow up assessments including virological and PK blood sampling for up to 3 weeks.
1 . Part A Cohort 1 safety/PK/virology data will be evaluated at interim, prior to initiating 
other cohorts in Part B, which are planned to run in a parallel, randomized fashion.  All 
doses will be given with 150 mg cobicistat.
2 . Part B doses are an illustration of the projected doses per cohort. The actual doses for 
each cohort are subject to modification based upon safety, PK and antiviral activity data 
from Cohort 1 (Part A). More doses/cohorts (including potential removal of cobicistat co-
dosing) may be added. (The maximum dose in Cohort B will likely not exceed 200 mg 
with cobicistat unless overall plasma exposure [as AUC and Cmax] is lower in HIV-
infected subjects than in healthy subjects at the same dose level).
 
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Section 4.2 Type and Number of Subjects
Rationale for change
Minor clarifications were made to this section.
Revised Text
At least 34 subjects will be enrolled such that approximately 6-10 evaluable subjects 
complete a number of cohorts.  Additional subjects/cohorts may be enrolled to allow for 
evaluation of additional dose levels as appropriate. 
If subjects prematurely discontinue the study, additionalreplacement subjects may be 
randomisedrandomized and assigned to the same treatment cohort at the discretion of the 
Sponsor in consultation with the Investigator.
Section 4.3 Design/Dose Justification
Rationale for change
Minor clarifications were made to this section to provide clarification regarding Study 
204953 (which is now completed).
Revised Text
Last paragraph
There is no a priori intention to study GSK2838232 unboosted, unless: i) following the 
preliminary analysis of Part A Cohort 1, there is such pronounced antiviral activity that it 
would seem the estimates of projected IQ are low, in which case GSK2838232 may be 
evaluated in a subsequent cohort unboosted, or ii) the data from ongoing and planned 
healthy volunteer trials,Cohort 7 in Study 204953 (planned, GSK2838232 200 mg BID 
unboosted) and Study 205820 (GSK2838232 500mg QD unboosted) support it.
Section 4.3.3
Interim Analysis
Rationale for change
Minor clarifications were made to this section to allow for flexibility around selecting 
dose cohorts for Part B based on emerging data from Part A.
Revised Text
An evaluation of GSK2838232 safety, efficacy and PK data will be done after Part A 
Cohort 1, if the exposure level of GSK2838232 is in the range of the maximum 
GSK2838232 exposure seen previously in healthy subjects and the Bayesian probability 
from Cohort 1 is less than 70%, the study will not move forward into Part B, otherwise 
doses will be selected for evaluation in Part B. If pharmacokinetic exposure after the 100 
mg GSK2838232/cobi dose is in the range of values observed after 100 mg 
GSK2838232/r in prior studies, the doses for Part B will be extended to both lower 
 
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(20 mg and/or, 50 mg) and higher (200 mg) doses. The highest dose tested in Part B will 
be selected to result in exposures similar to those seen with 200 mg/r in Study 204953.
Section 4.4.3
Overall Benefit:Risk Conclusion
Rationale for change
Minor clarifications were made to this section to provide clarification regarding Study 
204953 (which is now completed).
Revised Text
To date, 11553 healthy subjects have received GSK2838232 in fourthree completed 
studies. One study (204953) is ongoing (52 healthy subjects have completed this study so 
far).
Section 5
SELECTION OF STUDY POPULATION AND WITHDRAWAL 
CRITERIA
Rationale for change
This section was updated to reflect the new subject population, which is no longer limited 
to treatment naive patients.The reference to a parallel enrolment design for Part B was 
also removed to allow for prioritizing enrolment into any one dose cohort based on 
emerging data from Part A.
Revised Text
Second paragraph
Approximately 10-12 HIV-1 infected subjects will be enrolled into Part A. If warranted 
by an interim safety, virology and PK data analysis, approximately 8 subjects will be 
enrolled in each of Cohorts 2-4 in Part B, which will be a parallel group design. Eligible 
patients are those who are maturation inhibitorART-naïve and who are not currently 
receiving ART therapy.
Last paragraph
If subjects prematurely discontinue the study, additional subjects may be enrolled as 
replacement subjects and assigned to the same treatment at the discretion of the Sponsor.
Section 5.1 Inclusion Criteria
Rationale for change
The inclusion criteria were updated to reflect the new subject population, which is no 
longer limited to treatment naive patients. Also the upper limit of the BMI inclusion 
criteria was increased from 31 to 35 kg/m2. 
 
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Revised Text
5. Confirmed HIV positive; CD4+ cell count ≥350 cells/mm3 and plasma HIV-1 RNA 
≥5000 copies/mL at Screening. No current and no prior ART. (A previous course of pre-
or post-exposure prophylaxis is allowed provided that it was completed at least 6 weeks 
prior to the first dose of study drug).
5 .6. Antiretroviral treatment naive or ART-experienced (maturation inhibitor 
naive). No current ART (last dose completed at least 6 weeks prior to the first dose 
of study drug). (A previous course of pre- or post-exposure prophylaxis is allowed 
provided that it was completed at least 6 weeks prior to the first dose of study drug).
6 .7. Body weight 50 kg (110 lbs.) for men and 45 kg (99 lbs) for women and body 
mass index (BMI) within the range 18.5-351.0 kg/m2 (inclusive)
Section 6.2 Treatment Assignment
Rationale for change
A minor clarification was made to this section.
Revised Text
Subjects will be assigned to treatment (active) groups in accordance with the 
randomization schedule generated by Clinical Statistics, prior to the start of the study, 
using validated internal software.
Section 6.4 Blinding
Rationale for change
Minor clarifications were made to this section.
Revised Text
This will be an open-label study. Treatment allocation and GSK2838232 dose levels in 
Part B will be determined after the analysis of Part A data. randomised (to 
GSK2838232 dose level).
 
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1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A Phase 2a, Multicenter, Randomized, Adaptive, Open-label,  
Dose Ranging Study to Evaluate the Antiviral Effect, Safety, 
Tolerability and Pharmacokinetics of Cobicistat-boosted 
GSK2838232 Monotherapy Over 10 Days in HIV-1 Infected 
Treatment-Naive Adults
Compound Number:
GSK2838232
Development Phase:
IIA
Effective Date:
26-APR-2017
Protocol Amendment Number:  01
Author (s):
             PTS, Ware, UK
             GCSP, Stockley Park, UK
             Infectious Diseases, Clinical, Upper Providence, PA, US
             Clinical Statistics, GSK, Upper Providence, PA, US
            HIV DPU, Clinical RTP, NC, US
            Virology, HIV DPU, RTP, NC, US
            CPMS, GSK, RTP, NC, US
            HIV DPU, RTP, NC, US
            Clinical Pharmacology, ViiV Healthcare, RTP, NC, US
            PCPS, GSK, Upper Providence, PA, US
            PCPS, GSK, Collegeville, PA, US
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2015N227852_00
2016-NOV-09
Original
2015N227852_01
2017-APR-26
Amendment No. 1
Amendment 1 includes minor updates to Inclusion-Exclusion (IE) criteria, including
clarification on use of pre- or post-exposure prophylaxis, and removal of exclusionary 
requirements related to concomitant medications and tobacco and alcohol use during the 
study. Guidance around relevant habits is included in the Lifestyle section of the protocol 
and adjustments were made to reduce restrictions on these requirements. Modifications
were also made to the pharmacokinetics sampling, allowing for the 12 h PK collection 
timepoint on Day 1 and 10 to be optional. Minor alterations were made regarding the 
order of screening procedures, including the Holter monitoring requirements. 
Visit/procedure windows were included to allow more flexibility with scheduling of 
assessments. Furthermore, the serial ECG collection (up to 6h post-dose) was removed on 
Day 5. Finally, the post-study care guidance was updated to include an option for subjects 
to receive reimbursement for marketed ART for a limited period after completion of 
study treatment and follow up. Minor clarifications, reformatting of tables, re-numbering 
of sections and correction of typographical errors were also made throughout this 
amendment.
 
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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time 
Phone Number 
and email 
address
After-hours 
Phone/Cell/
Pager Number
Fax Number
Site Address
Primary 
Medical 
Monitor/SAE 
contact 
information 
Pharmaceutical 
Product 
Development 
(PPD) Safety 
Hotline 
PPD, 929 North 
Front Street, 
Wilmington, NC 
28401
Secondary 
Medical Monitor
 MD
GlaxoSmithKline
1250 St 
Collegeville Rd 
Collegeville, PA 
19426
Sponsor Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.   
Regulatory Agency Identifying Number(s):  116,094
 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol 200911 
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date
 
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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 200911........................................................9
2.
INTRODUCTION....................................................................................................13
2.1.
Study Rationale ..........................................................................................13
2.2.
Brief Background ........................................................................................13
2.2.1.
Preclinical Summary....................................................................14
2.2.2.
Clinical Summary of Safety and Pharmacokinetics ......................19
2.2.2.1.
Clinical Summary of Safety.........................................19
2.2.2.2.
Study 204953 (completed); Pharmacokinetic 
Data ...........................................................................20
2.2.2.3.
Overall Summary/Conclusions of PK data..................23
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................25
4.
STUDY DESIGN ....................................................................................................26
4.1.
Overall Design ............................................................................................26
4.2.
Type and Number of Subjects.....................................................................27
4.3.
Design/Dose Justification............................................................................28
4.3.1.
GSK2838232 with Ritonavir.........................................................28
4.3.2.
GSK2838232 with Cobicistat .......................................................29
4.3.3.
Interim Analysis ...........................................................................29
4.4.
Benefit:Risk Assessment ............................................................................30
4.4.1.
Risk Assessment .........................................................................31
4.4.2.
Benefit Assessment.....................................................................33
4.4.3.
Overall Benefit:Risk Conclusion...................................................33
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............33
5.1.
Inclusion Criteria.........................................................................................34
5.2.
Exclusion Criteria........................................................................................36
5.3.
Screening/Baseline/Run-in Failures............................................................38
5.4.
Withdrawal/Stopping Criteria.......................................................................39
5.4.1.
Liver Chemistry Stopping Criteria ................................................39
5.4.1.1.
Study Treatment Restart or Rechallenge....................40
5.4.2.
QTc Stopping Criteria ..................................................................40
5.5.
Stopping criteria based on Adverse Events.................................................41
5.6.
Subject and Study Completion....................................................................41
6.
STUDY TREATMENT ............................................................................................41
6.1.
Investigational Product and Other Study Treatment....................................41
6.2.
Treatment Assignment................................................................................42
6.3.
Planned Dose Adjustments.........................................................................42
6.4.
Blinding.......................................................................................................42
6.5.
Packaging and Labeling..............................................................................42
6.6.
Preparation/Handling/Storage/Accountability..............................................42
6.7.
Compliance with Study Treatment Administration.......................................43
6.8.
Treatment of Study Treatment Overdose....................................................43
6.9.
Treatment after the End of the Study ..........................................................44
6.10.
Lifestyle and/or Dietary Restrictions............................................................44
6.10.1.
Meals and Dietary Restrictions ....................................................44
 
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6.10.2.
Alcohol, Caffeine and Exercise ....................................................44
6.11.
Contraception .............................................................................................44
6.12.
Concomitant Medications and Non-Drug Therapies....................................45
6.12.1.
Permitted Medications and Non-Drug Therapies..........................45
6.12.2.
Prohibited Medications and Non-Drug Therapies.........................45
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................45
7.1.
Time and Events Table...............................................................................47
7.2.
Visit Windows .............................................................................................49
7.3.
Screening and Critical Baseline Assessments ............................................49
7.3.1.
Holter Monitoring (Screening criteria)...........................................49
7.4.
Efficacy.......................................................................................................50
7.4.1.
HIV-1 RNA Sampling ...................................................................50
7.4.2.
Lymphocyte Subsets by Flow Cytometry .....................................50
7.5.
Safety .........................................................................................................50
7.5.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........50
7.5.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................51
7.5.1.2.
Method of Detecting AEs and SAEs ...........................51
7.5.1.3.
Follow-up of AEs and SAEs........................................51
7.5.1.4.
Cardiovascular and Death Events ..............................52
7.5.1.5.
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ................52
7.5.1.6.
Regulatory Reporting Requirements for SAE..............53
7.5.2.
Pregnancy ...................................................................................53
7.5.3.
Physical Exams ...........................................................................53
7.5.4.
Vital Signs....................................................................................54
7.5.5.
Electrocardiogram (EGC).............................................................54
7.5.6.
Clinical Safety Laboratory Assessments ......................................54
7.6.
Pharmacokinetics .......................................................................................56
7.6.1.
Blood Sample Collection..............................................................56
7.6.2.
Sample Analysis ..........................................................................56
7.7.
Biomarker(s)/Pharmacodynamic Markers ...................................................56
7.7.1.
Viral Genotyping and Phenotyping...............................................56
7.8.
Genetics .....................................................................................................56
7.9.
Value Evidence and Outcomes...................................................................57
8.
DATA MANAGEMENT ...........................................................................................57
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................57
9.1.
Hypotheses.................................................................................................57
9.2.
Sample Size Considerations.......................................................................57
9.2.1.
Sample Size Assumptions ...........................................................57
9.2.2.
Sample Size Sensitivity................................................................58
9.2.3.
Sample Size Re-estimation or Adjustment...................................59
9.3.
Data Analysis Considerations .....................................................................59
9.3.1.
Analysis Populations....................................................................59
9.3.2.
Interim Analysis ...........................................................................59
9.4.
Key Elements of Analysis Plan ...................................................................60
9.4.1.
Primary Analyses.........................................................................60
9.4.1.1.
Safety Analyses..........................................................60
9.4.1.2.
Efficacy Analyses .......................................................60
 
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9.4.1.3.
Pharmacokinetic Analyses..........................................61
9.4.2.
Secondary Analyses ....................................................................61
9.4.2.1.
Pharmacokinetic/Pharmacodynamic Analyses ...........61
9.4.2.2.
Viral Genotyping and Phenotyping Analyses ..............62
10. STUDY GOVERNANCE CONSIDERATIONS........................................................62
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............62
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................62
10.3.
Quality Control (Study Monitoring) ..............................................................63
10.4.
Quality Assurance.......................................................................................63
10.5.
Study and Site Closure ...............................................................................63
10.6.
Records Retention......................................................................................64
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................65
10.8.
Review Committees....................................................................................65
11. REFERENCES.......................................................................................................66
12. APPENDICES........................................................................................................68
12.1.
Appendix 1: Abbreviations and Trademarks................................................68
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................71
12.3.
Appendix 3: Liver Safety – Study Treatment Restart or Rechallenge 
Guidelines...................................................................................................74
12.4.
Appendix 4: Genetic Research ...................................................................75
12.5.
Appendix 5: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................78
12.5.1.
Definition of Adverse Events........................................................78
12.5.2.
Definition of Serious Adverse Events...........................................79
12.5.3.
Definition of Cardiovascular Events .............................................81
12.5.4.
Recording of AEs and SAEs ........................................................81
12.5.5.
Evaluating AEs and SAEs............................................................82
12.5.6.
Reporting of SAEs to GSK...........................................................83
12.6.
Appendix 6: Collection of Pregnancy Information........................................85
12.7.
Appendix 7: Country Specific Requirements...............................................86
12.8.
Appendix 8: Division Of AIDS Table For Grading The Severity Of 
Adult And Pediatric Adverse Events Version 1.0, December 2004; 
Clarification August 2009............................................................................87
12.9.
Appendix 9: Toxicity Management ............................................................106
12.10. Appendix 10: Protocol Amendment Changes............................................111
 
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1.
PROTOCOL SYNOPSIS FOR STUDY 200911
Rationale
GSK2838232 is a novel human immunodeficiency virus (HIV-1) maturation inhibitor 
that is being developed for the treatment of HIV-1 in combination with other 
antiretrovirals.
Three clinical studies of GSK2838232 (n=53 healthy subjects) have been completed thus 
far. One study (Study 204953) is on-going. Healthy subjects have received GSK2838232 
or placebo in single or repeated dose designs, to a maximum single dose of 250 mg or 
repeated dose (for 11 days) of 200 mg QD, in combination with ritonavir (RTV). 
Study HMI116787 (completed November 2013) was the First Time in Human study of 
GSK2838232 and assessed safety and tolerability of escalating doses (5 mg to 100 mg), 
food effect, and the impact of steady-state ritonavir on GSK2838232 pharmacokinetics 
(PK). Following successful completion of 3-month toxicology studies in rat and dog in 
2014, clinical studies 200912 and 200207 were initiated. These were double-blind, 
placebo-controlled, single (Study 200912) and repeat-dose (Study 200207) escalation 
studies to investigate the safety, tolerability, and PK of GSK2838232 alone and when co-
administered with ritonavir 100 mg once daily (QD) for 8-11 days. Further assessment of 
an alternative formulation was also an objective in Study 200912.
Both studies were prematurely terminated/completed in March/April 2015 because of 
concerns over cardiovascular (CV) toxicity, in particular a clinical CV serious adverse 
event (SAE) whereby the Food and Drug Administrating (FDA) imposed a clinical hold. 
Following submission of long-term (6-month rat, 9-month dog) chronic toxicology data 
and follow up to the clinical SAE in November 2015, the hold was released in January 
2016 and Study 204953 was initiated.
Study 204953 is an on-going study and continues the single and repeat-dose exploration 
of safety and PK of GSK2838232 as well as the suitability of a new, capsule formulation. 
Doses of up to 250 mg GSK2838232/100 mg RTV (as single doses) or 200 mg 
GSK2838232/100 mg RTV (QD for 11 days) were studied. As of 26 October 2016, the 
study is ongoing with a cohort of subjects due to receive unboosted GSK2838232 
(200mg BID) for 11 days.
These studies have shown GSK2838232 with or without RTV to be well tolerated and, 
together with daily RTV dosing (“boosting”), demonstrate a PK profile suitable for 
progression to HIV patients in this Phase IIa proof of concept 10-day, monotherapy study 
design.  However, potential concerns over protease resistance necessitate a change to a 
pharmacoenhancer without antiviral effects in this study of GSK2838232 monotherapy. 
Therefore, for Study 200911, cobicistat (Tybost,150 mg QD) will be substituted for RTV.  
The objective of Study 200911 is to understand the safety, PK and HIV antiviral profile 
of GSK2838232/cobicistat (GSK2838232/cobi) when given to HIV-infected, treatment 
naive, otherwise healthy adults. Approximately 10 HIV-1 infected subjects will be 
enrolled into Part A. If warranted by an interim safety, virology, and PK data analysis, 
 
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approximately 8 subjects will be enrolled in each of between two and four Cohorts in Part 
B, which will be a parallel group design.
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

To evaluate antiviral activity of 
GSK2838232/cobi in HIV-1 infected 
patients during 10 days of 
monotherapy.

Change from baseline (Day 1) in plasma HIV-1 
RNA 

To assess safety and tolerability of 
GSK2838232/cobi when administered 
as monotherapy over 10 days.

Safety and tolerability parameters, including 
adverse event, concurrent medication, clinical 
laboratory, electrocardiogram (ECG) and vital 
signs assessments.

To characterize the pharmacokinetics 
of GSK2838232 in HIV-1 infected 
patients following GSK2838232/cobi 
dosing for 10 days.

GSK2838232 PK parameters following dose 
administration, as follows:
Day 1: area under the plasma concentration time 
curve AUC(0-24), maximum observed 
concentration (Cmax), time to maximum 
observed concentration (tmax), concentration at 
24 hours post dose (C24), absorption lag time 
(tlag); 
Following last repeat administration on Day 10:  
AUC(0-), pre-dose concentration (C0), 
concentration at end of dosing interval (C), 
Cmax, tmax, t½, and apparent oral clearance 
(CL/F), if data permit
Secondary

To explore the relationship between 
GSK2838232 exposure and change 
in plasma HIV-1 RNA

GSK2838232 PK parameters Day 10 AUC(0-), 
Cmax, Cwith Day 11 HIV-1 RNA change from 
baseline

To assess the immunologic effect of 
GSK2838232/cobi when 
administered over 10 days in HIV-1 
infected adults

Change from baseline in CD4+ cell count to Day 
11

To explore the relationship between 
GSK2838232 exposure and safety or 
immunologic parameters, if 
appropriate.

GSK2838232 PK parameters on Day 10: 
AUC(0-), Cmax, Cwith Day 11 change from 
baseline in CD4+ cell count
 
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Objectives
Endpoints

To assess the development of viral 
resistance (genotypic and 
phenotypic) over 10 days and 
correlate with viral response, if 
appropriate.

Emergence of drug resistance mutations, if 
appropriate

To estimate GSK2838232 
accumulation and to assess 
attainment of steady state following 
administration of GSK2838232/cobi 
for 10 days in HIV infected subjects.

Accumulation:
GSK2838232 PK accumulation ratios (R): Day 
10 AUC(0-), Cmax, and Ccompared to Day 1 
AUC(0-24), Cmax, and C24, respectively

Steady State:
pre-morning dose concentrations (C0) on Days 2 
through 11 

To examine dose proportionality of 
GSK2838232 pharmacokinetic 
parameters following 
GSK2838232/cobi dosing for 10 days
in HIV infected subjects.

Day 1 AUC(0-24), Cmax, and C24, and Day 10 
AUC(0-), Cmax, and Cat different dose levels 
for the assessment of dose proportionality
Note: Other exploratory objectives and endpoints will be specified in the RAP
Design, Treatment Arms and Duration
Approximately 34 HIV-1 infected treatment-naive subjects will be enrolled overall. 
This study is a 10-day monotherapy, open-label, adaptive, dose ranging, repeat-dose 
study and will be conducted as two parts with an interim (go/no-go) analysis performed 
after Part A (Table 1). Part A, Cohort 1 will evaluate a safe and well-tolerated dose level 
of GSK2838232 that has been tested (with RTV) in prior Phase I studies and that targets 
a high inhibitory quotient (IQ) value. Following the completion of an interim analysis of 
those data and according to criteria defined later in the protocol, further cohorts of 8 
subjects will then be studied in Part B in a parallel design in two or more cohorts 
(depending upon the data obtained in Part A). 
The totality of this data will provide a full dose-response of GSK2838232 over a wide 
dose range to explore the safety and PK/pharmacodynamics (PD) relationship of 
GSK2838232 in HIV-1 infected subjects and facilitate choice of doses for Phase IIb 
studies.
 
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Table 1
Study Design for 200911
Part A: GSK2838232/cobi 
Once Daily x 10 days1
Part B: GSK2838232/cobi 
Once Daily x 10 days1,2
Cohort
N
232 Dose
(mg)
Cohort
N
232 Dose 
(mg)
1
10
100
2
8
200
3
8
50
4
8
20
1. 
Part A Cohort 1 safety/PK/virology data will be evaluated at interim, prior to initiating other cohorts in Part B, which 
are planned to run in a parallel, randomized fashion. All doses will be given with 150 mg cobicistat.
2. 
Part B GSK2838232 doses are an illustration of the projected doses per cohort. The actual doses for each cohort 
are subject to modification based upon safety, PK and antiviral activity data from Cohort 1 (Part A). More 
doses/cohorts (including potential removal of cobi co-dosing) may be added (the maximum dose in Part B would 
not exceed 200 mg with cobicistat unless overall plasma exposure [as AUC and Cmax] was lower in HIV infected 
subjects than in healthy subjects at the same dose level).
The possibility that an additional, unboosted GSK2838232 monotherapy cohort will be 
assessed in Part B is dependent on analysis of the PK data from Study 204953 where 
unboosted GSK2838232 at a dose of 200 mg twice daily (BID) was assessed. 
Subjects in both parts 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 6 weeks.
HIV Drug Resistance: Following cessation of GSK2838232/cobi dosing for 10 days, 
there will be prolonged exposure to waning plasma concentrations of GSK2838232, 
because of the long t½ (i.e., in the “tail” of the PK profile). However, based on in vitro 
resistance passage data with GSK2838232 [and unlike with many other ARV therapies], 
there appears to be a limited likelihood of developing maturation resistance mutations in 
HIV-infected subjects due to its virologic profile. 
Analysis
The primary objectives of this study are to investigate the safety, tolerability, PK and 
antiviral activity of 10 days repeated doses of GSK2838232/cobi in HIV-1 infected 
otherwise healthy subjects. Descriptive summaries will be provided for safety, PK, and 
HIV viral load data.
 
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2.
INTRODUCTION
GSK2838232 is a novel human immunodeficiency virus (HIV)-1 maturation inhibitor 
(MI) that is being developed for the treatment of HIV-1 infection in combination with 
other antiretrovirals (ART).
2.1.
Study Rationale
This ‘proof of concept (PoC)’ open-label study is being conducted to characterize the 
acute antiviral activity, pharmacokinetics (PK), the relationship between PK and antiviral 
activity, and safety of GSK2838232 given with 150 mg once daily (QD) cobicistat 
(GSK283232/cobi), administered across a range of doses over 10 days in HIV-1 infected 
patients. A two part adaptive and dose ranging design is to be applied in this study. Data 
from this study will be utilized to select doses for further studies in Phase IIb.
2.2.
Brief Background
Combination antiviral therapy with inhibitors of HIV protease, integrase, entry and 
reverse transcriptase (RT) has demonstrated significant improvement in acquired 
immunodeficiency syndrome (AIDS)-related morbidity and mortality over the last 10-15 
years. Emerging multi-class drug resistant viral strains and long-term toxicities warrant 
development of new classes of antiretroviral therapies targeting various parts of the HIV-
1 viral life cycle [Wainburg, 2010]. The inhibition of maturation of HIV-1 is a novel 
target for drug development, distinct from viral protease RT or integrase [Saxena, 2012; 
Qian, 2009]. HIV maturation is the final cleavage step of the capsidSp1 (transcription 
factor) polyprotein that generates the functional capsid p24 protein. This mechanism of 
action results in accumulation of the uncleaved p25 protein with subsequent improper 
assembly of the HIV core, resulting in a non-infectious virion. Gel-based mechanism of 
action studies suggest that compound GSK2838232 acts as a maturation inhibitor. 
Western Blot analysis shows inhibition of capsid-Sp1 cleavage and accumulation of p25 
in the presence of GSK2838232.
Prior validation of this target was demonstrated with the HIV maturation inhibitor known 
as bevirimat (BVM; [Martin, 2007a; Martin, 2007b; Martin, 2008; NORVIR, 2013]). 
BVM reached Phase II studies in HIV patients; however, only modest reductions in 
plasma HIV-1 ribonucleic acid (RNA) concentrations were observed in Phase IIa 
monotherapy studies [Mahmood, 2006; Martin, 2007] and a pattern of polymorphic 
(differential) antiviral activity [Wainburg, 2010] led to termination of BVM development. 
The average decrease from baseline to Day 14 plasma HIV-1 ribonucleic acid (RNA) was 
0.54 and 0.70 log10 copies/mL for 200 mg and 300 mg twice daily regimens (Table 2); 
all subjects achieved plasma BVM concentrations above the in vitro EC90. Responders, 
classified based on 5 polymorphisms in HIV-1 gag (at positions 369, 370, and 371), 
achieved an average 1.15 log10 copies/mL reduction in plasma HIV-1 RNA, while an 
average 0.17 log10 copies/mL reduction was achieved for non-responders.
 
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Table 2
Summary of Bevirimat Antiviral Response and PK in a 14-day 
Monotherapy Study in HIV-infected Adults
BVM dosage 
regimen
Mean (SD) viral load 
change from 
baseline to Day 14
2IQ
Plasma BVM 
1Cmin (g/mL)
Plasma BVM 
1Cmax 
(g/mL)
Plasma BVM 
1AUC(0-) 
(g.h/mL)
200 mg BID
(N=14)
-0.54 (0.64)
1.70
46
(41, 51)
58
(53, 64)
632
(571, 699)
300 mg BID
(N=18)
-0.70 (0.77)
2.67
72
(65, 80)
91
(84, 99)
973
(890, 1064)
1.
Cmin, Cmax, and AUC reported as geometric mean (95% CI).
2.
IQ=geometric mean Cmin/in vitro EC90; reported EC90=27 g/mL; all subjects achieved IQ 1.
        AUC(0-) = Area under the concentration-time curve over the dosing interval; BVM = Bevirimat; CI = Confidence 
interval; Cmax = Maximum plasma concentration; Cmin = Minimum plasma concentration; EC90 = 50% protection 
against resistant mutant HIV infection; IQ = Inhibitory quotient; SD = Standard deviation.
Early clinical data for BMS955176, a second generation maturation inhibitor, have been 
recently presented [Nowicka-Sans, 2015]. In a 10-day monotherapy trial in HIV-infected 
patients, plasma HIV-1 RNA was reduced at doses of between 40 mg and 120 mg QD. 
All doses were well tolerated. The maximum change, seen between 10 and 12 days after 
starting dosing, was about 1.5 log10, which is substantially better than the effect 
demonstrated with BVM and may indicate the maximum expected clinical effect of 
inhibiting this viral target.
Although BMS955176 is currently in Phase II studies in HIV-infected patients, there are 
no maturation inhibitors approved for the treatment of HIV infection.  The uncertainties 
of early drug development and continuing need for novel ART, especially for heavily 
treated/experienced HIV-infected persons, support continued compound development. 
GSK2838232’s low nanomolar in vitro potency against multiple HIV-1 gag 
polymorphisms and broader spectrum across multiple HIV-1 subtypes indicates it has 
utility in this setting.
2.2.1.
Preclinical Summary
Nonclinical pharmacology
Virology
GSK2838232, in vitro, is an inhibitor of HIV maturation by preventing the cleavage of 
the HIV gag structural subunit p25 to p24. GSK2838232 is a potent antiviral agent with a 
mean 50% maximal inhibitory concentration (50% maximal inhibitory concentration 
[IC50]) value of 1.6 nM (range: 0.8 to 4.3 nM) when tested in a panel of 26 HIV-1 
isolates with various polymorphic gag genotypes in peripheral blood mononuclear cells 
(PBMCs), suggesting that GSK2838232 can inhibit a broad spectrum of HIV isolates. In 
another PBMC assay, GSK2838232 showed potent antiviral activity in 59 of 60 isolates 
with IC50 values ranging from 0.22 to 5.1 nM. GSK2838232 also inhibited HIV-1 strains 
containing the consensus Sp1 QVT region or the V370A polymorphism in MT4 cells
(IC50 = 0.73 to 0.81 nM). 
 
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In an MT2 cell-based assay utilizing recombinant viruses harboring gag and protease 
from subjects before and after a protease inhibitor (PI) based regimen, GSK2838232 
inhibited 12 of 15 viruses with a mean IC50 value of 1.7 nM (range = 0.4 to 3 nM). The 
remaining 3 viruses were not inhibited by GSK2838232 up to the top concentrations 
tested at 400 nM. There was no correlation of PI sensitivity and susceptibility to 
GSK2838232. GSK2838232 resistance mutations were selected for by serial passage of 
virus in a SupT1 cell-based assay with increasing concentrations of GSK2838232. In the 
lab strain NL4-3 and gag/protease recombinant viruses, the resistance mutation A364V 
arose and resistance confirmed by site-directed mutagenesis. This resistance mutation 
maintains susceptibility to other classes of anti-retrovirals including PIs and non-
nucleoside RT inhibitors.
GSK2838232 was tested in vitro in combination with two marketed PIs, atazanavir and 
darunavir. Using a dose-wise additivity model, GSK2838232A showed additive anti-viral 
activity with both PIs.
Secondary Pharmacology
In a secondary pharmacology study, GSK2838232 was tested against a panel of 
receptors, ion channels and transporters and demonstrated no significant effect (IC50 of 
1 M). It is important to note that the selectivity for antiviral activity of GSK2828232 
compared to all tested off-target activities was >100-fold, and the potential for organ 
toxicity was characterized in the nonclinical toxicology studies (see below).
In safety pharmacology studies in male rats, there were no hemodynamic changes or 
neurobehavioral effects following single oral doses up to 300 mg/kg. A single oral dose 
of GSK2838232 at 30 mg/kg or 300 mg/kg produced reversible increases in respiratory 
tidal volume (32% and 36%, respectively) and derived minute volume (17% and 26%, 
respectively) at 6 hours after dosing. These doses did not produce any effect on 
respiratory rate, airway resistance or body temperature. There were no respiratory effects 
in rats given 5 mg/kg (mean maximum plasma concentration [Cmax] 0.12 g/mL; AUC0-24
1.0 g.h/mL based on Day 1 of the 4-week repeat dose study). These findings were not 
considered to suggest a safety concern in humans.
GSK2838232 at the maximum feasible concentration, limited by solubility, of 4.09 M 
(3.31 g/mL) caused no inhibition of human ether-a-gogo related gene (hERG) tail 
current in Human Embryonic Kidney 293 cells stably transfected with hERG cDNA, 
indicating a low probability for interaction at the hERG channel.
In conscious telemetered male dogs (n=4), a single oral dose of GSK2838232 at 
60 mg/kg (Cmax 0.59 g/mL; AUC0-24 8.7 g.h/mL based on Day 1 exposure data from 
the 4-week oral repeat dose toxicity study) was associated with one episode of 
non-sustained ventricular tachycardia in one dog lasting ~1.2 seconds. There were no 
effects on arterial pressures, heart rate, or electrocardiogram (ECG) interval durations. An 
investigative safety pharmacology cardiovascular study was conducted in telemetered 
dogs given 60 mg/kg/day for 4 weeks with serial monitoring by echocardiography, 
cardiac biomarkers, qualitative and quantitative electrocardiology, microscopy, and 
transmission electron microscopy (TEM) of the heart. 
 
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There were no changes in echocardiography endpoints, ECG intervals, ECG waveforms, 
arterial pressures, heart rates, serum cTpnI, N-terminal prohormone of brain natriuretic 
peptide (NTproBNP), or in heart tissue as assessed by TEM. With routine microscopy, 
one treated dog had a single focus of degeneration/necrosis of the tunica media 
(moderate) in an extramural artery and another treated dog had localised, mixed-cell 
inflammation (mild) along the epicardium of the coronary groove. Both changes have 
been reported in normal beagles and were considered of uncertain relationship to 
treatment in the absence of changes in any other structural or functional cardiovascular 
endpoints. The 28-day exposures were similar to the previous 4-week toxicity study in 
dogs: the Cmax range at 60 mg/kg/day in this investigative safety pharmacology study was 
0.542 to 2.00 g/mL and range of AUC0-24 was 6.04 to 35.7 g.h/mL. In subsequent 
repeat-dose studies in dogs treated for up to 9 months with up to 70 mg/kg/day, no 
changes were evident in cardiac biomarkers (including cTpnI and NTproBNP), functional 
(including ECG waveform) or structural (including microscopic evaluation) 
cardiovascular endpoints at slightly higher exposures than those achieved than in 
previous studies. The end of the 9-month study, gender averaged Cmax at 70 mg/kg/day 
was 1.95 g/mL and AUC0-24 was 38.8 g.h/mL. These studies support an absence of 
GSK2838232-related functional or structural effects on the heart in preclinical testing. 
The No Observed Adverse Effect Level (NOAEL) was established at 20 mg/kg/day (on 
the basis of mild hepatic findings) with an associated area under the curve at 24 hours 
(AUC24) of 16.2 g.hr/mL and Cmax 0.847 g/mL.
Pharmacokinetics and product metabolism in animals
The PK of GSK2838232 were investigated in the mouse, rat, and dog. The oral 
bioavailability of GSK2838232 was low to moderate (~6% to 40%) depending on the 
species and formulation. Plasma and blood clearance were low and the volume of 
distribution at steady state was high relative to total body water. The half-life of 
GSK2838232 was short in the mouse and rat, but moderate in the dog. Systemic exposure 
of GSK2838232 generally increased in a less than dose-proportional manner.  In rats, 
there were no differences in systemic exposure between single and repeat-dose 
administration, or between males and females.  In a 7-day study in dogs, systemic 
exposures were generally similar between males and females and after single and repeat 
dosing; however, in a 4-week study, systemic exposures were higher in females than in 
males in the high-dose group (60 mg/kg/day) and higher after repeat dosing than after a 
single dose. The distribution of radioactivity in male pigmented rats following a single 
oral administration of [14C] GSK2838232 at a target dose level of 20 mg/kg showed 
radioactivity was rapidly absorbed and widely distributed throughout the body with all 
tissues, except the brain and spinal cord. There were no tissues that retained detectable 
levels of radioactivity at 28 days post dose. In a bile duct canulated rat study, 30% of the 
administered dose was excreted in the bile as an acylglucuronide. In the same study, 
unchanged drug and metabolites were eliminated primarily in the bile and feces, while a 
mean of <1% of the dose was eliminated in urine.
In vitro, GSK2838232 is highly protein bound (>99.9%) and has low passive 
permeability. In vivo evidence suggests active uptake of GSK2838232 by transporters in 
the rat liver. 
 
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After single oral doses of 5, 100, or 300 mg/kg, the average liver to plasma ratio was 51, 
17, and 10, respectively. After 7 days of dosing at 30, 100, or 300 mg/kg/day, liver to 
blood ratios ranged from 10 to 16.
In the 13-week repeat dose studies in dogs given 35 mg/kg BID (70 mg/kg/day), heart 
tissue collected at necropsy had GSK2838232 concentrations 2.5 to 5-times higher than 
the 24-hour post-dose plasma concentrations, similar to the previous 4-week CV 
investigative findings.  In the 13-week repeat dose studies in rats given 300 mg/kg/day, 
heart tissue collected at necropsy had GSK2838232 concentrations approximately 3 times 
higher than the 24-hour post-dose plasma concentrations, similar to the previous 7-day 
findings.  Overall GSK2838232 did not appear to be highly concentrated in heart tissue 
after repeat dosing and suggests that accumulation upon chronic dosing is unlikely.
Routes of metabolism identified in liver microsomal incubations and rat, dog, and human 
hepatocytes were N-dealkylation, oxidation, oxidative deamination, and glucuronidation, 
alone or in combination, with no human-specific metabolites detected.  N-dealkylated 
products and glucuronidation were observed in rat plasma and the bile. In general, in 
vitro metabolite profiles of the nonclinical species and human were qualitatively similar, 
such that all metabolites of [14C] GSK2838232 observed in human hepatocyte 
incubations were observed in rat and/or dog. Minor to trace levels of potential aldehydes 
metabolites formed as a result of N-dealkylation and oxidative deamination were 
observed in rat, dog and humans.  
GSK2838232 did not show evidence for glutathione adduct formation in rat or human 
liver microsomes.  Data from pooled human liver microsomes along with recombinant 
cytochrome P450 (CYP) enzymes suggest that in vitro the oxidative metabolism of 
GSK2838232 was primarily mediated by CYP3A4.  Preliminary in vitro investigations 
showed GSK2838232 did not inhibit CYP1A2, 2C9, 2C19, 2D6, 3A4 and was not a 
metabolism-dependent inhibitor of CYP3A4. No drug interaction risk was identified for 
co-administrated substrates of UGT1A1, 1A3, 1A6, 1A9, 2B7, and 2B15, OAT1, OAT3, 
OATP1B1, OATP1B3 or OCT2 at a clinical dose of 200 mg GSK2838232/ritonavir 
(predicted Cmax 0.32 µM). Extrapolation of the clinical risk (using FDA and EMA 
regulatory guidance) did indicate a risk for GSK2838232-mediated inhibition of 
UGT1A4 and of gut contributions of CYP3A4, P-gp, and BCRP at the same clinical 
exposure; however, the potential for clinically significant interactions via these 
mechanisms is predicted to be low (<2 fold change in AUC). GSK2838232 did show 
weak induction of CYP3A4 enzyme activity. However, based on the maximum predicted 
plasma concentrations and high protein binding, the potential for clinically significant 
drug interactions through CYP3A4 induction by GSK2838232 appears to be low.
The inclusion of cobicistat as a CYP3A4 inhibitor pharmacoenhancer in this Phase IIa 
study in place of ritonavir is unlikely to produce a significantly different profile of 
GSK2838232 ADME (and therefore systemic exposure); however, there have been no 
preclinical studies conducted with GSK2838232 and cobicistat to date.  
Toxicology
GSK2838232 administered by oral gavage in repeat dose studies up to 6 months duration 
resulted in no adverse treatment-related effects in rats given up to 300 mg/kg/day QD. 
 
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In dogs given up to 70 mg/kg/day (35 mg/kg/day BID), adverse liver effects were noted 
at this dose in the 9-month repeat dose study.  Though isolated, low grade changes in 
heart rate and cardiac troponin I (cTnI) had been noted in 4-week toxicity studies in rats 
and dogs; however, there were no treatment-related structural or functional 
cardiovascular changes in studies of 3 months and greater duration as assessed by 
echocardiography, ECG, microscopy, and cardiac biomarkers, indicating an absence of 
GSK2838232-related functional or structural effects on the heart in preclinical testing. 
Only non-adverse treatment-related changes were noted in the definitive 6-month rat 
study, which included occasional salivation in animals given 300mg/kg/day and minimal 
clinical pathology changes without histologic correlates (transient clinical chemistry 
changes at 5 mg/kg/day and reversible urine chemistry changes at 300 mg/kg/day). The 
NOAEL in this study was considered to be 300 mg/kg/day (mean AUC[0-t] 
21.3 g.h/mL, mean Cmax 1.77 g/mL [Week 26 values for males and females 
combined]).  
As noted above, dogs given GSK2838232 at 70 mg/kg/day for 9 months had minimal to 
moderate pigmentation (consistent with bile) with minimal to mild mixed cell infiltration 
in the liver and isolated mild increases in alanine aminotransferase (ALT) activity.  These 
findings were considered adverse, but were reversible after the 6-week off-dose period.  
The NOAEL for this dog study was considered to be the mid-dose level of 20 mg/kg/day 
(mean AUC[0-t] 16.2 g.h/mL, mean Cmax 0.847 g/mL [Week 39 values for males and 
females combined]).
Data from genotoxicity assessments suggest that GSK2838232 does not present a 
genotoxic hazard to humans.
During discussions with the FDA regarding the resolution of the clinical hold, the 
Agency recommended that the sporadic cardiovascular changes observed in the early (1-
month) rat GLP study at the highest dose level (300 mg/kg/day) should be considered 
when defining the NOAEL and establishing a safe dose of GlaxoSmithKline (GSK) for 
the initiation of this study protocol.  Accordingly, for the initial PK studies, the reference 
dose level of 30 mg/kg/day in the 1-month rat study was initially used to define the 
NOAEL and therefore the values for fold cover at maximum projected mean exposure 
and Cmax in human subjects were lower, at >2.5-fold.  However, based on the 
cumulative clinical safety data through Cohort 5 of Study 204953, the designated 
NOAEL for the most sensitive species (i.e., 20 mg/kg/day in the 9-month dog study 
based on liver endpoints) is currently used for assessing fold-cover for projected clinical 
dosing in this study.
The inclusion of cobicistat as a CYP3A4 inhibitor pharmacoenhancer in this Phase IIa 
study in place of ritonavir is unlikely to produce a significantly different profile of 
GSK2838232 ADME (and therefore systemic exposure and toxicity); however, there 
have been no preclinical studies conducted with GSK2838232 and cobicistat to date.  
Full details of non-clinical and clinical data may be found in the current Investigator’s 
Brochure (IB) [GSK Document Number 2012N151889_03].
 
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2.2.2.
Clinical Summary of Safety and Pharmacokinetics
To date, GSK2838232 has been evaluated in three completed clinical studies with or 
without ritonavir (RTV) (GSK2838232/r). A fourth study (204953) completed late 2016
and data analysis is ongoing. Full details of the clinical results can be found in the 
Investigator’s Brochure.
2.2.2.1.
Clinical Summary of Safety
As of November 2016 fifty-three subjects had been exposed to GSK2838232 in 3 
completed studies. One study (204953) completed in late 2016 and the analysis of results 
are ongoing (63 subjects were exposed to GSK2838232/r or placebo so far in this study).  
Overall, drug-related adverse events have been few and mild, and included headache, 
dizziness, fatigue, nausea, and palpitations and anxiety.  Similarly, treatment-emergent 
laboratory abnormalities have also been few and mostly grade 1.  There have been no 
discernible patterns, thus far, in terms of AEs or laboratory abnormalities.
One subject in study 200912 discontinued treatment with RTV due to an AE.  A 47-year-
old female who developed right upper quadrant abdominal pain, nausea and flatulence 
associated with grade 4 elevations in ALT and aspartate aminotransferase, and grade 2 
elevations in total bilirubin (BIL). She was diagnosed with a common bile duct 
obstruction due to gallstones that spontaneously resolved. The Investigator assessed this 
AE as unrelated to study treatment.
Due to sporadic CV-related safety signals in the early animal studies (see Section 2.2.2), 
intense CV monitoring was in place for all four studies.  
One AE occurred in HMI116787 that was initially considered a CV AE but after further 
evaluation was considered not to be of cardiac etiology.  Two CV AEs occurred in 
200207 that were initially considered possibly related to GSK2838232 exposure.  
However, further evaluation confirmed that there is a low likelihood that these events 
were due to GSK2838232 exposure.  A summary of each event is provided in the IB.
In ongoing Study 204953, there have been a small number of CV-related events of any 
sort: There have  been no serious adverse drug reactions, and no clinically significant 
drug-related abnormal findings for 12-lead ECGs, vital signs, safety laboratory results 
(including cardiac troponin I), or telemetry.  The following cardiovascular AEs were 
observed during the course of the study but were not considered to be caused by 
GSK2838232 exposure:

In Part 1A (Cohort 1), Period 2, a subject was withdrawn due to an AE (low 
hemoglobin) prior to GSK2838232 exposure Day -2.  A replacement subject 
was brought in, but was not dosed with GSK2838232 or placebo because during 
the 2-day RTV run-in, on Day -1, the replacement subject met the stopping 
criteria for telemetry due to as brief occurrence of asymptomatic, NSVT prior to 
the first dose of GSK2838232 or placebo.  Because the subject was excluded 
from the study prior to the first dose of investigational drug, the NSVT was not 
considered to be a serious and unexpected adverse drug reaction that would 
qualify for IND safety reporting.  
 
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
In Part 1A (Cohort 1), Period 3 (Period “3A” for the purpose of differentiating 
between 100 mg GSK2838232/r vs. 200 mg GSK2838232/r), one subject was 
discontinued prior to the first dose of study drug due to a series of 
cardiovascular findings (pre-ventricular contractions on telemetry).  None of the 
findings were abnormal or atypical, but the investigator determined that this 
would not be a good etiology to have in a subject about to receive 
investigational drug.  Because the event occurred prior to first dose of 
investigational drug, the finding was not considered to be due to GSK2838232 
exposure.  

In Part 1A (Cohort 1), Period 3 (Period “3A” for the purpose of differentiating 
between 100 mg GSK2838232/r vs. 200 mg GSK2838232/r), one subject who 
had already been dosed on 2 previous occasions (with either GSK2838232 or 
placebo) was dosed for 2 days with RTV, and then on 05 May 2016 was dosed 
with either GSK2838232/r or placebo/r as scheduled. On the following day (06 
May 2016), the subject experienced an asymptomatic, 6-beat run of NSVT, 
which was classified at the time as an SAE. Further monitoring, including 
continuous Holter monitoring revealed no further events. The subject had no 
troponin elevation throughout the study. After additional investigation it was 
determined that the NSVT had occurred after the subject had received placebo 
the previous day. Although the subject had received active on the two prior 
visits, the protocol allowed for sufficient washout between each dose.  
Therefore, because the subject had received placebo prior to experiencing the 
NSVT, the event was not considered to be due to GSK2838232 exposure or a 
serious and unexpected suspected adverse reaction that would qualify for IND 
safety reporting.

In Part 2 (Cohort 6, 200mg/r), a 40 year old male enrolled in the study with no 
significant medical history experienced an asymptomatic ventricular triplet 
(NSVT) while asleep at 5:33am on Day 8 (of 11 days worth of dosing) 
approximately 21 hours after receiving 200 mg GSK2838232/r on the previous 
day at 8.25am. This event was noted by the site staff and the subject was 
assessed and found to have no associated clinical symptoms or complaints. The 
GSK medical monitor was notified.  Because the subject was not symptomatic 
and this did not meet protocol-defined stopping criteria, the study was not 
unblinded at the time, and the subject was allowed to continue dosing. Dosing 
in the study is now complete and no further events have been noted. It was the 
assessment of the site PI and the GSK safety/monitoring team that a ventricular 
triplet can be seen in healthy volunteers on continuous Holter monitoring.
Therefore neither the PI nor GSK considered this event to be a serious and 
unexpected suspected adverse reaction.
2.2.2.2.
Study 204953 (completed); Pharmacokinetic Data
Study 204953 investigated the safety, tolerability, and PK of escalating doses of 
GSK2838232 as micronized API, with 100 mg RTV, initially as single doses and then as
repeated doses for 11 days.  
 
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In addition, it evaluated the relative bioavailability of a single fasted dose of micronized 
API powder blend in capsules with RTV compared to powder-in-bottle for oral 
suspension with RTV and the effect of a normal fat meal on the bioavailability of a single 
dose of GSK2838232 in the capsule formulation with RTV.  It will evaluate 
GSK2838232 exposure after repeated doses of unboosted GSK2838232 in the capsule 
formulation. Noncompartmental PK analysis was performed using scheduled sample 
times.  This study is ongoing; preliminary results are presented.
Pharmacokinetic analysis was performed on GSK2838232 plasma concentration-time 
data using nominal time following single doses of 50, 100, and 250 mg in combination 
with RTV in Part 1A of Study 204953 (Table 3).  On average, GSK2838232 Cmax 
values were reached 4-6 hours after dosing.  Terminal half-life values ranged from 15 to 
28 hours across the three dose levels.  Overall, broad dose proportionality was observed 
for Cmax and AUC(0-) values with ascending single doses of GSK2838232 (50, 100, 
and 250 mg with 100 mg RTV).
Table 3
Summary of Preliminary Pharmacokinetic Parameter Values after 
Single Doses of GSK2838232 in Combination with 100 mg Ritonavir 
(Study 204953, Part 1A)
Dose (mg)
n
t½ 
(h)
tlag 
(h)
tmax 
(h)
Cmax 
(ng/mL)
AUC(0-) 
(ng.h/mL)
50
8
22.7
(17%)
(17.2-28.5)
0.188
(138%)
(0-0.5)
3.63
(41%)
(2.5-6.0)
17.2
(43%)
(8.7-27.9)
458.6
(33%)
(210.6-662.0)
100
6
18.0
(14%)
(15.8-22.3)
0.167
(155%)
(0-0.5)
6.00
(59%)
(2.5-12.0)
25.2
(20%)
(17.5-31.5)
890.5
(20%)
(619.1-1053)
250
5
17.3
(6.4%)
(15.5-18.6)
0
(-)
(0-0)
5.50
(71%)
(2.0-12.0)
60.7
(23%)
(40.8-73.1)
1731
(29%)
(1222-2505)
Data are presented as mean (CV) (minimum-maximum).
Study 204953 Part 1B was an open label, 2x2+1 three-period, crossover design, 
evaluating the relative bioavailability of the micronized API GSK2838232 powder blend 
in capsules compared to the PiB reference formulation for the first two periods, with the 
assessment of food effect on the capsule formulation in Period 3.  
The relative bioavailability of the micronized powder blend in 50 mg hand-filled capsules 
compared to the micronized API as PiB for oral suspension was assessed as 100 mg 
GSK2838232 single doses with 100 mg RTV after two pre-doses (48 h) in the fasted state 
in a randomized crossover design in 12 subjects in the first two periods of Part 1B of 
Study 204953. Preliminary geometric mean AUC(0-) and Cmax values were 
approximately 45% and 60% higher, respectively, after administration in the capsule 
formulation compared to oral suspension from PiB (Table 4).
 
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Table 4
Preliminary Assessment of Relative Bioavailability of Capsule 
Formulation vs. Powder-in-Bottle Formulation of GSK2838232 (Study 
204953, Part 1B)
Parameter
Test
Reference
n
Ratio of Geometric 
Least Square Means
90% CIof Ratio
AUC(0-) 
Capsule
PiB
12
1.43
(1.194,1.702)
Cmax 
Capsule
PiB
12
1.58
(1.312,1.900)
PiB = powder-in-bottle.
The potential food effect with the capsule formulation was assessed as 100 mg 
GSK2838232 single doses with 100 mg RTV after two pre-doses (48 h) in the fasted state 
and with a normal fat meal in a non-randomized crossover design (fasted in either Period 
1 or 2, fed in Period 3).  Eleven subjects provided data for both dietary conditions.   
Preliminary geometric mean AUC(0-) and Cmax values were approximately 60% 
higher after administration in the capsule formulation with a normal fat meal compared to 
the fasted state (Table 5).
Table 5
Preliminary Assessment of the Effect of a Normal Fat Meal on 
GSK2838232 Exposure when Administered as a Capsule 
Formulation with Ritonavir (Study 204953, Part 1B)
Parameter
n
Capsule – food
Geometric mean
Capsule –
fasted
Geometric 
mean
Ratio of geometric 
means 
(food/fasted)
AUC(0-) (ng.h/mL)
11
2414
1539
1.57
Cmax (ng/mL)
11
76.9
47.2
1.63
Repeat dose PK parameter values in Study 204953 Part 2 were determined on Day 1 and 
Day 11 using nominal time in Part 2 of Study 204953 (Table 6). After the Day 11 dose of 
GSK2838232 with RTV, exposure (Cmax, AUC[0-]) appeared to increase
proportionally with the increase in dose level with the PiB and capsule formulations. 
 
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Table 6
Summary of Preliminary Pharmacokinetic Parameter Values on 
Day 1 and Day 11 during Repeated Dosing of GSK2838232 in 
Combination with 100 mg Ritonavir (Study 204953, Part 2)
Dose 
(mg)
n
t½ 
(h)
tlag 
(h)
tmax 
(h)
Cmax 
(ng/mL)
AUC(0-) 
(ng.h/mL)
C
(ng/mL)
Study Day 1
20
(PiB)
6
-
0.417
(49%)
(0-0.5)
3.67
(11%)
(3.0-4.0)
12.2
(47%)
(5.8-20.8)
189.4
(40%)
(83.7-284.4)
6.1
(39%)
(2.5-8.9)
50
(PiB)
6
-
0.167
(155%)
(0-0.5)
3.00
(51%)
(2.0-6.0)
18.7
(40%)
(9.0-25.9)
288.7
(39%)
(138.6-380.2)
9.5
(35%)
(5.1-12.6)
100
(capsules)
6
-
0.167
(155%)
(0-0.5)
2.25
(23%)
(1.5-3.0)
48.4
(32%)
(28.1-69.6)
664.1
(31%)
(422.5-932.7)
21.6
(33%)
(12.8-29.3)
200
(capsules)
6
-
0.083
(245%)
(0-0.5)
2.50
(25%)
(2.0-3.5)
79.4
(38%)
(50.8-125)
1124
(39%)
(636.7-1794)
38.9
(36%)
(21.7-58.6)
Study Day 11
20
(PiB)
6
19.2
(16%)
(15.1-
24.2)
-
5.00
(32%)
(2.5-6.0)
27.4
(38%)
(11.3-40.4)
474.3
(31%)
(214.3-613.2)
15.3
(30%)
(7.1-19.2)
50
(PiB)
6
27.3
(52%)
(15.2-
50.4)
-
3.50
(46%)
(1.5-6.0)
58.0
(24%)
(40.9-78.0)
1113
(23%)
(762.6-1459)
38.8
(29%)
(24.5-51.7)
100
(capsules)
6
17.9
(18%)
(15.2-
23.7)
-
4.00
(40%)
(2.5-6.0)
133
(23%)
(94.7-164)
2492
(27%)
(1624-3301)
81.7
(30%)
(45.9-113)
200
(capsules)
6
-1
-
3.33
(45%)
(1.5-6.0)
240
(38%)
(127-368)
4389
(45%)
(2095-7161)
151
(46%)
(67.8-250)
Data are presented as mean (CV) (minimum-maximum).
1.
Concentration data were available up to 24 h after the Day 11 dose, and t½ values were not 
calculated.
2.2.2.3.
Overall Summary/Conclusions of PK data
The original formulation used in the first three studies with GSK2838232 (HMI116787, 
200207, and 200912) was SDD.  Data from Study 200912 demonstrated that a change to 
the API formulation of GSK2838232 was feasible for future clinical studies. Study 
204953 utilized micronized API powder in a bottle as well as in a capsule. The capsule 
was shown to be a viable solid dosage form for subsequent studies.  A more detailed 
summary of the data from Study 204953 is in Section 2.2.2.2.
 
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
GSK2838232 SDD did not overall demonstrate significant escalation in exposure 
from an increase in dose from 100 mg to 200 mg in a cross-study comparison.  The 
API PiB formulation showed a proportional increase in AUC and Cmax for a 2-fold 
dose escalation from 100 mg to 200 mg.

The observed tmax of the API form was significantly increased over the SDD 
formulation (the API formulation also increased tlag relative to SDD).

The bioavailability of the GSK2838232 API formulation was on average 30-50% of 
the bioavailability of SDD formulation, but there was a large observed range of 
relative intra-subject exposures (11-150%).

Both 10 mg SDD and 20 mg API showed a 10-fold or greater increase in AUC with 
steady-state RTV (100 mg QD for 10 days) with a smaller (≤4-fold) increase in 
observed Cmax.  The t½ of GSK2838232 increased from 15-18 hours to 34-42 
hours in the presence of steady-state RTV, regardless of formulation.

After single doses of 50 to 250 mg GSK2838232 with RTV, increases in Cmax and 
AUC(0-) values were broadly proportional to the increase in dose.  On Day 11 
after repeated daily 20 to 200 mg doses of GSK2838232 with RTV, increases in 
Cmax and AUC(0-) values appeared to be proportional to the increase in dose with 
the PiB and capsule formulations.  

The relative bioavailability of the micronized API powder blend in capsules with 
RTV was approximately 45%-60% higher than the bioavailability of the micronized 
API administered as oral suspension from PiB with RTV.

Co-administration of the micronized API powder blend in capsules with RTV and a 
normal fat meal resulted in an approximately 60% increase in geometric mean 
Cmax and AUC(0-) values compared to the fasted state with RTV (Study 
204953).

Variability remains fairly constant across formulations and boosted versus 
unboosted at around 30%-40% (moderate-high).

Projections of potential future efficacious boosted GSK2838232 API regimens 
suggest that doses of 20 to 200 mg GSK2838232 API co-administered with RTV 
will result in mean trough values of at least 3-fold above the derived 90% maximal 
inhibitory concentration (IC90) target value (5 ng/mL). Even if protein binding has 
more impact than envisaged and causes a 5-fold increase in IC90 as seen in some 
preclinical virology studies, the predicted troughs will still be significantly higher 
than the 5-fold shifted IC90 (25 ng/mL) at doses of 50 mg or higher with RTV. 

The average and maximum AUC/Cmax values observed at the maximum dose 
studied to date are below NOAEL values in preclinical chronic toxicology studies 
(6-month rat, 9-month dog).
 
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3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To evaluate antiviral activity of 
GSK2838232/cobi in HIV-1 infected patients
during 10-days of monotherapy.

Maximum decline from baseline (Day 1) in 
plasma HIV-1 RNA 

To assess safety and tolerability of 
GSK2838232/cobi when administered as 
monotherapy over 10 days.

Safety and tolerability parameters, 
including adverse event, concurrent 
medication, clinical laboratory, 
electrocardiogram (ECG) and vital signs 
assessments.

To characterize pharmacokinetics (PK) of 
GSK2838232 in HIV-1 infected patients 
following GSK2838232/cobi dosing for 10 
days

GSK2838232 PK parameters following 
dose administration, as follows:
Day 1:  area under the plasma 
concentration time curve AUC(0-24), 
maximum observed concentration 
(Cmax), time to maximum observed 
concentration (tmax), concentration at 24 
hours post dose (C24), absorption lag 
time (tlag); 
Following last repeat administration on 
Day 10:  AUC(0-), pre-dose 
concentration (C0), concentration at end 
of dosing interval (C), Cmax, tmax, t½, 
and apparent oral clearance (CL/F), if 
data permit
Secondary

To explore the relationship between 
GSK2838232 exposure and change in 
plasma HIV-1 RNA

GSK2838232 PK parameters Day 10 
AUC(0-), Cmax, Cwith Day 11 HIV-1 
RNA change from baseline

To assess the immunologic effect of 
GSK2838232/cobi when administered over 
10 days in HIV-1 infected adults

Change from baseline in CD4+ cell count 
to Day 11

To explore the relationship between 
GSK2838232 exposure and safety or 
immunologic parameters, if appropriate.

GSK2838232 PK parameters on Day 10: 
AUC(0-), Cmax, C  with Day 11 change 
from baseline in CD4+ cell count

To assess the development of viral 
resistance (genotypic and phenotypic) over 
10 days and correlate with viral response, if 
appropriate.

Emergence of drug resistance mutations, 
if appropriate
 
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Objectives
Endpoints

To estimate GSK2838232 accumulation and 
to assess attainment of steady state 
following administration of 
GSK2838232/cobi for 10 days in HIV 
infected subjects.

Accumulation:
GSK2838232 PK accumulation ratios (R): 
Day 10 AUC(0-), Cmax, and C
compared to Day 1 AUC(0-24), Cmax, 
and C24, respectively

Steady State:
pre-morning dose concentrations (C0) on 
Day 2 through 11 

To examine dose proportionality of 
GSK2838232 PK parameters following 
GSK2838232/cobi dosing for 10 days in HIV 
infected subjects.

Day 1 AUC(0-24), Cmax, and C24, and 
Day 10 AUC(0-), Cmax and Cat 
different doses levels for the assessment 
of dose proportionality
Note: Other exploratory objectives and endpoints will be specified in the RAP
4.
STUDY DESIGN
4.1.
Overall Design
This is a Phase IIa, multicenter, open-label, adaptive dose ranging, study to evaluate the 
antiviral effect, safety, tolerability, and PK of GSK2838232/cobi monotherapy over 10 
days in ART-naïve HIV-1 infected adults who are not currently receiving ART therapy. 
Subjects who have received any ART (including prior MI) therapy will not be eligible for 
this study. To minimize the number of subjects exposed to suboptimal doses, an adaptive 
and dose ranging design is applied in this study.
This study consists of a screening visit, a 10-day treatment period, and follow-up 
evaluations for 2 weeks following last dose.
Screening will be performed as the patients are identified, within 30 days of the first dose 
of study drug.  Eligible HIV-1 infected subjects will receive study treatments for 10 days.
Study Design for 200911
GSK2838232/cobi Once Daily for 10 days1,2
Part A
Part B 
Cohort 1
Dose
(mg)
Interim Analysis
Cohort
N
(mg)
N=10
100
2
8
200
3
8
50
4
8
20
 
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1.
Part A Cohort 1 safety/PK/virology data will be evaluated at interim, prior to initiating other cohorts in Part B, which 
are planned to run in a parallel, randomized fashion.  All doses will be given with 150 mg cobicistat.
2.
Part B doses are an illustration of the projected doses per cohort. The actual doses for each cohort are subject to 
modification based upon safety, PK and antiviral activity data from Cohort 1 (Part A). More doses/cohorts 
(including potential removal of cobicistat co-dosing) may be added. (The maximum dose in Cohort B  will not  
exceed 200 mg with cobicistat unless overall plasma exposure [as AUC and Cmax] is lower in HIV-infected 
subjects than in healthy subjects at the same dose level).
After successfully completing screening evaluations, the first cohort will enroll 10 
subjects to receive the 100 mg GSK2838232/cobi dose.  Following interim analysis of 
Cohort 1, if warranted, Cohorts 2-4 will each enroll 8 subjects to receive a range of 
GSK2838232/cobi doses.
Day 1 – Day 10: Dosing 
Subjects will report to the clinic for outpatient visits in the morning on Days 1 through 10 
during the treatment period, except for the weekend (Days 6 and 7).  Subjects will arrive 
each day prior to administration of the morning dose for safety and lab assessments, 
including HIV-1 RNA blood draws, as described in the Time and Events Table (Section 
7.1).  Subjects will begin receiving study drug in the morning of Day 1.  
Serial, intensive blood PK samples will be collected on Day 1 (up to 24 hours post-
morning dose) and Day 10 (up to 96 hours post-morning dose), and limited, single blood 
PK samples pre-morning doses on Days 3 through 9, except for the weekend. Subjects 
will be required to fast for 10 hours [overnight] prior to the morning check in on the 
intensive PK sampling days (Days 1 and 10).  All dosing days will require co-
administration of treatment with a light snack/meal per cobicistat labeling guidelines. All 
doses of study medication will be taken with 240 mL of water.  Subjects will be required 
to stay in the clinic on Days 1 and 10 until all specified assessments are completed (12 
hours post-dose). Following Day 10, subjects will be required to attend the clinic for 
follow up assessments including virological and PK blood sampling for up to 3 weeks.
Subjects will be given morning doses on Days 1 through 10 (except for the weekend) in 
the clinic.  Weekend morning doses (Days 6 and 7) will be packaged and sent home for 
self-administration.  After Day 11, the subjects will return frequently for assessments 
including blood draws for PK and HIV viral load. A diary card will be used to monitor 
dosing adherence.
Follow-up Visits:
Subjects will return to the clinic on Days 11, 12, 14 (1 day), and 21 (1 day) for PK and 
measurement of HIV-1 RNA levels, viral genotype/phenotype and safety assessments as 
shown in the Time and Events Table (Section 7.1). 
4.2.
Type and Number of Subjects
At least 34 subjects will be enrolled such that approximately 6-10 evaluable subjects 
complete a number of cohorts.  Additional subjects/cohorts may be enrolled to allow for 
evaluation of additional dose levels as appropriate. 
 
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If subjects prematurely discontinue the study, additional replacement subjects may be 
randomised and assigned to the same treatment cohort at the discretion of the Sponsor in 
consultation with the Investigator.
4.3.
Design/Dose Justification
The fastest track to establishing antiviral potential of any novel HIV drug is to study a 
short course of monotherapy in HIV infected subjects. There is precedent for this across a 
number of classes of ART drugs. 
Uncertainties over the impact of protein binding on the activity of GSK2838232 and the 
inherent potency of inhibiting the HIV maturation process as a target remain key 
objectives for the GSK2838232 program. This two-part adaptive design will allow an 
early understanding of the potential of GSK2838232 in combination with cobicistat (and 
by implication, RTV), while not exposing HIV-infected subjects to longer courses of 
what may be suboptimal doses and possible development of resistance. 
Early clinical studies have indicated that in order to achieve reasonable IQ values likely 
to be associated with antiviral efficacy, GSK2838232 will need to be boosted with a 
pharmacoenhancer, such as RTV or cobicistat (in common with many CYP3A4 
substrates). 
There is no a priori intention to study GSK2838232 unboosted, unless: i) following the 
preliminary analysis of Part A Cohort 1, there is such pronounced antiviral activity that it 
would seem the estimates of projected IQ are low, in which case GSK2838232 may be 
evaluated in a subsequent cohort unboosted, or ii) the data from Cohort 7 in ongoing 
Study 204953 (planned, GSK2838232 200 mg BID unboosted) support it.
4.3.1.
GSK2838232 with Ritonavir
In Study HMI116787, a single dose of 10 mg GSK2838232 (SDD) given after 10 days of 
RTV 100 mg daily dosing (to steady state) demonstrated an increase in overall exposure 
(AUC) and Cmax by an average of 10.8- and 2.6-fold, respectively, compared to 10 mg 
GSK2838232 alone. Terminal phase half-life also increased from approximately 20 hours 
to 34 hours. This effect was presumably the result of an inhibition of a CYP3A4-
mediated pathway. Studies 200912 and 200207 also indicated the utility of RTV in 
boosting GSK2838232 concentrations.
These data indicate the viability of studying a number of GSK2838232+RTV regimens in 
this PoC study. Predicted exposures following different GSK2838232 doses with steady-
state RTV are presented in Table 7, based on the results of linear regression analyses of 
the preliminary Day 11 data in Study 204953 (dose levels of 20 to 200 mg) and assuming 
no significant differences in PK (ADME) between HIV-infected subjects and healthy 
subjects. 
 
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Table 7
Predicted Mean Steady-State GSK2838232 AUC(0-24), Cmax, and IQ, 
Following Repeated Dose Administration + RTV with Fold Cover to 
NOAEL
Dose 
(mg)
Projected AUC24 
(ng.h/mL)1
Fold cover to 
NOAEL Dog2
Projected 
Cmax 
(ng/mL)1
Fold cover to 
NOAEL Dog2
IQ3
20+RTV
451
36
24
35
3.1
50+ RTV
1127
14
61
14
7.7
100+ RTV
2253
7.2
122
6.9
15
150+RTV
3380
4.8
183
4.6
23
200+RTV
4506
3.6
244
3.5
31
1.
Predicted mean values based on linear regression analyses of preliminary Day 11 data in Study 204953.
2.
Lowest NOAEL, 20 mg/kg/day obtained from 9-month study in dogs (AUC24 16200 ng.h/mL and Cmax 847 
ng/mL)
3.
Mean IQs derived from predicted C/IC90 (with target of 5 ng/mL).
C= Pre-dose (trough) concentration at the end of the dosing interval, IQ= inhibitory quotient.
The IQ following 20 mg to 200 mg GSK2838232/r QD is predicted to be >3 to >30-fold 
above the minimal target value (5 ng/mL) which was derived from preclinical virological 
assessment as 4 × EC50. No protein binding adjustment has been made because there was 
a minimal (≤5 fold) shift in assays where the effect of protein was assessed. If protein 
binding has more impact than anticipated, it is possible that the target Cmin value is 
approximately 25 ng/mL. In that scenario, projected IQ values at 200 mg/r QD would still 
be >5.
4.3.2.
GSK2838232 with Cobicistat
There have been no preclinical or clinical studies with GSK2838232 and cobicistat to 
date; however, a review of the literature indicates that pharmacoenhancement of drugs 
that are known to have dominant CYP3A metabolic pathways is similar with either RTV 
or cobicistat [Kakuda, 2009; Elion, 2011; Gallant, 2013].  Thus, the use of cobicistat as 
the CYP3A4 inhibitor pharmacoenhancer in this Phase IIa study in place of ritonavir is 
expected to produce a similar profile of GSK2838232 ADME (and therefore systemic 
exposure).  The pharmacokinetic data available after Part A Cohort 1 will confirm this 
assumption.  
4.3.3.
Interim Analysis
An evaluation of GSK2838232 safety, efficacy and PK data will be done after Part A 
Cohort 1, if the exposure level of GSK2838232 is in the range of the maximum 
GSK2838232 exposure seen previously in healthy subjects and the Bayesian probability 
from Cohort 1 is less than 70%, the study will not move forward into Part B, otherwise 
doses will be selected for evaluation in Part B. If pharmacokinetic exposure after the 100 
mg GSK2838232/cobi dose is in the range of values observed after 100 mg 
GSK2838232/r in prior studies, the doses for Part B will be extended to both lower 
(20 mg, 50 mg) and higher (200 mg) doses. The highest dose tested in Part B will be 
selected to result in exposures similar to those seen with 200 mg/r in Study 204953. 
 
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4.4.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK2838232 can be found in the Investigator’s Brochure.  The following section 
outlines the risk assessment and mitigation strategy for this protocol:  
 
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4.4.1.
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) GSK2838232 
Cardiovascular
Pre-clinical studies have shown the following findings:  elevated heart rates, an 
isolated episode of non-sustained ventricular tachycardia and minimal to mild, 
sporadic troponin I elevations in dogs.  A subsequent investigative cardiovascular 
study in telemetered dogs treated for 4 weeks did not replicate these effects. 
Isolated microscopic cardiovascular changes were noted (focal extramural 
arteritis and localized epicardial inflammation), however these changes were 
considered of uncertain relationship to GSK2838232 because similar findings 
occur at low incidence in normal beagles and there were no GSK2838232-related 
functional changes by telemetry and echocardiography, or changes in cTpnI and 
NTproBNP.  In addition there was no correlation between histologic changes and 
plasma exposure or heart tissue concentrations of GSK2838232. 
3, 6 and 9 month toxicology studies in rat and dog did not demonstrate any 
evidence of cardiovascular injury or impact on cardiovascular function.
In the four GSK2838232 studies conducted so far there was no pattern of 
cardiovascular changes of clinical significance related to GSK2838232 and no 
clinically significant abnormality in electrocardiogram values other than the two 
SAEs documented and discussed.
Review of published bevirimat preclinical and clinical safety data indicates no 
significant toxicities or AEs of interest, other than a 30% incidence of 
gastrointestinal symptoms (including diarrhea). There were no significant 
cardiovascular AEs reported in published clinical studies.
Subjects will be clinically monitored for any signs 
of myocardial injury (chest pain, shortness of 
breath, pain with inspiration), elevated heart rate 
or arrhythmias. Samples for the assessment of 
troponin will be taken. Baseline EKG and Holter 
(to use for screening and for later comparisons if 
needed)
Exposures of GSK2838232 will be closely 
monitored in the clinical study so as to not 
exceed pharmacokinetic stopping criteria.  
 
 
 
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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Cobicistat (Tybost)
General
The cobicistat label includes the following information: 
TYBOST decreases estimated creatinine clearance due to inhibition of tubular 
secretion of creatinine without affecting actual renal glomerular function. This 
effect should be considered when interpreting changes in estimated creatinine 
clearance in patients initiating TYBOST
In one study investigating cobi+( atazanavir and tenofovir DF/emtricitabine) vs 
RTV+( atazanavir and tenofovir DF/emtricitabine), a higher frequency of reports 
of jaundice (6% and 3%) and ocular icterus (4% and 2%) were reported in the 
cobi group compared to the RTV group.  
Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, and 
triglycerides have been observed. The implications of these findings are 
unknown.
The vast majority of available safety data has been obtained in combination 
studies with other ART. There are no warnings of obvious cobicistat-related 
adverse events or safety concerns. 
Subjects will be closely monitored for any signs 
or symptoms potentially associated with 
cobicistat administration, in particularchanges in 
serum creatinine and liver chemistry.
HIV-1 Infection/Patient population
HIV Resistance
Propensity for co-meds and 
possible Drug-Drug 
Interactions (DDIs)
HIV Drug Resistance to unique mechanism
Recognize HIV patients have a higher chance of comorbidities/diseases and a 
risk of taking a medicine or product contraindicated in the study
Closely monitor HIV viral load and genotypic 
resistance
Strict adherence to protocol criteria around 
concurrent meds 
 
 
 
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4.4.2.
Benefit Assessment
This study in HIV-1 infected but otherwise healthy subjects is a 10-day monotherapy 
design. It is anticipated that all subjects receiving GSK2838232 will experience anti-HIV 
effects whereby their (blood) HIV viral titres are reduced, until administration stops and 
the viral load returns to baseline levels. There is no expected longer term anti-HIV 
benefit to administration of GSK2838232.  Participation in this study contributes to the 
process of developing GSK2838232 and other new therapies for the treatment of HIV 
infection.
4.4.3.
Overall Benefit:Risk Conclusion
To date, 53 healthy subjects have received GSK2838232 in three completed studies. One 
study (204953) is ongoing (52 healthy subjects have completed this study so far). 
Subjects have received single doses up to 200 mg SDD alone (studies HMI116787 and 
200912), 250 mg API in combination with RTV (204953), and then in repeated daily 
doses of up to 50 mg SDD alone (200207) for 5 days or 200 mg in combination with 
RTV (204953) for 11 days.
There have been two cardiovascular SAEs reported from clinical studies where the 
subject was receiving GSK2838232 to date (one in 200207, one in 204953). Neither is 
thought likely to be due to GSK2838232.
There have been no other withdrawals due to drug-related AEs and no trends relative to 
laboratory toxicity.  One subject was withdrawn in Part 1A of 204953 because of low 
haemoglobin lab values, thought unrelated to study drug or study procedures.
With respect to CV effects, with the exceptions noted, there have been no clinically 
significant changes in troponin, heart rate, blood pressure, ECG, or telemetry monitoring.
Subjects will also be at risk for AEs from cobicistat use and will be monitored closely for 
such events.
Given the preclinical profile and the clinical profile to date, the overall risk to HIV-1 
infected but otherwise healthy subjects at the proposed GSK2838232 doses (with or 
without cobicistat) for 10 days is predicted to be low.  Mean exposures at the highest 
dose studied are not projected to exceed NOAEL values obtained in chronic toxicology 
studies, further reducing potential risk. 
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on the GSK investigational product or other study treatment that 
may impact subject eligibility is provided in the Investigator’s Brochure.
 
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Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
Approximately 10-12 HIV-1 infected subjects will be enrolled into Part A. If warranted 
by an interim safety, virology and PK data analysis, approximately 8 subjects will be 
enrolled in each of Cohorts 2-4 in Part B, which will be a parallel group design. Eligible 
patients are those who are ART-naïve and who are not currently receiving ART therapy.
Additional subjects/cohorts may be enrolled to allow for evaluation of additional dose 
levels or configurations (e.g., GSK2838232 alone).
If subjects prematurely discontinue the study, additional subjects may be enrolled as 
replacement subjects and assigned to the same treatment at the discretion of the Sponsor.
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
1.
Between 18 and 55 years of age inclusive, at the time of signing the informed 
consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2.
Healthy (other than HIV infection) male or female as determined by the investigator 
or medically qualified designee based on a medical evaluation including medical 
history, physical examination, laboratory tests and cardiac monitoring. Defined as no 
other chronic medical conditions and taking no chronic medications.
3.
A subject with a clinical abnormality or laboratory parameter(s) which is/are not 
specifically listed in the inclusion or exclusion criteria, outside the reference range 
for the population being studied may be included only if the investigator in 
consultation with the Medical Monitor agree and document that the finding is 
unlikely to introduce additional risk factors and will not interfere with the study 
procedures. 
4.
A creatinine clearance >80 mL/min as determined by Cockcroft-Gault equation 
[Cockcroft, 1976] CLcr (mL/min) = (140 – age) * Wt / (72 * Scr) (times 0.85 if 
female) where age is in years, weight (Wt) is in kg, and serum creatinine (Scr) is in 
units of mg/dL.
5.
Confirmed HIV positive; CD4+ cell count ≥350 cells/mm3 and plasma HIV-1 RNA 
≥5000 copies/mL at Screening. No current and no prior ART. (A previous course of 
pre- or post-exposure prophylaxis is allowed provided that it was completed at least 
6 weeks prior to the first dose of study drug).
 
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WEIGHT
6.
Body weight 50 kg (110 lbs.) for men and 45 kg (99 lbs) for women and body 
mass index (BMI) within the range 18.5-31.0 kg/m2 (inclusive)
SEX
7.
Male or Female
A female subject of reproductive or non-reproductive potential is eligible to 
participate if she is not pregnant (as confirmed by a negative serum or urine human 
chorionic gonadotrophin (hCG) test at screening and prior to first dose), not 
lactating, and at least one of the following conditions applies:
Reproductive potential:
Females of reproductive potential may only be enrolled if they are using two forms 
of complementary contraception, which must include one barrier method. They will 
be counselled on safer sex practices
There is no definitive DDI information with GSK2838232 and an interaction with 
oral contraceptives is possible, so other (barrier, inter-uterine device etc.) methods of 
contraception will be required.
Fertile females, who have an established, long-term lifestyle of sexual abstinence, or 
only same sex partners, require no other means of birth control.  
Non-reproductive potential:

Pre-menopausal females with one of the following:

Documented tubal ligation

Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion 

Hysterectomy

Documented Bilateral Oophorectomy

Postmenopausal defined as 12 months of spontaneous amenorrhea in 
questionable cases a blood sample with simultaneous follicle stimulating 
hormone (FSH) and estradiol levels consistent with menopause (refer to 
laboratory reference ranges for confirmatory levels).  Females on hormone 
replacement therapy (HRT) must discontinue HRT to allow confirmation of 
post-menopausal status prior to study enrolment.
Male subjects with female partners of child bearing potential must comply with the 
following contraception requirements from the time of first dose of study medication 
until one week after the last dose of study medication.
a. Vasectomy with documentation of azoospermia.  
b. Male condom plus partner use of one of the contraceptive options below:

Contraceptive subdermal implant that meets the SOP effectiveness criteria 
 
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including a <1% rate of failure per year, as stated in the product label

Intrauterine device or intrauterine system that meets the SOP effectiveness 
criteria including a <1% rate of failure per year, as stated in the product 
label

Oral contraceptive, either combined or progestogen alone or Injectable 
progestogen 

Contraceptive vaginal ring 

Percutaneous contraceptive patches
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label.  The investigator is responsible 
for ensuring that subjects understand how to properly use these methods of 
contraception.
INFORMED CONSENT
8.
Capable of giving signed informed consent as described in Section 10.2, which 
includes compliance with the requirements and restrictions listed in the consent form 
and in this protocol.
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
1.
Alanine aminotransferase (ALT) and BIL >1.5xupper limit of normal (ULN; isolated 
BIL >1.5xULN is acceptable if BIL is fractionated and direct BIL <35%). 
2.
Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones); HBV and/or 
HCV positive.
3.
Subjects who have any other chronic medical condition, including CV, respiratory, 
neurologic, psychiatric, renal, gastrointestinal (GI), oncologic, rheumatologic, or 
dermatologic
4.
Medical history of cardiac arrhythmias or cardiac disease or a family or personal 
history of long QT syndrome.
 
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CONTRAINDICATIONS 
5.
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.
RELEVANT HABITS 
6.
Chronic marijuana or use of other elicit medications (cocaine, heroin) is an exclusion 
criteria.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
7.
Presence of hepatitis B surface antigen (HBsAg), positive (confirmed by 
Recombinant Immuno-Blot Assay [RIBA]) hepatitis C antibody test result at 
screening or within 3 months prior to first dose of study treatment.
8.
Screening or baseline cardiac troponin I greater than the 99% cutoff (>0.045 ng/mL 
by the Dimension Vista CTNI assay).
9.
A positive pre-study drug/alcohol screen.  
10. Prior history of receiving an HIV maturation inhibitor
11. Where participation in the study would result in donation of blood or blood products 
in excess of 500 mL within 56 days.
12. The subject has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day in the current 
study: 30 days, 5 half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer).
13. Exposure to more than four new chemical entities within 12 months prior to the first 
dosing day.
14. Treatment with radiation therapy or cytotoxic chemotherapeutic agents within 
30 days of study drug administration or anticipated need for such treatment within 
the study.
15. Treatment with immunomodulating agents (such as systemic corticosteroids, 
interleukins, interferons) or any agent with known anti-HIV activity (such as 
hydroxyurea or foscarnet) within 30 days of study drug administration.
16. An active Center for Disease Control and Prevention (CDC) Category C disease 
except cutaneous Kaposi’s sarcoma not requiring systemic therapy during the trial.
17. Treatment with any vaccine within 30 days prior to receiving study medication.
18. Exclusion Criteria for 24-Hour Screening Holter:

Any symptomatic arrhythmia (except isolated extra systoles).

Sustained cardiac arrhythmias (such as atrial fibrillation,flutter or 
supraventricular tachycardia (10 seconds)

Non-sustained or sustained ventricular tachycardia (defined as 3 consecutive 
 
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ventricular ectopic beats).

Any conduction abnormality including but not specific to left or complete 
bundle branch block, atrioventricular [AV] block, high grade or complete heart 
block Wolff-Parkinson-White [WPW] syndrome etc.).

Sinus Pauses >3 seconds.
19. Exclusion criteria for screening ECG (a single repeat is allowed for eligibility 
determination):
Males
Females
Heart rate
<45 and >100 bpm
<50 and >100 bpm
PR Interval
<120 and >220 msec
QRS duration
<70 and >120 msec
*QTc interval
>450 msec
*The QTc is the QT interval corrected for heart rate according to Bazett’s formula 
(QTcB), Fridericia’s formula (QTcF), and/or another method. It is either machine-
read or manually over-read. The specific formula used to determine eligibility and 
discontinuation for an individual participant in 200911 will be Fridericia’s formula. 

Note: A heart rate from 100 to 110 beats per minute (bpm) can be rechecked by 
ECG or vitals within 30 minutes to verify eligibility.

Evidence of previous myocardial infarction (Does not include ST segment 
changes associated with repolarization).

Any conduction abnormality (including but not specific to left or right complete
bundle branch block, AV block [2nd degree or higher], WPW syndrome).

Sinus Pauses >3 seconds.

Any significant arrhythmia which, in the opinion of the principal investigator 
OR GSK medical monitor, will interfere with the safety for the individual 
subject.

Non-sustained or sustained ventricular tachycardia (3 consecutive ventricular 
ectopic beats).
5.3.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and any SAEs.
 
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5.4.
Withdrawal/Stopping Criteria
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as 
soon as possible. 

The site must counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or should 
continue in the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and if necessary a certified letter to the subject’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be considered 
to have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this request has 
occurred in the site study records. 
5.4.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
 
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Phase II Liver Chemistry Stopping and Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus
Bilirubin≥2x
ULN (>35% 
direct) 
or plus
INR>1.5, if 
measured*
Possible
Hy’s Law
ALT≥3xULN
ALT≥5xULN
ALT≥3xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
ALT≥3xULN
but able to 
monitor 
weekly for 
4 weeks
No
Yes
Yes
Yes
Yes
No
No
No
No
Yes
ALT≥3xULN
persist for
4 weeks or 
stopping 
criteria 
met
Yes
No
*INR value not applicable to subjects on anticoagulants
Yes
If subject to be monitored weekly must refer to Liver Safety Required  Actions and  Follow  up 
Assessments  section  in  the  Appendix
Must refer to Liver Safety Required Actions and Follow  up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 2, Section 12.2 and Section 12.3. 
5.4.1.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed.
5.4.2.
QTc Stopping Criteria

The same QT correction formula must be used for each individual subject to 
determine eligibility for and discontinuation from the study.  This formula may 
not be changed or substituted once the subject has been enrolled.

For example, if a subject is eligible for the protocol based on QTcB, then QTcB 
must be used for discontinuation of this individual subject as well.

Once the QT correction formula has been chosen for a subject’s eligibility, the 
same formula must continue to be used for that subject for all QTc data being 
collected for data analysis.  Safety ECGs and other non-protocol specified 
ECGs are an exception.  

The QTc should be based on single or averaged QTc values of triplicate ECGs 
obtained over a brief (e.g., 5-10 minutes) recording period.  
A subject who meets either of the bulleted criteria below will be withdrawn from the 
study:
 
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
QTc >500 msec OR Uncorrected QT >600 msec

Change from baseline of QTc >60 msec
5.5.
Stopping criteria based on Adverse Events
Any grade 3 or higher treatment-related adverse events that occur in ≥2 subjects will be 
carefully reviewed and if considered clinically significant, dosing will be halted pending 
further discussion with the FDA.  Any single treatment-related SAE will also trigger 
immediate evaluation and reporting processes in accordance with applicable regulations.
5.6.
Subject and Study Completion
A completed subject is one who has completed all phases of the study including the 
follow-up visit.
The end of the study is defined as the last subject’s last visit.
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.
Treatment
Product name:
GSK2838232 
Capsule (API)
Tybost 
(cobicistat, cobi) tablet
Formulation 
description:
GSK2838232 powder blend in a 
capsule
Tablet
Dosage form:
Swedish orange, unmarked 
capsules (50 mg), and white, 
unmarked capsules (10 mg)
Orange, round, biconvex, film-coated 
tablets debossed with “GSI” on one side 
and plain faced on the other side 
providing 150 mg of cobicistat.
Unit dose strength(s)/
Dosage level(s):
50 mg capsule for 200 mg, 100 mg, 
50 mg doses and 10 mg capsule for 
20 mg doses 
150 mg for 150 mg doses
Route/
Administration/
Duration:
Administered orally QD for 10 days
Administer orally, QD for 10 days
 
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Treatment
Product name:
GSK2838232 
Capsule (API)
Tybost 
(cobicistat, cobi) tablet
Dosing instructions:
Administer with light meal and 240 
mL of water. 
Administer with light meal and 240 mL 
water.
Manufacturer/
source of 
procurement:
GSK
Gilead
Method for 
individualizing dosage:
Capsules supplied in high-density 
polyethylene bottles for 
individualized dosing by the clinic
Tablets supplied in bulk containers for 
individualized dosing by the clinic
6.2.
Treatment Assignment
Subjects will be assigned to treatment (active) in accordance with the randomization 
schedule generated by Clinical Statistics, prior to the start of the study, using validated 
internal software.
6.3.
Planned Dose Adjustments
Following the interim analysis of safety, virology and PK data from the first cohort of 
subjects in Part A, the option to adjust dose levels from those described exists. No dose 
will be administered that has an associated projected mean AUC or Cmax value higher 
than the most conservative NOAEL obtained from the chronic toxicity studies (i.e., from 
the 9-month dog toxicity study described in Section 2.2.1).
6.4.
Blinding
This will be an open-label study. Treatment allocation in Part B will be randomised (to 
GSK2838232 dose level).  
6.5.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.6.
Preparation/Handling/Storage/Accountability
A description of the methods and materials required for capsule/tablet storage and 
dispensing will be detailed in a Study Specific Technical Agreement/Memo or Pharmacy 
Manual, which will be accompanied by a Quality Agreement.
No special preparation of study treatment is required.

Only subjects enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment.  All study 
treatments must be stored in a secure environmentally controlled and monitored 
 
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(manual or automated) area in accordance with the labelled storage conditions 
with access limited to the investigator and authorized site staff. 

The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation and final disposition records).

Further guidance and information for final disposition of unused study treatment 
are provided in the study reference manual (SRM). 

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  

A Material Safety Data Sheet/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.
6.7.
Compliance with Study Treatment Administration
When subjects are dosed at the site, they will receive study treatment directly from the 
investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents.  The dose of study 
treatment and study subject identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study treatment.  
When subjects self-administer study treatment(s) at home, compliance with study 
treatment(s) will be assessed through querying the subject during the site visits and 
documented in the source documents and case report form (CRF).  A record of the 
number of study treatment(s) dispensed to and taken by each subject must be maintained 
and reconciled with study treatment and compliance records.  Treatment start and stop 
dates, including dates for treatment delays and/or dose reductions will also be recorded in 
the CRF.
6.8.
Treatment of Study Treatment Overdose
For this study, any dose of GSK2838232 >200 mg+cobicistat within a 28-hour time 
period will be considered an overdose.
GSK does not recommend specific treatment for an overdose; however, in the event of an 
overdose, the investigator or treating physician should:

Contact the Medical Monitor immediately

Closely monitor the subject for AEs/SAEs and laboratory abnormalities until 
GSK2838232 can no longer be detected systemically (at least 10 days for 
GSK2838232)

Obtain a plasma sample for PK analysis within 2 days from the date of the last dose 
of study treatment if requested by the Medical Monitor (determined on a case-by-case 
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
Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the subject.
6.9.
Treatment after the End of the Study
Subjects receiving GSK2838232 may opt to receive marketed antiretrovirals after the 
completion of 10 days of GSK2838232 dosing and study follow-up visits (through 
Day 21) eligible for sponsor company reimbursement up to a maximum of 90 days. The 
selection of antiretrovirals will be investigator-chosen.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing
reimbursement for post-study treatment.
6.10.
Lifestyle and/or Dietary Restrictions
6.10.1.
Meals and Dietary Restrictions

Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit juice 
from 7 days prior to the first dose of study medication until after the final dose.

Doses will be given in the fed state (light breakfast), following overnight fasting 
(>10 hours). 
6.10.2.
Alcohol, Caffeine and Exercise

During  the study  alcohol consumption should be limited to the following:

An average weekly intake of <14 drinks for males or <7 drinks for females.  One 
drink is equivalent to 12 g of alcohol: 12 ounces (360 mL) of beer, 5 ounces 
(150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.

Subjects should abstain from strenuous exercise during the treatment period.
6.11.
Contraception
Female subjects can be of childbearing or non-child bearing potential.  
Females of reproductive potential may only be enrolled if they are using two forms of 
complementary contraception, which must include one barrier method.  Although use of 
oral contraceptives is permitted, there is no definitive DDI information with 
GSK2838232 and an interaction with oral contraceptives is possible, so other (barrier, 
inter-uterine device etc.) methods of contraception will be required.
Females of reproductive potential, who have an established, long-term lifestyle of sexual 
abstinence, or only same sex partners, require no other means of birth control.  
Male subjects with female partners of child bearing potential must comply with the 
following contraception requirements from the time of first dose of study medication 
until one week after the last dose of study medication:
 
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1. Vasectomy with documentation of azoospermia. The documentation on male 
sterility can come from the site personnel’s review of subject’s medical records, 
medical examination and/or semen analysis, or medical history interview.
OR
2. Male condom plus partner use of one of the contraceptive options below that 
meets the SOP effectiveness criteria including a <1% rate of failure per year, as 
stated in the product label:
- Contraceptive subdermal implant
- Intrauterine device or intrauterine system
- Combined estrogen and progestogen oral contraceptive 
- Injectable progestogen
-Contraceptive vaginal ring 
- Percutaneous contraceptive patches 
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
6.12.
Concomitant Medications and Non-Drug Therapies
6.12.1.
Permitted Medications and Non-Drug Therapies

Acetaminophen at doses of 2 grams/day or NSAIDs are permitted for use any time 
during the study and their use documented in the CRF.  Other concomitant 
medication may be considered on a case by case basis by the investigator in 
consultation with the Medical Monitor if required.

Concomitant medications (prescription and non-prescription) should be administered 
only as medically necessary during the study. Subjects must notify their Investigator 
of any current or proposed concomitant medication, whether prescribed or over-the-
counter, because of the potential for interactions between such treatments and the 
study medications.
6.12.2.
Prohibited Medications and Non-Drug Therapies

Subjects must refrain from all illicit drugs throughout the study (from Screening until 
discharge from the study).  Drug screening will occur at Screening and Day -1 and at 
additional timepoints throughout the study.  A positive result will lead to exclusion 
from the remainder of the study.
7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table (Section 7.1), are essential and required for study 
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This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table Section 7.1. In 
overview, subjects will be screened, begin dosing and then continue assessments through 
and for up to 2 weeks after the completion of dosing.
The following points must be noted: 

If assessments are scheduled for the same nominal time, THEN the assessments 
should occur in the following order:
1. 12-lead ECG
2. vital signs
3. blood draws.  
Note: The timing of the assessments should allow the blood draw to occur at the 
exact nominal time.
 
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7.1.
Time and Events Table
Day:
Screen1
Random
1
2
3
4
5
62
7
8
9
10
11
12
141
211 
(FU)
ET
Informed Consent
X
Review inclusion/exclusion
X
X
Demography including height, weight 
and BMI
X
Brief physical
X
Medical/medication/
drug/alcohol history
X
X
CDC Classification
X
X
X
X
Prior antiretroviral therapy
X
12-lead ECG3
X
X
X
X
X
X
X
X
X
Holter (24 hr)
X
Vital signs4
X
X
X
X
X
X
X
X
X
Drug screen
X
X
X
X
X
Hepatitis B Surface antigen and 
hepatitis C antibody testing
X
Serum or urine -hCG (WoCBP only)
X
X
X
Clinical lab tests (inc troponin)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Fasting lipid panel
X
X
AE assessment5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Con Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HIV-1 RNA PCR6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lymphocyte subsets7
X
X
X
Plasma for genotype/phenotype8
X
X
X
X
X
X
X
HIV-associated conditions assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK blood sample9
X
X
X
X
X
X
X
X
X
X
X
X14
Plasma samples10
X
X
X
Dosing11
X
X
X
X
X
X
X
X
X
X
PGx12
X
 
 
 
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Day:
Screen1
Random
1
2
3
4
5
62
7
8
9
10
11
12
141
211 
(FU)
ET
Telephone call to IVRS13
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Plasma for storage15
X
X
X
X
X
X
X
X
X
X
X
X
X
Outpatient visit
X
X
X
X
X
X
X
X
X
X
X
X
1.
Screening will occur within 14 - 30 days prior to the first dose of study drug.
2.
Table is set up for the weekend during dosing to occur on Days 6 and 7.  If the weekend occurs on Days 5 and 6, perform all “Day 5” assessments on Day 7.
3.
On Day 1, ECGs will be performed pre-dose , and then 1, 1.5, 2, 3, 4 and 6 hours post dose.  The ECGs should be performed at least 5 minutes apart and preferably within 1 
hour prior to dose.  On Days 4 and 8, ECGs will be obtained prior to morning dosing and at 2, 4 and 6 hours post-dose. To accommodate scheduling, serial ECGs collected on 
Days 4 and 8 may be performed 1 day. On Day 10, ECGs will be performed pre-dose, and then 1, 1.5, 2, 3, 4 and 6 hours post dose.  On Day 11, an ECG will be obtained 
prior to the 24-hour PK sample. ECGs will be performed in triplicate at all timepoints. 
4.
BP, RR, HR and temperature will be obtained at Screening (x1) and Day 1 pre-dose (x2).  BP and HR will be obtained on Day 1 at 2 hours post-morning dose and on Days 4, 5 
and 8 pre-dose.  BP and HR will be obtained on Day 10 at pre-dose and 2 hours post-morning dose, and at day 12 and Follow-up (Day 21).
5.
Only SAEs related to study participation will be collected between screening and Day 1. An AE enquiry will be made at each visit, subjects will be asked if they have 
experienced any neuropsychiatric adverse events, including psychosis or altered mental status.
6.
On Days 1-5 and 8-10 samples for HIV-1 RNA PCR collected before morning dose.  On Days 1, 10 and 11 two samples for HIV-1 RNA PCR will be collected 5-30 minutes 
apart.  HIV-1 RNA PCR samples will also be collected on days 12, 14 & Follow-up (Day 21).
7.
Lymphocyte subsets by flow cytometry (total lymphocyte counts, percentage, and absolute CD4+and CD8+counts).
8.
Blood samples for phenotype and genotype will be collected at pre-dose on Days 1, 4, 5 and 8 in the morning on Day 11 and at follow-up. 
9.
Serial plasma samples (2 mL) for determination of GSK2838232 will be collected on Day 1 and Day 10 at pre dose (within 15 minutes prior to dose) and 0.5, 1, 1.5, 2, 3, 4, 6, 
8, 12 (optional), and 24 hours (to occur on morning of Day 2 post-am dose and in the morning on Day 11) .  Pre-dose PK samples (within 15 minutes prior to dose) will be 
taken on the mornings of Days 3, 4, 5, 8 and 9 and a single sample will be taken on Days 12 and 14.
10. Samples (2 x 0.5mL) of plasma for assessment of immunological markers at screen, baseline (pre-dose) and day 11 
11. Subjects will receive a single dose of GSK2838232 and cobicistat each morning with a light breakfast meal and 240 mL of water from Day 1 to Day 10.  Doses taken in the 
clinic will be administered after an overnight fast of at least 10 hours .On Days 6 and 7, doses will be self administered but confirmed by phone 
12. PGx sample should be collected on Day 1.
13. A screening/registration call should be made to the IVRS to register the subject at screening.   An additional call will be made to document a screen failure.   A randomization 
call should be made to the IVRS system approximately one week prior to scheduled Day 1.  Note: The randomization call must be made in order to have study drug on site for 
Day 1. Additional calls will be made every day that the subject has a scheduled study visit to the clinic.  If a subject terminates the study prematurely a call should be made to 
the IVRS
14. Only if early termination visits occur during the treatment period.
15. Plasma samples for storage will be collected at each visit starting at Day 1, including unscheduled visits (e.g. for HIV-1 RNA levels and immunological parameters).  
Additionally these samples will be used when needed, such as when samples are lost or arrive at the laboratory unevaluable.
AE = Adverse event; CDC= Center for Disease Control and Prevention; ECG = Electrocardiogram; ET = Early termination; hCG = Human chorionic gonadotrophin; HIV = Human 
immunodeficiency virus;  IVRS= Interactive Voice Response System; PCR = Polymerase chain reaction; PK=Pharmacokinetic.
 
 
 
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7.2.
Visit Windows
Screening (baseline to pre-dose): All screening assessments should take place within 
14-21 days prior to the first dose. The screening visit window may be extended to 30 
days upon discussion with the Medical Monitor (i.e.; subject has scheduling conflicts or 
any screening assessment needs to be repeated).
Days 4 and 8: Based on subject and clinic schedule, Day 4 and Day 8 serial (up to 6h 
post-dose) ECG assessments may be conducted 1 day. 
Weekend(s): The T&E table is set up for study start (Day 1) to occur on a Monday and 
Days 6 and 7 to fall on the weekend. If the weekend occurs instead on Days 5 and 6, Day 
5 assessments should be performed on Day 7. The study start (Day 1) may also be 
adjusted to allow visits with assessments to be conducted over the weekend based on 
subject and clinic schedule. 
Assessments: The following applies to timing of procedures:
-
Window for assessments 4 h post-dose = 5 minutes
-
Window for assessments >4 and < 12 h post-dose = 15 minutes
-
Window for assessments >12 h post-dose = 30 minutes
End of Treatment visit: should be within 14 days from last dose of study drug. If a 
subject is unable to return to the clinic for any reason site staff are encouraged to 
telephone the subject for assessment of adverse events.
7.3.
Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed at 
screening.
The following demographic parameters will be captured: year of birth, sex, race, and 
ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria.
Procedures conducted as part of the subject’s routine clinical management (e.g., blood 
count) and obtained prior to signing of informed consent may be utilized for Screening or 
baseline purposes provided the procedure meets the protocol-defined criteria and has 
been performed in the timeframe of the study.
7.3.1.
Holter Monitoring (Screening criteria)
The 24-hour Holter monitoring will be performed during the Screening period using a 
Holter monitoring device supplied by the Sponsor.
 
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Analysis of the Holter tapes will consider the following:

Heart rate (bradycardia and tachycardia)

Normal and aberrant beats

Number of supraventricular contractions, premature atrial contractions, premature 
ventricular contractions, couplets, triplets, and ventricular tachycardias

Atrio-ventricular conduction defects

Atrial fibrillation and flutter
7.4.
Efficacy
7.4.1.
HIV-1 RNA Sampling
Plasma for quantitative HIV-1 RNA will be collected at timepoints listed in the Time and 
Events Table in Section 7.1. To reduce sample variability, two plasma HIV-1 RNA 
samples will be collected on Days 1, 10, and 11.
An HIV-1 RNA PCR assay with a lower limit of detection (LLOD) of 50 copies/mL 
(ultrasensitive assay) will be used for post-baseline assessments. An HIV-1 RNA PCR 
assay with a LLOD of 400 copies/mL (standard assay) will be used for screening and 
baseline assessments and will include a re-test with and ultrasensitive assay for all 
baseline values below the LLOD. An HIV-1 RNA PCR assay with a LLOD of 2 
copies/mL (supersensitive assay) may be used for exploratory analysis.
7.4.2.
Lymphocyte Subsets by Flow Cytometry
Whole venous blood samples will be obtained from each subject for the analysis of 
lymphocyte subsets by flow cytometry at the timepoints listed in the Time and Events 
Table in Section 7.1.
Details concerning the handling, labeling and shipping of these samples will be supplied 
separately.
7.5.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).  Additional time points for safety tests (such as vital signs, physical exams 
and laboratory safety tests) may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring.
7.5.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 5, Section 12.5.
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
 
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7.5.1.1.
Time period and Frequency for collecting AE and SAE information

AEs and SAEs will be collected from the start of Study Treatment until the 
follow-up contact (see Section 7.5.1.3), at the timepoints specified in the Time 
and Events Table (Section 7.1). An AE enquiry will be made at each visit, where 
subjects will be specifically asked if they have experienced any neuropsychiatric 
adverse events, including psychosis or altered mental status  

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF.

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded from the time a subject consents to participate in the 
study up to and including any follow-up contact. 

All SAEs will be recorded and reported to Sponsor within 24 hours, as indicated 
in Appendix 5, Section 12.5.

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the
event reasonably related to the study treatment or study participation, the 
investigator must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 5
7.5.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?”

“Have you experienced any alteration in personality, behaviour, mood or any 
altered mental status?”
7.5.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, and non-serious AEs of special interest 
(as defined in Section 12.5) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
 
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(as defined in Section 5.4). Further information on follow-up procedures is given in 
Appendix 5.
7.5.1.4.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 5 (Section 12.5.3) and all deaths, 
whether or not they are considered SAEs, specific CV and Death sections of the CRF will 
be required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed 
within one week of when the death is reported.
7.5.1.5.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
The following disease-related events (DREs) are common in subjects with HIV-1 
infection and can be serious/life threatening:

events or outcomes listed in the CDC Classification System for HIV-1 Infections 
(see Appendix 9; Section 12.8)

sign, symptom, diagnosis, illness, and/or clinical laboratory abnormality that can 
be linked to any of these events or outcomes
Because these events are typically associated with the disease under study, they will not 
be reported according to the standard process for expedited reporting of SAEs to GSK 
(even though the event may meet the definition of a serious adverse event). 
These events will be recorded on the DRE page in the subject’s CRF using the HIV 
Associated Conditions eCRF. These DREs will be monitored by the medical monitor and 
study team on routine basis.
However, if any of the following conditions apply, then the event should be reported as 
an SAE using the standard process:

The event is, in the Investigator’s opinion, of greater intensity, frequency, or 
duration than expected for the individual subject, 
or

The Investigator considers that there is a reasonable possibility that the event was 
related to treatment with the investigational product.
or
 
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
Death occurring for any reason during a study, including death due to a disease 
related event, will always be reported promptly. 
If either of the above conditions is met then record the DRE on the SAE page rather than 
the HIV Associated Conditions eCRF page and report promptly to GSK.
7.5.1.6.
Regulatory Reporting Requirements for SAE
Prompt notification by the investigator to GSK or designee of SAEs and non-serious AEs 
related to study treatment (even for non- interventional post-marketing studies) is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a product under clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.5.2.
Pregnancy

Details of all pregnancies in female subjects and if indicated female partners of 
male subjects will be collected after the start of dosing and until one week post 
study

If a pregnancy is reported then the investigator should inform GSK within 24hrs 
of learning of the pregnancy and should follow the procedures outlined in 
Appendix 7, Section 12.6.
7.5.3.
Physical Exams

A complete physical examination will include, at a minimum, assessment of the 
Cardiovascular, Respiratory, GI 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 should pay special attention to clinical signs related to previous 
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7.5.4.
Vital Signs

Vital signs will be measured in semi-supine position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure and pulse rate 

Three readings of blood pressure and pulse rate will be taken

First reading should be rejected

Second and third readings should be averaged to give the measurement to be 
recorded in the CRF. 
7.5.5.
Electrocardiogram (EGC)

Triplicate 12-lead ECGs will be obtained at each timepoint during the study using 
an ECG machine that automatically calculates the heart rate and measures PR, 
QRS, QT, and QTc intervals.  Refer to Section 5.4.2 for QTc withdrawal criteria 
and additional QTc readings that may be necessary.
7.5.6.
Clinical Safety Laboratory Assessments
All protocol-required laboratory assessments as defined in the Tables below must be 
conducted in accordance with the SRM and Protocol Time and Events Schedule (Section 
7.1). Laboratory requisition forms must be completed and samples must be clearly 
labelled with the subject number, protocol number, site/centre number, and visit date.
Details for the preparation and shipment of samples will be provided by the laboratory 
and are detailed in the SRM. Reference ranges for all safety parameters will be provided 
to the site by the laboratory responsible for the assessments.
If additional non-protocol-specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the CRF.
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
All study-required laboratory assessments will be performed by a central laboratory:
NOTE:  Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either a treatment and/or response evaluation to be 
performed. 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 treatment or response evaluation, the results must be entered in the CRF.
 
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Haematology, clinical chemistry, urinalysis, and additional parameters to be tested are 
listed below. 
Table 8
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
WBC count with Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes with T-cell 
subsets
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry 1
BUN
Potassium
AST (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose 
Bicarbonates
Alkaline phosphatise
Albumin
Troponin I
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

HIV

Hepatitis B (HBsAg)

Hepatitis C (Hep C antibody)

FSH and estradiol (as needed in women of non-child bearing 
potential only)

Alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines)

Urine hCG Pregnancy test (as needed for women of child bearing 
potential) 2
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 12.2 and 
Section 12.3
2.
Local urine testing will be standard for the protocol unless serum testing is required 
by local regulation or ethics committee.
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study or within 7 days after the last dose of study treatment 
should be repeated until the values return to normal or baseline.  If such values do not 
return to normal within a period judged reasonable by the investigator, the etiology
should be identified and the sponsor notified.
 
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7.6.
Pharmacokinetics
7.6.1.
Blood Sample Collection
Blood samples for analysis of GSK2838232 concentrations will be collected at the time 
points indicated in Time and Events Tables (Section 7.1).  
The actual date and time of each blood sample collection will be recorded.  The timing of 
PK samples may be altered and/or PK samples may be obtained at additional time points 
to ensure thorough PK monitoring.  
Details of PK blood sample collection (including volume to be collected), processing, 
storage and shipping procedures are provided in the Study Reference Manual (SRM).
7.6.2.
Sample Analysis
Plasma analysis will be performed by Covance, Madison under the control of 
Bioanalysis, Immunogenicity and Biomarkers (BIB), PTS, GlaxoSmithKline.
Concentrations of GSK2838232 will be determined in plasma using the currently 
approved bioanalytical methodology. 
Once the plasma has been analyzed for GSK2838232 any remaining plasma may be 
analyzed qualitatively for other circulating metabolites and these results would be 
reported under a separate PTS protocol.
Raw data will be archived at the Covance, Madison facility.
7.7.
Biomarker(s)/Pharmacodynamic Markers
7.7.1.
Viral Genotyping and Phenotyping
Whole venous blood samples will be obtained from each subject to provide plasma for 
viral genotype and phenotype analysis, at the times listed in the Time and Events Table in 
Section 7.1. Details concerning the handling, labeling and shipping of these samples will 
be supplied separately.
Genotypic and phenotypic analyses will be carried out by Monogram Biosciences using 
their GAG/PR and PR/RT formats, in which PCR amplification is used to generate HIV 
cDNA products including the Gag and the PR and RT coding regions, respectively. 
Phenotypic analyses of the GAG/PR region will include susceptibility to GSK2838232 . 
Analysis will be done on Day 1 and Day 11 samples.  In the case of rebound HIV-1 viral 
load, analysis will be completed on samples corresponding to time point of rebound 
occurrence. 
7.8.
Genetics
Information regarding genetic research is included in Appendix 4, Section 12.4.
 
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7.9.
Value Evidence and Outcomes
Not required.
8.
DATA MANAGEMENT

For this study subject data will be entered into GSK defined CRFs, transmitted 
electronically to GSK or designee and combined with data provided from other 
sources in a validated data system, 

Management of clinical data will be performed in accordance with applicable 
GSK standards and data cleaning procedures to ensure the integrity of the data 
(e.g., removing errors and inconsistencies in the data).

Adverse events and concomitant medications terms will be coded using MedDRA 
and an internal validated medication dictionary, GSKDrug.  

CRFs (including queries and audit trails) will be retained by GSK, and copies will 
be sent to the investigator to maintain as the investigator copy.  Subject initials 
will not be collected or transmitted to GSK according to GSK policy.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
The primary objectives of this study are to investigate the safety, tolerability, and 
antiviral activity of GSK2838232 administered as monotherapy in combination with 
cobicistat in HIV-1 infected subjects, over a 10 day treatment period. The antiviral 
activity will be assessed by estimating plasma HIV-1 RNA max change from baseline 
during the study. 
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
The sample size for this study is based primarily on feasibility to provide adequate 
precision for the estimations.
Based on data from the short term monotherapy study of BMS-955176 PoC (AI468002) 
study and assuming viral load values for individual subjects follow a log-normal 
distribution, 1000 trial simulations in Fixed and Adaptive Clinical Trial Simulation 
(FACTS) software were conducted from the distribution with mean of change from 
baseline viral load drop on log scale at 1.0 to 1.5 copies and SD=0.4 and sample sizes=10 
for Part A.  Using Bayesian calculation with non-informative priors for the mean and 
weakly informative priors for the error parameters, Normal (0, 100) for mean and Inverse 
Gamma (0.35, 0.0875) for error parameters, the posterior probability to achieve a 
cutpoint 1.2 log was calculated for each simulated trial, and percentage of the trials with 
 
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posterior probability of viral load<-1.2log drop given true mean) ≥70% were calculated 
and are shown below in Table 9.
Table 9
Percentage of the trials with posterior probability>=70% for Part A
True Mean
Cutpoint
Posterior Prob>=70%
1.0
1.2
1.4%
1.1
1.2
9%
1.2
1.2
29%
1.3
1.2
59%
1.4
1.2
83%
1.5
1.2
96%
An Emax model with functional uniform priors [Bornkamp, 2014] was conducted using 
simulated data combining Part A and Part B with all doses. Success is defined as a 
posterior probability of the highest dose to achieve a cutpoint 1.2 log reduction in viral 
load.   This was calculated for each simulated trial and the percentage of the trials with 
posterior probability greater or equal to 70% were also calculated and are shown below 
(Table 10). The table lists different viral load drop scenarios. The last scenario assumes 
the flat drop for all doses are 0.5.  This scenario reflects the null hypothesis of no 
treatment effect. In this scenario 0% of the trials achieve the pre-specified decision rule 
for success.
Table 10
Percentage of the trials with posterior probability ≥70%
Cutpoint
Posterior Prob≥
Part A+ Part B 
mean VL drop for doses 
200, 100, 50, 20
Part A+ Part B
1.2
70%
1.5, 1.4, 1.2, 0
99%
1.5, 1.4, 1.2, 0.5
96%
1.5, 1.4, 1.0, 0.5
93%
1.5, 1.3, 1.2, 0.5
86%
0.5, 0.5, 0.5, 0.5
0%
9.2.2.
Sample Size Sensitivity
Similar simulations in FACTS were conducted from the distribution with mean of change 
from baseline viral load drop on log scale at 1.5 copies and SD=0.4 or 0.6 and sample 
sizes of 6-8 or 10 for Part A.  Using Bayesian calculation, the posterior probability to 
achieve a cutpoint 1.2 log (in Table 11) was calculated for each simulated trial, and 
percentage of the trials with posterior probability greater than or equal to 70% was 
calculated and are shown below.
 
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Table 11
Percentage of the trials with posterior probability ≥70% for Part A
True 
Mean
Cutpoint
Posterior 
Prob≥
Std for log10 
VL
N=6 
N=8
N=10
1.5
1.2
70%
0.4
90%
94%
96%
0.6
75%
81%
84%
9.2.3.
Sample Size Re-estimation or Adjustment
No sample size re-estimation will be performed.
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
Intent to Treat Exposed Population (ITT)
The ITT-Exposed Population is defined as all subjects who meet study criteria and are 
enrolled into the study with documented evidence of having received at least 1 dose of 
treatment and at least one post-baseline HIV-1 RNA measurement. This will be the 
primary population for the final efficacy analysis for all active treatment groups.
Per Protocol Population (PP)
The Per Protocol Population is defined as all subjects who meet study criteria and are 
enrolled into the study with documented evidence of having received all doses and all 
post-baseline HIV-1 RNA measurement, with exceptions of major protocol deviation. 
Safety Population
The Safety Population is defined as all subjects who are enrolled into the study with 
documented evidence of having received at least 1 dose of randomized treatment.
Pharmacokinetic Population
The PK Population will include all subjects who receive GSK2838232 and undergo 
plasma PK sampling during the study. Subjects for whom a plasma PK sample is 
obtained and assayed will be included in the listing of plasma GSK2838232 
concentration-time data.  Results from samples collected from a subject with emesis 
occurring within 4 hours of the dose will not be considered as evaluable.
9.3.2.
Interim Analysis
An interim analysis of preliminary safety, tolerability, PK and antiviral activity will occur 
after subjects of Part A Cohort 1 complete their Day 13 visit. If the Cohort 1 dose is 
determined to be the highest dose based on this review (e.g., the exposure level of 
GSK2838232 is in the range of the maximum GSK2838232 exposure seen previously in 
healthy subjects), the Bayesian posterior probability that the log10 viral load decline from 
baseline is greater than a cut-point will be calculated. If the Bayesian probability from 
Cohort 1 is less than 70%, this will provide evidence to not move forward into Part B. 
Otherwise, the study team will review the data in order to make a dose selection decision 
for the subsequent Part B Cohorts.  If the pharmacokinetic exposures after the 100 mg 
GSK2838232/cobi dose look similar to those obtained with 100 mg GSK2838232/r in 
 
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prior studies, the doses for Part B will be extended to both lower (20 mg, 50 mg) and 
higher (200 mg) GSK2838232 doses.
Maximum change and change from baseline in plasma HIV-1 RNA will be summarized 
by treatment or by assessment day. The proportion of subjects with plasma HIV-1 RNA 
<400 and <50 copies/mL will be summarized by treatment and assessment day. The 
analyses will be done for both PP and ITT exposed population if the two populations are 
not the same. 
9.4.
Key Elements of Analysis Plan
9.4.1.
Primary Analyses
The final analysis will be performed after the completion of the study and final datasets 
authorization. Data will be listed and summarized according to GlaxoSmithKline 
reporting standards, where applicable. Listings will be sorted by subject, period, 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, geometric mean with 
associated 95% confidence interval (CI), and %CVb for continuous variables, whereas n 
and percent will be used as summary statistics for categorical variables. Baseline or pre-
dose 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 9.1 or higher 
of the SAS system will be used to analyze the data as well as to generate tables, figures, 
and listings. Complete details will be documented in the Reporting and Analysis Plan 
(RAP).
9.4.1.1.
Safety Analyses
Safety data will be presented in tabular format and summarized descriptively according to 
GSK’s Integrated Data Standards Library standards and data will be in CDISC format. 
No formal statistical analysis of the safety data will be conducted. 
9.4.1.2.
Efficacy Analyses
Both the PP and ITT Populations will be used for all efficacy analyses if there are 
dropouts.  Plasma HIV-1 RNA max change and change from baseline during the study 
will be calculated for each subject on each assessment day.
Plasma HIV-1 RNA will be listed by treatment, subject, and assessment day and 
summarized by treatment and assessment day along with change from baseline.
Plots of mean and median plasma HIV-1 RNA actual and change from baseline data will 
be generated by treatment and assessment day.

Plasma HIV-1 RNA change from baseline to the on-treatment nadir (maximum 
change) will be calculated for each subject and summarized by treatment.
 
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Together, the data from Parts A and B will investigate the complete dose-response curve 
and the impact of lower doses on potential development of resistance. A dose-response 
curve will be fit to the data from Parts A & B using functional uniform priors.  
9.4.1.3.
Pharmacokinetic Analyses
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacokinetics 
Modeling and Simulation Department, GlaxoSmithKline. Plasma GSK2838232 
concentration-time data will be analyzed by non-compartmental methods with 
WinNonlin Version 6.1 or higher. Calculations will be based on the actual sampling 
times recorded during the study. From the plasma concentration-time data, the following 
pharmacokinetic parameters will be determined, as data permit:
Plasma GSK2838232 Pharmacokinetic Parameters to be Estimated:
Study Day
Parameters
1
AUC(0-24), Cmax, tmax, tlag, C24
10
AUC(0-), Cmax, tmax, t½, C0, C, CL/F, R_AUC, R_Cmax, R_C
Results based on samples collected from a subject with emesis within 4 hours of the dose 
will not be considered as evaluable.
All PK data will be stored in the R&D archives, GlaxoSmithKline.
Statistical analyses of the pharmacokinetic parameter data will be the responsibility of 
Clinical Statistics, GlaxoSmithKline. Details of the statistical analyses will be provided in 
the RAP. An outline is provided below:
Pharmacokinetic data will be presented in graphical and tabular form and will be 
summarized descriptively. Plasma GSK2838232 PK parameters, with the exception of 
tmax and tlag, will be log-transformed prior to analysis.
Dose proportionality of plasma GSK2838232 PK parameters from Day 1 [AUC(0-24) 
and Cmax] and Day 10 [AUC(0-τ) and Cmax] will be assessed using a power model if 
multiple dose levels are assessed. The power model will be fitted by restricted maximum 
likelihood (REML) using SAS Proc Mixed. A fixed effects power model will be used. 
The mean slope will be estimated from the power model with the corresponding 90% CI. 
The accumulation ratio (R) and steady-state assessments will be performed, if quality of 
the data permits. Comparisons of Day 10 with Day 1 PK for each dose will be used for 
the accumulation ratio (R) evaluation. Pre-dose concentrations between Days 7-10 will be 
used for steady-state assessment. 
9.4.2.
Secondary Analyses
9.4.2.1.
Pharmacokinetic/Pharmacodynamic Analyses
Relationships between various PK parameters (e.g., AUC, Cmax, Cτ, etc.) and PD 
measures (e.g., log10 reduction from baseline in plasma HIV-1 RNA on Day 11 or safety 
 
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parameters) will be explored using various models including Emax. The relationship 
between dose and PD measures will also be explored. Details of the PK/PD exploratory 
analyses will be provided in the RAP.
9.4.2.2.
Viral Genotyping and Phenotyping Analyses
Viral genotypic/phenotypic data will be listed and descriptive summaries will be 
provided. Details of the analyses will be provided in the clinical virology report.
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial
registers before enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

Obtaining signed informed consent

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, 
or both.

Signed informed consent must be obtained for each subject prior to participation 
in the study

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  
 
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
Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, 
written approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors or designee will contact the site prior to the start of the study to 
review with the site staff the protocol, study requirements, and their 
responsibilities to satisfy regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the CRF will 
serve as the source document.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
10.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and 
the regulatory agencies may conduct a regulatory inspection at any time during or 
after completion of the study. 

In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all
relevant documents and to allocate their time and the time of their staff to discuss 
the conduct of the study, any findings/relevant issues and to implement any 
corrective and/or preventative actions to address any findings/issues identified.
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor or 
designee will conduct site closure activities with the investigator or site staff, as 
appropriate, in accordance with applicable regulations including GCP, and GSK 
Standard Operating Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this 
study at any time for reasons including, but not limited to, safety or ethical issues 
or severe non-compliance. For multicenter studies, this can occur at one or more 
or at all sites.  
 
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
If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable).  When feasible, GSK will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.  

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical 
institution (where applicable) must maintain all site study records (except for 
those required by local regulations to be maintained elsewhere), in a safe and 
secure location.  

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review 
in conjunction with assessment of the facility, supporting systems, and relevant 
site staff.  

Where permitted by local laws/regulations or institutional policy, some or all of 
these records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.  

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, 
including re-generating a hard copy, if required.  Furthermore, the investigator 
must ensure there is an acceptable back-up of these reproductions and that an 
acceptable quality control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by 
any institutional requirements or local laws or regulations, GSK 
standards/procedures, and/or institutional requirements.  

The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of 
ownership of the records in the event the investigator is no longer associated with 
the site.
 
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10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.
10.8.
Review Committees
The Safety Review Team (SRT) is a GSK cross-functional team reviewing all available 
safety data related to the project, including in-stream data from this study, in an ongoing 
manner. The SRT is an internal GSK requirement put in place to ensure holistic 
evaluation of the safety profile of an investigational product with systematic, periodic and 
documented reviews of available safety data, with the appropriate communication and 
escalation of new findings that have the potential to impact patient safety
 
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11.
REFERENCES
Bloch M, Bodsworth N, Fidler M, Workman C, Balach A, Byakagwa H, et al. Efficacy, 
safety and pharmacokinetics of MPC-4326 (bevirimat dimeglumine) 200mg BID and 
300mg BID monotherapy administered for 14 days in subjects with HIV-1 infection. 
ICAAC. 2009; Abstract H-1230.
Bornkamp B, Practical considerations for using functional uniform prior distributions for 
dose-response estimation in clinical trials. Biometrical Journal 56 (2014) 6, 947-962
Cockcroft DW, Gault MH. Prediction of creatinine clearance form serum creatinine. 
Nephron. 1976;16:31-41.
Dang Z, Huang L, Chen C. HIV-1 maturation inhibitors:  An update. Drugs of the Future. 
2009;34 (10):797-802.
Elion R, Cohen C, Gathe J, Shalit P, Hawkins T, Liu HC, et al.  Phase 2 study of 
cobicistat versus ritonavir each with once-daily atazanavir and fixed-dose 
emtricitabine.tenofovir df in the initial treatment of HIV infection.  AIDS.  2011; 
25:1881-1886.
Food and Drug Administration (FDA). Guidance for industry: Estimating the maximum 
safe starting dose in initial clinical trials for therapeutics in adult healthy subjects. CDER, 
Rockville, MD; 2005. UCM078932.
Food and Drug Administration (FDA). Guidance for Industry: Human Immunodeficiency 
Virus-1 Infection: Developing Antiretroviral Drugs for Treatment. CDER, Rockville, 
MD; 2015. UCM355128.
Gallant JE, Koenig E, Andrade-Villaneuva J, Chetchotisakd P, deJesus E, Antunes F,
Arastéh K, et al.  Cobicistat versus ritonavir as a pharmacoenhancer of atazanavir plus 
emtricitabine/tenofovir disoproxil fumarate in treatment-naïve HIV type 1-infected 
patients:  week 48 results.  J. Infect. Dis.  2013; 208-:32-39.
GlaxoSmithKline Document Number 2012N151889_03 Compound GSK2838232. 
Investigator’s Brochure.  Effective November 2016.
GlaxoSmithKline Non-Clinical Research report. Document Number 2013N163221_00.
Hatcher RA, Trussel J, Nelson AL, Cates W, Stewart F, Kowal D, editors. Contraceptive 
Technology. 19th ed. New York:Ardent Media; 2007. 
Kakuda TN, Opsomer M, Timmers M, Iterbeke K, Van De Casteele T, Hillewaert V, et 
al.  Pharmacokinetics of darunavir in fixed-dose combination with cobicistat compared 
with coadministration of darunavir and ritonavir as single agents in healthy volunteers.  J. 
Clin. Pharmacol.  2009; 54:949-957.
 
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Lalezari J, McCallister S, Gigliotti M, Cohen C, Elion R, Brinson C, et al. Safety and 
efficacy study of bevirimat (BVM) in heavily treatment experienced HIV+ patients 
identifies the target phase 3 study profile. ICAAC. 2008; Abstract: H891. 
Mahmood I. Prediction of human drug clearance from animal data. Application of the 
rule of exponent and fu corrected intercept method (FCIM). J Pharm Sci. 
2006;95:1810-21. 
Martin D, Galbraith H, Ellis C, Schettler J and Doto J. Minimal effect of ritonavir (RTV) 
on the pharmacokinetics of bevirimat in healthy volunteers [abstract]. IAS Conference on 
HIV Pathogenesis, Treatment and Prevention. 2007; Abstract no. WEPEB015:Poster 
discussion.
Martin DE, Blum R, Doto J, Galbraith H, Ballow C. Multiple-dose pharmacokinetics and 
safety of bevirimat, a novel inhibitor of HIV maturation, in healthy volunteers. Clin 
Pharmacokinet. 2007(a);46(7):589-98.
Martin DE, Blum R, Wilton J, Doto J, Galbraith H, Burgess GL, et al. Safety and 
pharmacokinetics of bevirimat (PA-457), a novel inhibitor of human immunodeficiency 
virus maturation, in healthy volunteers. Antimicrobial Agents and Chemotherapy. 
2007(b);Sep:3063-6.
Martin DE, Galbraith H, Schettier J, Ellis C, Doto J. Pharmacokinetic properties and 
tolerability of bevirimat and atazanavir in healthy volunteers:  An open-label, parallel-
group study. Clinical Therapeutics. 2008;30(10):1794-1805.
NORVIR (ritonavir) Product Information. January, 2013.
Nowicka-Sans B, Protack T, Lin Z, Li Z, Zhang S, Meanwell N, et al. BMS-955176: 
Characterization of a second-generation HIV-1 maturation inhibitor. 8th IAS Conference 
on HIV Pathogenesis, Treatment and Prevention, July 19-22, 2015, Vancouver, Canada.
Qian K, Morris-Natschke SL, Lee KH. HIV entry inhibitors and their potential in HIV 
therapy. Medicinal Research Reviews. 2009;29(2):369-93.
Saxena SK, Gupta A, Bhagyashree K, Saxena R, Arora N, Banerjee AK, et al. Targeting 
strategies for human immunodeficiency virus: A combinatorial approach. Min Rev Med 
Chem. 2012;12(3):236-54.
TYBOST (cobicistat) Product Information. 2012
Wainburg MA, Albert J. Can the further clinical development of bevirimat be justified?. 
AIDS. 2010;24:773-4.
 
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
g/mL
Microgram per millilitre
ABC
Abacavir
AE
Adverse Event
AIDS
Acquired immunodeficiency syndrome
ALT
Alanine aminotransferase
API
Active Pharmaceutical Ingredient
ART
Antiretroviral therapy
AST
Aspartate aminotransferase
AUC
Area under the plasma concentration time curve
AUC(0-)
Area under the concentration-time curve from time zero 
(pre-dose) extrapolated to infinite time
AUC(0-)
Area under the concentration-time curve over the dosing 
interval 
AUC(0-24)
Area under the concentration-time curve from zero (pre-
dose) to 24 h
AUC(0-48)
Area under the concentration-time curve from zero (pre-
dose) to 48 h
AUC(0-t)
Area under the concentration-time curve from zero (pre-
dose) to time of last quantifiable concentration
BCRP
Breast cancer resistance protein
BID
Twice daily
Bpm
beats per minute
BVM
Bevirimat
BIL
Bilirubin
C
Pre-dose (trough) concentration at the end of the dosing 
interval
C24
24 hour trough concentration
CDC
Center for Disease Control and Prevention
CI
Confidence interval
CL/F
Oral Clearance
Cmax
Maximum plasma concentration
Cmin
Minimum plasma concentration
CPK
Creatine Phosphokinase
CRF
Case report form
cTnI
Cardiac troponin I
CV
Coefficient of variation
CVb
Between-subject variability
CYP
Cytochrome P450
DDI
Drug Drug Interaction
DNA
Deoxyribonucleic acid
EC50
50% protection against resistant mutant HIV infection 
 
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ECG
Electrocardiogram
FC
Fold Changes
FDA
Food and Drug Administration
FSH
Follicle stimulating hormone
FTIH
First time in Human Study
g
Gram
GI
Gastrointestinal
GSK
GlaxoSmithKline
h
Hour(s)
HBsAg
Hepatitis B surface antigen
hcG
Human chorionic gonadotrophin
HDPE
High density polyethylene
hERG
Human Ether-a-gogo Related Gene
HIV
Human Immunodeficiency Virus
IC50/90
50% or 90% maximal inhibitory concentration
IEC
International Ethics Committee
IQ
Inhibitory quotient
IRB
Institutional Review Board
ISR
Injection site reaction
IV
Intravenous
IVRS
Interactive voice response system
kg
Kilogram
L
Litre
LLOD
Lower limit of detection
MC
Melanocortin
MedDRA
Medical Dictionary for Regulatory Activities
mg/mL
Milligram per millilitre
MI
Maturation inhibitor
mL
Milliliter
mRNA
messenger Ribonucleic Acid
ND
Not done
ng/mL
Nanogram per millilitre 
nm
Nanometer
NO
Not observed
NOAEL
No Observed Adverse Effect Level
NTproBNP
N-terminal prohormone of brain natriuretic peptide
NSVT
Non-sustained ventricular tachycardia
OAT
Organic anion transporter
OATP
Organic anion transporting polypeptide
OCT
Organic cation transporter
PBL
Peripheral Blood Lymphocytes
PBMC
Peripheral Blood Mononuclear Cells
PD
Pharmacodynamics
PPD
Pharmaceutical Product Development
P-gp
P-glycoprotein
PHIV
Pseudo- HIV
 
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PiB
Powder-in-bottle
PK
Pharmacokinetic
PoC
Proof of Concept
PI
Protease Inhibitor
QD
Once daily
RAP
Reporting and analysis plan
RIBA
Recombinant Immuno-Blot Assay
RT
Reverse Transcriptase
SAE
Serious adverse event
SDD
Spray Dried Dispersion
SRM
Study reference manual
t½
Terminal elimination half-life
TEM
Transmission Electron Microscopy
tlag
Time of first quantifiable concentration
tmax
Time of occurrence of Cmax
U
Units
UGT
Uridine 5'-diphospho-glucuronosyltransferase
Vz/F
Mean apparent oral volume of distribution
WPW
Wolff-Parkinson-White
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Abbot, Roche HIV kit
Chiron RIBA 
Inform
Monogram
Phoenix WinNonlin 
SAS
Tybost (cobicistat)
 
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12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments
Phase II liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event etiology (in alignment with the 
FDA premarketing clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Phase II liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF and complete an 
SAE data collection tool if the event also meets 
the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries
resolve, stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge subject with study 
treatment unless allowed per protocol and GSK 
Medical Governance approval is granted 

If restart/rechallenge not allowed per protocol 
or not granted, permanently discontinue study 
treatment and may continue subject in the study 

Viral hepatitis serology4

Blood sample for pharmacokinetic (PK) 
analysis, obtained within 24hrs after 
last dose5

Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications 
on the concomitant medications report 
 
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for any protocol specified follow up assessments 
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 
24 hours

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to within 
baseline 

A specialist or hepatology consultation is 
recommended
For All other criteria: 

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24-
72 hours 

Monitor subjects weekly until liver chemistries 
resolve, stabilize or return to within baseline
form including acetaminophen, herbal 
remedies, other over the counter
medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG or gamma globulins).

Serum acetaminophen adduct high-
performance liquid chromatography
assay (quantifies potential 
acetaminophen contribution to liver 
injury in subjects with definite or likely 
acetaminophen use in the preceding 
week 

Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF 
forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN.. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
5.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.)  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.  
 
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Phase II liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 3xULN and <5xULN and bilirubin 
<2xULN, without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss subject safety. 

Subject can continue study treatment  

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to within 
baseline.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
 
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12.3.
Appendix 3: Liver Safety – Study Treatment Restart or 
Rechallenge Guidelines
Study treatment restart or re-challenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed.
 
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12.4.
Appendix 4: Genetic Research
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and: 

Response to medicine, including GSK2838232/RTV or any concomitant 
medicines;

HIV susceptibility, severity, and progression and related conditions
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic 
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research.  Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.  

A 6 ml blood or 2 ml saliva sample will be taken for Deoxyribonucleic acid 
(DNA) extraction. A sample is collected at the baseline visit, after the subject has 
been randomized and provided informed consent for genetic research. Instructions 
for collection and shipping of the genetic sample are described in the laboratory 
manual. The DNA from the blood/saliva sample may undergo quality control 
analyses to confirm the integrity of the sample. If there are concerns regarding the 
quality of the sample, then the sample may be destroyed. The blood/saliva sample 
is taken on a single occasion unless a duplicate sample is required due to an 
inability to utilize the original sample.  
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study.   This number can be traced or linked back to 
 
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the subject by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number). 
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study, or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form.  Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study.  Genetic informed consent must be obtained prior to any blood/saliva being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA 
sample is retained

Discontinue participation in the genetic research and destroy the genetic DNA 
sample 
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis. 

If a subject withdraws consent for genetic research and genotype data has not been 
analyzed, it will not be analyzed or used for future research.  

Genetic data that has been analyzed at the time of withdrawn consent will 
continue to be stored and used, as appropriate. 
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 
 
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reconciliation process.  In this instance a sample destruction form will not be available to 
include in the site files.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic 
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined.  Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care.
 
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12.5.
Appendix 5: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.5.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE.  However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition 
of an AE or SAE.

The signs and symptoms and/or clinical sequelae resulting from lack of efficacy will 
be reported if they fulfil the definition of an AE or SAE.  Also, "lack of efficacy" or 
"failure of expected pharmacological action" also constitutes an AE or SAE.
 
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Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
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.
12.5.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
c.
Results in death
d.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
e.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
 
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f.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption
g.
Is a congenital anomaly/birth defect
h.
Other situations:

Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.

Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse
i.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.

Refer to Appendix 2 for the required liver chemistry follow-up instructions
 
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12.5.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
12.5.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.

Subject-completed Value Evidence and Outcomes questionnaires and the collection 
of AE data are independent components of the study.

Responses to each question in the Value Evidence and Outcomes questionnaire will 
be treated in accordance with standard scoring and statistical procedures detailed by 
 
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the scale’s developer.

The use of a single question from a multidimensional health survey to designate a 
cause-effect relationship to an AE is inappropriate.
12.5.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important 
that the investigator always make an assessment of causality for every event 
prior to the initial transmission of the SAE data to GSK.
 
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
The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

By specific request, the investigator is obligated to report any grade 2 or higher 
“alteration in personality-behavior or in mood” or “altered mental status” adverse 
events that occur in subjects taking this drug, to GSK within 3 days.

The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.

If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any post-mortem findings, 
including histopathology. 

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
12.5.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the Medical Monitor

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data

If a site receives a report of a new SAE from a study subject or receives updated data 
 
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on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the Medical 
Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
SAE reporting to GSK via paper CRF

Facsim0ile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the Medical Monitor 

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable, with a copy of the SAE data collection tool sent by 
overnight mail

Initial notification via the 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 receipt can be found at this beginning of the protocol on the 
Sponsor/Medical Monitor Contact Information page.
SAE reporting to GSK via PIMS

Facsimile transmission of the following PIMS listings for the corresponding subject 
is the preferred method to transmit SAE information to the Medical Monitor or 
protocol contact:
SAE listing
Demographic listing
Study treatment listing

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable, with a copy of all required information sent by overnight 
mail.

If the PIMS system is unavailable when the SAE occurs, the site will use the paper 
SAE form and fax that to the Medical Monitor or protocol contact. The site will enter 
the SAE data into PIMS as soon as the system becomes available.
 
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12.6.
Appendix 6: Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 
24hrs of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, which will be 
forwarded to GSK.  Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in Appendix 5. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
Any female subject who becomes pregnant while participating 

will discontinue study medication and be withdrawn from the study

This will only be included if either of the following apply:

Investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study.  This 
applies only to subjects who are randomized to receive study medication. 

After obtaining the necessary signed informed consent from the female partner 
directly, the investigator will record pregnancy information on the appropriate form 
report the event and submit it to GSK within 24hrs 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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12.7.
Appendix 7: Country Specific Requirements
No country-specific requirements exist.
 
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12.8.
Appendix 8: Division Of AIDS Table For Grading The 
Severity Of Adult And Pediatric Adverse Events Version 1.0, 
December 2004; Clarification August 2009
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
ESTIMATING SEVERITY GRADE
Clinical adverse 
event NOT identified 
elsewhere in the 
grading table
Mild symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities with 
intervention not 
indicated
Moderate 
symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
with intervention not 
indicated
Severe symptoms 
causing inability to 
perform usual social 
& functional activities 
with intervention or 
hospitalization 
indicated
Potentially life-
threatening symptoms 
causing inability to 
perform basic self-care 
functions OR Medical or 
operative intervention 
indicated to prevent 
permanent impairment, 
persistent disability, or 
death 
CARDIOVASCULAR
Arrhythmia
(by ECG or physical 
examination)
Specify type, if
applicable
No symptoms 
AND No 
intervention 
indicated
No symptoms AND
non-urgent 
intervention 
indicated
Non-life-threatening 
symptoms AND Non-
urgent intervention 
indicated
Life-threatening 
arrhythmia OR Urgent 
intervention indicated
Blood Pressure 
Abnormalities1 
Hypertension (with 
the lowest reading 
taken after repeat 
testing during a visit) 
≥ 18 years of age 
140 to < 160 
mmHg systolic 
OR 90 to < 100 
mmHg diastolic 
≥ 160 to < 180 
mmHg systolic OR 
≥ 100 to < 110 
mmHg diastolic 
≥ 180 mmHg systolic 
OR ≥ 110 mmHg 
diastolic 
Life-threatening 
consequences in a 
participant not 
previously diagnosed 
with hypertension (e.g., 
malignant hypertension) 
OR Hospitalization 
indicated 
< 18 years of age 
> 120/80 mmHg 
≥ 95th to < 99th 
percentile + 5 
mmHg adjusted for 
age, height, and 
gender (systolic 
and/or diastolic) 
≥ 99th percentile + 5
mmHg adjusted for 
age, height, and 
gender (systolic 
and/or diastolic) 
Life-threatening 
consequences in a 
participant not 
previously diagnosed 
with hypertension (e.g., 
malignant hypertension) 
OR Hospitalization 
indicated 
Hypotension 
No symptoms 
Symptoms 
corrected with oral 
fluid replacement 
Symptoms AND IV 
fluids indicated 
Shock requiring use of 
vasopressors or 
mechanical assistance 
to maintain blood 
pressure 
Cardiac Ischemia or 
Infarction 
Report only one 
NA 
NA 
New symptoms with 
ischemia (stable 
angina) OR New 
testing consistent 
with ischemia 
Unstable angina OR 
Acute myocardial 
infarction 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Heart Failure 
No symptoms 
AND Laboratory 
or cardiac imaging 
abnormalities 
Symptoms with mild 
to moderate activity 
or exertion 
Symptoms at rest or 
with minimal activity 
or exertion (e.g., 
hypoxemia) OR 
Intervention indicated 
(e.g., oxygen) 
Life-threatening 
consequences OR 
Urgent intervention 
indicated (e.g., 
vasoactive medications, 
ventricular assist device, 
heart transplant) 
Hemorrhage (with 
significant acute 
blood loss) 
NA 
Symptoms AND No 
transfusion 
indicated 
Symptoms AND 
Transfusion of ≤ 2 
units packed RBCs 
indicated 
Life-threatening 
hypotension OR 
Transfusion of > 2 units 
packed RBCs (for 
children, packed RBCs 
> 10 cc/kg) indicated 
Prolonged PR
Interval or AV Block 
Report only one 
> 16 years of age 
PR interval 0.21 
to < 0.25 seconds 
PR interval ≥ 0.25 
seconds OR Type I 
2nd degree AV 
block 
Type II 2nd degree 
AV block OR 
Ventricular pause ≥ 
3.0 seconds 
Complete AV block 
≤ 16 years of age 
1st degree AV 
block (PR interval 
> normal for age 
and rate) 
Type I 2nd degree 
AV block 
Type II 2nd degree 
AV block OR 
Ventricular pause ≥ 
3.0 seconds 
Complete AV block 
Prolonged QTc 
Interval2 
0.45 to 0.47 
seconds 
> 0.47 to 0.50 
seconds 
> 0.50 seconds OR ≥ 
0.06 seconds above 
baseline 
Life-threatening 
consequences (e.g., 
Torsade de pointes, 
other associated serious 
ventricular dysrhythmia) 
Thrombosis or 
Embolism 
Report only one 
NA 
Symptoms AND No 
intervention 
indicated 
Symptoms AND 
Intervention indicated 
Life-threatening embolic 
event (e.g., pulmonary 
embolism, thrombus) 
DERMATOLOGIC
Alopecia (scalp only) 
Detectable by 
study participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional 
activities
Obvious on visual 
inspection AND 
Causing greater 
than minimal 
interference with 
usual social & 
functional activities 
NA 
NA 
Bruising 
Localized to one 
area 
Localized to more 
than one area 
Generalized 
NA 
Cellulitis 
NA 
Non-parenteral 
treatment indicated 
(e.g., oral 
antibiotics, 
antifungals, 
antivirals) 
IV treatment 
indicated (e.g., IV 
antibiotics, 
antifungals, antivirals) 
Life-threatening 
consequences (e.g., 
sepsis, tissue necrosis) 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Hyperpigmentation 
Slight or localized 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Marked or 
generalized causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
NA 
NA 
Hypopigmentation 
Slight or localized 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Marked or 
generalized causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
NA 
NA 
Petechiae 
Localized to one 
area 
Localized to more 
than one area 
Generalized 
NA 
Pruritus3 (without 
skin lesions) 
Itching causing no 
or minimal 
interference with 
usual social & 
functional 
activities 
Itching causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Itching causing 
inability to perform 
usual social & 
functional activities 
NA 
Rash 
Specify type, if 
applicable 
Localized rash 
Diffuse rash OR 
Target lesions 
Diffuse rash AND 
Vesicles or limited 
number of bullae or 
superficial ulcerations 
of mucous membrane 
limited to one site 
Extensive or generalized 
bullous lesions OR 
Ulceration of mucous 
membrane involving two 
or more distinct mucosal 
sites OR Stevens-
Johnson syndrome OR 
Toxic epidermal 
necrolysis 
ENDOCRINE AND METABOLIC
Diabetes Mellitus 
Controlled without 
medication 
Controlled with 
medication OR 
Modification of 
current medication 
regimen 
Uncontrolled despite 
treatment 
modification OR 
Hospitalization for 
immediate glucose 
control indicated 
Life-threatening 
consequences (e.g., 
ketoacidosis, 
hyperosmolar non-
ketotic coma, end organ 
failure) 
Gynecomastia 
Detectable by 
study participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Obvious on visual 
inspection AND 
Causing pain with 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Disfiguring changes 
AND Symptoms 
requiring intervention 
or causing inability to 
perform usual social 
& functional activities 
NA 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Hyperthyroidism 
No symptoms 
AND Abnormal 
laboratory value 
Symptoms causing 
greater than 
minimal 
interference with
usual social & 
functional activities 
OR Thyroid 
suppression 
therapy indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Uncontrolled 
despite treatment 
modification 
Life-threatening 
consequences (e.g., 
thyroid storm) 
Hypothyroidism 
No symptoms 
AND Abnormal 
laboratory value 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
OR Thyroid 
replacement 
therapy indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Uncontrolled 
despite treatment 
modification 
Life-threatening 
consequences (e.g., 
myxedema coma) 
Lipoatrophy4 
Detectable by 
study participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional
activities 
Obvious on visual 
inspection AND 
Causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Disfiguring changes 
NA 
Lipohypertrophy5
Detectable by 
study participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Obvious on visual 
inspection AND 
Causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Disfiguring changes 
NA 
GASTROINTESTINAL
Anorexia 
Loss of appetite 
without decreased 
oral intake 
Loss of appetite 
associated with 
decreased oral 
intake without 
significant weight 
loss 
Loss of appetite 
associated with 
significant weight loss 
Life-threatening 
consequences OR 
Aggressive intervention 
indicated (e.g., tube 
feeding, total parenteral 
nutrition) 
Ascites 
No symptoms 
Symptoms AND 
Intervention 
indicated (e.g., 
diuretics, 
therapeutic 
paracentesis) 
Symptoms recur or 
persist despite 
intervention 
Life-threatening 
consequences 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Bloating or 
Distension 
Report only one 
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Cholecystitis 
NA 
Symptoms AND 
Medical intervention 
indicated 
Radiologic, 
endoscopic, or 
operative intervention 
indicated 
Life-threatening 
consequences (e.g., 
sepsis, perforation) 
Constipation 
NA 
Persistent 
constipation 
requiring regular 
use of dietary 
modifications, 
laxatives, or 
enemas 
Obstipation with 
manual evacuation 
indicated 
Life-threatening 
consequences (e.g., 
obstruction) 
Diarrhea ≥ 1 year of 
age 
Transient or 
intermittent 
episodes of 
unformed stools 
OR Increase of ≤ 
3 stools over 
baseline per 24-
hour period 
Persistent episodes 
of unformed to 
watery stools OR 
Increase of 4 to 6 
stools over baseline 
per 24-hour period 
Increase of ≥ 7 stools 
per 24-hour period 
OR IV fluid 
replacement 
indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Dysphagia or 
Odynophagia 
Report only one 
and specify 
location 
Symptoms but 
able to eat usual 
diet 
Symptoms causing 
altered dietary 
intake with no 
intervention 
indicated 
Symptoms causing 
severely altered 
dietary intake with 
intervention indicated 
Life-threatening 
reduction in oral intake 
Gastrointestinal 
Bleeding 
Not requiring 
intervention other 
than iron 
supplement 
Endoscopic 
intervention 
indicated 
Transfusion indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Mucositis or 
Stomatitis 
Report only one and 
specify location 
Mucosal erythema 
Patchy 
pseudomembranes 
or ulcerations 
Confluent 
pseudomembranes 
or ulcerations OR 
Mucosal bleeding 
with minor trauma 
Life-threatening 
consequences (e.g., 
aspiration, choking) OR 
Tissue necrosis OR 
Diffuse spontaneous 
mucosal bleeding 
Nausea 
Transient (< 24 
hours) or 
intermittent AND 
No or minimal 
interference with 
oral intake 
Persistent nausea 
resulting in 
decreased oral 
intake for 24 to 48 
hours 
Persistent nausea 
resulting in minimal 
oral intake for > 48 
hours OR 
Rehydration indicated 
(e.g., IV fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Pancreatitis 
NA 
Symptoms with 
hospitalization not 
indicated 
Symptoms with 
hospitalization 
indicated 
Life-threatening 
consequences (e.g., 
circulatory failure, 
hemorrhage, sepsis) 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Perforation 
(colon or rectum) 
NA 
NA 
Intervention indicated 
Life-threatening 
consequences 
Proctitis 
Rectal discomfort 
with no 
intervention 
indicated 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
OR Medical 
intervention 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
perforation) 
Rectal Discharge 
Visible discharge 
Discharge requiring 
the use of pads 
NA 
NA 
Vomiting 
Transient or 
intermittent AND 
No or minimal 
interference with 
oral intake 
Frequent episodes 
with no or mild 
dehydration 
Persistent vomiting 
resulting in 
orthostatic 
hypotension OR 
Aggressive 
rehydration indicated 
(e.g., IV fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
MUSCULOSKELETAL
Arthralgia 
Joint pain causing 
no or minimal 
interference with 
usual social & 
functional 
activities 
Joint pain causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Joint pain causing 
inability to perform 
usual social & 
functional activities 
Disabling joint pain 
causing inability to 
perform basic self-care 
functions 
Arthritis 
Stiffness or joint 
swelling causing 
no or minimal 
interference with 
usual social & 
functional 
activities 
Stiffness or joint 
swelling causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Stiffness or joint 
swelling causing 
inability to perform 
usual social & 
functional activities 
Disabling joint stiffness 
or swelling causing 
inability to perform basic 
self-care functions 
Myalgia 
(generalized) 
Muscle pain 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Muscle pain 
causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Muscle pain causing 
inability to perform 
usual social & 
functional activities 
Disabling muscle pain 
causing inability to 
perform basic self-care 
functions 
Osteonecrosis 
NA 
No symptoms but 
with radiographic 
findings AND No 
operative 
intervention 
indicated 
Bone pain with 
radiographic findings 
OR Operative 
intervention indicated 
Disabling bone pain with 
radiographic findings 
causing inability to 
perform basic self-care 
functions 
Osteopenia6
≥ 30 years of age 
BMD t-score -2.5 
to -1 
NA 
NA 
NA 
 
2018N360917_00


2015N227852_01
CONFIDENTIAL
200911
93
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
< 30 years of age 
BMD z-score -2 to 
-1 
NA 
NA 
NA 
Osteoporosis6
≥ 30 years of age 
NA 
BMD t-score < -2.5 
Pathologic fracture 
(e.g., compression 
fracture causing loss 
of vertebral height) 
Pathologic fracture 
causing life-threatening 
consequences 
< 30 years of age 
NA 
BMD z-score < -2 
Pathologic fracture 
(e.g., compression 
fracture causing loss 
of vertebral height) 
Pathologic fracture 
causing life-threatening 
consequences 
NEUROLOGIC
Acute Central 
nervous system 
(CNS) Ischemia 
NA 
NA 
Transient ischemic 
attack 
Cerebral vascular 
accident (e.g., stroke 
with neurological deficit) 
Altered Mental 
Status (for 
Dementia, see 
Cognitive, 
Behavioral, or 
Attentional 
Disturbance below) 
Changes causing 
no or minimal 
interference with 
usual social & 
functional 
activities 
Mild lethargy or 
somnolence 
causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Confusion, memory 
impairment, lethargy, 
or somnolence 
causing inability to 
perform usual social 
& functional activities 
Delirium OR 
Obtundation OR Coma 
Ataxia 
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities OR No 
symptoms with 
ataxia detected on 
examination 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Disabling symptoms 
causing inability to 
perform basic self-care 
functions 
Cognitive, 
Behavioral, or 
Attentional 
Disturbance 
(includes dementia 
and attention deficit 
disorder) 
Specify type, if 
applicable 
Disability causing 
no or minimal 
interference with 
usual social & 
functional 
activities OR 
Specialized 
resources not 
indicated 
Disability causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
OR Specialized 
resources on part-
time basis indicated 
Disability causing 
inability to perform 
usual social & 
functional activities 
OR Specialized 
resources on a full-
time basis indicated 
Disability causing 
inability to perform basic 
self-care functions OR 
Institutionalization 
indicated 
 
2018N360917_00


2015N227852_01
CONFIDENTIAL
200911
94
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Developmental 
Delay < 18 years of 
age 
Specify type, if 
applicable 
Mild 
developmental 
delay, either 
motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Moderate 
developmental 
delay, either motor 
or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Severe 
developmental delay, 
either motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Developmental 
regression, either motor 
or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Headache 
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Symptoms causing 
inability to perform basic 
self-care functions OR 
Hospitalization indicated 
OR Headache with 
significant impairment of 
alertness or other 
neurologic function 
Neuromuscular 
Weakness (includes 
myopathy and 
neuropathy) 
Specify type, if 
applicable 
Minimal muscle 
weakness causing 
no or minimal 
interference with 
usual social & 
functional 
activities OR No 
symptoms with 
decreased 
strength on 
examination 
Muscle weakness 
causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Muscle weakness 
causing inability to 
perform usual social 
& functional activities 
Disabling muscle 
weakness causing 
inability to perform basic 
self-care functions OR 
Respiratory muscle 
weakness impairing 
ventilation 
Neurosensory 
Alteration (includes 
paresthesia and 
painful neuropathy) 
Specify type, if 
applicable 
Minimal 
paresthesia 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities OR No 
symptoms with 
sensory alteration 
on examination 
Sensory alteration 
or paresthesia 
causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Sensory alteration or 
paresthesia causing 
inability to perform 
usual social & 
functional activities 
Disabling sensory 
alteration or paresthesia 
causing inability to 
perform basic self-care 
functions 
Seizures New Onset 
Seizure 
≥ 18 years of age 
NA 
NA 
1 to 3 seizures 
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR Difficult 
to control (e.g., 
refractory epilepsy) 
< 18 years of age 
(includes new or pre-
existing febrile 
seizures) 
Seizure lasting < 
5 minutes with < 
24 hours postictal 
state 
Seizure lasting 5 to 
< 20 minutes with < 
24 hours postictal 
state 
Seizure lasting ≥ 20 
minutes OR > 24 
hours postictal state 
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR Difficult 
to control (e.g., 
refractory epilepsy) 
 
2018N360917_00


2015N227852_01
CONFIDENTIAL
200911
95
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Pre-existing Seizure 
NA 
Increased 
frequency from 
previous level of 
control without 
change in seizure 
character 
Change in seizure 
character either in 
duration or quality 
(e.g., severity or 
focality) 
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR Difficult 
to control (e.g., 
refractory epilepsy) 
Syncope 
Near syncope 
without loss of 
consciousness 
(e.g., pre-
syncope) 
Loss of 
consciousness with 
no intervention 
indicated 
Loss of 
consciousness AND 
Hospitalization or 
intervention required 
NA 
PREGNANCY, PUERPERIUM, AND PERINATAL
Fetal Death or 
Stillbirth (report 
using mother’s 
participant ID) 
Report only one 
NA 
NA 
Fetal loss occurring 
at ≥ 20 weeks 
gestation 
NA 
Preterm Delivery7
(report using 
mother’s participant 
ID) 
Delivery at 34 to < 
37 weeks 
gestational age 
Delivery at 28 to < 
34 weeks 
gestational age 
Delivery at 24 to < 28 
weeks gestational 
age 
Delivery at < 24 weeks 
gestational age 
Spontaneous 
Abortion or 
Miscarriage8 (report 
using mother’s 
participant ID) 
Report only one 
Chemical 
pregnancy 
Uncomplicated 
spontaneous 
abortion or 
miscarriage 
Complicated 
spontaneous abortion 
or miscarriage 
NA 
PSYCHIATRIC
Insomnia 
Mild difficulty 
falling asleep, 
staying asleep, or 
waking up early 
Moderate difficulty 
falling asleep, 
staying asleep, or 
waking up early 
Severe difficulty 
falling asleep, staying 
asleep, or waking up 
early 
NA 
Psychiatric 
Disorders 
(includes anxiety, 
depression, mania, 
and 
psychosis) 
Specify disorder 
Symptoms with 
intervention not 
indicated OR 
Behavior causing 
no or minimal 
interference with 
usual social & 
functional 
activities 
Symptoms with 
intervention 
indicated OR 
Behavior causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms with 
hospitalization 
indicated OR 
Behavior causing 
inability to perform 
usual social & 
functional activities 
Threatens harm to self 
or others OR Acute 
psychosis OR Behavior 
causing inability to 
perform basic self-care 
functions 
 
2018N360917_00


2015N227852_01
CONFIDENTIAL
200911
96
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Suicidal Ideation or 
Attempt 
Report only one 
Preoccupied with 
thoughts of death 
AND No wish to 
kill oneself 
Preoccupied with 
thoughts of death 
AND Wish to kill 
oneself with no 
specific plan or 
intent 
Thoughts of killing 
oneself with partial or 
complete plans but 
no attempt to do so 
OR Hospitalization 
indicated 
Suicide attempted 
RESPIRATORY
Acute 
Bronchospasm 
Forced expiratory 
volume in 1 
second or peak 
flow reduced to ≥ 
70 to < 80% OR 
Mild symptoms 
with intervention 
not indicated 
Forced expiratory 
volume in 1 second 
or peak flow 50 to < 
70% OR Symptoms 
with intervention 
indicated OR 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Forced expiratory 
volume in 1 second 
or peak flow 25 to < 
50% OR Symptoms 
causing inability to 
perform usual social 
& functional activities 
Forced expiratory 
volume in 1 second or 
peak flow < 25% OR 
Life-threatening 
respiratory or 
hemodynamic 
compromise OR 
Intubation 
Dyspnea or 
Respiratory 
Distress 
Report only one 
Dyspnea on 
exertion with no or 
minimal 
interference with 
usual social & 
functional 
activities OR 
Wheezing OR 
Minimal increase 
in respiratory rate 
for age 
Dyspnea on 
exertion causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
OR Nasal flaring 
OR Intercostal 
retractions OR 
Pulse oximetry 90 
to < 95% 
Dyspnea at rest 
causing inability to 
perform usual social 
& functional activities 
OR Pulse oximetry < 
90% 
Respiratory failure with 
ventilator support 
indicated (e.g., 
Continuous positive 
airway pressure [CPAP], 
Bilevel positive airway 
pressure [BPAP], 
intubation) 
SENSORY
Hearing Loss 
≥ 12 years of age 
NA 
Hearing aid or 
intervention not 
indicated 
Hearing aid or 
intervention indicated 
Profound bilateral 
hearing loss (> 80 dB at 
2 kHz and above) OR 
Non-serviceable hearing 
(i.e., >50 dB audiogram 
and <50% speech 
discrimination) 
< 12 years of age 
(based on a 1, 2, 3, 
4, 6 and 8 kHz 
audiogram) 
> 20 dB hearing 
loss at ≤ 4 kHz 
> 20 dB hearing 
loss at > 4 kHz 
> 20 dB hearing loss 
at ≥ 3 kHz in one ear 
with additional 
speech language 
related services 
indicated (where 
available) OR 
Hearing loss 
sufficient to indicate 
therapeutic 
intervention, including 
hearing aids 
Audiologic indication for 
cochlear implant and 
additional speech-
language related 
services indicated 
(where available) 
 
2018N360917_00


2015N227852_01
CONFIDENTIAL
200911
97
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Tinnitus 
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities with 
intervention not 
indicated 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
with intervention 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Uveitis 
No symptoms 
AND Detectable 
on examination 
Anterior uveitis with 
symptoms OR 
Medicamylasal 
intervention 
indicated 
Posterior or pan-
uveitis OR Operative 
intervention indicated 
Disabling visual loss in 
affected eye(s) 
Vertigo 
Vertigo causing 
no or minimal 
interference with 
usual social & 
functional 
activities 
Vertigo causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Vertigo causing 
inability to perform 
usual social & 
functional activities 
Disabling vertigo 
causing inability to 
perform basic self-care 
functions 
Visual Changes 
(assessed from 
baseline) 
Visual changes 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Visual changes 
causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Visual changes 
causing inability to 
perform usual social 
& functional activities 
Disabling visual loss in 
affected eye(s) 
SYSTEMIC
Acute Allergic 
Reaction 
Localized urticaria 
(wheals) with no 
medical 
intervention 
indicated 
Localized urticaria 
with intervention 
indicated OR Mild 
angioedema with 
no intervention 
indicated 
Generalized urticaria 
OR Angioedema with 
intervention indicated 
OR Symptoms of 
mild bronchospasm 
Acute anaphylaxis OR 
Life-threatening 
bronchospasm OR 
Laryngeal edema 
Chills 
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Cytokine Release 
Syndrome9
Mild signs and 
symptoms AND 
Therapy (i.e., 
antibody infusion) 
interruption not 
indicated 
Therapy (i.e., 
antibody infusion) 
interruption 
indicated AND 
Responds promptly 
to symptomatic 
treatment OR 
Prophylactic 
medications 
indicated for ≤ 24 
hours 
Prolonged severe 
signs and symptoms 
OR Recurrence of 
symptoms following 
initial improvement 
Life-threatening 
consequences (e.g., 
requiring pressor or 
ventilator support) 
 
2018N360917_00


2015N227852_01
CONFIDENTIAL
200911
98
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Fatigue or Malaise 
Report only one 
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Incapacitating 
symptoms of fatigue or 
malaise causing inability 
to perform basic self-
care functions 
Fever (non-axillary 
temperatures only) 
38.0 to < 38.6°C 
or 100.4 to < 
101.5°F 
≥ 38.6 to < 39.3°C 
or ≥ 101.5 to < 
102.7°F 
≥ 39.3 to < 40.0°C or 
≥ 102.7 to < 104.0°F 
≥ 40.0°C or ≥ 104.0°F 
Pain10 (not 
associated with study 
agent injections and 
not specified 
elsewhere) 
Specify location 
Pain causing no 
or minimal 
interference with 
usual social & 
functional 
activities 
Pain causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Pain causing inability 
to perform usual 
social & functional 
activities 
Disabling pain causing 
inability to perform basic 
self-care functions OR 
Hospitalization indicated 
Serum Sickness11 
Mild signs and 
symptoms 
Moderate signs and 
symptoms AND 
Intervention 
indicated (e.g., 
antihistamines) 
Severe signs and 
symptoms AND 
Higher level 
intervention indicated 
(e.g., steroids or IV 
fluids) 
Life-threatening 
consequences (e.g., 
requiring pressor or 
ventilator support) 
Underweight12
> 5 to 19 years of 
age 
NA 
World Health 
Organization 
(WHO) BMI z-score 
< -2 to ≤ -3 
WHO BMI z-score < -
3 
WHO BMI z-score < -3 
with life-threatening 
consequences 
2 to 5 years of age 
NA 
WHO Weight-for-
height z-score 
< -2 to ≤ -3 
WHO Weight-for-
height z-score < -3 
WHO Weight-for-height 
z-score < -3 with life-
threatening 
consequences 
< 2 years of age 
NA 
WHO Weight-for-
length z-score 
< -2 to ≤ -3
WHO Weight-for-
length z-score < -3 
WHO Weight-for-length 
z-score < -3 with life-
threatening 
consequences 
Weight Loss 
(excludes postpartum 
weight loss) 
NA 
5 to < 9% loss in 
body weight from 
baseline 
≥ 9 to < 20% loss in 
body weight from 
baseline 
≥ 20% loss in body 
weight from baseline OR 
Aggressive intervention 
indicated (e.g., tube 
feeding, total parenteral 
nutrition) 
URINARY
Urinary Tract 
Obstruction 
NA 
Signs or symptoms 
of urinary tract 
obstruction without 
hydronephrosis or 
renal dysfunction
Signs or symptoms of 
urinary tract 
obstruction with 
hydronephrosis or 
renal dysfunction 
Obstruction causing life-
threatening 
consequences 
 
2018N360917_00


2015N227852_01
CONFIDENTIAL
200911
99
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
SITE REACTIONS TO INJECTIONS AND INFUSIONS
Injection Site Pain 
or Tenderness 
Report only one 
Pain or 
tenderness 
causing no or 
minimal limitation 
of use of limb 
Pain or tenderness 
causing greater 
than minimal 
limitation of use of 
limb 
Pain or tenderness 
causing inability to 
perform usual social 
& functional activities 
Pain or tenderness 
causing inability to 
perform basic self-care 
function OR 
Hospitalization indicated 
Injection Site 
Erythema or 
Redness13 
Report only one 
> 15 years of age 
2.5 to < 5 cm in 
diameter OR 6.25 
to < 25 cm2 
surface area AND 
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
≥ 5 to < 10 cm in 
diameter OR ≥ 25 
to < 100 cm2 
surface area OR 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
≥ 10 cm in diameter 
OR ≥ 100 cm2 
surface area OR 
Ulceration OR 
Secondary infection 
OR Phlebitis OR 
Sterile abscess OR 
Drainage OR 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Potentially life-
threatening 
consequences (e.g., 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue) 
≤ 15 years of age 
≤ 2.5 cm in 
diameter 
> 2.5 cm in 
diameter with < 
50% surface area 
of the extremity 
segment involved 
(e.g., upper arm or 
thigh) 
≥ 50% surface area 
of the extremity 
segment involved 
(e.g., upper arm or 
thigh) OR Ulceration 
OR Secondary 
infection OR Phlebitis 
OR Sterile abscess 
OR Drainage 
Potentially life-
threatening 
consequences (e.g., 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue) 
Injection Site 
Induration or 
Swelling 
Report only one 
> 15 years of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 
years of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 
years of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, > 15 years of 
age 
≤ 15 years of age 
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15 
years of age 
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15 
years of age 
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, ≤ 15 years of 
age 
Injection Site 
Pruritus 
Itching localized 
to the injection 
site that is 
relieved 
spontaneously or 
in < 48 hours of 
treatment 
Itching beyond the 
injection site that is 
not generalized OR 
Itching localized to 
the injection site 
requiring ≥ 48 
hours treatment 
Generalized itching 
causing inability to 
perform usual social 
& functional activities 
NA 
LABORATORY VALUES Chemistries
Acidosis 
NA 
pH ≥ 7.3 to < Lower 
limit of normal 
(LLN) 
pH < 7.3 without life-
threatening 
consequences 
pH < 7.3 with life-
threatening 
consequences 
Albumin, Low (g/dL; 
g/L) 
3.0 to < LLN 
30 to < LLN 
≥ 2.0 to < 3.0
≥ 20 to < 30 
< 2.0 
< 20 
NA 
 
2018N360917_00


2015N227852_01
CONFIDENTIAL
200911
100
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Alkaline 
Phosphatase, High 
1.25 to < 2.5 x 
ULN 
2.5 to < 5.0 x ULN 
5.0 to < 10.0 x ULN 
≥ 10.0 x ULN 
Alkalosis 
NA 
pH > ULN to ≤ 7.5 
pH > 7.5 without life-
threatening 
consequences 
pH > 7.5 with life-
threatening 
consequences 
ALT or SGPT, High 
Report only one 
1.25 to < 2.5 x 
ULN 
2.5 to < 5.0 x ULN 
5.0 to < 10.0 x ULN 
≥ 10.0 x ULN
Amylase 
(Pancreatic) or 
Amylase (Total), 
High 
Report only one 
1.1 to < 1.5 x ULN 
1.5 to < 3.0 x ULN 
3.0 to < 5.0 x ULN 
≥ 5.0 x ULN 
AST or SGOT, High 
Report only one 
1.25 to < 2.5 x 
ULN 
2.5 to < 5.0 x ULN 
5.0 to < 10.0 x ULN 
≥ 10.0 x ULN 
Bicarbonate, Low 
(mEq/L; mmol/L) 
16.0 to < LLN 
16.0 to < LLN 
11.0 to < 16.0 
11.0 to < 16.0 
8.0 to < 11.0 
8.0 to < 11.0 
< 8.0 
< 8.0 
Bilirubin Direct 
Bilirubin14, High 
> 28 days of age 
NA 
NA 
> ULN 
> ULN with life-
threatening 
consequences (e.g., 
signs and symptoms of 
liver failure) 
≤ 28 days of age 
ULN to ≤ 1 mg/dL 
> 1 to ≤ 1.5 mg/dL 
> 1.5 to ≤ 2 mg/dL 
> 2 mg/dL 
Total Bilirubin, High 
> 28 days of age 
1.1 to < 1.6 x ULN 
1.6 to < 2.6 x ULN 
2.6 to < 5.0 x ULN 
≥ 5.0 x ULN 
≤ 28 days of age 
Total Bilirubin for 
Term and Preterm 
Neonates 
Total Bilirubin for 
Term and Preterm 
Neonates 
Total Bilirubin for 
Term and Preterm 
Neonates 
Total Bilirubin for Term 
and Preterm Neonates 
Calcium, High 
(mg/dL; mmol/L) 
≥ 7 days of age 
10.6 to < 11.5 
2.65 to < 2.88 
11.5 to < 12.5 
2.88 to < 3.13 
12.5 to < 13.5 
3.13 to < 3.38 
≥ 13.5 
≥ 3.38 
< 7 days of age 
11.5 to < 12.4 
2.88 to < 3.10 
12.4 to < 12.9 
3.10 to < 3.23 
12.9 to < 13.5 
3.23 to < 3.38 
≥ 13.5 
≥ 3.38 
Calcium (Ionized), 
High (mg/dL; 
mmol/L) 
> ULN to < 6.0
> ULN to < 1.5 
6.0 to < 6.4 
1.5 to < 1.6 
6.4 to < 7.2 
1.6 to < 1.8 
≥ 7.2 
≥ 1.8 
 
2018N360917_00


2015N227852_01
CONFIDENTIAL
200911
101
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Calcium, Low 
(mg/dL; mmol/L) 
≥ 7 days of age 
7.8 to < 8.4 
1.95 to < 2.10 
7.0 to < 7.8 
1.75 to < 1.95 
6.1 to < 7.0 
1.53 to < 1.75 
< 6.1 
< 1.53 
< 7 days of age 
6.5 to < 7.5 
1.63 to < 1.88 
6.0 to < 6.5 
1.50 to < 1.63 
5.50 to < 6.0 
1.38 to < 1.50 
< 5.50 
< 1.38 
Calcium (Ionized), 
Low (mg/dL; mmol/L) 
< LLN to 4.0 
< LLN to 1.0 
3.6 to < 4.0 
0.9 to < 1.0 
3.2 to < 3.6 
0.8 to < 0.9 
< 3.2 
< 0.8 
Cardiac Troponin I, 
High 
NA 
NA 
NA 
Levels consistent with 
myocardial infarction or 
unstable angina as 
defined by the local 
laboratory 
Creatine Kinase, 
High 
3 to < 6 x ULN 
6 to < 10 x ULN 
10 to < 20 x ULN 
≥ 20 x ULN 
Creatinine, High 
1.1 to 1.3 x ULN 
> 1.3 to 1.8 x ULN 
OR Increase of > 
0.3 mg/dL above 
baseline 
> 1.8 to < 3.5 x ULN 
OR Increase of 1.5 to 
< 2.0 x above 
baseline 
≥ 3.5 x ULN OR 
Increase of ≥ 2.0 x 
above baseline 
Creatinine 
Clearance15 or
Estimated 
glomerular filtration 
rate (eGFR), Low 
Report only one 
NA 
< 90 to 60 mL/min 
or mL/min/1.73 m2 
OR 10 to < 30% 
decrease from 
baseline 
< 60 to 30 mL/min or 
mL/min/1.73 m2 OR 
≥ 30 to < 50% 
decrease from 
baseline 
< 30 mL/min or 
mL/min/1.73 m2 OR ≥ 
50% decrease from 
baseline or dialysis 
needed 
Glucose 
(mg/dL; mmol/L) 
Fasting, High 
110 to 125 
6.11 to < 6.95 
> 125 to 250 
6.95 to < 13.89 
> 250 to 500 
13.89 to < 27.75 
> 500 
≥ 27.75 
Nonfasting, High 
116 to 160 
6.44 to < 8.89 
> 160 to 250 
8.89 to < 13.89 
> 250 to 500 
13.89 to < 27.75 
> 500 
≥ 27.75 
Glucose, Low 
(mg/dL; mmol/L) 
≥ 1 month of age 
55 to 64 
3.05 to 3.55 
40 to < 55 
2.22 to < 3.05 
30 to < 40 
1.67 to < 2.22 
< 30 
< 1.67 
Lactate, High 
ULN to < 2.0 x 
ULN without 
acidosis 
≥ 2.0 x ULN without 
acidosis 
Increased lactate with 
pH < 7.3 without life-
threatening 
consequences 
Increased lactate with 
pH < 7.3 with life-
threatening 
consequences 
Lipase, High 
1.1 to < 1.5 x ULN 
1.5 to < 3.0 x ULN 
3.0 to < 5.0 x ULN 
≥ 5.0 x ULN 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Lipid Disorders 
(mg/dL; mmol/L) 
Cholesterol, 
Fasting, High 
≥ 18 years of age 
200 to < 240 
5.18 to < 6.19 
240 to < 300 
6.19 to < 7.77 
≥ 300 
≥ 7.77 
NA 
< 18 years of age 
170 to < 200 4.40 
to < 5.15 
200 to < 300 5.15 to 
< 7.77 
≥ 300 ≥7.77 
NA 
Low Density 
Lipoprotein (LDL),
Fasting, High 
≥ 18 years of age 
130 to < 160 3.37 
to < 4.12 
160 to < 190 4.12 to 
< 4.90 
≥ 190 ≥ 4.90 
NA 
> 2 to < 18 years of 
age 
110 to < 130 2.85 
to < 3.34 
130 to < 190 3.34 to 
< 4.90 
≥ 190 ≥ 4.90 
NA 
Triglycerides, 
Fasting, High 
150 to 300 
1.71 to 3.42 
>300 to 500 
>3.42 to 5.7 
>500 to < 1,000 
>5.7 to 11.4 
> 1,000 
> 11.4 
Magnesium16, Low 
(mEq/L; mmol/L) 
1.2 to < 1.4 
0.60 to < 0.70 
0.9 to < 1.2 
0.45 to < 0.60 
0.6 to < 0.9 
0.30 to < 0.45 
< 0.6 
< 0.30 
Phosphate, Low 
(mg/dL; mmol/L) 
> 14 years of age 
2.0 to < LLN 
0.81 to < LLN 
1.4 to < 2.0 
0.65 to < 0.81 
1.0 to < 1.4 
0.32 to < 0.65 
< 1.0 
< 0.32 
1 to 14 years of age 
3.0 to < 3.5 
0.97 to < 1.13 
2.5 to < 3.0 
0.81 to < 0.97 
1.5 to < 2.5 
0.48 to < 0.81 
< 1.5 
< 0.48 
< 1 year of age 
3.5 to < 4.5 
1.13 to < 1.45 
2.5 to < 3.5 
0.81 to < 1.13 
1.5 to < 2.5 
0.48 to < 0.81 
< 1.5 
< 0.48 
Potassium, High 
(mEq/L; mmol/L) 
5.6 to < 6.0 
5.6 to < 6.0 
6.0 to < 6.5 
6.0 to < 6.5 
6.5 to < 7.0 
6.5 to < 7.0 
≥ 7.0 
≥ 7.0 
Potassium, Low 
(mEq/L; mmol/L) 
3.0 to < 3.4 
3.0 to < 3.4 
2.5 to < 3.0 
2.5 to < 3.0 
2.0 to < 2.5 
2.0 to < 2.5 
< 2.0 
< 2.0 
Sodium, High 
(mEq/L; mmol/L) 
146 to < 150 
146 to < 150 
150 to < 154 
150 to < 154 
154 to < 160 
154 to < 160 
≥ 160 
≥ 160 
Sodium, Low 
(mEq/L; mmol/L) 
130 to < 135 
130 to < 135 
125 to < 130 
125 to < 135 
121 to < 125 
121 to < 125 
≤ 120 
≤ 120 
Uric Acid, High 
(mg/dL; mmol/L) 
7.5 to < 10.0 
0.45 to < 0.59 
10.0 to < 12.0 
0.59 to < 0.71 
12.0 to < 15.0 
0.71 to < 0.89 
≥ 15.0 
≥ 0.89 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
HEMATOLOGY
Absolute cluster of 
differentiation 4 
(CD4+) Count, Low 
(cell/mm3; cells/L) 
> 5 years of age (not 
HIV infected) 
300 to < 400 
300 to < 400 
200 to < 300 
200 to < 300 
100 to < 200 
100 to < 200 
< 100 
< 100 
Absolute 
Lymphocyte Count, 
Low 
(cell/mm3; cells/L) 
> 5 years of age 
(not HIV infected) 
600 to < 650 
0.600 x 109 to < 
0.650 x 109
500 to < 600 
0.500 x 109 to < 
0.600 x 109
350 to < 500 
0.350 x 109 to < 
0.500 x 109
< 350 
< 0.350 x 109
Absolute Neutrophil 
Count (ANC), Low 
(cells/mm3; cells/L) 
> 7 days of age 
800 to 1,000 
0.800 x 109 to 
1.000 x 109
600 to 799 
0.600 x 109 to 0.799 
x 109
400 to 599 
0.400 x 109 to 0.599 
x 109
< 400 
< 0.400 x 109
2 to 7 days of age 
1,250 to 1,500 
1.250 x 109 to 
1.500 x 109
1,000 to 1,249 
1.000 x 109 to 1.249 
x 109
750 to 999 
0.750 x 109 to 0.999 
x 109
< 750 
< 0.750 x 109
≤ 1 day of age 
4,000 to 5,000 
4.000 x 109 to 
5.000 x 109 
3,000 to 3,999 
3.000 x 109 to 3.999 
x 109
1,500 to 2,999 
1.500 x 109 to 2.999 
x 109
< 1,500 
< 1.500 x 109
Fibrinogen, 
Decreased (mg/dL; 
g/L) 
100 to < 200 
1.00 to < 2.00 OR 
0.75 to < 1.00 x 
LLN 
75 to < 100 
0.75 to < 1.00 OR ≥ 
0.50 to < 0.75 x 
LLN 
50 to < 75 
0.50 to < 0.75 OR 
0.25 to < 0.50 x LLN 
< 50 
< 0.50 OR < 0.25 x LLN 
OR Associated with 
gross bleeding 
Hemoglobin17, Low 
(g/dL; mmol/L)18 
≥ 13 years of age 
(male only) 
10.0 to 10.9 
6.19 to 6.76 
9.0 to < 10.0 
5.57 to < 6.19 
7.0 to < 9.0 
4.34 to < 5.57 
< 7.0 
< 4.34 
≥ 13 years of age 
(female only) 
9.5 to 10.4 
5.88 to 6.48 
8.5 to < 9.5 
5.25 to < 5.88 
6.5 to < 8.5 
4.03 to < 5.25 
< 6.5 
< 4.03 
57 days of age to < 
13 years of age 
(male and female) 
9.5 to 10.4 
5.88 to 6.48 
8.5 to < 9.5 
5.25 to < 5.88 
6.5 to < 8.5 
4.03 to < 5.25 
< 6.5 
< 4.03 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
36 to 56 days of age 
(male and female) 
8.5 to 9.6 
5.26 to 5.99 
7.0 to < 8.5 
4.32 to < 5.26 
6.0 to < 7.0 
3.72 to < 4.32 
< 6.0 
< 3.72 
22 to 35 days of age 
(male and female) 
9.5 to 11.0 
5.88 to 6.86 
8.0 to < 9.5 
4.94 to < 5.88 
6.7 to < 8.0 
4.15 to < 4.94 
< 6.7 
< 4.15 
8 to ≤ 21 days of age 
(male and female) 
11.0 to 13.0 
6.81 to 8.10 
9.0 to < 11.0 
5.57 to < 6.81 
8.0 to < 9.0 
4.96 to < 5.57 
< 8.0 
< 4.96 
≤ 7 days of age 
(male and female) 
13.0 to 14.0 
8.05 to 8.72 
10.0 to < 13.0 
6.19 to < 8.05 
9.0 to < 10.0 
5.59 to < 6.19 
< 9.0 
< 5.59 
INR, High 
(not on 
anticoagulation 
therapy) 
1.1 to < 1.5 x ULN 
1.5 to < 2.0 x ULN 
2.0 to < 3.0 x ULN 
≥ 3.0 x ULN 
Methemoglobin (% 
hemoglobin) 
5.0 to < 10.0% 
10.0 to < 15.0% 
15.0 to < 20.0% 
≥ 20.0% 
PTT, High 
(not on 
anticoagulation 
therapy) 
1.1 to < 1.66 x 
ULN 
1.66 to < 2.33 x 
ULN 
2.33 to < 3.00 x ULN 
≥ 3.00 x ULN 
Platelets, 
Decreased 
(cells/mm3; cells/L) 
100,000 to < 
124,999 100.000 
x 109 to < 124.999 
x 109
50,000 to < 100,000 
50.000 x 109 to < 
100.000 x 109 
25,000 to < 50,000 
25.000 x 109 to < 
50.000 x 109
< 25,000 < 25.000 x 109
PT, High 
(not on 
anticoagulation 
therapy 
1.1 to < 1.25 x 
ULN 
1.25 to < 1.50 x 
ULN 
1.50 to < 3.00 x ULN 
≥ 3.00 x ULN 
WBC, Decreased
(cells/mm3; cells/L) 
> 7 days of age 
2,000 to 2,499 
2.000 x 109 to 
2.499 x 109
1,500 to 1,999 
1.500 x 109 to 1.999 
x 109
1,000 to 1,499 
1.000 x 109 to 1.499 
x 109
< 1,000 
< 1.000 x 109
≤ 7 days of age 
5,500 to 6,999 
5.500 x 109 to 
6.999 x 109 
4,000 to 5,499 
4.000 x 109 to 5.499 
x 109
2,500 to 3,999 
2.500 x 109 to 3.999 
x 109
< 2,500 
< 2.500 x 109
URINALYSIS
Glycosuria (random 
collection tested by 
dipstick) 
Trace to 1+ or 
≤ 250 mg 
2+ or ˃ 250 to 
≤ 500 mg 
> 2+ or > 500 mg 
NA 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Hematuria (not to be 
reported based on 
dipstick findings or 
on blood believed to 
be of menstrual 
origin) 
6 to < 10 RBCs 
per high power 
field 
≥ 10 RBCs per high 
power field 
Gross, with or without 
clots OR With RBC 
casts OR Intervention 
indicated 
Life-threatening 
consequences 
Proteinuria (random 
collection tested by 
dipstick) 
1+ 
2+ 
3+ or higher 
NA 
1.
Blood pressure norms for children <18 years of age can be found in: Expert Panel on Integrated Guidelines for 
Cardiovascular Health and Risk Reduction in Children and Adolescents. Pediatrics 2011;128;S213; originally 
published online November 14, 2011; DOI: 10.1542/peds.2009-2107C.  
2.
As per Bazett’s formula.  
3.
For pruritus associated with injections or infusions, see the Site Reactions to Injections and Infusions section.  
4.
Definition: A disorder characterized by fat loss in the face, extremities, and buttocks. 
5.
Definition: A disorder characterized by abnormal fat accumulation on the back of the neck, breasts, and abdomen.  
6.
Bone mineral density (BMD) t and z scores can be found in: Kanis JA on behalf of the World Health Organization 
Scientific Group (2007). Assessment of osteoporosis at the primary health-care level. Technical Report. World 
Health Organization Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, UK. 2007: Printed 
by the University of Sheffield.  
7.
Definition: A delivery of a live-born neonate occurring at ≥20 to <37 weeks gestational age. 
8.
Definition: A clinically recognized pregnancy occurring at <20 weeks gestational age.  
9.
Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and/or shortness of 
breath. 
10. For pain associated with injections or infusions, see the Site Reactions to Injections and Infusions section.
11. Definition: A disorder characterized by fever, arthralgia, myalgia, skin eruptions, lymphadenopathy, marked 
discomfort, and/or dyspnea.
12. WHO reference tables may be accesed by clicking the desired age range or by accessing the following URLs: 
http://www.who.int/growthref/who2007_bmi_for_age/en/ for participants >5 to 19 years of age and 
http://www.who.int/childgrowth/standards/chart_catalogue/en/ for those ≤ 5 years of age.  
13. Injection Site Erythema or Redness should be evaluated and graded using the greatest single diameter or
measured surface area. 
14. Direct bilirubin >1.5 mg/dL in a participant <28 days of age should be graded as Grade 2, if <10% of the total 
bilirubin.  
15. Use the applicable formula (i.e., Cockroft-Gault in mL/min or Schwatrz in mL/min/1.73m2).  
16. To convert a magnesium value from mg/dL to mmol/L, laboratories should multiply by 0.4114.  
17. Male and female sexes are defined as sex at birth. 
18. The conversion factor used to convert g/dL to mmol/L is 0.6206 and is the most commonly used conversion factor. 
For grading hemoglobin results obtained by an analytic method with a conversion factor other than 0.6206, the 
result must be converted to g/dL using the appropriate conversion factor for the particular laboratory.  
 
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12.9.
Appendix 9: Toxicity Management
ANEMIA
Grade 1 (mild) hemoglobin decrease:
Any hemoglobin decrease meeting the definition of Grade 1 must be repeated with the 
following additional tests:
3.
peripheral blood smear
4.
indirect bilirubin
(abnormal if increased >50% from baseline)
5.
haptoglobin
(abnormal if 25 mg/dL)
6.
reticulocyte count
(abnormal if 4%) 
If the additional tests are within the normal range, subjects may continue study 
medication.  If one or more of the additional tests is abnormal or suggestive of hemolytic 
anemia as specified above, subjects will permanently discontinue study medication and 
be withdrawn from the trial.  Subjects should be followed up until resolution of anemia.
Grade 2 (moderate) hemoglobin decrease:
Any hemoglobin decrease meeting the definition of Grade 2 must be repeated with the 
following additional tests:
7.
peripheral blood smear
8.
indirect bilirubin
(abnormal if increased > 50% from baseline)
9.
haptoglobin
(abnormal if 25 mg/dL)
10. reticulocyte count
(abnormal if 4%) 
If the additional tests are within the normal range, subjects may continue study 
medication.  If one or more of the additional tests is abnormal or suggestive of hemolytic 
anemia as specified above, subjects will permanently discontinue study medication and 
be withdrawn from the trial.  Consultation with a Hematologist should be considered.  
Subjects should be followed up until resolution of anemia.
Grade 3 (severe) or Grade 4 (potentially life threatening) hemoglobin decrease:
Any hemoglobin decrease meeting the definition of Grade 3 or 4 must be repeated with 
the following additional tests:
11. peripheral blood smear
12. indirect bilirubin
13. haptoglobin
14. reticulocyte count 
 
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Subjects will permanently discontinue study medication and be withdrawn from the trial.  
Consultation with a Hematologist should be considered.  Subjects should be followed up 
until resolution of anemia.
TOTAL BILIRUBIN ELEVATION
Grade 1 (mild) bilirubin elevation (1.1 - 1.5 times ULN) or Grade 2 (moderate 
- 1.6-2.5 times ULN):
Any bilirubin value above the upper limit of normal must be repeated and fractionated 
(direct and indirect bilirubin).  Subjects may continue study medication.  Subjects should 
be followed up until resolution (return to baseline) of elevation.
Grade 3 (severe – 2.6-5.0 times ULN) or 4 (life-threatening - > 5.0 times ULN) 
bilirubin elevation:
Any bilirubin value above the upper limit of normal must be repeated and fractionated 
(direct and indirect bilirubin).  Subjects will permanently discontinue study medication 
and be withdrawn from the trial.  Subjects should be followed up until resolution (return 
to baseline) of bilirubin elevation.
AST AND ALT ELEVATION
See Appendix 9.
RASH
Grade 1 rash (Localized macular rash):
Subjects with Grade 1 rash should be evaluated by the Investigator immediately.  A 
dermatologist may be consulted and a biopsy may be obtained if recommended by the 
dermatologist.  The study drug should be permanently discontinued if the following signs 
or symptoms are noted at any time:
15. Temperature > 38.5°C
16. Lymphadenopathy
17. Pharyngitis
18. Any indication of internal organ involvement (hepatitis, nephritis)
In the absence of the above signs or symptoms, subjects with Grade 1 rash may continue 
the study drug at the discretion of the Investigator.  The subject should be advised to 
contact the Investigator immediately if there is any worsening of the rash, if any systemic 
signs or symptoms worsen, or if mucosal ulceration develops. If the rash is considered to 
be most likely due to concomitant illness or non-study medication, standard management, 
including discontinuation of the likely causative agent, should be undertaken. If no other 
causative factor is found after clinical evaluation, the subject may be treated 
symptomatically until the rash resolves. Antihistamines, topical corticosteroids or 
antipruritic agents may be prescribed.  The subject should remain on the study to be 
followed for safety and PK as outlined in Section 10.5.
 
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Grade 2 rash (Diffuse macular, maculopapular, or morbilliform rash OR Target
lesions):
Subjects with Grade 2 rash should be evaluated by the Investigator immediately.  Digital 
photographs should be obtained.  A dermatologist may be consulted and a biopsy may be 
obtained if recommended by the dermatologist.  The study drug should be permanently 
discontinued if the following signs or symptoms are noted at any time:
19. Temperature > 38.5°C
20. Lymphadenopathy
21. Pharyngitis
22. Any indication of internal organ involvement (hepatitis, nephritis)
In the absence of the above signs or symptoms, subjects with Grade 2 rash may continue 
the study drug at the discretion of the Investigator.  It should be noted that oral mucosal 
erosions may be part of a Grade 2 rash.  Any mucosal ulceration increases the severity 
of the rash to at least Grade 3.  The subject should be advised to contact the Investigator 
immediately if there is any worsening of the rash, if any systemic signs or symptoms 
worsen, or if mucosal ulceration develops. If the rash is considered to be most likely due 
to concomitant illness or non-study medication, standard management, including 
discontinuation of the likely causative agent, should be undertaken. If no other causative 
factor is found after clinical evaluation, the subject may be treated symptomatically until 
the rash resolves. Antihistamines, topical corticosteroids or antipruritic agents may be 
prescribed.  The subject should remain on the study to be followed for safety and PK as 
outlined in Section 10.5.
Grade 3 rash (Diffuse macular, maculopapular, or morbilliform rash with vesicles 
or limited number of bullae OR Superficial ulcerations of mucous membrane 
limited to one site):
Subjects with a Grade 3 rash will permanently discontinue the study medication.  The 
subject should be evaluated in the physician’s office immediately and should be seen in 
the physician’s office or contacted by phone every 2 days until the rash resolves.  A 
dermatologist should be consulted and digital photographs and a biopsy should be 
obtained.  Antihistamines, topical corticosteroids or antipruritic agents may be prescribed 
at the discretion of the Investigator.  The subject should be advised to contact the 
Investigator immediately if there is any worsening of the rash, if any systemic signs or 
symptoms appear, or if mucosal involvement develops.  The subject should remain on the 
study to be followed for safety and PK as outlined in Section 10.5.
Grade 4 rash (Extensive or generalized bullous lesions OR Stevens-Johnson 
syndrome OR Ulceration of mucous membrane involving two or more distinct 
mucosal sites OR Toxic epidermal necrolysis (TEN)):
Subjects with a Grade 4 rash will permanently discontinue the study medication.  A 
dermatologist should be consulted and digital photographs and a biopsy should be 
obtained.  Sponsor and GSK Medical Monitor should be notified of this serious adverse 
event within 24 hours via phone or fax.  The subject should be closely followed everyday 
until resolution of the reaction.  The subject should remain on the study to be followed 
for safety and PK as outlined in Section 10.5.
 
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ALLERGIC REACTION
Grade 1 allergic reaction (Pruritis without rash):
Subjects with Grade 1 allergic reaction should be evaluated by the Investigator 
immediately.  The study drug should be permanently discontinued if the following signs 
or symptoms are noted at any time:
23. Temperature > 38.5°C
24. Eosinophilia
25. Respiratory involvement including bronchospasm, laryngospasm, or 
angioedema
26. Any indication of internal organ involvement (hepatitis, nephritis)
In the absence of the above signs or symptoms, subjects with Grade 1 allergic reaction 
may continue the study drug at the discretion of the Investigator.  The subject should be 
advised to contact the Investigator immediately if there is any worsening of the allergic 
reaction and/or if any systemic signs or symptoms worsen.  If the allergic reaction is 
considered to be most likely due to concomitant illness or non-study medication, standard
management, including discontinuation of the likely causative agent, should be 
undertaken.  If no other causative factor is found after clinical evaluation, the subject may 
be treated symptomatically until the rash resolves. Antihistamines, topical corticosteroids 
or antipruritic agents may be prescribed.  The subject should remain on the study to be 
followed for safety and PK as outlined.
Grade 2 allergic reaction (Localized urticaria):
Subjects with Grade 2 allergic reaction should be evaluated by the Investigator 
immediately.  The study drug should be permanently discontinued if the following signs 
or symptoms are noted at any time:
27. Temperature > 38.5°C
28. Eosinophilia
29. Respiratory involvement including bronchospasm, laryngospasm, or 
angioedema
30. Any indication of internal organ involvement (hepatitis, nephritis)
In the absence of the above signs or symptoms, subjects with Grade 2 allergic reaction 
may continue the study drug at the discretion of the Investigator.  The subject should be 
advised to contact the Investigator immediately if there is any worsening of the allergic 
reaction and/or if any systemic signs or symptoms worsen.  If the allergic reaction is 
considered to be most likely due to concomitant illness or non-study medication, standard 
management, including discontinuation of the likely causative agent, should be 
undertaken.  If no other causative factor is found after clinical evaluation, the subject may 
be treated symptomatically until the rash resolves. Antihistamines, topical corticosteroids 
or antipruritic agents may be prescribed.  The subject should remain on the study to be 
followed for safety and PK as outlined in Section 7.
 
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Grade 3 allergic reaction (Generalized urticaria or angioedema):
Subjects will permanently discontinue the study medication and be withdrawn from the 
trial.  Subjects will be treated as clinically appropriate.  Subjects should be followed up 
until resolution of the adverse event and standard management should be undertaken.
Grade 4 allergic reaction (Anaphylaxis):
Subjects will permanently discontinue the study medication and be withdrawn from the 
trial.  Subjects will be treated as clinically appropriate.  Subjects should be followed up 
until resolution of the adverse event and standard management should be undertaken.
Revised ACTG Toxicity Grade
Definitions
Investigator Action
Grade 1
Pruritus without rash
May continue therapy
Grade 2
Localized urticaria
May continue therapy
Grade 3
Generalized urticaria
Angioedema
Discontinue Therapy
Grade 4
Anaphylaxis
Discontinue Therapy
 
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12.10.
Appendix 10: Protocol Amendment Changes
Protocol Amendment 1 (26-Apr-2017) from the original protocol (09-Nov-2016)
Where the Amendment Applies
This amendment applies to all subjects who will participate in this study in all countries.
List of Specific Changes: (bold indicates text added and strikethrough indicates text 
removed)
Summary of Protocol Amendment Changes with Rationale
Amendment 1 includes minor updates to Inclusion criteria (IE) criteria, including 
clarification on use of pre- or post-exposure prophylaxis, and removal of exclusionary 
requirements related to concomitant medications and tobacco and alcohol use during the 
study. Guidance around relevant habits is included in the Lifestyle section of the protocol 
and adjustments were made to reduce restrictions on these requirements. Modifications 
were also made to the pharmacokinetics sampling, allowing for the 12 h PK collection 
timepoint on Day 1 and 10 to be optional. Minor alterations were made regarding the 
order of screening procedures, including the Holter monitoring requirements. 
Visit/procedure windows were included to allow more flexibility with scheduling of 
assessments. Furthermore, the serial ECG collection (up to 6h post-dose) was removed on 
Day 5. Finally, the post-study care guidance was updated to include an option for subjects 
to receive reimbursement for marketed ART for a limited period after completion of 
study treatment and follow up. Minor clarifications, reformatting of tables, re-numbering 
of sections and correction of typographical errors were also made throughout this 
amendment.
List of Authors
Rationale for change
The list of authors was updated based on internal GSK team personnel changes.
Revised Text
PTS, Ware, UK
GCSP, Stockley Park, UK
Infectious Diseases, Clinical, Upper Providence, PA, US
Clinical Statistics, GSK, Upper Providence, PA, US
HIV DPU, RTP, NC, US
Virology, HIV DPU, RTP, NC, US
CPMS, GSK, RTP, NC, US
 
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HIV DPU, RTP, NC, US
Clinical Pharmacology, ViiV Healthcare, RTP, NC, US
PCPS, GSK, Upper Providence, PA, US
PCPS, GSK, Collegeville, PA, US 
Clinical Statistics, PAREXEL, RTP, NC, US
Infectious Diseases, Clinical, Cambridge, MA, US
Medical Monitor/SAE Contact Information
Rationale for change
The sponsor and medical monitoring information was updated to reflect the current 
contact information for safety and medical monitoring. 
Revised Text
Role
Name
Day Time 
Phone Number 
and email 
address
After-hours 
Phone/Cell/
Pager Number
Fax Number
Site Address
Primary 
Medical 
Monitor/SAE 
contact 
information
MD
Pharmaceutical 
Product 
Development
(PPD) Safety 
Hotline 
Boston, 
MAPPD, 929 
North Front 
Street, 
Wilmington, 
NC 28401
Secondary 
Medical 
Monitor
MD
GlaxoSmithKline
1250 St 
Collegeville Rd 
Collegeville, PA 
19426
SAE contact 
information
 MD
Boston, MA
Synopsis:
Design, Treatment Arms and Duration
Rationale for change
Minor clarifications were made to this section to reflect current status of studies being 
referenced. As synopsis being a standalone document, cross-referenced has been 
removed.
 
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Revised Text
Fourth paragraph
The possibility that an additional, unboosted GSK2838232 monotherapy cohort will be 
assessed in Part B is dependent on analysis of the PK data from ongoing Study 204953 
where unboosted GSK2838232 at a dose of 200 mg twice daily (BID) is being was
assessed.
Sixth paragraph
HIV Drug Resistance: Following cessation of GSK2838232/cobi dosing for 10 days, 
there will be prolonged exposure to waning plasma concentrations of GSK2838232, 
because of the long t½ (i.e., in the “tail” of the PK profile). However, based on in vitro 
resistance passage data with GSK2838232 [and unlike with many other ARV therapies], 
there appears to be a limited likelihood of developing maturation resistance mutations in 
HIV-infected subjects due to its virologic profile [GSK Document Number 
2013N163221_00]. 
Section 2
Introduction
Rationale for change
Abbreviation used on first instance has been defined.
Revised Text
GSK2838232 is a novel human immunodeficiency virus (HIV)-1 maturation inhibitor 
(MI) that is being developed for the treatment of HIV-1 infection in combination with 
other antiretrovirals (ART).
Section 2.1 Study Rationale
Rationale for change
Abbreviation used on first instance has been defined.
Revised Text
This ‘proof of concept (PoC)’ open-label study is being conducted to characterize the 
acute antiviral activity, pharmacokinetics (PK), the relationship between PK and antiviral 
activity, and safety of GSK2838232 given with 150 mg once daily (QD) cobicistat 
(GSK283232/cobi), administered across a range of doses over 10 days in HIV-1 infected 
patients. A two part adaptive and dose ranging design is to be applied in this study. Data 
from this study will be utilized to select doses for further studies in Phase IIb.
 
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Section 2.2 Brief Background
Rationale for change
Abbreviation used on first instance has been defined.
Addition of abbreviation for AIDS in first paragraph
Combination antiviral therapy with inhibitors of HIV protease, integrase, entry and 
reverse transcriptase (RT) has demonstrated significant improvement in acquired 
immunodeficiency syndrome (AIDS)-related morbidity and mortality over the last 10-
15 years.
Addition of abbreviation for RNA in second paragraph
Prior validation of this target was demonstrated with the HIV maturation inhibitor known 
as bevirimat (BVM; [Martin, 2007a; Martin, 2007b; Martin, 2008; NORVIR, 2013]). 
BVM reached Phase II studies in HIV patients; however, only modest reductions in 
plasma HIV-1 ribonucleic acid (RNA) concentrations were observed in Phase IIa 
monotherapy studies [Mahmood, 2006; Martin, 2007] and a pattern of polymorphic 
(differential) antiviral activity [Wainburg, 2010] led to termination of BVM development. 
The average decrease from baseline to Day 14 plasma HIV-1 ribonucleic acid (RNA) 
was 0.54 and 0.70 log10 copies/mL for 200 mg and 300 mg twice daily regimens (Table 
2); all subjects achieved plasma BVM concentrations above the in vitro EC90. 
Responders, classified based on 5 polymorphisms in HIV-1 gag (at positions 369, 370, 
and 371), achieved an average 1.15 log10 copies/mL reduction in plasma HIV-1 RNA, 
while an average 0.17 log10 copies/mL reduction was achieved for non-responders.
Section 2.2.2
Clinical Summary of Safety and Pharmacokinetics
Rationale for change
Minor clarifications were made to this section to reflect current status of studies being 
referenced.
Revised Text
To date, GSK2838232 has been evaluated in three completed clinical studies with or 
without ritonavir (RTV) (GSK2838232/r). A fourth study (204953) is on-going as of 1st
November completed late 2016 and data analysis is ongoing. Full details of the clinical 
results can be found in the Investigator’s Brochure.
Section 2.2.2.1
Clinical Summary of Safety
Rationale for change
Minor clarifications were made to this section to reflect current status of studies being 
referenced.
 
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Revised Text
Fifty As of November 2016 fifty-three subjects have had been exposed to GSK2838232 
in 3 completed studies. One study (204953) is completed in late 2016 and the analysis 
of results are ongoing (52 subjects have been 63 subjects were exposed to 
GSK2838232/r or placebo so far in this study). Overall, drug-related adverse events have 
been few and mild, and included headache, dizziness, fatigue, nausea, and palpitations 
and anxiety.  Similarly, treatment-emergent laboratory abnormalities have also been few 
and mostly grade 1.  There have been no discernible patterns, thus far, in terms of AEs or 
laboratory abnormalities.
Section 2.2.2.2
Study 204953 (completed); Pharmacokinetic Data
Rationale for change
Minor clarifications were made to this section to reflect current status of studies being 
referenced.
Change in Heading
Section 2.2.2.2
Study 204953 (on-going completed); Pharmacokinetic Data
Section 4.4.1
Risk Assessment
Rationale for change
Abbreviation used on first instance has been defined.
Revised Text
 
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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
HIV-1 Infection/Patient population
HIV Resistance
Propensity for co-meds and 
possible Drug-Drug 
Interactions (DDIs)
HIV Drug Resistance to unique mechanism
Recognize HIV patients have a higher chance of comorbidities/diseases and a 
risk of taking a medicine or product contraindicated in the study
Closely monitor HIV viral load and genotypic 
resistance
Strict adherence to protocol criteria around 
concurrent meds 
 
 
 
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Section 5.1
Inclusion Criteria
Rationale for change
Changes were made to this inclusion criteria to clarify that prior  use of pre- or post-
exposure prophylaxis would not exclude a subject from participation as long as last dose 
was 6 weeks before starting study treatment.
Revised Text
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
5 . Confirmed HIV positive; CD4+ cell count ≥350 cells/mm3 and plasma HIV-1 RNA 
≥5000 copies/mL at Screening. No current and no prior ART. (A previous course of 
pre- or post-exposure prophylaxis is allowed provided that it was completed at least 
6 weeks prior to the first dose of study drug).
Section 5.2
Exclusion Criteria
Rationale for change
This exclusion criteria was removed and the guidance for use of concomitant medications 
was further addressed in Section 6.12, Concomitant Medications and Non-Drug 
Therapies. The Relevant Habits section of the Exclusionary criteria was also removed and 
addressed in Section 6.10, Lifestyle and/or Dietary Restrictions, with the exception of 
illicit drug use. Smoking and limited alcohol use are no longer exclusionary. Additional 
clarification added to note that positive Hepatitis C result would need to be confirmed by 
RIBA. Abbreviation used on first instance has been defined.  Additional minor 
typographical errors were corrected.
Revised Text
CONCOMITANT MEDICATIONS
5.
Unable to refrain from the use of prescription or non-prescription drugs, including 
vitamins, herbal and dietary supplements (including St John’s Wort) within 7 days 
(or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is 
longer) prior to the first dose of study medication, unless in the opinion of the 
Investigator and GSK Medical Monitor the medication will not interfere with the 
study procedures or compromise subject safety. 
RELEVANT HABITS
6.
History of regular alcohol consumption within 6 months of the study defined as: 

An average weekly intake of >14 drinks for males or >7 drinks for females.  One 
drink is equivalent to 12 g of alcohol: 12 ounces (360 mL) of beer, 5 ounces 
(150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.
7.
Smoking is an exclusion criteria for this study. Urinary cotinine levels indicative of 
 
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smoking at screening.
6.
Chronic marijuana or use of other elicit medications (cocaine, heroin) is an exclusion 
criteria.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
7 . Presence of hepatitis B surface antigen (HBsAg), positive (confirmed by 
Recombinant Immuno-Blot Assay [RIBA]) hepatitis C antibody test result at screening 
or within 3 months prior to first dose of study treatment.
19 . Exclusion criteria for screening ECG (a single repeat is allowed for eligibility 
determination):
Males
Females
Heart rate
<45 and >100 bpm
<50 and >100 bpm
PR Interval
<120 and >220 msec
QRS duration
<70 and >120 msec
*QTc interval
>450 msec
*The QTc is the QT interval corrected for heart rate according to Bazett’s formula 
(QTcB), Fridericia’s formula (QTcF), and/or another method. It is either machine-
read or manually over-read. The specific formula used to determine eligibility and 
discontinuation for an individual participant in 204953200911 will be Fridericia’s 
formula. 
Section 6.1
Investigational Product and Other Study Treatment
Rationale for change
Minor typographical error corrected in this section. 
Revised Text
Treatment
Product name:
GSK2838232 
Capsule (API)
Tybost 
(cobicistat, cobi) tablet
Method for 
individualizing dosage:
Capsules supplied in high-density 
polyethylene bottles for 
individualized dosing by the clinic
Capsules Tablets supplied in bulk 
containers for individualized dosing by 
the clinic
Section 6.9
Treatment after the End of the Study
Rationale for change
Additional language was included in this section to allow subjects to opt to receive 
reimbursement from GSK for up to 3 months for marketed antiretroviral therapy (as 
 
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directed and prescribed by physician) based on the CDC guideline recommendations that 
patients be put on ARTs when diagnosed with HIV (test and treat guidelines). 
Revised Text
Subjects will not receive any additional treatment from GSK.
Subjects receiving GSK2838232 may opt to receive marketed antiretrovirals after 
the completion of 10 days of GSK2838232 dosing and study follow-up visits (through 
Day 21) eligible for sponsor company reimbursement up to a maximum of 90 days.
The selection of antiretrovirals will be investigator-chosen.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific
reimbursement for post-study treatment.
Section 6.10.1
Meals and Dietary Restrictions
Previous section number 6.12
Rationale for change
This section was updated to remove language around meal provisions (language 
consistent for an in-patient trial). As this is an out-patient trial, it will be up to trial site to 
arrange when/how meals are provided during a subject’s participation in the trial. The 
section ‘Lifestyle and/or Dietary Restrictions’ had no content described under it. The 
sections ‘Meals and Dietary Restrictions’ and ‘Alcohol, Caffeine and Exercise’ has been 
moved as sub-sections under the section ‘Lifestyle and/or Dietary Restrictions’, as the 
sub-sections are related to this section.  
Revised Text
Second Bullet
Doses will be given in the fed state (light breakfast), following overnight fasting (>10 
hours). Lunch will provided 4 hours after the dose; water will be allowed ad libitum 
throughout.
Section 6.10.2
Alcohol, Caffeine and Exercise
Previous section number 6.13
Rationale for change
Adjustments were made to these lifestyle habits to eliminate restrictions on use of 
tobacco products, reduce restrictions on alcohol use and to allow occasional and light 
exercise during study treatment. 
 
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Revised Text
Alcohol, Caffeine, Tobacco and Exercise

Subjects should refrain from alcohol for 48 hours before screening and then for 48 
hours prior to admission and baseline assessments (on Day 1). Alcohol is then not 
permitted for the duration of the treatment period (through Day 10) and until the final 
follow-up visit.  

Use of tobacco products is not allowed from screening until after the final follow-up 
visit

Subjects will During  the study  alcohol consumption should be limited to the 
following:

An average weekly intake of <14 drinks for males or <7 drinks for females.  
One drink is equivalent to 12 g of alcohol: 12 ounces (360 mL) of beer, 5 
ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.

Subjects will should abstain from strenuous exercise for 72 hours prior to each blood 
collection for clinical laboratory tests.  Subjects may participate in light recreational 
activities during studies (e.g., watch television, read).the treatment period.
Section 6.11
Contraception
Rationale for change
This section was updated to clarify that use of oral contraceptives are permitted during 
the study.
Revised Text
Second paragraph
Females of reproductive potential may only be enrolled if they are using two forms of 
complementary contraception, which must include one barrier method.  There Although 
use of oral contraceptives is permitted, tThere is no definitive DDI information with 
GSK2838232 and an interaction with oral contraceptives is possible, so other (barrier, 
inter-uterine device etc.) methods of contraception will be required.
Section 6.12
Concomitant Medications and Non-Drug Therapies
Previous section number 6.14
Rationale for change
Adjustments were made to the concomitant medication section to clarify that certain 
(medically necessary) medications were allowed and that all medication use should be 
discussed with the investigator. As section on ‘Meals and Dietary Restrictions’ (previous 
section 6.12) and ‘Alcohol, Caffeine and Exercise’ (previous section 6.13) has been 
moved under Lifestyle and/or Dietary Restrictions’ (Section 6.10), the section has been 
re-numbered.
 
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Deleted Text

Subjects must refrain from all illicit drugs throughout the study (from Screening until 
discharge from the study).  Drug screening will occur at Screening and Day -1 for 
each treatment period.  A positive result will lead to exclusion from the remainder of 
the study.

The Principal Investigator must be informed as soon as possible about any 
medications taken from the time of screening until the subject is discharged from the 
study.  Over-the-counter medications will not be permitted during the treatment 
period except as needed to treat an AE. If medication is needed, use should be 
restricted to 4 hours after dosing if possible. 
Section 6.12.1
Permitted Medications and Non-Drug Therapies
Previous section number 6.14.1
Rationale for change
Adjustments were made to the concomitant medication section to clarify that certain 
(medically necessary) medications were allowed and that all medication use should be 
discussed with the investigator. As section on ‘Meals and Dietary Restrictions’ (previous 
section 6.12) and ‘Alcohol, Caffeine and Exercise’ (previous section 6.13) has been 
moved under Lifestyle and/or Dietary Restrictions’ (Section 10), the section has been re-
numbered.
Revised Text
Addition of Second bullet

Concomitant medications (prescription and non-prescription) should be 
administered only as medically necessary during the study. Subjects must 
notify their Investigator of any current or proposed concomitant medication, 
whether prescribed or over-the-counter, because of the potential for 
interactions between such treatments and the study medications.
Section 6.12.2
Prohibited Medications and Non-Drug Therapies
Rationale for change
Adjustments were made to the concomitant medication section to clarify that certain 
(medically necessary) medications were allowed and that all medication use should be 
discussed with the investigator. As section on ‘Meals and Dietary Restrictions’ (previous 
section 6.12) and ‘Alcohol, Caffeine and Exercise’ (previous section 6.13) has been 
moved under Lifestyle and/or Dietary Restrictions’ (Section 10), the section has been re-
numbered.
 
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Previous section number 6.14.2
Revised Text

Subjects must abstain from taking prescription or non-prescription drugs (including 
vitamins and dietary or herbal supplements), within 7 days (or 14 days if the drug is 
a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first 
dose of study medication until completion of the follow-up visit, unless in the 
opinion of the Investigator and sponsor the medication will not interfere with the 
study. 

Subjects must refrain from all illicit drugs throughout the study (from 
Screening until discharge from the study).  Drug screening will occur at 
Screening and Day -1 and at additional timepoints throughout the study.  A 
positive result will lead to exclusion from the remainder of the study.
Section 7.1
Time and Events Table
Rationale for change
The Time and Events table was updated to remove the post-dose 12-lead ECG on Day 5, 
which remains in line with the FDA’s guidance regarding days on which to perform post-
dose (2 & 6 hours to capture near Tmax) ECGs. Modifications were also made to the 
pharmacokinetics sampling, allowing for the 12 h PK collection timepoint on Day 1 and 
10 to be optional. Visit/procedure windows were included to allow more flexibility with 
scheduling of assessments. Also minor clarifications were made and typographical errors 
were corrected.
Revised Text
 
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Day:
Screen1
Random
1
2
3
4
5
62
7
8
9
10
11
12
141
211 
(FU)
ET
Informed Consent
X
Review inclusion/exclusion
X
X
Demography including height, weight and 
BMI
X
Brief physical
X
Medical/medication/
drug/alcohol history
X
X
CDC Classification
X
X
X
X
Prior antiretroviral therapy
X
12-lead ECG3
X
X
X
X
X
X
X
X
X
X
Holter (24 hr)
X
Vital signs4
X
X
X
X
X
X
X
X
X
Drug screen
X
X
X
X
X
Hepatitis B Surface antigen and hepatitis 
C antibody testing
X
Serum or urine -hCG (WoCBP only)
X
X
X
Clinical lab tests (inc troponin)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Fasting lipid panel
X
X
AE assessment5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Con Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HIV-1 RNA PCR6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lymphocyte subsets7
X
X
X
Plasma for genotype/phenotype8
X
X
X
X
X
X
X
HIV-associated conditions assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK blood sample9
X
X
X
X
X
X
X
X
X
X
X
XX14
Plasma samples10
X
X
X
Dosing11
X
X
X
X
X
X
X
X
X
X
PGx12
X
AE enquiry13
X
X
X
X
X
X
X
X
X
X
X
X
X
Telephone call to IVRS1314
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
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Day:
Screen1
Random
1
2
3
4
5
62
7
8
9
10
11
12
141
211 
(FU)
ET
Plasma for storage15
X
X
X
X
X
X
X
X
X
X
X
X
X
Outpatient visit
X
X
X
X
X
X
X
X
X
X
X
X
1.
Screening will occur within 14-30 days prior to the first dose of study drug.
2.
Table is set up for the weekend during dosing to occur on Days 6 and 7.  If the weekend occurs on Days 5 and 6, perform all “Day 5” assessments on Day 7.
3.
On Day 1, ECGs (x2) will be performed pre-dose , and then 1, 1.5, 2, 3, 4 and 6 hours post dose.  The pre-dose ECGs should be performed at least 5 minutes apart and 
preferably within 1 hour prior to dose.  On Days 4, 5 and 8, ECGs will be obtained prior to morning dosing and at 2, 4 and 6 hours post-dose. To accommodate scheduling, 
serial ECGs collected on Days 4 and 8 may be performed 1 day.  On Day 10, ECGs (x2) will be performed pre-dose, and then 1, 1.5, 2, 3, 4 and 6 hours post dose.  On 
Day 11, an ECG will be obtained prior to the 24-hour PK sample. ECGs will be performed in triplicate at all timepoints.
4.
BP, RR, HR and temperature will be obtained at Screening (x1) and Day 1 pre-dose (x2).  BP and HR will be obtained on Day 1 at 2 hours post-morning dose and on Days 4, 5 
and 8 pre-dose.  BP and HR will be obtained on Day 10 at pre-dose and 2 hours post-morning dose, and at day 12 and Follow-up (Day 21).
5.
Only SAEs related to study participation will be collected between screening and Day 1. An AE enquiry will be made at each visit, subjects will be asked if they have 
experienced any neuropsychiatric adverse events, including psychosis or altered mental status.
6.
On Days 1-5 and 8-10 samples for HIV-1 RNA PCR collected before morning dose.  On Days 1, 10 and 11 two samples for HIV-1 RNA PCR will be collected 5-30 minutes 
apart. HIV-1 RNA PCR samples will also be collected on days 12, 14 & Follow-up (Day 21).
7.
Lymphocyte subsets by flow cytometry (total lymphocyte counts, percentage, and absolute CD4+and CD8+counts).
8.
Blood samples for phenotype and genotype will be collected at pre-dose on Days 1, 4, 5 and 8 in the morning on Day 11 and at follow-up. 
9.
Serial plasma samples (2 mL) for determination of GSK2838232 will be collected on Day 1 and Day 10 at pre dose (within 15 minutes prior to dose) and 0.5, 1, 1.5, 2, 3, 4, 6, 
8, 12 (optional), and 24 hours (to occur on morning of Day 2 post-am dose and in the morning on Day 11) .  Pre-dose PK samples (within 15 minutes prior to dose) will be 
taken on the mornings of Days 3, 4, 5, 8 and 9 and a single sample will be taken on Days 12 and 14.
10. Samples (2 x 0.5mL) of plasma for assessment of immunological markers at screen, baseline (pre-dose) and day 11 
11. Subjects will receive a single dose of GSK2838232 and cobicistat each morning with a light breakfast meal and 240 mL of water from Day 1 to Day 10.  Doses taken in the 
clinic will be administered after an overnight fast of at least 10 hours .On Days 6 and 7, doses will be self administered but confirmed by phone 
12. PGx sample should be collected on Day 1.
13. An AE enquiry will be made at each visit, subjects will be asked if they have experienced any neuropsychiatric adverse events, including psychosis or altered mental status
13. A screening/registration call should be made to the IVRS to register the subject at screening.   An additional call will be made to document a screen failure.   A randomization 
call should be made to the IVRS system approximately one week prior to scheduled Day 1.  Note: The randomization call must be made in order to have study drug on site for 
Day 1. Additional calls will be made every day that the subject has a scheduled study visit to the clinic.  If a subject terminates the study prematurely a call should be made to 
the IVRS
14. Only if early termination visits occur during the treatment period.
15. Plasma samples for storage will be collected at each visit starting at Day 1, including unscheduled visits (e.g. for HIV-1 RNA levels and immunological 
parameters).  Additionally these samples will be used when needed, such as when samples are lost or arrive at the laboratory unevaluable.
AE = Adverse event; CDC= Center for Disease Control and Prevention; ECG = Electrocardiogram; ET = Early termination; hCG = Human chorionic gonadotrophin; HIV = Human 
immunodeficiency virus;  IVRS= Interactive Voice Response System; PCR = Polymerase chain reaction; PK=Pharmacokinetic.
 
 
 
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Section 7.2
Visit Windows
Rationale for Addition
Visit/procedure windows were included to allow more flexibility with scheduling of 
assessments. 
New Section
Screening (baseline to pre-dose): All screening assessments should take place within 
14-21 days prior to the first dose. The screening visit window may be extended to 30 
days upon discussion with the Medical Monitor (i.e.; subject has scheduling conflicts 
or any screening assessment needs to be repeated).
Days 4 and 8: Based on subject and clinic schedule, Day 4 and Day 8 serial (up to 6h 
post-dose) ECG assessments may be conducted 1 day.  
Weekend(s): The T&E table is set up for study start (Day 1) to occur on a Monday 
and Days 6 and 7 to fall on the weekend. If the weekend occurs instead on Days 5 
and 6, Day 5 assessments should be performed on Day 7. The study start (Day 1) 
may also be adjusted to allow visits with assessments to be conducted over the 
weekend based on subject and clinic schedule.  
Assessments: The following applies to timing of procedures:
-
Window for assessments 4 h post-dose = 5 minutes 
-
Window for assessments >4 and < 12 h post-dose = 15 minutes
-
Window for assessments >12 h post-dose = 30 minutes
End of Treatment visit: should be within 14 days from last dose of study drug. If a 
subject is unable to return to the clinic for any reason site staff are encouraged to 
telephone the subject for assessment of adverse events.
Section 7.3.1
Holter Monitoring (Screening criteria)
After addition of new section before this section, the section numbers from this section 
until Sections under 7.0 are re-numbered using the next available section number.  
Rationale for Change
Minor alterations were made regarding the order of screening procedures, including the 
Holter monitoring requirement to allow flexibility based on clinic and subject schedule.
Revised Text
The 24-hour Holter monitoring should only will be performed at during the Screening 
after the subject has met all other inclusion criteria. period using a Holter monitoring 
device supplied by the Sponsor.
Analysis of the Holter tapes will consider the following:

Heart rate (bradycardia and tachycardia)
 
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
Normal and aberrant beats

Number of supraventricular contractions, premature atrial contractions, premature 
ventricular contractions, couplets, triplets, and ventricular tachycardias

Atrio-ventricular conduction defects

Atrial fibrillation and flutter
Section 7.5.1.1
Time period and Frequency for collecting AE and      
SAE information
Rationale for Change
Minor clarifications made regarding Sponsor (to include PPD). 
Revised Text
Bullet 4

All SAEs will be recorded and reported to GSK Sponsor within 24 hours, as 
indicated in Appendix 5, Section 12.5.
Section 9.3.2
Interim Analysis
Rationale for Change
Minor corrections and clarifications were made to this section.
Revised Text
An interim analysis of preliminary safety, tolerability, PK and antiviral activity will occur 
after subjects of Part A Cohort 1 complete their Day 13 visit. If based on this review the 
Cohort 1 dose is determined to be the highest dose based on this review (e.g., the 
exposure level of GSK2838232 is in the range of the maximum GSK2838232 exposure 
seen previously in healthy subjects), the Bayesian posterior probability that the log10 
viral load decline from baseline is greater than a cut-point will be calculated. If the 
Bayesian probability from Cohort 1 is less than 70%, this will provide evidenceto
evidence to not move forward into Part B. Otherwise, the study team will review the data 
in order to make a dose selection decision for the subsequent Part B Cohorts.  If the 
pharmacokinetic exposures after the 100 mg GSK2838232/cobi dose look similar to those 
obtained with 100 mg GSK2838232/r in prior studies, the doses for Part B will be 
extended to both lower (20 mg, 50 mg) and higher (200 mg) GSK2838232 doses.
Maximum change and change from baseline in plasma HIV-1 RNA will be summarized 
by treatment or by assessment day. The proportion of subjects with plasma HIV-1 RNA 
<400 and <50 copies/mL will be summarized by treatment and assessment day. The 
analyses will be done for both PP and ITT exposed population if the two populations are 
not the same.
Section 10.3
Quality Control (Study Monitoring)
Rationale for Change
Minor clarifications made regarding Sponsor (to include PPD). 
 
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Revised Text
First Bullet
In accordance with applicable regulations including GCP, and GSK procedures, GSK 
monitors or designee will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy regulatory, 
ethical, and GSK requirements.
Section 10.5
Study and Site Closure
Rationale for Change
Minor clarifications made regarding Sponsor (to include PPD). 
Revised Text
First Bullet
Upon completion or premature discontinuation of the study, the GSK monitor or 
designee will conduct site closure activities with the investigator or site staff, as 
appropriate, in accordance with applicable regulations including GCP, and GSK Standard 
Operating Procedures.
Section 11 References
Rationale for Change 
Have mentioned the references as per GSK style guide and template.
Revised Text
Elion R, Cohen C, Gathe J, Shalit P, Hawkins T, Liu HC, et al. Mathias AA, Chuck SL, 
Kearney BP, Warren DR.  Phase 2 study of cobicistat versus ritonavir each with once-
daily atazanavir and fixed-dose emtricitabine.tenofovir df in the initial treatment of HIV 
infection.  AIDS.  2011; 25:1881-1886.
Gallant JE, Koenig E, Andrade-Villaneuva J, Chetchotisakd P, deJesus E, Antunes F, 
Arastéh K, et al. Moyle G, Rizzardini G, Fehr J, Liu Y, Zhong L, Callebaut C, 
Scwarcberg J, Rhee MS, Cheng AK.  Cobicistat versus ritonavir as a pharmacoenhancer 
of atazanavir plus emtricitabine/tenofovir disoproxil fumarate in treatment-naïve HIV 
type 1-infected patients:  week 48 results.  J. Infect. Dis.  2013; 208-:32-39.
Kakuda TN, Opsomer M, Timmers M, Iterbeke K, Van De Casteele T, Hillewaert V, et 
al. Petrovic R, Hoetelmans RMW.  Pharmacokinetics of darunavir in fixed-dose 
combination with cobicistat compared with coadministration of darunavir and ritonavir as 
single agents in healthy volunteers.  J. Clin. Pharmacol.  2009; 54:949-957.
Lalezari J, McCallister S, Gigliotti M, Cohen C, Elion R, Brinson C, et al. Safety and 
efficacy study of bevirimat (BVM) in heavily treatment experienced HIV+ patients 
identifies the target phase 3 study profile. ICAAC. 2008; Abstract: H891. 
Martin DE, Blum R, Wilton J, Doto J, Galbraith H, Burgess GL, et al. Safety and 
pharmacokinetics of bevirimat (PA-457), a novel inhibitor of human immunodeficiency 
 
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virus maturation, in healthy volunteers. Antimicrobial Agents and Chemotherapy. 
2007(b);Sep:3063-6.
Appendix 1
Abbreviations
Rationale for Change 
The abbreviations used in the document are added to the list of abbreviations.
AIDS
Auto Acquired immunodeficiency syndrome
BID 
Twice daily
DDI
Drug-Drug Interaction
PPD
Pharmaceutical Product Development
QD
Once daily
RIBA
Recombinant Immuno-Blot Assay
t1/2t½
Terminal elimination half-life
 
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TITLE PAGE
Division:  Worldwide Development
Information Type: Clinical Protocol
Title:
A Phase 2a, Multicenter, Randomized, Adaptive, Open-label,  
Dose Ranging Study to Evaluate the Antiviral Effect, Safety, 
Tolerability and Pharmacokinetics of Cobicistat-boosted 
GSK2838232 Monotherapy Over 10 Days in HIV-1 Infected 
Treatment-Naive Adults
Compound Number:
GSK2838232
Development Phase
IIA
Effective Date:
09-NOV-2016
Author(s):
Clinical Pharmacology, ViiV Healthcare, RTP, NC, US
PCPS, GSK, Collegeville, PA, US 
HIV DPU, RTP, NC, US
Clinical Statistics, PAREXEL, RTP, NC, US
Clinical Statistics, GSK, Upper Providence, PA, US
Infectious Diseases, Clinical, Cambridge, MA, US
PCPS, GSK, Upper Providence, PA, US
Virology, HIV DPU, RTP, NC, US
GCSP, Stockley Park, UK
PTS, Ware, UK
CPMS, GSK, RTP, NC, US
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information:
Role
Name
Day Time 
Phone Number
and email 
address
After-hours 
Phone/Cell/
Pager Number
Fax Number
Site Address
Primary 
Medical 
Monitor 
MD
Boston, MA
Secondary
Medical 
Monitor
 MD
GlaxoSmithKline
1250 St 
Collegeville Rd 
Collegeville, PA 
19426
SAE contact  
information 
MD
Boston, MA
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.   
Regulatory Agency Identifying Number(s): 116,094
 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE

I confirm agreement to conduct the study in compliance with the protocol.

I acknowledge that I am responsible for overall study conduct. I agree to 
personally conduct or supervise the described study.

I agree to ensure that all associates, colleagues and employees assisting in the 
conduct of the study are informed about their obligations. Mechanisms are in 
place to ensure that site staff receives the appropriate information throughout the 
study.
Investigator Name:  ______________________________
Investigator Signature
Date
 
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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 200911........................................................8
2.
INTRODUCTION....................................................................................................12
2.1.
Study Rationale ..........................................................................................12
2.2.
Brief Background ........................................................................................12
2.2.1.
Preclinical Summary....................................................................13
2.2.2.
Clinical Summary of Safety and Pharmacokinetics ......................18
2.2.2.1.
Clinical Summary of Safety.........................................18
2.2.2.2.
Study 204953 (on-going); Pharmacokinetic 
Data ...........................................................................19
2.2.2.3.
Overall Summary/Conclusions of PK data..................22
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................24
4.
STUDY DESIGN ....................................................................................................25
4.1.
Overall Design ............................................................................................25
4.2.
Type and Number of Subjects.....................................................................27
4.3.
Design/Dose Justification............................................................................27
4.3.1.
GSK2838232 with Ritonavir.........................................................27
4.3.2.
GSK2838232 with Cobicistat .......................................................28
4.3.3.
Interim Analysis ...........................................................................28
4.4.
Benefit:Risk Assessment ............................................................................29
4.4.1.
Risk Assessment .........................................................................30
4.4.2.
Benefit Assessment.....................................................................32
4.4.3.
Overall Benefit:Risk Conclusion...................................................32
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............32
5.1.
Inclusion Criteria.........................................................................................33
5.2.
Exclusion Criteria........................................................................................35
5.3.
Screening/Baseline/Run-in Failures............................................................38
5.4.
Withdrawal/Stopping Criteria.......................................................................38
5.4.1.
Liver Chemistry Stopping Criteria ................................................38
5.4.1.1.
Study Treatment Restart or Rechallenge....................39
5.4.2.
QTc Stopping Criteria ..................................................................39
5.5.
Stopping criteria based on Adverse Events.................................................40
5.6.
Subject and Study Completion....................................................................40
6.
STUDY TREATMENT ............................................................................................40
6.1.
Investigational Product and Other Study Treatment....................................40
6.2.
Treatment Assignment................................................................................41
6.3.
Planned Dose Adjustments.........................................................................41
6.4.
Blinding.......................................................................................................41
6.5.
Packaging and Labeling..............................................................................41
6.6.
Preparation/Handling/Storage/Accountability..............................................41
6.7.
Compliance with Study Treatment Administration.......................................42
6.8.
Treatment of Study Treatment Overdose....................................................42
6.9.
Treatment after the End of the Study ..........................................................43
6.10.
Lifestyle and/or Dietary Restrictions............................................................43
 
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6.11.
Contraception .............................................................................................43
6.12.
Meals and Dietary Restrictions ...................................................................44
6.13.
Caffeine, Tobacco and Exercise .................................................................44
6.14.
Concomitant Medications and Non-Drug Therapies....................................44
6.14.1.
Permitted Medications and Non-Drug Therapies..........................44
6.14.2.
Prohibited Medications and Non-Drug Therapies.........................44
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................45
7.1.
Time and Events Table...............................................................................46
7.2.
Screening and Critical Baseline Assessments ............................................48
7.2.1.
Holter Monitoring (Screening criteria)...........................................48
7.3.
Efficacy.......................................................................................................48
7.3.1.
HIV-1 RNA Sampling ...................................................................48
7.3.2.
Lymphocyte Subsets by Flow Cytometry .....................................49
7.4.
Safety .........................................................................................................49
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........49
7.4.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................49
7.4.1.2.
Method of Detecting AEs and SAEs ...........................50
7.4.1.3.
Follow-up of AEs and SAEs........................................50
7.4.1.4.
Cardiovascular and Death Events ..............................50
7.4.1.5.
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ................50
7.4.1.6.
Regulatory Reporting Requirements for SAE..............51
7.4.2.
Pregnancy ...................................................................................52
7.4.3.
Physical Exams ...........................................................................52
7.4.4.
Vital Signs....................................................................................52
7.4.5.
Electrocardiogram (EGC).............................................................52
7.4.6.
Clinical Safety Laboratory Assessments ......................................52
7.5.
Pharmacokinetics .......................................................................................54
7.5.1.
Blood Sample Collection..............................................................54
7.5.2.
Sample Analysis ..........................................................................54
7.6.
Biomarker(s)/Pharmacodynamic Markers ...................................................54
7.6.1.
Viral Genotyping and Phenotyping...............................................54
7.7.
Genetics .....................................................................................................55
7.8.
Value Evidence and Outcomes...................................................................55
8.
DATA MANAGEMENT ...........................................................................................55
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................55
9.1.
Hypotheses.................................................................................................55
9.2.
Sample Size Considerations.......................................................................56
9.2.1.
Sample Size Assumptions ...........................................................56
9.2.2.
Sample Size Sensitivity................................................................57
9.2.3.
Sample Size Re-estimation or Adjustment...................................57
9.3.
Data Analysis Considerations .....................................................................57
9.3.1.
Analysis Populations....................................................................57
9.3.2.
Interim Analysis ...........................................................................58
9.4.
Key Elements of Analysis Plan ...................................................................58
9.4.1.
Primary Analyses.........................................................................58
9.4.1.1.
Safety Analyses..........................................................59
9.4.1.2.
Efficacy Analyses .......................................................59
 
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9.4.1.3.
Pharmacokinetic Analyses..........................................59
9.4.2.
Secondary Analyses ....................................................................60
9.4.2.1.
Pharmacokinetic/Pharmacodynamic Analyses ...........60
9.4.2.2.
Viral Genotyping and Phenotyping Analyses ..............60
10. STUDY GOVERNANCE CONSIDERATIONS........................................................60
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............60
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................60
10.3.
Quality Control (Study Monitoring) ..............................................................61
10.4.
Quality Assurance.......................................................................................62
10.5.
Study and Site Closure ...............................................................................62
10.6.
Records Retention......................................................................................62
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................63
10.8.
Review Committees....................................................................................63
11. REFERENCES.......................................................................................................64
12. APPENDICES........................................................................................................66
12.1.
Appendix 1: Abbreviations and Trademarks................................................66
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................69
12.3.
Appendix 3: Liver Safety – Study Treatment Restart or Rechallenge 
Guidelines...................................................................................................72
12.4.
Appendix 4: Genetic Research ...................................................................73
12.5.
Appendix 5: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................76
12.5.1.
Definition of Adverse Events........................................................76
12.5.2.
Definition of Serious Adverse Events...........................................77
12.5.3.
Definition of Cardiovascular Events .............................................79
12.5.4.
Recording of AEs and SAEs ........................................................79
12.5.5.
Evaluating AEs and SAEs............................................................80
12.5.6.
Reporting of SAEs to GSK...........................................................81
12.6.
Appendix 6: Collection of Pregnancy Information........................................83
12.7.
Appendix 7: Country Specific Requirements...............................................84
12.8.
Appendix 8: Division Of AIDS Table For Grading The Severity Of 
Adult And Pediatric Adverse Events Version 1.0, December 2004; 
Clarification August 2009............................................................................85
12.9.
Appendix 9: Toxicity Management ............................................................104
 
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1.
PROTOCOL SYNOPSIS FOR STUDY 200911
Rationale
GSK2838232 is a novel human immunodeficiency virus (HIV-1) maturation inhibitor 
that is being developed for the treatment of HIV-1 in combination with other 
antiretrovirals.
Three clinical studies of GSK2838232 (n=53 healthy subjects) have been completed thus 
far. One study (Study 204953) is on-going. Healthy subjects have received GSK2838232 
or placebo in single or repeated dose designs, to a maximum single dose of 250 mg or 
repeated dose (for 11 days) of 200 mg QD, in combination with ritonavir (RTV). 
Study HMI116787 (completed November 2013) was the First Time in Human study of 
GSK2838232 and assessed safety and tolerability of escalating doses (5 mg to 100 mg), 
food effect, and the impact of steady-state ritonavir on GSK2838232 pharmacokinetics
(PK). Following successful completion of 3-month toxicology studies in rat and dog in 
2014, clinical studies 200912 and 200207 were initiated. These were double-blind, 
placebo-controlled, single (Study 200912) and repeat-dose (Study 200207) escalation 
studies to investigate the safety, tolerability, and PK of GSK2838232 alone and when co-
administered with ritonavir 100 mg once daily (QD) for 8-11 days. Further assessment of 
an alternative formulation was also an objective in Study 200912.
Both studies were prematurely terminated/completed in March/April 2015 because of 
concerns over cardiovascular (CV) toxicity, in particular a clinical CV serious adverse 
event (SAE) whereby the Food and Drug Administrating (FDA) imposed a clinical hold. 
Following submission of long-term (6-month rat, 9-month dog) chronic toxicology data 
and follow up to the clinical SAE in November 2015, the hold was released in January 
2016 and Study 204953 was initiated.
Study 204953 is an on-going study and continues the single and repeat-dose exploration 
of safety and PK of GSK2838232 as well as the suitability of a new, capsule formulation. 
Doses of up to 250 mg GSK2838232/100 mg RTV (as single doses) or 200 mg
GSK2838232/100 mg RTV (QD for 11 days) were studied. As of 26 October 2016, the 
study is ongoing with a cohort of subjects due to receive unboosted GSK2838232 
(200mg BID) for 11 days.
These studies have shown GSK2838232 with or without RTV to be well tolerated and, 
together with daily RTV dosing (“boosting”), demonstrate a PK profile suitable for 
progression to HIV patients in this Phase IIa proof of concept 10-day, monotherapy study 
design. However, potential concerns over protease resistance necessitate a change to a 
pharmacoenhancer without antiviral effects in this study of GSK2838232 monotherapy. 
Therefore, for Study 200911, cobicistat (Tybost,150 mg QD) will be substituted for RTV.  
The objective of Study 200911 is to understand the safety, PK and HIV antiviral profile 
of GSK2838232/cobicistat (GSK2838232/cobi) when given to HIV-infected, treatment 
naive, otherwise healthy adults. Approximately 10 HIV-1 infected subjects will be 
enrolled into Part A. If warranted by an interim safety, virology, and PK data analysis, 
 
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approximately 8 subjects will be enrolled in each of between two and four Cohorts in Part 
B, which will be a parallel group design.
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

To evaluate antiviral activity of 
GSK2838232/cobi in HIV-1 infected 
patients during 10 days of 
monotherapy.

Change from baseline (Day 1) in plasma HIV-1 
RNA 

To assess safety and tolerability of 
GSK2838232/cobi when administered 
as monotherapy over 10 days.

Safety and tolerability parameters, including 
adverse event, concurrent medication, clinical 
laboratory, electrocardiogram (ECG) and vital 
signs assessments.

To characterize the pharmacokinetics 
of GSK2838232 in HIV-1 infected 
patients following GSK2838232/cobi 
dosing for 10 days.

GSK2838232 PK parameters following dose 
administration, as follows:
Day 1: area under the plasma concentration time 
curve AUC(0-24), maximum observed 
concentration (Cmax), time to maximum 
observed concentration (tmax), concentration at 
24 hours post dose (C24), absorption lag time 
(tlag); 
Following last repeat administration on Day 10:  
AUC(0-), pre-dose concentration (C0), 
concentration at end of dosing interval (C), 
Cmax, tmax, t½, and apparent oral clearance 
(CL/F), if data permit
Secondary

To explore the relationship between 
GSK2838232 exposure and change 
in plasma HIV-1 RNA

GSK2838232 PK parameters Day 10 AUC(0-), 
Cmax, Cwith Day 11 HIV-1 RNA change from 
baseline

To assess the immunologic effect of 
GSK2838232/cobi when 
administered over 10 days in HIV-1 
infected adults

Change from baseline in CD4+ cell count to Day 
11

To explore the relationship between 
GSK2838232 exposure and safety or 
immunologic parameters, if 
appropriate.

GSK2838232 PK parameters on Day 10: 
AUC(0-), Cmax, Cwith Day 11 change from 
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Objectives
Endpoints

To assess the development of viral 
resistance (genotypic and 
phenotypic) over 10 days and 
correlate with viral response, if 
appropriate.

Emergence of drug resistance mutations, if 
appropriate

To estimate GSK2838232 
accumulation and to assess 
attainment of steady state following 
administration of GSK2838232/cobi
for 10 days in HIV infected subjects.

Accumulation:
GSK2838232 PK accumulation ratios (R): Day 
10 AUC(0-), Cmax, and Ccompared to Day 1 
AUC(0-24), Cmax, and C24, respectively

Steady State:
pre-morning dose concentrations (C0) on Days 2 
through 11

To examine dose proportionality of 
GSK2838232 pharmacokinetic 
parameters following 
GSK2838232/cobi dosing for 10 days
in HIV infected subjects.

Day 1 AUC(0-24), Cmax, and C24, and Day 10 
AUC(0-), Cmax, and Cat different dose levels 
for the assessment of dose proportionality
Note: Other exploratory objectives and endpoints will be specified in the RAP
Design, Treatment Arms and Duration
Approximately 34 HIV-1 infected treatment-naive subjects will be enrolled overall. 
This study is a 10-day monotherapy, open-label, adaptive, dose ranging, repeat-dose 
study and will be conducted as two parts with an interim (go/no-go) analysis performed 
after Part A (Table 1). Part A, Cohort 1 will evaluate a safe and well-tolerated dose level
of GSK2838232 that has been tested (with RTV) in prior Phase I studies and that targets 
a high inhibitory quotient (IQ) value. Following the completion of an interim analysis of 
those data and according to criteria defined later in the protocol, further cohorts of 8 
subjects will then be studied in Part B in a parallel design in two or more cohorts 
(depending upon the data obtained in Part A). 
The totality of this data will provide a full dose-response of GSK2838232 over a wide 
dose range to explore the safety and PK/pharmacodynamics (PD) relationship of 
GSK2838232 in HIV-1 infected subjects and facilitate choice of doses for Phase IIb
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Table 1
Study Design for 200911
Part A: GSK2838232/cobi
Once Daily x 10 days1
Part B: GSK2838232/cobi
Once Daily x 10 days1,2
Cohort
N
232 Dose
(mg)
Cohort
N
232 Dose 
(mg)
1
10
100
2
8
200
3
8
50
4
8
20
1. 
Part A Cohort 1 safety/PK/virology data will be evaluated at interim, prior to initiating other cohorts in Part B, which 
are planned to run in a parallel, randomized fashion. All doses will be given with 150 mg cobicistat.
2. 
Part B GSK2838232 doses are an illustration of the projected doses per cohort. The actual doses for each cohort 
are subject to modification based upon safety, PK and antiviral activity data from Cohort 1 (Part A). More 
doses/cohorts (including potential removal of cobi co-dosing) may be added (the maximum dose in Part B would 
not exceed 200 mg with cobicistat unless overall plasma exposure [as AUC and Cmax] was lower in HIV infected 
subjects than in healthy subjects at the same dose level).
The possibility that an additional, unboosted GSK2838232 monotherapy cohort will be 
assessed in Part B is dependent on analysis of the PK data from ongoing Study 204953 
where unboosted GSK2838232 at a dose of 200 mg twice daily (BID) is being assessed. 
Subjects in both parts 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 6 weeks.
HIV Drug Resistance: Following cessation of GSK2838232/cobi dosing for 10 days,
there will be prolonged exposure to waning plasma concentrations of GSK2838232, 
because of the long t½ (i.e., in the “tail” of the PK profile). However, based on in vitro 
resistance passage data with GSK2838232 [and unlike with many other ARV therapies],
there appears to be a limited likelihood of developing maturation resistance mutations in 
HIV-infected subjects due to its virologic profile [GSK Document Number 
2013N163221_00]. 
Analysis
The primary objectives of this study are to investigate the safety, tolerability, PK and 
antiviral activity of 10 days repeated doses of GSK2838232/cobi in HIV-1 infected 
otherwise healthy subjects. Descriptive summaries will be provided for safety, PK, and 
HIV viral load data.
 
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2.
INTRODUCTION
GSK2838232 is a novel HIV-1 maturation inhibitor (MI) that is being developed for the 
treatment of HIV-1 infection in combination with other antiretrovirals (ART).
2.1.
Study Rationale
This ‘proof of concept (PoC)’ open-label study is being conducted to characterize the 
acute antiviral activity, pharmacokinetics (PK), the relationship between PK and antiviral 
activity, and safety of GSK2838232 given with 150 mg QD cobicistat
(GSK283232/cobi), administered across a range of doses over 10 days in HIV-1 infected 
patients. A two part adaptive and dose ranging design is to be applied in this study. Data 
from this study will be utilized to select doses for further studies in Phase IIb.
2.2.
Brief Background
Combination antiviral therapy with inhibitors of HIV protease, integrase, entry and 
reverse transcriptase (RT) has demonstrated significant improvement in AIDS-related 
morbidity and mortality over the last 10-15 years. Emerging multi-class drug resistant 
viral strains and long-term toxicities warrant development of new classes of antiretroviral 
therapies targeting various parts of the HIV-1 viral life cycle [Wainburg, 2010]. The 
inhibition of maturation of HIV-1 is a novel target for drug development, distinct from 
viral protease RT or integrase [Saxena, 2012; Qian, 2009]. HIV maturation is the final 
cleavage step of the capsidSp1 (transcription factor) polyprotein that generates the 
functional capsid p24 protein. This mechanism of action results in accumulation of the 
uncleaved p25 protein with subsequent improper assembly of the HIV core, resulting in a 
non-infectious virion. Gel-based mechanism of action studies suggest that compound 
GSK2838232 acts as a maturation inhibitor. Western Blot analysis shows inhibition of 
capsid-Sp1 cleavage and accumulation of p25 in the presence of GSK2838232.
Prior validation of this target was demonstrated with the HIV maturation inhibitor known 
as bevirimat (BVM; [Martin, 2007a; Martin, 2007b; Martin, 2008; NORVIR, 2013]).
BVM reached Phase II studies in HIV patients; however, only modest reductions in 
plasma HIV-1 ribonucleic acid (RNA) concentrations were observed in Phase IIa 
monotherapy studies [Mahmood, 2006; Martin, 2007] and a pattern of polymorphic 
(differential) antiviral activity [Wainburg, 2010] led to termination of BVM development. 
The average decrease from baseline to Day 14 plasma HIV-1 RNA was 0.54 and 0.70 
log10 copies/mL for 200 mg and 300 mg twice daily regimens (Table 2); all subjects 
achieved plasma BVM concentrations above the in vitro EC90. Responders, classified 
based on 5 polymorphisms in HIV-1 gag (at positions 369, 370, and 371), achieved an 
average 1.15 log10 copies/mL reduction in plasma HIV-1 RNA, while an average 0.17 
log10 copies/mL reduction was achieved for non-responders.
 
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Table 2
Summary of Bevirimat Antiviral Response and PK in a 14-day 
Monotherapy Study in HIV-infected Adults
BVM dosage 
regimen
Mean (SD) viral load 
change from 
baseline to Day 14
2IQ
Plasma BVM 
1Cmin (g/mL)
Plasma BVM 
1Cmax 
(g/mL)
Plasma BVM 
1AUC(0-) 
(g.h/mL)
200 mg BID
(N=14)
-0.54 (0.64)
1.70
46
(41, 51)
58
(53, 64)
632
(571, 699)
300 mg BID
(N=18)
-0.70 (0.77)
2.67
72
(65, 80)
91
(84, 99)
973
(890, 1064)
1.
Cmin, Cmax, and AUC reported as geometric mean (95% CI).
2.
IQ=geometric mean Cmin/in vitro EC90; reported EC90=27 g/mL; all subjects achieved IQ 1.
        AUC(0-) = Area under the concentration-time curve over the dosing interval; BVM = Bevirimat; CI = Confidence 
interval; Cmax = Maximum plasma concentration; Cmin = Minimum plasma concentration; EC90 = 50% protection 
against resistant mutant HIV infection; IQ = Inhibitory quotient; SD = Standard deviation.
Early clinical data for BMS955176, a second generation maturation inhibitor, have been 
recently presented [Nowicka-Sans, 2015]. In a 10-day monotherapy trial in HIV-infected 
patients, plasma HIV-1 RNA was reduced at doses of between 40 mg and 120 mg QD. 
All doses were well tolerated. The maximum change, seen between 10 and 12 days after 
starting dosing, was about 1.5 log10, which is substantially better than the effect 
demonstrated with BVM and may indicate the maximum expected clinical effect of 
inhibiting this viral target.
Although BMS955176 is currently in Phase II studies in HIV-infected patients, there are 
no maturation inhibitors approved for the treatment of HIV infection.  The uncertainties 
of early drug development and continuing need for novel ART, especially for heavily 
treated/experienced HIV-infected persons, support continued compound development. 
GSK2838232’s low nanomolar in vitro potency against multiple HIV-1 gag 
polymorphisms and broader spectrum across multiple HIV-1 subtypes indicates it has 
utility in this setting.
2.2.1.
Preclinical Summary
Nonclinical pharmacology
Virology
GSK2838232, in vitro, is an inhibitor of HIV maturation by preventing the cleavage of 
the HIV gag structural subunit p25 to p24. GSK2838232 is a potent antiviral agent with a 
mean 50% maximal inhibitory concentration (50% maximal inhibitory concentration 
[IC50]) value of 1.6 nM (range: 0.8 to 4.3 nM) when tested in a panel of 26 HIV-1 
isolates with various polymorphic gag genotypes in peripheral blood mononuclear cells 
(PBMCs), suggesting that GSK2838232 can inhibit a broad spectrum of HIV isolates. In 
another PBMC assay, GSK2838232 showed potent antiviral activity in 59 of 60 isolates 
with IC50 values ranging from 0.22 to 5.1 nM. GSK2838232 also inhibited HIV-1 strains 
containing the consensus Sp1 QVT region or the V370A polymorphism in MT4 cells
(IC50 = 0.73 to 0.81 nM). 
 
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In an MT2 cell-based assay utilizing recombinant viruses harboring gag and protease 
from subjects before and after a protease inhibitor (PI) based regimen, GSK2838232 
inhibited 12 of 15 viruses with a mean IC50 value of 1.7 nM (range = 0.4 to 3 nM). The 
remaining 3 viruses were not inhibited by GSK2838232 up to the top concentrations 
tested at 400 nM. There was no correlation of PI sensitivity and susceptibility to 
GSK2838232. GSK2838232 resistance mutations were selected for by serial passage of 
virus in a SupT1 cell-based assay with increasing concentrations of GSK2838232. In the 
lab strain NL4-3 and gag/protease recombinant viruses, the resistance mutation A364V 
arose and resistance confirmed by site-directed mutagenesis. This resistance mutation 
maintains susceptibility to other classes of anti-retrovirals including PIs and non-
nucleoside RT inhibitors.
GSK2838232 was tested in vitro in combination with two marketed PIs, atazanavir and 
darunavir. Using a dose-wise additivity model, GSK2838232A showed additive anti-viral 
activity with both PIs.
Secondary Pharmacology
In a secondary pharmacology study, GSK2838232 was tested against a panel of 
receptors, ion channels and transporters and demonstrated no significant effect (IC50 of 
1 M). It is important to note that the selectivity for antiviral activity of GSK2828232 
compared to all tested off-target activities was >100-fold, and the potential for organ 
toxicity was characterized in the nonclinical toxicology studies (see below).
In safety pharmacology studies in male rats, there were no hemodynamic changes or 
neurobehavioral effects following single oral doses up to 300 mg/kg. A single oral dose 
of GSK2838232 at 30 mg/kg or 300 mg/kg produced reversible increases in respiratory 
tidal volume (32% and 36%, respectively) and derived minute volume (17% and 26%, 
respectively) at 6 hours after dosing. These doses did not produce any effect on 
respiratory rate, airway resistance or body temperature. There were no respiratory effects 
in rats given 5 mg/kg (mean maximum plasma concentration [Cmax] 0.12 g/mL; AUC0-24
1.0 g.h/mL based on Day 1 of the 4-week repeat dose study). These findings were not 
considered to suggest a safety concern in humans.
GSK2838232 at the maximum feasible concentration, limited by solubility, of 4.09 M 
(3.31 g/mL) caused no inhibition of human ether-a-gogo related gene (hERG) tail 
current in Human Embryonic Kidney 293 cells stably transfected with hERG cDNA, 
indicating a low probability for interaction at the hERG channel.
In conscious telemetered male dogs (n=4), a single oral dose of GSK2838232 at 
60 mg/kg (Cmax 0.59 g/mL; AUC0-24 8.7 g.h/mL based on Day 1 exposure data from
the 4-week oral repeat dose toxicity study) was associated with one episode of 
non-sustained ventricular tachycardia in one dog lasting ~1.2 seconds. There were no 
effects on arterial pressures, heart rate, or electrocardiogram (ECG) interval durations. An 
investigative safety pharmacology cardiovascular study was conducted in telemetered 
dogs given 60 mg/kg/day for 4 weeks with serial monitoring by echocardiography, 
cardiac biomarkers, qualitative and quantitative electrocardiology, microscopy, and 
transmission electron microscopy (TEM) of the heart. 
 
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There were no changes in echocardiography endpoints, ECG intervals, ECG waveforms, 
arterial pressures, heart rates, serum cTpnI, N-terminal prohormone of brain natriuretic 
peptide (NTproBNP), or in heart tissue as assessed by TEM. With routine microscopy, 
one treated dog had a single focus of degeneration/necrosis of the tunica media 
(moderate) in an extramural artery and another treated dog had localised, mixed-cell 
inflammation (mild) along the epicardium of the coronary groove. Both changes have 
been reported in normal beagles and were considered of uncertain relationship to 
treatment in the absence of changes in any other structural or functional cardiovascular 
endpoints. The 28-day exposures were similar to the previous 4-week toxicity study in 
dogs: the Cmax range at 60 mg/kg/day in this investigative safety pharmacology study was 
0.542 to 2.00 g/mL and range of AUC0-24 was 6.04 to 35.7 g.h/mL. In subsequent 
repeat-dose studies in dogs treated for up to 9 months with up to 70 mg/kg/day, no 
changes were evident in cardiac biomarkers (including cTpnI and NTproBNP), functional 
(including ECG waveform) or structural (including microscopic evaluation) 
cardiovascular endpoints at slightly higher exposures than those achieved than in 
previous studies. The end of the 9-month study, gender averaged Cmax at 70 mg/kg/day 
was 1.95 g/mL and AUC0-24 was 38.8 g.h/mL. These studies support an absence of 
GSK2838232-related functional or structural effects on the heart in preclinical testing.
The No Observed Adverse Effect Level (NOAEL) was established at 20 mg/kg/day (on 
the basis of mild hepatic findings) with an associated are under the curve at 24 hours 
(AUC24) of 16.2 g.hr/mL and Cmax 0.847 g/mL.
Pharmacokinetics and product metabolism in animals
The PK of GSK2838232 were investigated in the mouse, rat, and dog. The oral 
bioavailability of GSK2838232 was low to moderate (~6% to 40%) depending on the 
species and formulation. Plasma and blood clearance were low and the volume of 
distribution at steady state was high relative to total body water. The half-life of 
GSK2838232 was short in the mouse and rat, but moderate in the dog. Systemic exposure 
of GSK2838232 generally increased in a less than dose-proportional manner.  In rats, 
there were no differences in systemic exposure between single and repeat-dose 
administration, or between males and females.  In a 7-day study in dogs, systemic 
exposures were generally similar between males and females and after single and repeat 
dosing; however, in a 4-week study, systemic exposures were higher in females than in 
males in the high-dose group (60 mg/kg/day) and higher after repeat dosing than after a 
single dose. The distribution of radioactivity in male pigmented rats following a single 
oral administration of [14C] GSK2838232 at a target dose level of 20 mg/kg showed 
radioactivity was rapidly absorbed and widely distributed throughout the body with all 
tissues, except the brain and spinal cord. There were no tissues that retained detectable 
levels of radioactivity at 28 days post dose. In a bile duct canulated rat study, 30% of the 
administered dose was excreted in the bile as an acylglucuronide. In the same study, 
unchanged drug and metabolites were eliminated primarily in the bile and feces, while a 
mean of <1% of the dose was eliminated in urine.
In vitro, GSK2838232 is highly protein bound (>99.9%) and has low passive 
permeability. In vivo evidence suggests active uptake of GSK2838232 by transporters in 
the rat liver. 
 
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After single oral doses of 5, 100, or 300 mg/kg, the average liver to plasma ratio was 51, 
17, and 10, respectively. After 7 days of dosing at 30, 100, or 300 mg/kg/day, liver to 
blood ratios ranged from 10 to 16.
In the 13-week repeat dose studies in dogs given 35 mg/kg BID (70 mg/kg/day), heart 
tissue collected at necropsy had GSK2838232 concentrations 2.5 to 5-times higher than 
the 24-hour post-dose plasma concentrations, similar to the previous 4-week CV 
investigative findings.  In the 13-week repeat dose studies in rats given 300 mg/kg/day, 
heart tissue collected at necropsy had GSK2838232 concentrations approximately 3 times 
higher than the 24-hour post-dose plasma concentrations, similar to the previous 7-day 
findings.  Overall GSK2838232 did not appear to be highly concentrated in heart tissue 
after repeat dosing and suggests that accumulation upon chronic dosing is unlikely.
Routes of metabolism identified in liver microsomal incubations and rat, dog, and human 
hepatocytes were N-dealkylation, oxidation, oxidative deamination, and glucuronidation, 
alone or in combination, with no human-specific metabolites detected.  N-dealkylated 
products and glucuronidation were observed in rat plasma and the bile. In general, in 
vitro metabolite profiles of the nonclinical species and human were qualitatively similar, 
such that all metabolites of [14C] GSK2838232 observed in human hepatocyte 
incubations were observed in rat and/or dog. Minor to trace levels of potential aldehydes 
metabolites formed as a result of N-dealkylation and oxidative deamination were 
observed in rat, dog and humans.  
GSK2838232 did not show evidence for glutathione adduct formation in rat or human 
liver microsomes.  Data from pooled human liver microsomes along with recombinant 
cytochrome P450 (CYP) enzymes suggest that in vitro the oxidative metabolism of 
GSK2838232 was primarily mediated by CYP3A4.  Preliminary in vitro investigations 
showed GSK2838232 did not inhibit CYP1A2, 2C9, 2C19, 2D6, 3A4 and was not a 
metabolism-dependent inhibitor of CYP3A4. No drug interaction risk was identified for 
co-administrated substrates of UGT1A1, 1A3, 1A6, 1A9, 2B7, and 2B15, OAT1, OAT3, 
OATP1B1, OATP1B3 or OCT2 at a clinical dose of 200 mg GSK2838232/ritonavir 
(predicted Cmax 0.32 µM). Extrapolation of the clinical risk (using FDA and EMA 
regulatory guidance) did indicate a risk for GSK2838232-mediated inhibition of 
UGT1A4 and of gut contributions of CYP3A4, P-gp, and BCRP at the same clinical 
exposure; however, the potential for clinically significant interactions via these 
mechanisms is predicted to be low (<2 fold change in AUC). GSK2838232 did show 
weak induction of CYP3A4 enzyme activity. However, based on the maximum predicted 
plasma concentrations and high protein binding, the potential for clinically significant 
drug interactions through CYP3A4 induction by GSK2838232 appears to be low.
The inclusion of cobicistat as a CYP3A4 inhibitor pharmacoenhancer in this Phase IIa 
study in place of ritonavir is unlikely to produce a significantly different profile of 
GSK2838232 ADME (and therefore systemic exposure); however, there have been no 
preclinical studies conducted with GSK2838232 and cobicistat to date.  
Toxicology
GSK2838232 administered by oral gavage in repeat dose studies up to 6 months duration
resulted in no adverse treatment-related effects in rats given up to 300 mg/kg/day QD. 
 
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In dogs given up to 70 mg/kg/day (35 mg/kg/day BID), adverse liver effects were noted 
at this dose in the 9-month repeat dose study.  Though isolated, low grade changes in 
heart rate and cardiac troponin I (cTnI) had been noted in 4-week toxicity studies in rats 
and dogs; however, there were no treatment-related structural or functional 
cardiovascular changes in studies of 3 months and greater duration as assessed by 
echocardiography, ECG, microscopy, and cardiac biomarkers, indicating an absence of 
GSK2838232-related functional or structural effects on the heart in preclinical testing. 
Only non-adverse treatment-related changes were noted in the definitive 6-month rat 
study, which included occasional salivation in animals given 300mg/kg/day and minimal 
clinical pathology changes without histologic correlates (transient clinical chemistry 
changes at 5 mg/kg/day and reversible urine chemistry changes at 300 mg/kg/day). The 
NOAEL in this study was considered to be 300 mg/kg/day (mean AUC[0-t] 
21.3 g.h/mL, mean Cmax 1.77 g/mL [Week 26 values for males and females 
combined]).  
As noted above, dogs given GSK2838232 at 70 mg/kg/day for 9 months had minimal to 
moderate pigmentation (consistent with bile) with minimal to mild mixed cell infiltration 
in the liver and isolated mild increases in alanine aminotransferase (ALT) activity.  These 
findings were considered adverse, but were reversible after the 6-week off-dose period.  
The NOAEL for this dog study was considered to be the mid-dose level of 20 mg/kg/day 
(mean AUC[0-t] 16.2 g.h/mL, mean Cmax 0.847 g/mL [Week 39 values for males and 
females combined]).
Data from genotoxicity assessments suggest that GSK2838232 does not present a 
genotoxic hazard to humans.
During discussions with the FDA regarding the resolution of the clinical hold, the 
Agency recommended that the sporadic cardiovascular changes observed in the early (1-
month) rat GLP study at the highest dose level (300 mg/kg/day) should be considered 
when defining the NOAEL and establishing a safe dose of GlaxoSmithKline (GSK) for 
the initiation of this study protocol.  Accordingly, for the initial PK studies, the reference
dose level of 30 mg/kg/day in the 1-month rat study was initially used to define the 
NOAEL and therefore the values for fold cover at maximum projected mean exposure 
and Cmax in human subjects were lower, at >2.5-fold.  However, based on the 
cumulative clinical safety data through Cohort 5 of Study 204953, the designated 
NOAEL for the most sensitive species (i.e., 20 mg/kg/day in the 9-month dog study 
based on liver endpoints) is currently used for assessing fold-cover for projected clinical 
dosing in this study.
The inclusion of cobicistat as a CYP3A4 inhibitor pharmacoenhancer in this Phase IIa 
study in place of ritonavir is unlikely to produce a significantly different profile of 
GSK2838232 ADME (and therefore systemic exposure and toxicity); however, there 
have been no preclinical studies conducted with GSK2838232 and cobicistat to date.  
Full details of non-clinical and clinical data may be found in the current Investigator’s 
Brochure (IB) [GSK Document Number 2012N151889_03].
 
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2.2.2.
Clinical Summary of Safety and Pharmacokinetics
To date, GSK2838232 has been evaluated in three completed clinical studies with or 
without RTV (GSK2838232/r). A fourth study (204953) is on-going as of 1st November 
2016. Full details of the clinical results can be found in the Investigator’s Brochure.
2.2.2.1.
Clinical Summary of Safety
Fifty-three subjects have been exposed to GSK2838232 in 3 completed studies. One 
study (204953) is ongoing (52 subjects have been exposed to GSK2838232/r or placebo 
so far).  Overall, drug-related adverse events have been few and mild, and included 
headache, dizziness, fatigue, nausea, and palpitations and anxiety.  Similarly, treatment-
emergent laboratory abnormalities have also been few and mostly grade 1.  There have 
been no discernible patterns, thus far, in terms of AEs or laboratory abnormalities.
One subject in study 200912 discontinued treatment with RTV due to an AE.  A 47-year-
old female who developed right upper quadrant abdominal pain, nausea and flatulence 
associated with grade 4 elevations in ALT and aspartate aminotransferase, and grade 2 
elevations in total bilirubin (BIL). She was diagnosed with a common bile duct 
obstruction due to gallstones that spontaneously resolved. The Investigator assessed this 
AE as unrelated to study treatment.
Due to sporadic CV-related safety signals in the early animal studies (see Section 2.2.2), 
intense CV monitoring was in place for all four studies.  
One AE occurred in HMI116787 that was initially considered a CV AE but after further 
evaluation was considered not to be of cardiac etiology.  Two CV AEs occurred in 
200207 that were initially considered possibly related to GSK2838232 exposure.  
However, further evaluation confirmed that there is a low likelihood that these events 
were due to GSK2838232 exposure.  A summary of each event is provided in the IB.
In ongoing Study 204953, there have been a small number of CV-related events of any 
sort: There have been no serious adverse drug reactions, and no clinically significant 
drug-related abnormal findings for 12-lead ECGs, vital signs, safety laboratory results 
(including cardiac troponin I), or telemetry.  The following cardiovascular AEs were 
observed during the course of the study but were not considered to be caused by 
GSK2838232 exposure:

In Part 1A (Cohort 1), Period 2, a subject was withdrawn due to an AE (low 
hemoglobin) prior to GSK2838232 exposure Day -2.  A replacement subject 
was brought in, but was not dosed with GSK2838232 or placebo because during 
the 2-day RTV run-in, on Day -1, the replacement subject met the stopping 
criteria for telemetry due to as brief occurrence of asymptomatic, NSVT prior to 
the first dose of GSK2838232 or placebo.  Because the subject was excluded 
from the study prior to the first dose of investigational drug, the NSVT was not 
considered to be a serious and unexpected adverse drug reaction that would 
qualify for IND safety reporting.  
 
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
In Part 1A (Cohort 1), Period 3 (Period “3A” for the purpose of differentiating 
between 100 mg GSK2838232/r vs. 200 mg GSK2838232/r), one subject was 
discontinued prior to the first dose of study drug due to a series of 
cardiovascular findings (pre-ventricular contractions on telemetry).  None of the 
findings were abnormal or atypical, but the investigator determined that this 
would not be a good etiology to have in a subject about to receive 
investigational drug.  Because the event occurred prior to first dose of 
investigational drug, the finding was not considered to be due to GSK2838232 
exposure.  

In Part 1A (Cohort 1), Period 3 (Period “3A” for the purpose of differentiating 
between 100 mg GSK2838232/r vs. 200 mg GSK2838232/r), one subject who 
had already been dosed on 2 previous occasions (with either GSK2838232 or 
placebo) was dosed for 2 days with RTV, and then on 05 May 2016 was dosed 
with either GSK2838232/r or placebo/r as scheduled. On the following day (06 
May 2016), the subject experienced an asymptomatic, 6-beat run of NSVT, 
which was classified at the time as an SAE. Further monitoring, including 
continuous Holter monitoring revealed no further events. The subject had no 
troponin elevation throughout the study. After additional investigation it was 
determined that the NSVT had occurred after the subject had received placebo 
the previous day. Although the subject had received active on the two prior 
visits, the protocol allowed for sufficient washout between each dose.  
Therefore, because the subject had received placebo prior to experiencing the 
NSVT, the event was not considered to be due to GSK2838232 exposure or a 
serious and unexpected suspected adverse reaction that would qualify for IND 
safety reporting.

In Part 2 (Cohort 6, 200mg/r), a 40 year old male enrolled in the study with no 
significant medical history experienced an asymptomatic ventricular triplet 
(NSVT) while asleep at 5:33am on Day 8 (of 11 days worth of dosing) 
approximately 21 hours after receiving 200 mg GSK2838232/r on the previous 
day at 8.25am. This event was noted by the site staff and the subject was 
assessed and found to have no associated clinical symptoms or complaints. The 
GSK medical monitor was notified.  Because the subject was not symptomatic 
and this did not meet protocol-defined stopping criteria, the study was not 
unblinded at the time, and the subject was allowed to continue dosing. Dosing 
in the study is now complete and no further events have been noted. It was the 
assessment of the site PI and the GSK safety/monitoring team that a ventricular 
triplet can be seen in healthy volunteers on continuous Holter monitoring.
Therefore neither the PI nor GSK considered this event to be a serious and 
unexpected suspected adverse reaction.
2.2.2.2.
Study 204953 (on-going); Pharmacokinetic Data
Study 204953 investigated the safety, tolerability, and PK of escalating doses of 
GSK2838232 as micronized API, with 100 mg RTV, initially as single doses and then as 
repeated doses for 11 days.  
 
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In addition, it evaluated the relative bioavailability of a single fasted dose of micronized 
API powder blend in capsules with RTV compared to powder-in-bottle for oral 
suspension with RTV and the effect of a normal fat meal on the bioavailability of a single 
dose of GSK2838232 in the capsule formulation with RTV.  It will evaluate 
GSK2838232 exposure after repeated doses of unboosted GSK2838232 in the capsule 
formulation. Noncompartmental PK analysis was performed using scheduled sample 
times.  This study is ongoing; preliminary results are presented.
Pharmacokinetic analysis was performed on GSK2838232 plasma concentration-time 
data using nominal time following single doses of 50, 100, and 250 mg in combination 
with RTV in Part 1A of Study 204953 (Table 3).  On average, GSK2838232 Cmax 
values were reached 4-6 hours after dosing.  Terminal half-life values ranged from 15 to 
28 hours across the three dose levels.  Overall, broad dose proportionality was observed 
for Cmax and AUC(0-) values with ascending single doses of GSK2838232 (50, 100, 
and 250 mg with 100 mg RTV).
Table 3
Summary of Preliminary Pharmacokinetic Parameter Values after 
Single Doses of GSK2838232 in Combination with 100 mg Ritonavir 
(Study 204953, Part 1A)
Dose (mg)
n
t½ 
(h)
tlag 
(h)
tmax 
(h)
Cmax 
(ng/mL)
AUC(0-) 
(ng.h/mL)
50
8
22.7
(17%)
(17.2-28.5)
0.188
(138%)
(0-0.5)
3.63
(41%)
(2.5-6.0)
17.2
(43%)
(8.7-27.9)
458.6
(33%)
(210.6-662.0)
100
6
18.0
(14%)
(15.8-22.3)
0.167
(155%)
(0-0.5)
6.00
(59%)
(2.5-12.0)
25.2
(20%)
(17.5-31.5)
890.5
(20%)
(619.1-1053)
250
5
17.3
(6.4%)
(15.5-18.6)
0
(-)
(0-0)
5.50
(71%)
(2.0-12.0)
60.7
(23%)
(40.8-73.1)
1731
(29%)
(1222-2505)
Data are presented as mean (CV) (minimum-maximum).
Study 204953 Part 1B was an open label, 2x2+1 three-period, crossover design, 
evaluating the relative bioavailability of the micronized API GSK2838232 powder blend 
in capsules compared to the PiB reference formulation for the first two periods, with the 
assessment of food effect on the capsule formulation in Period 3.  
The relative bioavailability of the micronized powder blend in 50 mg hand-filled capsules 
compared to the micronized API as PiB for oral suspension was assessed as 100 mg 
GSK2838232 single doses with 100 mg RTV after two pre-doses (48 h) in the fasted state 
in a randomized crossover design in 12 subjects in the first two periods of Part 1B of 
Study 204953. Preliminary geometric mean AUC(0-) and Cmax values were 
approximately 45% and 60% higher, respectively, after administration in the capsule 
formulation compared to oral suspension from PiB (Table 4).
 
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Table 4
Preliminary Assessment of Relative Bioavailability of Capsule 
Formulation vs. Powder-in-Bottle Formulation of GSK2838232 (Study 
204953, Part 1B)
Parameter
Test
Reference
n
Ratio of Geometric 
Least Square Means
90% CIof Ratio
AUC(0-) 
Capsule
PiB
12
1.43
(1.194,1.702)
Cmax 
Capsule
PiB
12
1.58
(1.312,1.900)
PiB = powder-in-bottle.
The potential food effect with the capsule formulation was assessed as 100 mg 
GSK2838232 single doses with 100 mg RTV after two pre-doses (48 h) in the fasted state 
and with a normal fat meal in a non-randomized crossover design (fasted in either Period 
1 or 2, fed in Period 3).  Eleven subjects provided data for both dietary conditions.   
Preliminary geometric mean AUC(0-) and Cmax values were approximately 60%
higher after administration in the capsule formulation with a normal fat meal compared to 
the fasted state (Table 5).
Table 5
Preliminary Assessment of the Effect of a Normal Fat Meal on 
GSK2838232 Exposure when Administered as a Capsule 
Formulation with Ritonavir (Study 204953, Part 1B)
Parameter
n
Capsule – food
Geometric mean
Capsule –
fasted
Geometric 
mean
Ratio of geometric 
means 
(food/fasted)
AUC(0-) (ng.h/mL)
11
2414
1539
1.57
Cmax (ng/mL)
11
76.9
47.2
1.63
Repeat dose PK parameter values in Study 204953 Part 2 were determined on Day 1 and 
Day 11 using nominal time in Part 2 of Study 204953 (Table 6). After the Day 11 dose of 
GSK2838232 with RTV, exposure (Cmax, AUC[0-]) appeared to increase 
proportionally with the increase in dose level with the PiB and capsule formulations. 
 
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Table 6
Summary of Preliminary Pharmacokinetic Parameter Values on 
Day 1 and Day 11 during Repeated Dosing of GSK2838232 in 
Combination with 100 mg Ritonavir (Study 204953, Part 2)
Dose 
(mg)
n
t½ 
(h)
tlag 
(h)
tmax 
(h)
Cmax 
(ng/mL)
AUC(0-) 
(ng.h/mL)
C
(ng/mL)
Study Day 1
20
(PiB)
6
-
0.417
(49%)
(0-0.5)
3.67
(11%)
(3.0-4.0)
12.2
(47%)
(5.8-20.8)
189.4
(40%)
(83.7-284.4)
6.1
(39%)
(2.5-8.9)
50
(PiB)
6
-
0.167
(155%)
(0-0.5)
3.00
(51%)
(2.0-6.0)
18.7
(40%)
(9.0-25.9)
288.7
(39%)
(138.6-380.2)
9.5
(35%)
(5.1-12.6)
100
(capsules)
6
-
0.167
(155%)
(0-0.5)
2.25
(23%)
(1.5-3.0)
48.4
(32%)
(28.1-69.6)
664.1
(31%)
(422.5-932.7)
21.6
(33%)
(12.8-29.3)
200
(capsules)
6
-
0.083
(245%)
(0-0.5)
2.50
(25%)
(2.0-3.5)
79.4
(38%)
(50.8-125)
1124
(39%)
(636.7-1794)
38.9
(36%)
(21.7-58.6)
Study Day 11
20
(PiB)
6
19.2
(16%)
(15.1-
24.2)
-
5.00
(32%)
(2.5-6.0)
27.4
(38%)
(11.3-40.4)
474.3
(31%)
(214.3-613.2)
15.3
(30%)
(7.1-19.2)
50
(PiB)
6
27.3
(52%)
(15.2-
50.4)
-
3.50
(46%)
(1.5-6.0)
58.0
(24%)
(40.9-78.0)
1113
(23%)
(762.6-1459)
38.8
(29%)
(24.5-51.7)
100
(capsules)
6
17.9
(18%)
(15.2-
23.7)
-
4.00
(40%)
(2.5-6.0)
133
(23%)
(94.7-164)
2492
(27%)
(1624-3301)
81.7
(30%)
(45.9-113)
200
(capsules)
6
-1
-
3.33
(45%)
(1.5-6.0)
240
(38%)
(127-368)
4389
(45%)
(2095-7161)
151
(46%)
(67.8-250)
Data are presented as mean (CV) (minimum-maximum).
1.
Concentration data were available up to 24 h after the Day 11 dose, and t½ values were not 
calculated.
2.2.2.3.
Overall Summary/Conclusions of PK data
The original formulation used in the first three studies with GSK2838232 (HMI116787, 
200207, and 200912) was SDD.  Data from Study 200912 demonstrated that a change to 
the API formulation of GSK2838232 was feasible for future clinical studies. Study 
204953 utilized micronized API powder in a bottle as well as in a capsule. The capsule 
was shown to be a viable solid dosage form for subsequent studies.  A more detailed 
summary of the data from Study 204953 is in Section 2.2.2.2.
 
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
GSK2838232 SDD did not overall demonstrate significant escalation in exposure 
from an increase in dose from 100 mg to 200 mg in a cross-study comparison.  The 
API PiB formulation showed a proportional increase in AUC and Cmax for a 2-fold 
dose escalation from 100 mg to 200 mg.

The observed tmax of the API form was significantly increased over the SDD 
formulation (the API formulation also increased tlag relative to SDD).

The bioavailability of the GSK2838232 API formulation was on average 30-50% of 
the bioavailability of SDD formulation, but there was a large observed range of 
relative intra-subject exposures (11-150%).

Both 10 mg SDD and 20 mg API showed a 10-fold or greater increase in AUC with 
steady-state RTV (100 mg QD for 10 days) with a smaller (≤4-fold) increase in 
observed Cmax.  The t½ of GSK2838232 increased from 15-18 hours to 34-42 
hours in the presence of steady-state RTV, regardless of formulation.

After single doses of 50 to 250 mg GSK2838232 with RTV, increases in Cmax and 
AUC(0-) values were broadly proportional to the increase in dose.  On Day 11 
after repeated daily 20 to 200 mg doses of GSK2838232 with RTV, increases in 
Cmax and AUC(0-) values appeared to be proportional to the increase in dose with 
the PiB and capsule formulations.  

The relative bioavailability of the micronized API powder blend in capsules with 
RTV was approximately 45%-60% higher than the bioavailability of the micronized 
API administered as oral suspension from PiB with RTV.

Co-administration of the micronized API powder blend in capsules with RTV and a 
normal fat meal resulted in an approximately 60% increase in geometric mean 
Cmax and AUC(0-) values compared to the fasted state with RTV (Study 
204953).

Variability remains fairly constant across formulations and boosted versus 
unboosted at around 30%-40% (moderate-high).

Projections of potential future efficacious boosted GSK2838232 API regimens 
suggest that doses of 20 to 200 mg GSK2838232 API co-administered with RTV 
will result in mean trough values of at least 3-fold above the derived 90% maximal 
inhibitory concentration (IC90) target value (5 ng/mL). Even if protein binding has 
more impact than envisaged and causes a 5-fold increase in IC90 as seen in some 
preclinical virology studies, the predicted troughs will still be significantly higher 
than the 5-fold shifted IC90 (25 ng/mL) at doses of 50 mg or higher with RTV. 

The average and maximum AUC/Cmax values observed at the maximum dose 
studied to date are below NOAEL values in preclinical chronic toxicology studies 
(6-month rat, 9-month dog).
 
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3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To evaluate antiviral activity of 
GSK2838232/cobi in HIV-1 infected patients 
during 10-days of monotherapy.

Maximum decline from baseline (Day 1) in 
plasma HIV-1 RNA 

To assess safety and tolerability of 
GSK2838232/cobi when administered as 
monotherapy over 10 days.

Safety and tolerability parameters, 
including adverse event, concurrent 
medication, clinical laboratory, 
electrocardiogram (ECG) and vital signs 
assessments.

To characterize pharmacokinetics (PK) of 
GSK2838232 in HIV-1 infected patients 
following GSK2838232/cobi dosing for 10 
days

GSK2838232 PK parameters following 
dose administration, as follows:
Day 1:  area under the plasma 
concentration time curve AUC(0-24), 
maximum observed concentration 
(Cmax), time to maximum observed 
concentration (tmax), concentration at 24 
hours post dose (C24), absorption lag 
time (tlag); 
Following last repeat administration on 
Day 10:  AUC(0-), pre-dose 
concentration (C0), concentration at end 
of dosing interval (C), Cmax, tmax, t½, 
and apparent oral clearance (CL/F), if 
data permit
Secondary

To explore the relationship between 
GSK2838232 exposure and change in 
plasma HIV-1 RNA

GSK2838232 PK parameters Day 10 
AUC(0-), Cmax, Cwith Day 11 HIV-1 
RNA change from baseline

To assess the immunologic effect of 
GSK2838232/cobi when administered over 
10 days in HIV-1 infected adults

Change from baseline in CD4+ cell count 
to Day 11

To explore the relationship between 
GSK2838232 exposure and safety or 
immunologic parameters, if appropriate.

GSK2838232 PK parameters on Day 10: 
AUC(0-), Cmax, Cwith Day 11 change 
from baseline in CD4+ cell count

To assess the development of viral 
resistance (genotypic and phenotypic) over 
10 days and correlate with viral response, if 

Emergence of drug resistance mutations, 
if appropriate
 
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Objectives
Endpoints
appropriate.

To estimate GSK2838232 accumulation and 
to assess attainment of steady state 
following administration of 
GSK2838232/cobi for 10 days in HIV 
infected subjects.

Accumulation:
GSK2838232 PK accumulation ratios (R): 
Day 10 AUC(0-), Cmax, and C
compared to Day 1 AUC(0-24), Cmax, 
and C24, respectively

Steady State:
pre-morning dose concentrations (C0) on 
Day 2 through 11 

To examine dose proportionality of 
GSK2838232 PK parameters following 
GSK2838232/cobi dosing for 10 days in HIV 
infected subjects.

Day 1 AUC(0-24), Cmax, and C24, and 
Day 10 AUC(0-), Cmax and C  at 
different doses levels for the assessment 
of dose proportionality
Note: Other exploratory objectives and endpoints will be specified in the RAP
4.
STUDY DESIGN
4.1.
Overall Design
This is a Phase IIa, multicenter, open-label, adaptive dose ranging, study to evaluate the 
antiviral effect, safety, tolerability, and PK of GSK2838232/cobi monotherapy over 10 
days in ART-naïve HIV-1 infected adults who are not currently receiving ART therapy.
Subjects who have received any ART (including prior MI) therapy will not be eligible for 
this study. To minimize the number of subjects exposed to suboptimal doses, an adaptive 
and dose ranging design is applied in this study.
This study consists of a screening visit, a 10-day treatment period, and follow-up 
evaluations for 2 weeks following last dose.
Screening will be performed as the patients are identified, within 30 days of the first dose 
of study drug.  Eligible HIV-1 infected subjects will receive study treatments for 10 days.
 
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Study Design for 200911
GSK2838232/cobi Once Daily for 10 days1,2
Part A
Part B
Cohort 1
Dose
(mg)
Interim Analysis
Cohort
N
(mg)
N=10
100
2
8
200
3
8
50
4
8
20
1.
Part A Cohort 1 safety/PK/virology data will be evaluated at interim, prior to initiating other cohorts in Part B, which 
are planned to run in a parallel, randomized fashion.  All doses will be given with 150 mg cobicistat.
2.
Part B doses are an illustration of the projected doses per cohort. The actual doses for each cohort are subject to 
modification based upon safety, PK and antiviral activity data from Cohort 1 (Part A). More doses/cohorts 
(including potential removal of cobicistat co-dosing) may be added. (The maximum dose in Cohort B will not  
exceed 200 mg with cobicistat unless overall plasma exposure [as AUC and Cmax] is lower in HIV-infected 
subjects than in healthy subjects at the same dose level).
After successfully completing screening evaluations, the first cohort will enroll 10 
subjects to receive the 100 mg GSK2838232/cobi dose.  Following interim analysis of 
Cohort 1, if warranted, Cohorts 2-4 will each enroll 8 subjects to receive a range of 
GSK2838232/cobi doses.
Day 1 – Day 10: Dosing 
Subjects will report to the clinic for outpatient visits in the morning on Days 1 through 10 
during the treatment period, except for the weekend (Days 6 and 7).  Subjects will arrive 
each day prior to administration of the morning dose for safety and lab assessments, 
including HIV-1 RNA blood draws, as described in the Time and Events Table (Section 
7.1).  Subjects will begin receiving study drug in the morning of Day 1.  
Serial, intensive blood PK samples will be collected on Day 1 (up to 24 hours post-
morning dose) and Day 10 (up to 96 hours post-morning dose), and limited, single blood 
PK samples pre-morning doses on Days 3 through 9, except for the weekend. Subjects 
will be required to fast for 10 hours [overnight] prior to the morning check in on the 
intensive PK sampling days (Days 1 and 10).  All dosing days will require co-
administration of treatment with a light snack/meal per cobicistat labeling guidelines. All 
doses of study medication will be taken with 240 mL of water.  Subjects will be required 
to stay in the clinic on Days 1 and 10 until all specified assessments are completed (12 
hours post-dose). Following Day 10, subjects will be required to attend the clinic for 
follow up assessments including virological and PK blood sampling for up to 3 weeks.
Subjects will be given morning doses on Days 1 through 10 (except for the weekend) in 
the clinic.  Weekend morning doses (Days 6 and 7) will be packaged and sent home for 
self-administration. After Day 11, the subjects will return frequently for assessments 
including blood draws for PK and HIV viral load. A diary card will be used to monitor 
dosing adherence.
 
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Follow-up Visits:
Subjects will return to the clinic on Days 11, 12, 14 (1 day), and 21 (1 day) for PK and 
measurement of HIV-1 RNA levels, viral genotype/phenotype and safety assessments as 
shown in the Time and Events Table (Section 7.1). 
4.2.
Type and Number of Subjects
At least 34 subjects will be enrolled such that approximately 6-10 evaluable subjects 
complete a number of cohorts.  Additional subjects/cohorts may be enrolled to allow for 
evaluation of additional dose levels as appropriate. 
If subjects prematurely discontinue the study, additional replacement subjects may be 
randomised and assigned to the same treatment cohort at the discretion of the Sponsor in 
consultation with the Investigator.
4.3.
Design/Dose Justification
The fastest track to establishing antiviral potential of any novel HIV drug is to study a 
short course of monotherapy in HIV infected subjects. There is precedent for this across a 
number of classes of ART drugs. 
Uncertainties over the impact of protein binding on the activity of GSK2838232 and the 
inherent potency of inhibiting the HIV maturation process as a target remain key 
objectives for the GSK2838232 program. This two-part adaptive design will allow an 
early understanding of the potential of GSK2838232 in combination with cobicistat (and 
by implication, RTV), while not exposing HIV-infected subjects to longer courses of 
what may be suboptimal doses and possible development of resistance. 
Early clinical studies have indicated that in order to achieve reasonable IQ values likely 
to be associated with antiviral efficacy, GSK2838232 will need to be boosted with a 
pharmacoenhancer, such as RTV or cobicistat (in common with many CYP3A4 
substrates). 
There is no a priori intention to study GSK2838232 unboosted, unless: i) following the 
preliminary analysis of Part A Cohort 1, there is such pronounced antiviral activity that it 
would seem the estimates of projected IQ are low, in which case GSK2838232 may be 
evaluated in a subsequent cohort unboosted, or ii) the data from Cohort 7 in ongoing 
Study 204953 (planned, GSK2838232 200 mg BID unboosted) support it.
4.3.1.
GSK2838232 with Ritonavir
In Study HMI116787, a single dose of 10 mg GSK2838232 (SDD) given after 10 days of 
RTV 100 mg daily dosing (to steady state) demonstrated an increase in overall exposure 
(AUC) and Cmax by an average of 10.8- and 2.6-fold, respectively, compared to 10 mg 
GSK2838232 alone. Terminal phase half-life also increased from approximately 20 hours 
to 34 hours. This effect was presumably the result of an inhibition of a CYP3A4-
mediated pathway. Studies 200912 and 200207 also indicated the utility of RTV in 
boosting GSK2838232 concentrations.
 
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These data indicate the viability of studying a number of GSK2838232+RTV regimens in 
this PoC study. Predicted exposures following different GSK2838232 doses with steady-
state RTV are presented in Table 7, based on the results of linear regression analyses of
the preliminary Day 11 data in Study 204953 (dose levels of 20 to 200 mg) and assuming 
no significant differences in PK (ADME) between HIV-infected subjects and healthy 
subjects.
Table 7
Predicted Mean Steady-State GSK2838232 AUC(0-24), Cmax, and IQ, 
Following Repeated Dose Administration + RTV with Fold Cover to
NOAEL
Dose 
(mg)
Projected AUC24 
(ng.h/mL)1
Fold cover to 
NOAEL Dog2
Projected 
Cmax 
(ng/mL)1
Fold cover to 
NOAEL Dog2
IQ3
20+RTV
451
36
24
35
3.1
50+ RTV
1127
14
61
14
7.7
100+ RTV
2253
7.2
122
6.9
15
150+RTV
3380
4.8
183
4.6
23
200+RTV
4506
3.6
244
3.5
31
1.
Predicted mean values based on linear regression analyses of preliminary Day 11 data in Study 204953.
2.
Lowest NOAEL, 20 mg/kg/day obtained from 9-month study in dogs (AUC24 16200 ng.h/mL and Cmax 847 
ng/mL)
3.
Mean IQs derived from predicted C/IC90 (with target of 5 ng/mL).
C= Pre-dose (trough) concentration at the end of the dosing interval, IQ= inhibitory quotient.
The IQ following 20 mg to 200 mg GSK2838232/r QD is predicted to be >3 to >30-fold 
above the minimal target value (5 ng/mL) which was derived from preclinical virological 
assessment as 4 × EC50. No protein binding adjustment has been made because there was 
a minimal (≤5 fold) shift in assays where the effect of protein was assessed. If protein 
binding has more impact than anticipated, it is possible that the target Cmin value is 
approximately 25 ng/mL. In that scenario, projected IQ values at 200 mg/r QD would still 
be >5.
4.3.2.
GSK2838232 with Cobicistat
There have been no preclinical or clinical studies with GSK2838232 and cobicistat to 
date; however, a review of the literature indicates that pharmacoenhancement of drugs 
that are known to have dominant CYP3A metabolic pathways is similar with either RTV 
or cobicistat [Kakuda, 2009; Elion, 2011; Gallant, 2013].  Thus, the use of cobicistat as 
the CYP3A4 inhibitor pharmacoenhancer in this Phase IIa study in place of ritonavir is 
expected to produce a similar profile of GSK2838232 ADME (and therefore systemic 
exposure).  The pharmacokinetic data available after Part A Cohort 1 will confirm this 
assumption.  
4.3.3.
Interim Analysis
An evaluation of GSK2838232 safety, efficacy and PK data will be done after Part A 
Cohort 1, if the exposure level of GSK2838232 is in the range of the maximum 
GSK2838232 exposure seen previously in healthy subjects and the Bayesian probability 
 
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from Cohort 1 is less than 70%, the study will not move forward into Part B, otherwise 
doses will be selected for evaluation in Part B. If pharmacokinetic exposure after the 100
mg GSK2838232/cobi dose is in the range of values observed after 100 mg 
GSK2838232/r in prior studies, the doses for Part B will be extended to both lower 
(20 mg, 50 mg) and higher (200 mg) doses. The highest dose tested in Part B will be 
selected to result in exposures similar to those seen with 200 mg/r in Study 204953.
4.4.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK2838232 can be found in the Investigator’s Brochure.  The following section 
outlines the risk assessment and mitigation strategy for this protocol:  
 
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4.4.1.
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) GSK2838232 
Cardiovascular
Pre-clinical studies have shown the following findings:  elevated heart rates, an 
isolated episode of non-sustained ventricular tachycardia and minimal to mild, 
sporadic troponin I elevations in dogs.  A subsequent investigative cardiovascular 
study in telemetered dogs treated for 4 weeks did not replicate these effects. 
Isolated microscopic cardiovascular changes were noted (focal extramural 
arteritis and localized epicardial inflammation), however these changes were 
considered of uncertain relationship to GSK2838232 because similar findings 
occur at low incidence in normal beagles and there were no GSK2838232-related 
functional changes by telemetry and echocardiography, or changes in cTpnI and 
NTproBNP.  In addition there was no correlation between histologic changes and 
plasma exposure or heart tissue concentrations of GSK2838232. 
3, 6 and 9 month toxicology studies in rat and dog did not demonstrate any 
evidence of cardiovascular injury or impact on cardiovascular function.
In the four GSK2838232 studies conducted so far there was no pattern of 
cardiovascular changes of clinical significance related to GSK2838232 and no 
clinically significant abnormality in electrocardiogram values other than the two 
SAEs documented and discussed.
Review of published bevirimat preclinical and clinical safety data indicates no 
significant toxicities or AEs of interest, other than a 30% incidence of 
gastrointestinal symptoms (including diarrhea). There were no significant 
cardiovascular AEs reported in published clinical studies.
Subjects will be clinically monitored for any signs 
of myocardial injury (chest pain, shortness of 
breath, pain with inspiration), elevated heart rate 
or arrhythmias. Samples for the assessment of 
troponin will be taken. Baseline EKG and Holter 
(to use for screening and for later comparisons if 
needed)
Exposures of GSK2838232 will be closely 
monitored in the clinical study so as to not 
exceed pharmacokinetic stopping criteria.  
 
 
 
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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Cobicistat (Tybost)
General
The cobicistat label includes the following information: 
TYBOST decreases estimated creatinine clearance due to inhibition of tubular 
secretion of creatinine without affecting actual renal glomerular function. This 
effect should be considered when interpreting changes in estimated creatinine 
clearance in patients initiating TYBOST
In one study investigating cobi+( atazanavir and tenofovir DF/emtricitabine) vs 
RTV+( atazanavir and tenofovir DF/emtricitabine), a higher frequency of reports 
of jaundice (6% and 3%) and ocular icterus (4% and 2%) were reported in the 
cobi group compared to the RTV group.  
Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, and 
triglycerides have been observed. The implications of these findings are 
unknown.
The vast majority of available safety data has been obtained in combination 
studies with other ART. There are no warnings of obvious cobicistat-related 
adverse events or safety concerns. 
Subjects will be closely monitored for any signs 
or symptoms potentially associated with 
cobicistat administration, in particularchanges in 
serum creatinine and liver chemistry.
HIV-1 Infection/Patient population
HIV Resistance
Propensity for co-meds and 
possible DDIs
HIV Drug Resistance to unique mechanism
Recognize HIV patients have a higher chance of comorbidities/diseases and a 
risk of taking a medicine or product contraindicated in the study
Closely monitor HIV viral load and genotypic 
resistance
Strict adherence to protocol criteria around 
concurrent meds 
 
 
 
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4.4.2.
Benefit Assessment
This study in HIV-1 infected but otherwise healthy subjects is a 10-day monotherapy
design. It is anticipated that all subjects receiving GSK2838232 will experience anti-HIV 
effects whereby their (blood) HIV viral titres are reduced, until administration stops and 
the viral load returns to baseline levels. There is no expected longer term anti-HIV 
benefit to administration of GSK2838232. Participation in this study contributes to the 
process of developing GSK2838232 and other new therapies for the treatment of HIV
infection.
4.4.3.
Overall Benefit:Risk Conclusion
To date, 53 healthy subjects have received GSK2838232 in three completed studies. One 
study (204953) is ongoing (52 healthy subjects have completed this study so far). 
Subjects have received single doses up to 200 mg SDD alone (studies HMI116787 and 
200912), 250 mg API in combination with RTV (204953), and then in repeated daily 
doses of up to 50 mg SDD alone (200207) for 5 days or 200 mg in combination with 
RTV (204953) for 11 days.
There have been two cardiovascular SAEs reported from clinical studies where the 
subject was receiving GSK2838232 to date (one in 200207, one in 204953). Neither is 
thought likely to be due to GSK2838232.
There have been no other withdrawals due to drug-related AEs and no trends relative to 
laboratory toxicity.  One subject was withdrawn in Part 1A of 204953 because of low 
haemoglobin lab values, thought unrelated to study drug or study procedures.
With respect to CV effects, with the exceptions noted, there have been no clinically 
significant changes in troponin, heart rate, blood pressure, ECG, or telemetry monitoring.
Subjects will also be at risk for AEs from cobicistat use and will be monitored closely for 
such events.
Given the preclinical profile and the clinical profile to date, the overall risk to HIV-1 
infected but otherwise healthy subjects at the proposed GSK2838232 doses (with or 
without cobicistat) for 10 days is predicted to be low. Mean exposures at the highest 
dose studied are not projected to exceed NOAEL values obtained in chronic toxicology 
studies, further reducing potential risk. 
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on the GSK investigational product or other study treatment that 
may impact subject eligibility is provided in the Investigator’s Brochure.
 
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Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
Approximately 10-12 HIV-1 infected subjects will be enrolled into Part A. If warranted 
by an interim safety, virology and PK data analysis, approximately 8 subjects will be 
enrolled in each of Cohorts 2-4 in Part B, which will be a parallel group design. Eligible 
patients are those who are ART-naïve and who are not currently receiving ART therapy.
Additional subjects/cohorts may be enrolled to allow for evaluation of additional dose
levels or configurations (e.g., GSK2838232 alone).
If subjects prematurely discontinue the study, additional subjects may be enrolled as
replacement subjects and assigned to the same treatment at the discretion of the Sponsor.
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
1.
Between 18 and 55 years of age inclusive, at the time of signing the informed 
consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2.
Healthy (other than HIV infection) male or female as determined by the investigator 
or medically qualified designee based on a medical evaluation including medical 
history, physical examination, laboratory tests and cardiac monitoring. Defined as no 
other chronic medical conditions and taking no chronic medications.
3.
A subject with a clinical abnormality or laboratory parameter(s) which is/are not 
specifically listed in the inclusion or exclusion criteria, outside the reference range 
for the population being studied may be included only if the investigator in 
consultation with the Medical Monitor agree and document that the finding is 
unlikely to introduce additional risk factors and will not interfere with the study 
procedures. 
4.
A creatinine clearance >80 mL/min as determined by Cockcroft-Gault equation 
[Cockcroft, 1976] CLcr (mL/min) = (140 – age) * Wt / (72 * Scr) (times 0.85 if 
female) where age is in years, weight (Wt) is in kg, and serum creatinine (Scr) is in 
units of mg/dL.
5.
Confirmed HIV positive; CD4+ cell count ≥350 cells/mm3 and plasma HIV-1 RNA 
≥5000 copies/mL at Screening.
6.
No current and no prior ART.
 
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WEIGHT
7.
Body weight 50 kg (110 lbs.) for men and 45 kg (99 lbs) for women and body 
mass index (BMI) within the range 18.5-31.0 kg/m2 (inclusive)
SEX
8.
Male or Female
A female subject of reproductive or non-reproductive potential is eligible to 
participate if she is not pregnant (as confirmed by a negative serum or urine human 
chorionic gonadotrophin (hCG) test at screening and prior to first dose), not 
lactating, and at least one of the following conditions applies:
Reproductive potential:
Females of reproductive potential may only be enrolled if they are using two forms 
of complementary contraception, which must include one barrier method. They will 
be counselled on safer sex practices
There is no definitive DDI information with GSK2838232 and an interaction with 
oral contraceptives is possible, so other (barrier, inter-uterine device etc.) methods of 
contraception will be required.
Fertile females, who have an established, long-term lifestyle of sexual abstinence, or 
only same sex partners, require no other means of birth control. 
Non-reproductive potential:

Pre-menopausal females with one of the following:

Documented tubal ligation

Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion 

Hysterectomy

Documented Bilateral Oophorectomy

Postmenopausal defined as 12 months of spontaneous amenorrhea in 
questionable cases a blood sample with simultaneous follicle stimulating 
hormone (FSH) and estradiol levels consistent with menopause (refer to 
laboratory reference ranges for confirmatory levels).  Females on hormone 
replacement therapy (HRT) must discontinue HRT to allow confirmation of 
post-menopausal status prior to study enrolment.
Male subjects with female partners of child bearing potential must comply with the 
following contraception requirements from the time of first dose of study medication 
until one week after the last dose of study medication.
a. Vasectomy with documentation of azoospermia.  
b. Male condom plus partner use of one of the contraceptive options below:

Contraceptive subdermal implant that meets the SOP effectiveness criteria 
 
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including a <1% rate of failure per year, as stated in the product label

Intrauterine device or intrauterine system that meets the SOP effectiveness 
criteria including a <1% rate of failure per year, as stated in the product 
label

Oral contraceptive, either combined or progestogen alone or Injectable 
progestogen 

Contraceptive vaginal ring 

Percutaneous contraceptive patches
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label.  The investigator is responsible 
for ensuring that subjects understand how to properly use these methods of 
contraception.
INFORMED CONSENT
9.
Capable of giving signed informed consent as described in Section 10.2, which 
includes compliance with the requirements and restrictions listed in the consent form 
and in this protocol.
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
1.
Alanine aminotransferase (ALT) and BIL >1.5xupper limit of normal (ULN; isolated 
BIL >1.5xULN is acceptable if BIL is fractionated and direct BIL <35%). 
2.
Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones); HBV and/or
HCV positive.
3.
Subjects who have any other chronic medical condition, including CV, respiratory, 
neurologic, psychiatric, renal, gastrointestinal (GI), oncologic, rheumatologic, or 
dermatologic
4.
Medical history of cardiac arrhythmias or cardiac disease or a family or personal 
history of long QT syndrome.
 
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CONCOMITANT MEDICATIONS
5.
Unable to refrain from the use of prescription or non-prescription drugs, including 
vitamins, herbal and dietary supplements (including St John’s Wort) within 7 days 
(or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is 
longer) prior to the first dose of study medication, unless in the opinion of the 
Investigator and GSK Medical Monitor the medication will not interfere with the 
study procedures or compromise subject safety. 
RELEVANT HABITS
6.
History of regular alcohol consumption within 6 months of the study defined as: 

An average weekly intake of >14 drinks for males or >7 drinks for females.  One 
drink is equivalent to 12 g of alcohol: 12 ounces (360 mL) of beer, 5 ounces 
(150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.
7.
Smoking is an exclusion criteria for this study. Urinary cotinine levels indicative of 
smoking at screening.
8.
Chronic marijuana or use of other elicit medications (cocaine, heroin) is an exclusion 
criteria.
CONTRAINDICATIONS 
9.
History of sensitivity to any of the study medications, or components thereof or a 
history of drug or other allergy that, in the opinion of the investigator or Medical 
Monitor, contraindicates their participation.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
10. Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test 
result at screening or within 3 months prior to first dose of study treatment. 
11. Screening or baseline cardiac troponin I greater than the 99% cutoff (>0.045 ng/mL 
by the Dimension Vista CTNI assay).
12. A positive pre-study drug/alcohol screen.  
13. Prior history of receiving an HIV maturation inhibitor
14. Where participation in the study would result in donation of blood or blood products 
in excess of 500 mL within 56 days.
15. The subject has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day in the current 
study: 30 days, 5 half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer).
16. Exposure to more than four new chemical entities within 12 months prior to the first 
dosing day.
 
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17. Treatment with radiation therapy or cytotoxic chemotherapeutic agents within 
30 days of study drug administration or anticipated need for such treatment within 
the study.
18. Treatment with immunomodulating agents (such as systemic corticosteroids, 
interleukins, interferons) or any agent with known anti-HIV activity (such as 
hydroxyurea or foscarnet) within 30 days of study drug administration.
19. An active Center for Disease Control and Prevention (CDC) Category C disease 
except cutaneous Kaposi’s sarcoma not requiring systemic therapy during the trial.
20. Treatment with any vaccine within 30 days prior to receiving study medication.
21. Exclusion Criteria for 24-Hour Screening Holter:

Any symptomatic arrhythmia (except isolated extra systoles).

Sustained cardiac arrhythmias (such as atrial fibrillation,flutter or
supraventricular tachycardia (10 seconds)

Non-sustained or sustained ventricular tachycardia (defined as 3 consecutive 
ventricular ectopic beats).

Any conduction abnormality including but not specific to left or complete 
bundle branch block, atrioventricular [AV] block, high grade or complete heart 
block Wolff-Parkinson-White [WPW] syndrome etc.).

Sinus Pauses >3 seconds.
22. Exclusion criteria for screening ECG (a single repeat is allowed for eligibility 
determination):
Males
Females
Heart rate
<45 and >100 bpm
<50 and >100 bpm
PR Interval
<120 and >220 msec
QRS duration
<70 and >120 msec
*QTc interval
>450 msec
*The QTc is the QT interval corrected for heart rate according to Bazett’s formula 
(QTcB), Fridericia’s formula (QTcF), and/or another method. It is either machine-
read or manually over-read. The specific formula used to determine eligibility and 
discontinuation for an individual participant in 204953 will be Fridericia’s formula. 

Note: A heart rate from 100 to 110 beats per minute (bpm) can be rechecked by 
ECG or vitals within 30 minutes to verify eligibility.

Evidence of previous myocardial infarction (Does not include ST segment 
changes associated with repolarization).

Any conduction abnormality (including but not specific to left or right complete 
bundle branch block, AV block [2nd degree or higher], WPW syndrome).

Sinus Pauses >3 seconds.
 
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
Any significant arrhythmia which, in the opinion of the principal investigator 
OR GSK medical monitor, will interfere with the safety for the individual 
subject. 

Non-sustained or sustained ventricular tachycardia (3 consecutive ventricular 
ectopic beats).
5.3.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and any SAEs.
5.4.
Withdrawal/Stopping Criteria
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as 
soon as possible. 

The site must counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or should 
continue in the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and if necessary a certified letter to the subject’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be considered 
to have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this request has 
occurred in the site study records. 
5.4.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 
 
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http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Phase II Liver Chemistry Stopping and Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus
Bilirubin≥2x
ULN (>35% 
direct) 
or plus
INR>1.5, if 
measured*
Possible
Hy’s Law
ALT≥3xULN
ALT≥5xULN
ALT≥3xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
ALT≥3xULN
but able to 
monitor 
weekly for 
4 weeks
No
Yes
Yes
Yes
Yes
No
No
No
No
Yes
ALT≥3xULN
persist for
4 weeks or 
stopping 
criteria 
met
Yes
No
*INR value not applicable to subjects on anticoagulants
Yes
If subject to be monitored weekly must refer to Liver Safety Required  Actions and  Follow  up 
Assessments  section  in  the  Appendix
Must refer to Liver Safety Required Actions and Follow  up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 2, Section 12.2 and Section 12.3.
5.4.1.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed.
5.4.2.
QTc Stopping Criteria

The same QT correction formula must be used for each individual subject to 
determine eligibility for and discontinuation from the study.  This formula may 
not be changed or substituted once the subject has been enrolled.

For example, if a subject is eligible for the protocol based on QTcB, then QTcB 
must be used for discontinuation of this individual subject as well.

Once the QT correction formula has been chosen for a subject’s eligibility, the 
same formula must continue to be used for that subject for all QTc data being 
collected for data analysis.  Safety ECGs and other non-protocol specified 
ECGs are an exception.  
 
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
The QTc should be based on single or averaged QTc values of triplicate ECGs 
obtained over a brief (e.g., 5-10 minutes) recording period.  
A subject who meets either of the bulleted criteria below will be withdrawn from the 
study:

QTc >500 msec OR Uncorrected QT >600 msec

Change from baseline of QTc >60 msec
5.5.
Stopping criteria based on Adverse Events
Any grade 3 or higher treatment-related adverse events that occur in ≥2 subjects will be 
carefully reviewed and if considered clinically significant, dosing will be halted pending 
further discussion with the FDA.  Any single treatment-related SAE will also trigger 
immediate evaluation and reporting processes in accordance with applicable regulations.
5.6.
Subject and Study Completion
A completed subject is one who has completed all phases of the study including the 
follow-up visit.
The end of the study is defined as the last subject’s last visit.
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.
Treatment
Product name:
GSK2838232 
Capsule (API)
Tybost 
(cobicistat, cobi) tablet
Formulation 
description:
GSK2838232 powder blend in a 
capsule
Tablet
Dosage form:
Swedish orange, unmarked 
capsules (50 mg), and white, 
unmarked capsules (10 mg)
Orange, round, biconvex, film-coated 
tablets debossed with “GSI” on one side 
and plain faced on the other side 
providing 150 mg of cobicistat.
Unit dose strength(s)/
Dosage level(s):
50 mg capsule for 200 mg, 100 mg, 
50 mg doses and 10 mg capsule for 
20 mg doses
150 mg for 150 mg doses
 
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Treatment
Product name:
GSK2838232 
Capsule (API)
Tybost 
(cobicistat, cobi) tablet
Route/
Administration/
Duration:
Administered orally QD for 10 days
Administer orally, QD for 10 days
Dosing instructions:
Administer with light meal and 240 
mL of water. 
Administer with light meal and 240 mL 
water.
Manufacturer/
source of 
procurement:
GSK
Gilead
Method for 
individualizing dosage:
Capsules supplied in high-density 
polyethylene bottles for 
individualized dosing by the clinic
Capsules supplied in bulk containers for 
individualized dosing by the clinic
6.2.
Treatment Assignment
Subjects will be assigned to treatment (active) in accordance with the randomization 
schedule generated by Clinical Statistics, prior to the start of the study, using validated 
internal software.
6.3.
Planned Dose Adjustments
Following the interim analysis of safety, virology and PK data from the first cohort of 
subjects in Part A, the option to adjust dose levels from those described exists. No dose 
will be administered that has an associated projected mean AUC or Cmax value higher 
than the most conservative NOAEL obtained from the chronic toxicity studies (i.e., from 
the 9-month dog toxicity study described in Section 2.2.1).
6.4.
Blinding
This will be an open-label study. Treatment allocation in Part B will be randomised (to 
GSK2838232 dose level). 
6.5.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.6.
Preparation/Handling/Storage/Accountability
A description of the methods and materials required for capsule/tablet storage and 
dispensing will be detailed in a Study Specific Technical Agreement/Memo or Pharmacy 
Manual, which will be accompanied by a Quality Agreement.
No special preparation of study treatment is required.
 
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
Only subjects enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment.  All study 
treatments must be stored in a secure environmentally controlled and monitored 
(manual or automated) area in accordance with the labelled storage conditions 
with access limited to the investigator and authorized site staff. 

The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation and final disposition records).

Further guidance and information for final disposition of unused study treatment 
are provided in the study reference manual (SRM).

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  

A Material Safety Data Sheet/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.
6.7.
Compliance with Study Treatment Administration
When subjects are dosed at the site, they will receive study treatment directly from the 
investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents.  The dose of study 
treatment and study subject identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study treatment.  
When subjects self-administer study treatment(s) at home, compliance with study 
treatment(s) will be assessed through querying the subject during the site visits and 
documented in the source documents and case report form (CRF).  A record of the 
number of study treatment(s) dispensed to and taken by each subject must be maintained 
and reconciled with study treatment and compliance records.  Treatment start and stop 
dates, including dates for treatment delays and/or dose reductions will also be recorded in 
the CRF.
6.8.
Treatment of Study Treatment Overdose
For this study, any dose of GSK2838232 >200 mg+cobicistat within a 28-hour time 
period will be considered an overdose.
GSK does not recommend specific treatment for an overdose; however, in the event of an 
overdose, the investigator or treating physician should:

Contact the Medical Monitor immediately

Closely monitor the subject for AEs/SAEs and laboratory abnormalities until 
GSK2838232 can no longer be detected systemically (at least 10 days for 
GSK2838232)
 
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
Obtain a plasma sample for PK analysis within 2 days from the date of the last dose 
of study treatment if requested by the Medical Monitor (determined on a case-by-case 
basis)

Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the subject.
6.9.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
post-study treatment.
6.10.
Lifestyle and/or Dietary Restrictions
6.11.
Contraception
Female subjects can be of childbearing or non-child bearing potential.  
Females of reproductive potential may only be enrolled if they are using two forms of 
complementary contraception, which must include one barrier method.  There is no 
definitive DDI information with GSK2838232 and an interaction with oral contraceptives 
is possible, so other (barrier, inter-uterine device etc.) methods of contraception will be 
required.
Females of reproductive potential, who have an established, long-term lifestyle of sexual 
abstinence, or only same sex partners, require no other means of birth control.  
Male subjects with female partners of child bearing potential must comply with the 
following contraception requirements from the time of first dose of study medication 
until one week after the last dose of study medication:
1. Vasectomy with documentation of azoospermia. The documentation on male 
sterility can come from the site personnel’s review of subject’s medical records, 
medical examination and/or semen analysis, or medical history interview.
OR
2. Male condom plus partner use of one of the contraceptive options below that 
meets the SOP effectiveness criteria including a <1% rate of failure per year, as 
stated in the product label:
- Contraceptive subdermal implant
- Intrauterine device or intrauterine system
- Combined estrogen and progestogen oral contraceptive 
- Injectable progestogen
-Contraceptive vaginal ring 
 
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- Percutaneous contraceptive patches 
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
6.12.
Meals and Dietary Restrictions

Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit juice 
from 7 days prior to the first dose of study medication until after the final dose.

Doses will be given in the fed state (light breakfast), following overnight fasting 
(>10 hours). Lunch will provided 4 hours after the dose; water will be allowed ad 
libitum throughout.
6.13.
Caffeine, Tobacco and Exercise

Subjects should refrain from alcohol for 48 hours before screening and then for 48 
hours prior to admission and baseline assessments (on Day 1). Alcohol is then not 
permitted for the duration of the treatment period (through Day 10) and until the 
final follow-up visit.  

Use of tobacco products is not allowed from screening until after the final follow-up 
visit

Subjects will abstain from strenuous exercise for 72 hours prior to each blood 
collection for clinical laboratory tests.  Subjects may participate in light recreational 
activities during studies (e.g., watch television, read).
6.14.
Concomitant Medications and Non-Drug Therapies

Subjects must refrain from all illicit drugs throughout the study (from Screening until 
discharge from the study).  Drug screening will occur at Screening and Day -1 for 
each treatment period.  A positive result will lead to exclusion from the remainder of 
the study.

The Principal Investigator must be informed as soon as possible about any 
medications taken from the time of screening until the subject is discharged from the 
study.  Over-the-counter medications will not be permitted during the treatment 
period except as needed to treat an AE. If medication is needed, use should be 
restricted to 4 hours after dosing if possible.  
6.14.1.
Permitted Medications and Non-Drug Therapies

Acetaminophen at doses of 2 grams/day or NSAIDs are permitted for use any time 
during the study and their use documented in the CRF.  Other concomitant 
medication may be considered on a case by case basis by the investigator in 
consultation with the Medical Monitor if required.
6.14.2.
Prohibited Medications and Non-Drug Therapies

Subjects must abstain from taking prescription or non-prescription drugs (including 
vitamins and dietary or herbal supplements), within 7 days (or 14 days if the drug is 
 
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a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first 
dose of study medication until completion of the follow-up visit, unless in the 
opinion of the Investigator and sponsor the medication will not interfere with the 
study. 
7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table (Section 7.1), are essential and required for study 
conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table Section 7.1. In 
overview, subjects will be screened, begin dosing and then continue assessments through 
and for up to 2 weeks after the completion of dosing.
The following points must be noted: 

If assessments are scheduled for the same nominal time, THEN the assessments 
should occur in the following order:
1. 12-lead ECG
2. vital signs
3. blood draws.  
Note: The timing of the assessments should allow the blood draw to occur at the 
exact nominal time.
 
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7.1.
Time and Events Table
Day:
Screen1
Random
1
2
3
4
5
62
7
8
9
10
11
12
141
211 
(FU)
ET
Informed Consent
X
Review inclusion/exclusion
X
X
Demography including height, weight 
and BMI
X
Brief physical
X
Medical/medication/
drug/alcohol history
X
X
CDC Classification
X
X
X
X
Prior antiretroviral therapy
X
12-lead ECG3
X
X
X
X
X
X
X
X
X
Holter (24 hr)
X
Vital signs4
X
X
X
X
X
X
X
X
X
Drug screen
X
X
X
X
X
Hepatitis B Surface antigen and 
hepatitis C antibody testing
X
Serum or urine -hCG (WoCBP only)
X
X
X
Clinical lab tests (inc troponin)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Fasting lipid panel
X
X
AE assessment5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Con Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HIV-1 RNA PCR6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lymphocyte subsets7
X
X
X
Plasma for genotype/phenotype8
X
X
X
X
X
X
X
HIV-associated conditions assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK blood sample9
X
X
X
X
X
X
X
X
X
X
X
X
Plasma samples10
X
X
X
Dosing11
X
X
X
X
X
X
X
X
X
X
PGx12
X
 
 
 
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Day:
Screen1
Random
1
2
3
4
5
62
7
8
9
10
11
12
141
211 
(FU)
ET
AE enquiry13
X
X
X
X
X
X
X
X
X
X
X
X
X
Telephone call to IVRS14
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Outpatient visit
X
X
X
X
X
X
X
X
X
X
X
X
1.
Screening will occur within 30 days prior to the first dose of study drug.
2.
Table is set up for the weekend during dosing to occur on Days 6 and 7.  If the weekend occurs on Days 5 and 6, perform all “Day 5” assessments on Day 7.
3.
On Day 1, ECGs (x2) will be performed pre-dose , and then 1, 1.5, 2, 3, 4 and 6 hours post dose.  The pre-dose ECGs should be performed at least 5 minutes apart and 
preferably within 1 hour prior to dose.  On Days 4, 5 and 8, ECGs will be obtained prior to morning dosing and at 2, 4 and 6 hours post-dose. On Day 10, ECGs (x2) will be 
performed pre-dose, and then 1, 1.5, 2, 3, 4 and 6 hours post dose.  On Day 11, an ECG will be obtained prior to the 24-hour PK sample.
4.
BP, RR, HR and temperature will be obtained at Screening (x1) and Day 1 pre-dose (x2).  BP and HR will be obtained on Day 1 at 2 hours post-morning dose and on Days 4, 5 
and 8 pre-dose.  BP and HR will be obtained on Day 10 at pre-dose and 2 hours post-morning dose, and at Follow-up.
5.
Only SAEs related to study participation will be collected between screening and Day 1.
6.
On Days 1-5 and 8-10 samples for HIV-1 RNA PCR collected before morning dose.  On Days 1, 10 and 11 two samples for HIV-1 RNA PCR will be collected 5-30 minutes 
apart.  
7.
Lymphocyte subsets by flow cytometry (total lymphocyte counts, percentage, and absolute CD4+and CD8+counts).
8.
Blood samples for phenotype and genotype will be collected at pre-dose on Days 1, 4, 5 and 8 in the morning on Day 11 and at follow-up. 
9.
Serial plasma samples (2 mL) for determination of GSK2838232 will be collected on Day 1 and Day 10 at pre dose (within 15 minutes prior to dose) and 0.5, 1, 1.5, 2, 3, 4, 6, 
8, 12, and 24 hours post-am dose.  Pre-dose PK samples (within 15 minutes prior to dose) will be taken on the mornings of Days 3, 4, 5, 8 and 9 and a single sample will be 
taken on Days 12 and 14.
10. Samples (2 x 0.5mL) of plasma for assessment of immunological markers at screen, baseline (pre-dose) and day 11 
11. Subjects will receive a single dose of GSK2838232 and cobicistat each morning with a light breakfast meal and 240 mL of water from Day 1 to Day 10.  Doses taken in the 
clinic will be administered after an overnight fast of at least 10 hours .On Days 6 and 7, doses will be self administered but confirmed by phone 
12. PGx sample should be collected on Day 1.
13. An AE enquiry will be made at each visit, subjects will be asked if they have experienced any neuropsychiatric adverse events, including psychosis or altered mental status  
14. A screening/registration call should be made to the IVRS to register the subject at screening.   An additional call will be made to document a screen failure.   A randomization 
call should be made to the IVRS system approximately one week prior to scheduled Day 1.  Note: The randomization call must be made in order to have study drug on site for 
Day 1. Additional calls will be made every day that the subject has a scheduled study visit to the clinic.  If a subject terminates the study prematurely a call should be made to 
the IVRS
15. Only if early termination visits occur during the treatment period.
AE = Adverse event; CDC= Center for Disease Control and Prevention; ECG = Electrocardiogram; ET = Early termination; hCG = Human chorionic gonadotrophin; HIV = Human 
immunodeficiency virus;  IVRS= Interactive Voice Response System; PCR = Polymerase chain reaction; PK=Pharmacokinetic.
 
 
 
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7.2.
Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed at 
screening.
The following demographic parameters will be captured: year of birth, sex, race, and 
ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria.
Procedures conducted as part of the subject’s routine clinical management (e.g., blood
count) and obtained prior to signing of informed consent may be utilized for Screening or 
baseline purposes provided the procedure meets the protocol-defined criteria and has 
been performed in the timeframe of the study.
7.2.1.
Holter Monitoring (Screening criteria)
The 24-hour Holter monitoring should only be performed at Screening after the subject 
has met all other inclusion criteria.
Analysis of the Holter tapes will consider the following:

Heart rate (brady and tachycardia)

Normal and aberrant beats

Number of supraventricular contractions, premature atrial contractions, premature 
ventricular contractions, couplets, triplets, and ventricular tachycardias

Atrio-ventricular conduction defects

Atrial fibrillation and flutter.
7.3.
Efficacy
7.3.1.
HIV-1 RNA Sampling
Plasma for quantitative HIV-1 RNA will be collected at timepoints listed in the Time and
Events Table in Section 7.1. To reduce sample variability, two plasma HIV-1 RNA
samples will be collected on Days 1, 10, and 11.
An HIV-1 RNA PCR assay with a lower limit of detection (LLOD) of 50 copies/mL
(ultrasensitive assay) will be used for post-baseline assessments. An HIV-1 RNA PCR
assay with a LLOD of 400 copies/mL (standard assay) will be used for screening and
baseline assessments and will include a re-test with and ultrasensitive assay for all
baseline values below the LLOD. An HIV-1 RNA PCR assay with a LLOD of 2 
copies/mL (supersensitive assay) may be used for exploratory analysis.
 
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7.3.2. 
Lymphocyte Subsets by Flow Cytometry 
Whole venous blood samples will be obtained from each subject for the analysis of 
lymphocyte subsets by flow cytometry at the timepoints listed in the Time and Events 
Table in Section 7.1. 
Details concerning the handling, labeling and shipping of these samples will be supplied 
separately. 
7.4. 
Safety 
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).  Additional time points for safety tests (such as vital signs, physical exams 
and laboratory safety tests) may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring. 
7.4.1. 
Adverse Events (AE) and Serious Adverse Events (SAEs) 
The definitions of an AE or SAE can be found in Appendix 5, Section 12.5. 
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE.  
7.4.1.1. 
Time period and Frequency for collecting AE and SAE information 
• 
AEs and SAEs will be collected from the start of Study Treatment until the 
follow-up contact (see Section 7.4.1.3), at the timepoints specified in the Time 
and Events Table (Section 7.1). An AE enquiry will be made at each visit, where 
subjects will be specifically asked if they have experienced any neuropsychiatric 
adverse events, including psychosis or altered mental status   
• 
Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF. 
• 
Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded from the time a subject consents to participate in the 
study up to and including any follow-up contact.  
• 
All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 5, Section 12.5. 
• 
Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the 
investigator must promptly notify GSK. 
 
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NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 5
7.4.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?”

“Have you experienced any alteration in personality, behaviour, mood or any 
altered mental status?”
7.4.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, and non-serious AEs of special interest 
(as defined in Section 12.5) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.4). Further information on follow-up procedures is given in 
Appendix 5.
7.4.1.4.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 5 (Section 12.5.3) and all deaths, 
whether or not they are considered SAEs, specific CV and Death sections of the CRF will 
be required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed 
within one week of when the death is reported.
7.4.1.5.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
The following disease-related events (DREs) are common in subjects with HIV-1 
infection and can be serious/life threatening:
 
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
events or outcomes listed in the CDC Classification System for HIV-1 Infections 
(see Appendix 9; Section 12.8)

sign, symptom, diagnosis, illness, and/or clinical laboratory abnormality that can 
be linked to any of these events or outcomes
Because these events are typically associated with the disease under study, they will not 
be reported according to the standard process for expedited reporting of SAEs to GSK 
(even though the event may meet the definition of a serious adverse event). 
These events will be recorded on the DRE page in the subject’s CRF using the HIV 
Associated Conditions eCRF. These DREs will be monitored by the medical monitor and 
study team on routine basis.
However, if any of the following conditions apply, then the event should be reported as 
an SAE using the standard process:

The event is, in the Investigator’s opinion, of greater intensity, frequency, or 
duration than expected for the individual subject, 
or

The Investigator considers that there is a reasonable possibility that the event was 
related to treatment with the investigational product.
or

Death occurring for any reason during a study, including death due to a disease 
related event, will always be reported promptly. 
If either of the above conditions is met then record the DRE on the SAE page rather than 
the HIV Associated Conditions eCRF page and report promptly to GSK.
7.4.1.6.
Regulatory Reporting Requirements for SAE
Prompt notification by the investigator to GSK or designee of SAEs and non-serious AEs 
related to study treatment (even for non- interventional post-marketing studies) is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a product under clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
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An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.4.2.
Pregnancy

Details of all pregnancies in female subjects and if indicated female partners of 
male subjects will be collected after the start of dosing and until one week post 
study

If a pregnancy is reported then the investigator should inform GSK within 24hrs
of learning of the pregnancy and should follow the procedures outlined in 
Appendix 7, Section 12.6.
7.4.3.
Physical Exams

A complete physical examination will include, at a minimum, assessment of the 
Cardiovascular, Respiratory, GI 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 should pay special attention to clinical signs related to previous 
serious illnesses
7.4.4.
Vital Signs

Vital signs will be measured in semi-supine position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure and pulse rate

Three readings of blood pressure and pulse rate will be taken

First reading should be rejected

Second and third readings should be averaged to give the measurement to be 
recorded in the CRF. 
7.4.5.
Electrocardiogram (EGC)

Triplicate 12-lead ECGs will be obtained at each timepoint during the study using 
an ECG machine that automatically calculates the heart rate and measures PR,
QRS, QT, and QTc intervals.  Refer to Section 5.4.2 for QTc withdrawal criteria 
and additional QTc readings that may be necessary.
7.4.6.
Clinical Safety Laboratory Assessments
All protocol-required laboratory assessments as defined in the Tables below must be 
conducted in accordance with the SRM and Protocol Time and Events Schedule (Section 
7.1). Laboratory requisition forms must be completed and samples must be clearly 
labelled with the subject number, protocol number, site/centre number, and visit date.
Details for the preparation and shipment of samples will be provided by the laboratory 
and are detailed in the SRM. Reference ranges for all safety parameters will be provided 
to the site by the laboratory responsible for the assessments.
 
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If additional non-protocol-specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the CRF.
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
All study-required laboratory assessments will be performed by a central laboratory:
NOTE: Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either a treatment and/or response evaluation to be 
performed. 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 treatment or response evaluation, the results must be entered in the CRF.
Haematology, clinical chemistry, urinalysis, and additional parameters to be tested are 
listed below.
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
WBC count with Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes with T-cell 
subsets
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry 1
BUN
Potassium
AST (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose 
Bicarbonates
Alkaline phosphatise
Albumin
Troponin I
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

HIV

Hepatitis B (HBsAg)

Hepatitis C (Hep C antibody)

FSH and estradiol (as needed in women of non-child bearing 
potential only)

Alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines)

Urine hCG Pregnancy test (as needed for women of child bearing 
potential) 2
 
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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 12.2 and 
Section 12.3
2.
Local urine testing will be standard for the protocol unless serum testing is required 
by local regulation or ethics committee.
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study or within 7 days after the last dose of study treatment 
should be repeated until the values return to normal or baseline.  If such values do not 
return to normal within a period judged reasonable by the investigator, the etiology
should be identified and the sponsor notified.
7.5.
Pharmacokinetics
7.5.1.
Blood Sample Collection
Blood samples for analysis of GSK2838232 concentrations will be collected at the time 
points indicated in Time and Events Tables (Section 7.1).  
The actual date and time of each blood sample collection will be recorded.  The timing of 
PK samples may be altered and/or PK samples may be obtained at additional time points 
to ensure thorough PK monitoring.  
Details of PK blood sample collection (including volume to be collected), processing, 
storage and shipping procedures are provided in the Study Reference Manual (SRM).
7.5.2.
Sample Analysis
Plasma analysis will be performed by Covance, Madison under the control of 
Bioanalysis, Immunogenicity and Biomarkers (BIB), PTS, GlaxoSmithKline.
Concentrations of GSK2838232 will be determined in plasma using the currently 
approved bioanalytical methodology. 
Once the plasma has been analyzed for GSK2838232 any remaining plasma may be 
analyzed qualitatively for other circulating metabolites and these results would be 
reported under a separate PTS protocol.
Raw data will be archived at the Covance, Madison facility.
7.6.
Biomarker(s)/Pharmacodynamic Markers
7.6.1.
Viral Genotyping and Phenotyping
Whole venous blood samples will be obtained from each subject to provide plasma for
viral genotype and phenotype analysis, at the times listed in the Time and Events Table in
 
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Section 7.1. Details concerning the handling, labeling and shipping of these samples will
be supplied separately.
Genotypic and phenotypic analyses will be carried out by Monogram Biosciences using
their GAG/PR and PR/RT formats, in which PCR amplification is used to generate HIV 
cDNA products including the Gag and the PR and RT coding regions, respectively. 
Phenotypic analyses of the GAG/PR region will include susceptibility to GSK2838232 . 
Analysis will be done on Day 1 and Day 11 samples.  In the case of rebound HIV-1 viral 
load, analysis will be completed on samples corresponding to time point of rebound 
occurrence. 
7.7.
Genetics
Information regarding genetic research is included in Appendix 4, Section 12.4.
7.8.
Value Evidence and Outcomes
Not required.
8.
DATA MANAGEMENT

For this study subject data will be entered into GSK defined CRFs, transmitted 
electronically to GSK or designee and combined with data provided from other 
sources in a validated data system, 

Management of clinical data will be performed in accordance with applicable 
GSK standards and data cleaning procedures to ensure the integrity of the data 
(e.g., removing errors and inconsistencies in the data).

Adverse events and concomitant medications terms will be coded using MedDRA 
and an internal validated medication dictionary, GSKDrug.  

CRFs (including queries and audit trails) will be retained by GSK, and copies will 
be sent to the investigator to maintain as the investigator copy.  Subject initials 
will not be collected or transmitted to GSK according to GSK policy.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
The primary objectives of this study are to investigate the safety, tolerability, and 
antiviral activity of GSK2838232 administered as monotherapy in combination with 
cobicistat in HIV-1 infected subjects, over a 10 day treatment period. The antiviral 
activity will be assessed by estimating plasma HIV-1 RNA max change from baseline 
during the study. 
 
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9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
The sample size for this study is based primarily on feasibility to provide adequate 
precision for the estimations.
Based on data from the short term monotherapy study of BMS-955176 PoC (AI468002) 
study and assuming viral load values for individual subjects follow a log-normal 
distribution, 1000 trial simulations in Fixed and Adaptive Clinical Trial Simulation 
(FACTS) software were conducted from the distribution with mean of change from 
baseline viral load drop on log scale at 1.0 to 1.5 copies and SD=0.4 and sample sizes=10 
for Part A.  Using Bayesian calculation with non-informative priors for the mean and 
weakly informative priors for the error parameters, Normal (0, 100) for mean and Inverse 
Gamma (0.35, 0.0875) for error parameters, the posterior probability to achieve a 
cutpoint 1.2 log was calculated for each simulated trial, and percentage of the trials with 
posterior probability of viral load<-1.2log drop given true mean) ≥70% were calculated 
and are shown below in Table 8.
Table 8
Percentage of the trials with posterior probability>=70% for Part A
True Mean
Cutpoint
Posterior Prob>=70%
1.0
1.2
1.4%
1.1
1.2
9%
1.2
1.2
29%
1.3
1.2
59%
1.4
1.2
83%
1.5
1.2
96%
An Emax model with functional uniform priors [Bornkamp, 2014] was conducted using 
simulated data combining Part A and Part B with all doses. Success is defined as a
posterior probability of the highest dose to achieve a cutpoint 1.2 log reduction in viral 
load.   This was calculated for each simulated trial and the percentage of the trials with 
posterior probability greater or equal to 70% were also calculated and are shown below 
(Table 9). The table lists different viral load drop scenarios. The last scenario assumes the 
flat drop for all doses are 0.5.  This scenario reflects the null hypothesis of no treatment 
effect.   In this scenario 0% of the trials achieve the pre-specified decision rule for 
success.  
 
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Table 9
Percentage of the trials with posterior probability ≥70%
Cutpoint
Posterior Prob≥
Part A+ Part B 
mean VL drop for doses 
200, 100, 50, 20
Part A+ Part B
1.2
70%
1.5, 1.4, 1.2, 0
99%
1.5, 1.4, 1.2, 0.5
96%
1.5, 1.4, 1.0, 0.5
93%
1.5, 1.3, 1.2, 0.5
86%
0.5, 0.5, 0.5, 0.5
0%
9.2.2.
Sample Size Sensitivity
Similar simulations in FACTS were conducted from the distribution with mean of change 
from baseline viral load drop on log scale at 1.5 copies and SD=0.4 or 0.6 and sample 
sizes of 6-8 or 10 for Part A.  Using Bayesian calculation, the posterior probability to 
achieve a cutpoint 1.2 log (in Table 10) was calculated for each simulated trial, and 
percentage of the trials with posterior probability greater than or equal to 70% was 
calculated and are shown below.
Table 10
Percentage of the trials with posterior probability ≥70% for Part A
True 
Mean
Cutpoint
Posterior
Prob≥
Std for log10 
VL
N=6 
N=8
N=10
1.5
1.2
70%
0.4
90%
94%
96%
0.6
75%
81%
84%
9.2.3.
Sample Size Re-estimation or Adjustment
No sample size re-estimation will be performed.
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
Intent to Treat Exposed Population (ITT)
The ITT-Exposed Population is defined as all subjects who meet study criteria and are 
enrolled into the study with documented evidence of having received at least 1 dose of 
treatment and at least one post-baseline HIV-1 RNA measurement. This will be the 
primary population for the final efficacy analysis for all active treatment groups.
Per Protocol Population (PP)
The Per Protocol Population is defined as all subjects who meet study criteria and are 
enrolled into the study with documented evidence of having received all doses and all 
post-baseline HIV-1 RNA measurement, with exceptions of major protocol deviation. 
 
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Safety Population
The Safety Population is defined as all subjects who are enrolled into the study with
documented evidence of having received at least 1 dose of randomized treatment.
Pharmacokinetic Population
The PK Population will include all subjects who receive GSK2838232 and undergo 
plasma PK sampling during the study. Subjects for whom a plasma PK sample is
obtained and assayed will be included in the listing of plasma GSK2838232
concentration-time data. Results from samples collected from a subject with emesis 
occurring within 4 hours of the dose will not be considered as evaluable.
9.3.2.
Interim Analysis
An interim analysis of preliminary safety, tolerability, PK and antiviral activity will occur
after subjects of Part A Cohort 1 complete their Day 13 visit. If based on this review the 
Cohort 1 dose is determined to be the highest dose (e.g. the exposure level of 
GSK2838232 is in the range of the maximum GSK2838232 exposure seen previously in 
healthy subjects), the Bayesian posterior probability that the log10 viral load decline from 
baseline is greater than a cut-point will be calculated. If the Bayesian probability from 
Cohort 1 is less than 70% this will provide evidenceto not move forward into Part B. 
Otherwise, the study team will review the data in order to make a dose selection decision 
for the subsequent Part B Cohorts. If the pharmacokinetic exposures after the 100 mg 
GSK2838232/cobi dose look similar to those obtained with 100 mg GSK2838232/r in 
prior studies, the doses for Part B will be extended to both lower (20 mg, 50 mg) and 
higher (200 mg) doses.
Maximum change and change from baseline in plasma HIV-1 RNA will be summarized 
by treatment or by assessment day. The proportion of subjects with plasma HIV-1 RNA < 
400 and < 50 copies/mL will be summarized by treatment and assessment day. The 
analyses will be done for both PP and ITT exposed population if two populations are not 
the same.
9.4.
Key Elements of Analysis Plan
9.4.1.
Primary Analyses
The final analysis will be performed after the completion of the study and final datasets
authorization. Data will be listed and summarized according to GlaxoSmithKline 
reporting standards, where applicable. Listings will be sorted by subject, period, 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, geometric mean with 
associated 95% confidence interval (CI), and %CVb for continuous variables, whereas n 
and percent will be used as summary statistics for categorical variables. Baseline or pre-
dose 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 9.1 or higher 
of the SAS system will be used to analyze the data as well as to generate tables, figures, 
 
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and listings. Complete details will be documented in the Reporting and Analysis Plan 
(RAP).
9.4.1.1.
Safety Analyses
Safety data will be presented in tabular format and summarized descriptively according to
GSK’s Integrated Data Standards Library standards and data will be in CDISC format. 
No formal statistical analysis of the safety data will be conducted. 
9.4.1.2.
Efficacy Analyses
Both the PP and ITT Populations will be used for all efficacy analyses if there are 
dropouts.  Plasma HIV-1 RNA max change and change from baseline during the study 
will be calculated for each subject on each assessment day.
Plasma HIV-1 RNA will be listed by treatment, subject, and assessment day and 
summarized by treatment and assessment day along with change from baseline.
Plots of mean and median plasma HIV-1 RNA actual and change from baseline data will 
be generated by treatment and assessment day.

Plasma HIV-1 RNA change from baseline to the on-treatment nadir (maximum 
change) will be calculated for each subject and summarized by treatment.
Together, the data from Parts A and B will investigate the complete dose-response curve 
and the impact of lower doses on potential development of resistance. A dose-response 
curve will be fit to the data from Parts A & B using functional uniform priors.  
9.4.1.3.
Pharmacokinetic Analyses
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacokinetics
Modeling and Simulation Department, GlaxoSmithKline. Plasma GSK2838232
concentration-time data will be analyzed by non-compartmental methods with
WinNonlin Version 6.1 or higher. Calculations will be based on the actual sampling
times recorded during the study. From the plasma concentration-time data, the following
pharmacokinetic parameters will be determined, as data permit:
Plasma GSK2838232 Pharmacokinetic Parameters to be Estimated:
Study Day
Parameters
1
AUC(0-24), Cmax, tmax, tlag, C24
10
AUC(0-), Cmax, tmax, t½, C0, C, CL/F, R_AUC, R_Cmax, R_C
Results based on samples collected from a subject with emesis within 4 hours of the dose 
will not be considered as evaluable.
All PK data will be stored in the R&D archives, GlaxoSmithKline.
 
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Statistical analyses of the pharmacokinetic parameter data will be the responsibility of
Clinical Statistics, GlaxoSmithKline. Details of the statistical analyses will be provided in 
the RAP. An outline is provided below:
Pharmacokinetic data will be presented in graphical and tabular form and will be 
summarized descriptively. Plasma GSK2838232 PK parameters, with the exception of 
tmax and tlag, will be log-transformed prior to analysis.
Dose proportionality of plasma GSK2838232 PK parameters from Day 1 [AUC(0-24)
and Cmax] and Day 10 [AUC(0-τ) and Cmax] will be assessed using a power model if 
multiple dose levels are assessed. The power model will be fitted by restricted maximum 
likelihood (REML) using SAS Proc Mixed. A fixed effects power model will be used. 
The mean slope will be estimated from the power model with the corresponding 90% CI.
The accumulation ratio (R) and steady-state assessments will be performed, if quality of 
the data permits. Comparisons of Day 10 with Day 1 PK for each dose will be used for 
the accumulation ratio (R) evaluation. Pre-dose concentrations between Days 7-10 will be 
used for steady-state assessment. 
9.4.2.
Secondary Analyses
9.4.2.1.
Pharmacokinetic/Pharmacodynamic Analyses
Relationships between various PK parameters (e.g., AUC, Cmax, Cτ, etc.) and PD 
measures (e.g., log10 reduction from baseline in plasma HIV-1 RNA on Day 11 or safety 
parameters) will be explored using various models including Emax. The relationship 
between dose and PD measures will also be explored. Details of the PK/PD exploratory 
analyses will be provided in the RAP.
9.4.2.2.
Viral Genotyping and Phenotyping Analyses
Viral genotypic/phenotypic data will be listed and descriptive summaries will be
provided. Details of the analyses will be provided in the clinical virology report.
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
 
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The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

Obtaining signed informed consent

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, 
or both.

Signed informed consent must be obtained for each subject prior to participation 
in the study

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, 
written approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the CRF will 
serve as the source document.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements.
 
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The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
10.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and 
the regulatory agencies may conduct a regulatory inspection at any time during or 
after completion of the study. 

In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss 
the conduct of the study, any findings/relevant issues and to implement any 
corrective and/or preventative actions to address any findings/issues identified.
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard 
Operating Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this 
study at any time for reasons including, but not limited to, safety or ethical issues 
or severe non-compliance. For multicenter studies, this can occur at one or more 
or at all sites.  

If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable).  When feasible, GSK will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK will
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.  

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical 
institution (where applicable) must maintain all site study records (except for 
those required by local regulations to be maintained elsewhere), in a safe and 
secure location.  

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review 
 
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in conjunction with assessment of the facility, supporting systems, and relevant 
site staff.  

Where permitted by local laws/regulations or institutional policy, some or all of 
these records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.  

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, 
including re-generating a hard copy, if required.  Furthermore, the investigator 
must ensure there is an acceptable back-up of these reproductions and that an 
acceptable quality control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by 
any institutional requirements or local laws or regulations, GSK 
standards/procedures, and/or institutional requirements. 

The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of 
ownership of the records in the event the investigator is no longer associated with
the site.
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.
10.8.
Review Committees
The Safety Review Team (SRT) is a GSK cross-functional team reviewing all available 
safety data related to the project, including in-stream data from this study, in an ongoing 
manner. The SRT is an internal GSK requirement put in place to ensure holistic 
evaluation of the safety profile of an investigational product with systematic, periodic and 
documented reviews of available safety data, with the appropriate communication and 
escalation of new findings that have the potential to impact patient safety
 
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11.
REFERENCES
Bloch M, Bodsworth N, Fidler M, Workman C, Balach A, Byakagwa H, et al. Efficacy, 
safety and pharmacokinetics of MPC-4326 (bevirimat dimeglumine) 200mg BID and 
300mg BID monotherapy administered for 14 days in subjects with HIV-1 infection. 
ICAAC. 2009; Abstract H-1230.
Bornkamp B, Practical considerations for using functional uniform prior distributions for 
dose-response estimation in clinical trials. Biometrical Journal 56 (2014) 6, 947-962
Cockcroft DW, Gault MH. Prediction of creatinine clearance form serum creatinine. 
Nephron. 1976;16:31-41.
Dang Z, Huang L, Chen C. HIV-1 maturation inhibitors:  An update. Drugs of the Future. 
2009;34 (10):797-802.
Elion R, Cohen C, Gathe J, Shalit P, Hawkins T, Liu HC, Mathias AA, Chuck SL, 
Kearney BP, Warren DR.  Phase 2 study of cobicistat versus ritonavir each with once-
daily atazanavir and fixed-dose emtricitabine.tenofovir df in the initial treatment of HIV 
infection.  AIDS.  2011; 25:1881-1886.
Food and Drug Administration (FDA). Guidance for industry: Estimating the maximum 
safe starting dose in initial clinical trials for therapeutics in adult healthy subjects. CDER, 
Rockville, MD; 2005. UCM078932.
Food and Drug Administration (FDA). Guidance for Industry: Human Immunodeficiency 
Virus-1 Infection: Developing Antiretroviral Drugs for Treatment. CDER, Rockville, 
MD; 2015. UCM355128.
Gallant JE, Koenig E, Andrade-Villaneuva J, Chetchotisakd P, deJesus E, Antunes F, 
Arastéh K, Moyle G, Rizzardini G, Fehr J, Liu Y, Zhong L, Callebaut C, Scwarcberg J, 
Rhee MS, Cheng AK.  Cobicistat versus ritonavir as a pharmacoenhancer of atazanavir 
plus emtricitabine/tenofovir disoproxil fumarate in treatment-naïve HIV type 1-infected 
patients:  week 48 results.  J. Infect. Dis.  2013; 208-:32-39.
GlaxoSmithKline Document Number 2012N151889_03 Compound GSK2838232. 
Investigator’s Brochure.  Effective November 2016.
GlaxoSmithKline Non-Clinical Research report. Document Number 2013N163221_00.
Hatcher RA, Trussel J, Nelson AL, Cates W, Stewart F, Kowal D, editors. Contraceptive 
Technology. 19th ed. New York:Ardent Media; 2007. 
Kakuda TN, Opsomer M, Timmers M, Iterbeke K, Van De Casteele T, Hillewaert V, 
Petrovic R, Hoetelmans RMW.  Pharmacokinetics of darunavir in fixed-dose 
combination with cobicistat compared with coadministration of darunavir and ritonavir as 
single agents in healthy volunteers.  J. Clin. Pharmacol.  2009; 54:949-957.
 
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Lalezari J, McCallister S, Gigliotti M, Cohen C, Elion R, et al. Safety and efficacy study 
of bevirimat (BVM) in heavily treatment experienced HIV+ patients identifies the target 
phase 3 study profile. ICAAC. 2008; Abstract: H891. 
Mahmood I. Prediction of human drug clearance from animal data. Application of the 
rule of exponent and fu corrected intercept method (FCIM). J Pharm Sci. 
2006;95:1810-21. 
Martin D, Galbraith H, Ellis C, Schettler J and Doto J. Minimal effect of ritonavir (RTV) 
on the pharmacokinetics of bevirimat in healthy volunteers [abstract]. IAS Conference on 
HIV Pathogenesis, Treatment and Prevention. 2007; Abstract no. WEPEB015:Poster 
discussion.
Martin DE, Blum R, Doto J, Galbraith H, Ballow C. Multiple-dose pharmacokinetics and 
safety of bevirimat, a novel inhibitor of HIV maturation, in healthy volunteers. Clin 
Pharmacokinet. 2007(a);46(7):589-98.
Martin DE, Blum R, Wilton J, Doto J, Galbraith H, et al. Safety and pharmacokinetics of 
bevirimat (PA-457), a novel inhibitor of human immunodeficiency virus maturation, in 
healthy volunteers. Antimicrobial Agents and Chemotherapy. 2007(b);Sep:3063-6.
Martin DE, Galbraith H, Schettier J, Ellis C, Doto J. Pharmacokinetic properties and 
tolerability of bevirimat and atazanavir in healthy volunteers:  An open-label, parallel-
group study. Clinical Therapeutics. 2008;30(10):1794-1805.
NORVIR (ritonavir) Product Information. January, 2013.
Nowicka-Sans B, Protack T, Lin Z, Li Z, Zhang S, Meanwell N, et al. BMS-955176: 
Characterization of a second-generation HIV-1 maturation inhibitor. 8th IAS Conference 
on HIV Pathogenesis, Treatment and Prevention, July 19-22, 2015, Vancouver, Canada.
Qian K, Morris-Natschke SL, Lee KH. HIV entry inhibitors and their potential in HIV 
therapy. Medicinal Research Reviews. 2009;29(2):369-93.
Saxena SK, Gupta A, Bhagyashree K, Saxena R, Arora N, Banerjee AK, et al. Targeting 
strategies for human immunodeficiency virus: A combinatorial approach. Min Rev Med 
Chem. 2012;12(3):236-54.
TYBOST (cobicistat) Product Information. 2012
Wainburg MA, Albert J. Can the further clinical development of bevirimat be justified?. 
AIDS. 2010;24:773-4.
 
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
g/mL
Microgram per millilitre
ABC
Abacavir
AE
Adverse Event
AIDS
Auto immunodeficiency syndrome
ALT
Alanine aminotransferase
API
Active Pharmaceutical Ingredient
ART
Antiretroviral therapy
AST
Aspartate aminotransferase
AUC
Area under the plasma concentration time curve
AUC(0-)
Area under the concentration-time curve from time zero 
(pre-dose) extrapolated to infinite time
AUC(0-)
Area under the concentration-time curve over the dosing 
interval 
AUC(0-24)
Area under the concentration-time curve from zero (pre-
dose) to 24 h
AUC(0-48)
Area under the concentration-time curve from zero (pre-
dose) to 48 h
AUC(0-t)
Area under the concentration-time curve from zero (pre-
dose) to time of last quantifiable concentration
BCRP
Breast cancer resistance protein
Bpm
beats per minute
BVM
Bevirimat
BIL
Bilirubin
C
Pre-dose (trough) concentration at the end of the dosing 
interval
C24
24 hour trough concentration
CDC
Center for Disease Control and Prevention
CI
Confidence interval
CL/F
Oral Clearance
Cmax
Maximum plasma concentration
Cmin
Minimum plasma concentration
CPK
Creatine Phosphokinase
CRF
Case report form
cTnI
Cardiac troponin I
CV
Coefficient of variation
CVb
Between-subject variability
CYP
Cytochrome P450
DDI
DNA
Deoxyribonucleic acid
EC50
50% protection against resistant mutant HIV infection 
ECG
Electrocardiogram
 
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FC
Fold Changes
FDA
Food and Drug Administration
FSH
Follicle stimulating hormone
FTIH
First time in Human Study
g
Gram
GI
Gastrointestinal
GSK
GlaxoSmithKline
h
Hour(s)
HBsAg
Hepatitis B surface antigen
hcG
Human chorionic gonadotrophin
HDPE
High density polyethylene
hERG
Human Ether-a-gogo Related Gene
HIV
Human Immunodeficiency Virus
IC50/90
50% or 90% maximal inhibitory concentration
IEC
International Ethics Committee
IQ
Inhibitory quotient
IRB
Institutional Review Board
ISR
Injection site reaction
IV
Intravenous
IVRS
Interactive voice response system
kg
Kilogram
L
Litre
LLOD
Lower limit of detection
MC
Melanocortin
MedDRA
Medical Dictionary for Regulatory Activities
mg/mL
Milligram per millilitre
MI
Maturation inhibitor
mL
Milliliter
mRNA
messenger Ribonucleic Acid
ND
Not done
ng/mL
Nanogram per millilitre 
nm
Nanometer
NO
Not observed
NOAEL
No Observed Adverse Effect Level
NTproBNP
N-terminal prohormone of brain natriuretic peptide
NSVT
Non-sustained ventricular tachycardia
OAT
Organic anion transporter
OATP
Organic anion transporting polypeptide
OCT
Organic cation transporter
PBL
Peripheral Blood Lymphocytes
PBMC
Peripheral Blood Mononuclear Cells
PD
Pharmacodynamics
P-gp
P-glycoprotein
PHIV
Pseudo- HIV
PiB
Powder-in-bottle
PK
Pharmacokinetic
 
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PoC
Proof of Concept
PI
Protease Inhibitor
RAP
Reporting and analysis plan
RT
Reverse Transcriptase
SAE
Serious adverse event
SDD
Spray Dried Dispersion
SRM
Study reference manual
t1/2
Terminal elimination half-life
TEM
Transmission Electron Microscopy
tlag
Time of first quantifiable concentration
tmax
Time of occurrence of Cmax
U
Units
UGT
Uridine 5'-diphospho-glucuronosyltransferase
Vz/F
Mean apparent oral volume of distribution
WPW
Wolff-Parkinson-White
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Abbot, Roche HIV kit
Chiron RIBA 
Inform
Monogram
Phoenix WinNonlin 
SAS
Tybost (cobicistat)
 
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12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments
Phase II liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event etiology (in alignment with the 
FDA premarketing clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Phase II liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF and complete an 
SAE data collection tool if the event also meets 
the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries
resolve, stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge subject with study 
treatment unless allowed per protocol and GSK 
Medical Governance approval is granted 

If restart/rechallenge not allowed per protocol 
or not granted, permanently discontinue study 
treatment and may continue subject in the study 

Viral hepatitis serology4

Blood sample for pharmacokinetic (PK) 
analysis, obtained within 24hrs after 
last dose5

Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications 
on the concomitant medications report 
 
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for any protocol specified follow up assessments 
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 
24 hours

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to within 
baseline 

A specialist or hepatology consultation is 
recommended
For All other criteria: 

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24-
72 hours 

Monitor subjects weekly until liver chemistries 
resolve, stabilize or return to within baseline
form including acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG or gamma globulins).

Serum acetaminophen adduct high-
performance liquid chromatography
assay (quantifies potential 
acetaminophen contribution to liver 
injury in subjects with definite or likely 
acetaminophen use in the preceding 
week 

Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF 
forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN.. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
5.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.)  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.  
 
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Phase II liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 3xULN and <5xULN and bilirubin 
<2xULN, without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss subject safety. 

Subject can continue study treatment  

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to within 
baseline.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
 
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12.3.
Appendix 3: Liver Safety – Study Treatment Restart or 
Rechallenge Guidelines
Study treatment restart or re-challenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed.
 
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12.4.
Appendix 4: Genetic Research
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and: 

Response to medicine, including GSK2838232/RTV or any concomitant 
medicines;

HIV susceptibility, severity, and progression and related conditions
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic 
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research.  Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.  

A 6 ml blood or 2 ml saliva sample will be taken for Deoxyribonucleic acid 
(DNA) extraction. A sample is collected at the baseline visit, after the subject has 
been randomized and provided informed consent for genetic research. Instructions 
for collection and shipping of the genetic sample are described in the laboratory
manual. The DNA from the blood/saliva sample may undergo quality control 
analyses to confirm the integrity of the sample. If there are concerns regarding the 
quality of the sample, then the sample may be destroyed. The blood/saliva sample 
is taken on a single occasion unless a duplicate sample is required due to an 
inability to utilize the original sample.  
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study.   This number can be traced or linked back to 
 
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the subject by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number). 
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study, or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form.  Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study.  Genetic informed consent must be obtained prior to any blood/saliva being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA 
sample is retained

Discontinue participation in the genetic research and destroy the genetic DNA 
sample 
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis. 

If a subject withdraws consent for genetic research and genotype data has not been 
analyzed, it will not be analyzed or used for future research.  

Genetic data that has been analyzed at the time of withdrawn consent will 
continue to be stored and used, as appropriate. 
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 
 
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reconciliation process.  In this instance a sample destruction form will not be available to 
include in the site files.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic 
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined.  Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care.
 
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12.5.
Appendix 5: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.5.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE.  However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition 
of an AE or SAE.

The signs and symptoms and/or clinical sequelae resulting from lack of efficacy will 
be reported if they fulfil the definition of an AE or SAE.  Also, "lack of efficacy" or 
"failure of expected pharmacological action" also constitutes an AE or SAE.
Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
 
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investigator to be more severe than expected for the subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
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.
12.5.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
c.
Results in death
d.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
e.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
 
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f.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption
g.
Is a congenital anomaly/birth defect
h.
Other situations:

Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.

Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse
i.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.

Refer to Appendix 2 for the required liver chemistry follow-up instructions
 
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12.5.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
12.5.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.

Subject-completed Value Evidence and Outcomes questionnaires and the collection 
of AE data are independent components of the study.

Responses to each question in the Value Evidence and Outcomes questionnaire will 
be treated in accordance with standard scoring and statistical procedures detailed by 
 
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the scale’s developer.

The use of a single question from a multidimensional health survey to designate a 
cause-effect relationship to an AE is inappropriate.
12.5.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important 
that the investigator always make an assessment of causality for every event 
prior to the initial transmission of the SAE data to GSK.
 
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
The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

By specific request, the investigator is obligated to report any grade 2 or higher 
“alteration in personality-behavior or in mood” or “altered mental status” adverse 
events that occur in subjects taking this drug, to GSK within 3 days.

The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.

If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any post-mortem findings, 
including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
12.5.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the Medical Monitor

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data

If a site receives a report of a new SAE from a study subject or receives updated data 
 
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on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the Medical 
Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
SAE reporting to GSK via paper CRF

Facsim0ile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the Medical Monitor 

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable, with a copy of the SAE data collection tool sent by 
overnight mail

Initial notification via the 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 receipt can be found at this beginning of the protocol on the 
Sponsor/Medical Monitor Contact Information page.
SAE reporting to GSK via PIMS

Facsimile transmission of the following PIMS listings for the corresponding subject 
is the preferred method to transmit SAE information to the Medical Monitor or 
protocol contact:
SAE listing
Demographic listing
Study treatment listing

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable, with a copy of all required information sent by overnight 
mail.

If the PIMS system is unavailable when the SAE occurs, the site will use the paper 
SAE form and fax that to the Medical Monitor or protocol contact. The site will enter 
the SAE data into PIMS as soon as the system becomes available.
 
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12.6.
Appendix 6: Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 
24hrs of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, which will be 
forwarded to GSK.  Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in Appendix 5. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
Any female subject who becomes pregnant while participating 

will discontinue study medication and be withdrawn from the study

This will only be included if either of the following apply:

Investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study.  This 
applies only to subjects who are randomized to receive study medication. 

After obtaining the necessary signed informed consent from the female partner 
directly, the investigator will record pregnancy information on the appropriate form 
report the event and submit it to GSK within 24hrs 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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12.7.
Appendix 7: Country Specific Requirements
No country-specific requirements exist.
 
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12.8.
Appendix 8: Division Of AIDS Table For Grading The 
Severity Of Adult And Pediatric Adverse Events Version 1.0, 
December 2004; Clarification August 2009
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
ESTIMATING SEVERITY GRADE
Clinical adverse 
event NOT identified 
elsewhere in the 
grading table
Mild symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities with 
intervention not 
indicated
Moderate 
symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
with intervention not 
indicated
Severe symptoms 
causing inability to 
perform usual social 
& functional activities 
with intervention or 
hospitalization 
indicated
Potentially life-
threatening symptoms 
causing inability to 
perform basic self-care 
functions OR Medical or 
operative intervention 
indicated to prevent 
permanent impairment, 
persistent disability, or 
death 
CARDIOVASCULAR
Arrhythmia
(by ECG or physical 
examination)
Specify type, if
applicable
No symptoms 
AND No 
intervention 
indicated
No symptoms AND
non-urgent 
intervention 
indicated
Non-life-threatening 
symptoms AND Non-
urgent intervention
indicated
Life-threatening 
arrhythmia OR Urgent 
intervention indicated
Blood Pressure 
Abnormalities1 
Hypertension (with 
the lowest reading 
taken after repeat 
testing during a visit) 
≥ 18 years of age 
140 to < 160 
mmHg systolic 
OR 90 to < 100 
mmHg diastolic 
≥ 160 to < 180 
mmHg systolic OR 
≥ 100 to < 110 
mmHg diastolic 
≥ 180 mmHg systolic 
OR ≥ 110 mmHg 
diastolic 
Life-threatening 
consequences in a 
participant not 
previously diagnosed
with hypertension (e.g., 
malignant hypertension) 
OR Hospitalization 
indicated 
< 18 years of age 
> 120/80 mmHg 
≥ 95th to < 99th 
percentile + 5 
mmHg adjusted for 
age, height, and 
gender (systolic 
and/or diastolic) 
≥ 99th percentile + 5 
mmHg adjusted for 
age, height, and 
gender (systolic 
and/or diastolic) 
Life-threatening 
consequences in a 
participant not 
previously diagnosed 
with hypertension (e.g., 
malignant hypertension) 
OR Hospitalization 
indicated 
Hypotension 
No symptoms 
Symptoms 
corrected with oral 
fluid replacement 
Symptoms AND IV 
fluids indicated 
Shock requiring use of 
vasopressors or 
mechanical assistance 
to maintain blood 
pressure 
Cardiac Ischemia or 
Infarction 
Report only one 
NA 
NA 
New symptoms with 
ischemia (stable 
angina) OR New 
testing consistent 
with ischemia 
Unstable angina OR 
Acute myocardial 
infarction 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Heart Failure 
No symptoms 
AND Laboratory 
or cardiac imaging 
abnormalities 
Symptoms with mild 
to moderate activity 
or exertion 
Symptoms at rest or 
with minimal activity 
or exertion (e.g., 
hypoxemia) OR 
Intervention indicated 
(e.g., oxygen) 
Life-threatening 
consequences OR 
Urgent intervention 
indicated (e.g., 
vasoactive medications, 
ventricular assist device, 
heart transplant) 
Hemorrhage (with 
significant acute 
blood loss) 
NA 
Symptoms AND No 
transfusion 
indicated 
Symptoms AND 
Transfusion of ≤ 2 
units packed RBCs 
indicated 
Life-threatening 
hypotension OR 
Transfusion of > 2 units 
packed RBCs (for 
children, packed RBCs 
> 10 cc/kg) indicated 
Prolonged PR 
Interval or AV Block 
Report only one 
> 16 years of age 
PR interval 0.21 
to < 0.25 seconds 
PR interval ≥ 0.25 
seconds OR Type I 
2nd degree AV 
block 
Type II 2nd degree 
AV block OR 
Ventricular pause ≥ 
3.0 seconds 
Complete AV block 
≤ 16 years of age 
1st degree AV 
block (PR interval 
> normal for age 
and rate) 
Type I 2nd degree 
AV block 
Type II 2nd degree 
AV block OR 
Ventricular pause ≥ 
3.0 seconds 
Complete AV block 
Prolonged QTc 
Interval2 
0.45 to 0.47 
seconds 
> 0.47 to 0.50 
seconds 
> 0.50 seconds OR ≥ 
0.06 seconds above 
baseline 
Life-threatening 
consequences (e.g., 
Torsade de pointes, 
other associated serious 
ventricular dysrhythmia) 
Thrombosis or 
Embolism 
Report only one 
NA 
Symptoms AND No 
intervention 
indicated 
Symptoms AND 
Intervention indicated 
Life-threatening embolic 
event (e.g., pulmonary 
embolism, thrombus) 
DERMATOLOGIC
Alopecia (scalp only) 
Detectable by 
study participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Obvious on visual 
inspection AND 
Causing greater 
than minimal 
interference with 
usual social & 
functional activities 
NA 
NA 
Bruising 
Localized to one 
area 
Localized to more 
than one area 
Generalized 
NA 
Cellulitis 
NA 
Non-parenteral 
treatment indicated 
(e.g., oral 
antibiotics, 
antifungals, 
antivirals) 
IV treatment 
indicated (e.g., IV 
antibiotics, 
antifungals, antivirals) 
Life-threatening 
consequences (e.g., 
sepsis, tissue necrosis) 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Hyperpigmentation 
Slight or localized 
causing no or 
minimal 
interference with
usual social & 
functional 
activities 
Marked or 
generalized causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
NA 
NA 
Hypopigmentation 
Slight or localized 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Marked or 
generalized causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
NA 
NA 
Petechiae 
Localized to one 
area 
Localized to more 
than one area 
Generalized 
NA 
Pruritus3 (without 
skin lesions) 
Itching causing no 
or minimal 
interference with 
usual social & 
functional 
activities 
Itching causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Itching causing 
inability to perform 
usual social & 
functional activities 
NA 
Rash 
Specify type, if 
applicable 
Localized rash 
Diffuse rash OR 
Target lesions 
Diffuse rash AND 
Vesicles or limited 
number of bullae or 
superficial ulcerations 
of mucous membrane 
limited to one site 
Extensive or generalized 
bullous lesions OR 
Ulceration of mucous 
membrane involving two 
or more distinct mucosal 
sites OR Stevens-
Johnson syndrome OR 
Toxic epidermal 
necrolysis 
ENDOCRINE AND METABOLIC
Diabetes Mellitus 
Controlled without 
medication 
Controlled with 
medication OR 
Modification of 
current medication 
regimen 
Uncontrolled despite 
treatment 
modification OR 
Hospitalization for 
immediate glucose 
control indicated 
Life-threatening 
consequences (e.g., 
ketoacidosis, 
hyperosmolar non-
ketotic coma, end organ 
failure) 
Gynecomastia 
Detectable by 
study participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Obvious on visual 
inspection AND 
Causing pain with 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Disfiguring changes 
AND Symptoms 
requiring intervention 
or causing inability to 
perform usual social 
& functional activities 
NA 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Hyperthyroidism 
No symptoms 
AND Abnormal 
laboratory value 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
OR Thyroid 
suppression 
therapy indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Uncontrolled 
despite treatment 
modification 
Life-threatening 
consequences (e.g., 
thyroid storm) 
Hypothyroidism 
No symptoms 
AND Abnormal 
laboratory value 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
OR Thyroid 
replacement 
therapy indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Uncontrolled 
despite treatment 
modification 
Life-threatening 
consequences (e.g., 
myxedema coma) 
Lipoatrophy4 
Detectable by 
study participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Obvious on visual 
inspection AND 
Causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Disfiguring changes 
NA 
Lipohypertrophy5
Detectable by 
study participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Obvious on visual 
inspection AND 
Causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Disfiguring changes 
NA 
GASTROINTESTINAL
Anorexia 
Loss of appetite 
without decreased 
oral intake 
Loss of appetite 
associated with 
decreased oral 
intake without 
significant weight 
loss 
Loss of appetite 
associated with 
significant weight loss 
Life-threatening 
consequences OR 
Aggressive intervention 
indicated (e.g., tube 
feeding, total parenteral 
nutrition) 
Ascites 
No symptoms 
Symptoms AND 
Intervention 
indicated (e.g., 
diuretics, 
therapeutic 
paracentesis) 
Symptoms recur or 
persist despite 
intervention 
Life-threatening 
consequences 
 
2018N360917_00


2015N227852_00
CONFIDENTIAL
200911
89
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Bloating or 
Distension 
Report only one 
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Cholecystitis
NA 
Symptoms AND 
Medical intervention 
indicated 
Radiologic, 
endoscopic, or 
operative intervention 
indicated 
Life-threatening 
consequences (e.g., 
sepsis, perforation) 
Constipation 
NA 
Persistent 
constipation 
requiring regular 
use of dietary 
modifications, 
laxatives, or 
enemas 
Obstipation with 
manual evacuation 
indicated 
Life-threatening 
consequences (e.g., 
obstruction) 
Diarrhea ≥ 1 year of 
age 
Transient or 
intermittent 
episodes of 
unformed stools 
OR Increase of ≤ 
3 stools over 
baseline per 24-
hour period 
Persistent episodes 
of unformed to 
watery stools OR 
Increase of 4 to 6 
stools over baseline 
per 24-hour period 
Increase of ≥7 stools 
per 24-hour period 
OR IV fluid 
replacement 
indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Dysphagia or 
Odynophagia 
Report only one 
and specify 
location 
Symptoms but 
able to eat usual 
diet 
Symptoms causing 
altered dietary 
intake with no 
intervention 
indicated 
Symptoms causing 
severely altered 
dietary intake with 
intervention indicated 
Life-threatening 
reduction in oral intake 
Gastrointestinal 
Bleeding 
Not requiring 
intervention other 
than iron 
supplement 
Endoscopic 
intervention 
indicated 
Transfusion indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Mucositis or 
Stomatitis 
Report only one and 
specify location 
Mucosal erythema 
Patchy 
pseudomembranes 
or ulcerations 
Confluent 
pseudomembranes 
or ulcerations OR 
Mucosal bleeding 
with minor trauma 
Life-threatening 
consequences (e.g., 
aspiration, choking) OR 
Tissue necrosis OR 
Diffuse spontaneous 
mucosal bleeding 
Nausea 
Transient (< 24 
hours) or 
intermittent AND 
No or minimal 
interference with 
oral intake 
Persistent nausea 
resulting in 
decreased oral 
intake for 24 to 48 
hours 
Persistent nausea 
resulting in minimal 
oral intake for > 48 
hours OR 
Rehydration indicated 
(e.g., IV fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Pancreatitis 
NA 
Symptoms with 
hospitalization not 
indicated 
Symptoms with 
hospitalization 
indicated 
Life-threatening 
consequences (e.g., 
circulatory failure, 
hemorrhage, sepsis) 
 
2018N360917_00


2015N227852_00
CONFIDENTIAL
200911
90
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Perforation 
(colon or rectum) 
NA 
NA 
Intervention indicated 
Life-threatening 
consequences 
Proctitis 
Rectal discomfort 
with no 
intervention 
indicated 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
OR Medical 
intervention 
indicated 
Symptoms causing 
inability to perform 
usual social &
functional activities 
OR Operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
perforation) 
Rectal Discharge 
Visible discharge 
Discharge requiring 
the use of pads 
NA 
NA 
Vomiting 
Transient or 
intermittent AND 
No or minimal 
interference with 
oral intake 
Frequent episodes 
with no or mild 
dehydration 
Persistent vomiting 
resulting in 
orthostatic 
hypotension OR 
Aggressive 
rehydration indicated 
(e.g., IV fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
MUSCULOSKELETAL
Arthralgia 
Joint pain causing 
no or minimal 
interference with 
usual social & 
functional 
activities 
Joint pain causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Joint pain causing 
inability to perform 
usual social & 
functional activities 
Disabling joint pain 
causing inability to 
perform basic self-care 
functions 
Arthritis 
Stiffness or joint 
swelling causing 
no or minimal 
interference with 
usual social & 
functional 
activities 
Stiffness or joint 
swelling causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Stiffness or joint 
swelling causing 
inability to perform 
usual social & 
functional activities 
Disabling joint stiffness 
or swelling causing 
inability to perform basic 
self-care functions 
Myalgia 
(generalized) 
Muscle pain 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Muscle pain 
causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Muscle pain causing 
inability to perform 
usual social & 
functional activities 
Disabling muscle pain 
causing inability to 
perform basic self-care 
functions 
Osteonecrosis 
NA 
No symptoms but 
with radiographic 
findings AND No 
operative 
intervention 
indicated 
Bone pain with 
radiographic findings 
OR Operative 
intervention indicated 
Disabling bone pain with 
radiographic findings 
causing inability to 
perform basic self-care 
functions 
Osteopenia6
≥ 30 years of age 
BMD t-score -2.5 
to -1 
NA 
NA 
NA 
 
2018N360917_00


2015N227852_00
CONFIDENTIAL
200911
91
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
< 30 years of age 
BMD z-score -2 to 
-1 
NA
NA 
NA 
Osteoporosis6
≥ 30 years of age 
NA 
BMD t-score < -2.5 
Pathologic fracture 
(e.g., compression 
fracture causing loss 
of vertebral height) 
Pathologic fracture 
causing life-threatening 
consequences 
< 30 years of age 
NA 
BMD z-score < -2 
Pathologic fracture 
(e.g., compression 
fracture causing loss 
of vertebral height) 
Pathologic fracture 
causing life-threatening 
consequences 
NEUROLOGIC
Acute Central 
nervous system 
(CNS) Ischemia 
NA 
NA 
Transient ischemic 
attack 
Cerebral vascular 
accident (e.g., stroke 
with neurological deficit) 
Altered Mental 
Status (for 
Dementia, see 
Cognitive, 
Behavioral, or 
Attentional 
Disturbance below) 
Changes causing 
no or minimal 
interference with 
usual social & 
functional 
activities 
Mild lethargy or 
somnolence 
causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Confusion, memory 
impairment, lethargy, 
or somnolence 
causing inability to 
perform usual social 
& functional activities 
Delirium OR 
Obtundation OR Coma 
Ataxia 
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities OR No 
symptoms with 
ataxia detected on 
examination 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Disabling symptoms 
causing inability to 
perform basic self-care 
functions 
Cognitive, 
Behavioral, or 
Attentional 
Disturbance 
(includes dementia 
and attention deficit 
disorder) 
Specify type, if 
applicable 
Disability causing 
no or minimal 
interference with 
usual social & 
functional 
activities OR 
Specialized 
resources not 
indicated 
Disability causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
OR Specialized 
resources on part-
time basis indicated 
Disability causing 
inability to perform 
usual social & 
functional activities 
OR Specialized 
resources on a full-
time basis indicated 
Disability causing 
inability to perform basic 
self-care functions OR 
Institutionalization 
indicated 
 
2018N360917_00


2015N227852_00
CONFIDENTIAL
200911
92
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Developmental 
Delay < 18 years of 
age 
Specify type, if 
applicable 
Mild 
developmental 
delay, either 
motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Moderate 
developmental 
delay, either motor
or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Severe 
developmental delay, 
either motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Developmental 
regression, either motor 
or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Headache 
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Symptoms causing 
inability to perform basic 
self-care functions OR 
Hospitalization indicated 
OR Headache with 
significant impairment of 
alertness or other 
neurologic function 
Neuromuscular 
Weakness (includes 
myopathy and 
neuropathy) 
Specify type, if 
applicable 
Minimal muscle 
weakness causing 
no or minimal 
interference with 
usual social & 
functional
activities OR No 
symptoms with 
decreased 
strength on 
examination 
Muscle weakness 
causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Muscle weakness 
causing inability to 
perform usual social 
& functional activities 
Disabling muscle 
weakness causing 
inability to perform basic 
self-care functions OR 
Respiratory muscle 
weakness impairing 
ventilation 
Neurosensory 
Alteration (includes 
paresthesia and 
painful neuropathy) 
Specify type, if 
applicable 
Minimal 
paresthesia 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities OR No 
symptoms with 
sensory alteration 
on examination 
Sensory alteration 
or paresthesia 
causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Sensory alteration or 
paresthesia causing 
inability to perform 
usual social & 
functional activities 
Disabling sensory 
alteration or paresthesia 
causing inability to 
perform basic self-care 
functions 
Seizures New Onset 
Seizure 
≥ 18 years of age 
NA 
NA 
1 to 3 seizures 
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR Difficult 
to control (e.g., 
refractory epilepsy) 
< 18 years of age 
(includes new or pre-
existing febrile 
seizures) 
Seizure lasting < 
5 minutes with < 
24 hours postictal 
state 
Seizure lasting 5 to 
< 20 minutes with < 
24 hours postictal 
state 
Seizure lasting ≥ 20 
minutes OR > 24 
hours postictal state 
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR Difficult 
to control (e.g., 
refractory epilepsy) 
 
2018N360917_00


2015N227852_00
CONFIDENTIAL
200911
93
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Pre-existing Seizure 
NA 
Increased 
frequency from 
previous level of 
control without 
change in seizure 
character 
Change in seizure 
character either in 
duration or quality 
(e.g., severity or 
focality) 
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR Difficult 
to control (e.g., 
refractory epilepsy) 
Syncope 
Near syncope 
without loss of 
consciousness 
(e.g., pre-
syncope) 
Loss of 
consciousness with 
no intervention 
indicated 
Loss of 
consciousness AND 
Hospitalization or 
intervention required 
NA 
PREGNANCY, PUERPERIUM, AND PERINATAL
Fetal Death or 
Stillbirth (report 
using mother’s 
participant ID) 
Report only one 
NA 
NA 
Fetal loss occurring 
at ≥ 20 weeks 
gestation 
NA 
Preterm Delivery7
(report using 
mother’s participant 
ID) 
Delivery at 34 to < 
37 weeks 
gestational age 
Delivery at 28 to < 
34 weeks 
gestational age 
Delivery at 24 to < 28 
weeks gestational 
age 
Delivery at < 24 weeks 
gestational age 
Spontaneous 
Abortion or 
Miscarriage8 (report 
using mother’s 
participant ID) 
Report only one 
Chemical 
pregnancy 
Uncomplicated 
spontaneous 
abortion or 
miscarriage 
Complicated 
spontaneous abortion 
or miscarriage 
NA 
PSYCHIATRIC
Insomnia 
Mild difficulty 
falling asleep, 
staying asleep, or 
waking up early 
Moderate difficulty 
falling asleep, 
staying asleep, or 
waking up early 
Severe difficulty 
falling asleep, staying 
asleep, or waking up 
early 
NA 
Psychiatric 
Disorders 
(includes anxiety, 
depression, mania, 
and 
psychosis) 
Specify disorder 
Symptoms with 
intervention not 
indicated OR 
Behavior causing 
no or minimal 
interference with 
usual social & 
functional 
activities 
Symptoms with 
intervention 
indicated OR 
Behavior causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms with 
hospitalization 
indicated OR 
Behavior causing 
inability to perform 
usual social & 
functional activities 
Threatens harm to self 
or others OR Acute 
psychosis OR Behavior 
causing inability to 
perform basic self-care 
functions 
 
2018N360917_00


2015N227852_00
CONFIDENTIAL
200911
94
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Suicidal Ideation or 
Attempt 
Report only one 
Preoccupied with 
thoughts of death 
AND No wish to 
kill oneself 
Preoccupied with 
thoughts of death 
AND Wish to kill 
oneself with no 
specific plan or 
intent 
Thoughts of killing 
oneself with partial or 
complete plans but 
no attempt to do so 
OR Hospitalization 
indicated 
Suicide attempted 
RESPIRATORY
Acute 
Bronchospasm 
Forced expiratory 
volume in 1 
second or peak 
flow reduced to ≥ 
70 to < 80% OR 
Mild symptoms 
with intervention 
not indicated 
Forced expiratory 
volume in 1 second 
or peak flow 50 to < 
70% OR Symptoms 
with intervention 
indicated OR 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Forced expiratory 
volume in 1 second 
or peak flow 25 to < 
50% OR Symptoms 
causing inability to 
perform usual social 
& functional activities 
Forced expiratory 
volume in 1 second or 
peak flow < 25% OR 
Life-threatening 
respiratory or 
hemodynamic 
compromise OR 
Intubation 
Dyspnea or 
Respiratory 
Distress 
Report only one 
Dyspnea on 
exertion with no or 
minimal 
interference with 
usual social & 
functional 
activities OR 
Wheezing OR 
Minimal increase 
in respiratory rate 
for age 
Dyspnea on 
exertion causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
OR Nasal flaring 
OR Intercostal 
retractions OR 
Pulse oximetry 90 
to < 95% 
Dyspnea at rest 
causing inability to 
perform usual social 
& functional activities 
OR Pulse oximetry < 
90% 
Respiratory failure with 
ventilator support 
indicated (e.g., 
Continuous positive 
airway pressure [CPAP], 
Bilevel positive airway 
pressure [BPAP], 
intubation) 
SENSORY
Hearing Loss 
≥ 12 years of age 
NA 
Hearing aid or 
intervention not 
indicated 
Hearing aid or 
intervention indicated 
Profound bilateral 
hearing loss (> 80 dB at 
2 kHz and above) OR 
Non-serviceable hearing 
(i.e., >50 dB audiogram 
and <50% speech 
discrimination) 
< 12 years of age 
(based on a 1, 2, 3, 
4, 6 and 8 kHz 
audiogram) 
> 20 dB hearing 
loss at ≤ 4 kHz 
> 20 dB hearing 
loss at > 4 kHz 
> 20 dB hearing loss 
at ≥ 3 kHz in one ear 
with additional 
speech language 
related services 
indicated (where 
available) OR 
Hearing loss 
sufficient to indicate 
therapeutic 
intervention, including 
hearing aids 
Audiologic indication for 
cochlear implant and 
additional speech-
language related 
services indicated 
(where available) 
 
2018N360917_00


2015N227852_00
CONFIDENTIAL
200911
95
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Tinnitus 
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities with 
intervention not 
indicated 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
with intervention 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Uveitis 
No symptoms 
AND Detectable 
on examination 
Anterior uveitis with 
symptoms OR 
Medicamylasal 
intervention 
indicated 
Posterior or pan-
uveitis OR Operative 
intervention indicated 
Disabling visual loss in 
affected eye(s) 
Vertigo 
Vertigo causing 
no or minimal 
interference with 
usual social & 
functional 
activities 
Vertigo causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Vertigo causing 
inability to perform 
usual social & 
functional activities 
Disabling vertigo 
causing inability to 
perform basic self-care 
functions 
Visual Changes 
(assessed from 
baseline) 
Visual changes 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Visual changes 
causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Visual changes 
causing inability to 
perform usual social 
& functional activities 
Disabling visual loss in 
affected eye(s) 
SYSTEMIC
Acute Allergic 
Reaction 
Localized urticaria 
(wheals) with no 
medical 
intervention 
indicated 
Localized urticaria 
with intervention 
indicated OR Mild 
angioedema with 
no intervention 
indicated 
Generalized urticaria 
OR Angioedema with 
intervention indicated
OR Symptoms of 
mild bronchospasm 
Acute anaphylaxis OR 
Life-threatening 
bronchospasm OR 
Laryngeal edema 
Chills 
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Cytokine Release 
Syndrome9
Mild signs and 
symptoms AND 
Therapy (i.e., 
antibody infusion) 
interruption not 
indicated 
Therapy (i.e., 
antibody infusion) 
interruption 
indicated AND 
Responds promptly 
to symptomatic 
treatment OR 
Prophylactic 
medications 
indicated for ≤ 24 
hours 
Prolonged severe 
signs and symptoms 
OR Recurrence of 
symptoms following 
initial improvement 
Life-threatening 
consequences (e.g., 
requiring pressor or 
ventilator support) 
 
2018N360917_00


2015N227852_00
CONFIDENTIAL
200911
96
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Fatigue or Malaise 
Report only one 
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Incapacitating 
symptoms of fatigue or 
malaise causing inability 
to perform basic self-
care functions 
Fever (non-axillary 
temperatures only) 
38.0 to < 38.6°C 
or 100.4 to < 
101.5°F 
≥ 38.6 to < 39.3°C 
or ≥ 101.5 to < 
102.7°F 
≥ 39.3 to < 40.0°C or 
≥ 102.7 to < 104.0°F 
≥ 40.0°C or ≥ 104.0°F 
Pain10 (not 
associated with study 
agent injections and 
not specified 
elsewhere) 
Specify location 
Pain causing no 
or minimal 
interference with 
usual social & 
functional 
activities 
Pain causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Pain causing inability 
to perform usual 
social & functional 
activities 
Disabling pain causing 
inability to perform basic 
self-care functions OR 
Hospitalization indicated 
Serum Sickness11 
Mild signs and 
symptoms 
Moderate signs and 
symptoms AND 
Intervention 
indicated (e.g., 
antihistamines) 
Severe signs and 
symptoms AND 
Higher level 
intervention indicated 
(e.g., steroids or IV 
fluids) 
Life-threatening 
consequences (e.g., 
requiring pressor or 
ventilator support) 
Underweight12
> 5 to 19 years of 
age 
NA 
World Health 
Organization 
(WHO) BMI z-score 
< -2 to ≤ -3 
WHO BMI z-score < -
3 
WHO BMI z-score < -3 
with life-threatening 
consequences 
2 to 5 years of age 
NA 
WHO Weight-for-
height z-score 
< -2 to ≤ -3 
WHO Weight-for-
height z-score < -3 
WHO Weight-for-height 
z-score < -3 with life-
threatening 
consequences 
< 2 years of age 
NA 
WHO Weight-for-
length z-score 
< -2 to ≤ -3 
WHO Weight-for-
length z-score < -3 
WHO Weight-for-length 
z-score < -3 with life-
threatening 
consequences 
Weight Loss 
(excludes postpartum 
weight loss) 
NA 
5 to < 9% loss in 
body weight from 
baseline 
≥ 9 to < 20% loss in 
body weight from 
baseline 
≥ 20% loss in body 
weight from baseline OR 
Aggressive intervention 
indicated (e.g., tube 
feeding, total parenteral 
nutrition) 
URINARY
Urinary Tract 
Obstruction 
NA 
Signs or symptoms 
of urinary tract 
obstruction without 
hydronephrosis or 
renal dysfunction 
Signs or symptoms of 
urinary tract 
obstruction with 
hydronephrosis or 
renal dysfunction 
Obstruction causing life-
threatening 
consequences 
 
2018N360917_00


2015N227852_00
CONFIDENTIAL
200911
97
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
SITE REACTIONS TO INJECTIONS AND INFUSIONS
Injection Site Pain 
or Tenderness 
Report only one 
Pain or 
tenderness 
causing no or 
minimal limitation 
of use of limb 
Pain or tenderness 
causing greater 
than minimal 
limitation of use of 
limb 
Pain or tenderness 
causing inability to 
perform usual social 
& functional activities 
Pain or tenderness 
causing inability to 
perform basic self-care 
function OR 
Hospitalization indicated 
Injection Site 
Erythema or 
Redness13 
Report only one 
> 15 years of age 
2.5 to < 5 cm in 
diameter OR 6.25 
to < 25 cm2 
surface area AND 
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities 
≥ 5 to < 10 cm in 
diameter OR ≥ 25 
to < 100 cm2 
surface area OR 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
≥ 10 cm in diameter 
OR ≥ 100 cm2 
surface area OR 
Ulceration OR 
Secondary infection 
OR Phlebitis OR
Sterile abscess OR 
Drainage OR 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Potentially life-
threatening 
consequences (e.g., 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue) 
≤ 15 years of age 
≤2.5 cm in 
diameter 
> 2.5 cm in 
diameter with < 
50% surface area 
of the extremity 
segment involved 
(e.g., upper arm or 
thigh) 
≥ 50% surface area 
of the extremity 
segment involved 
(e.g., upper arm or 
thigh) OR Ulceration 
OR Secondary 
infection OR Phlebitis 
OR Sterile abscess 
OR Drainage 
Potentially life-
threatening 
consequences (e.g., 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue) 
Injection Site 
Induration or 
Swelling 
Report only one 
> 15 years of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 
years of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 
years of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, > 15 years of 
age 
≤ 15 years of age 
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15 
years of age 
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15 
years of age 
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, ≤ 15 years of 
age 
Injection Site 
Pruritus 
Itching localized 
to the injection 
site that is 
relieved 
spontaneously or 
in < 48 hours of 
treatment 
Itching beyond the 
injection site that is 
not generalized OR 
Itching localized to 
the injection site 
requiring ≥ 48 
hours treatment 
Generalized itching 
causing inability to 
perform usual social 
& functional activities 
NA 
LABORATORY VALUES Chemistries
Acidosis 
NA 
pH ≥ 7.3 to < Lower 
limit of normal 
(LLN) 
pH < 7.3 without life-
threatening 
consequences 
pH < 7.3 with life-
threatening 
consequences 
Albumin, Low (g/dL; 
g/L) 
3.0 to < LLN 
30 to < LLN 
≥ 2.0 to < 3.0
≥ 20 to < 30 
< 2.0 
< 20 
NA 
 
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98
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Alkaline 
Phosphatase, High 
1.25 to < 2.5 x 
ULN 
2.5 to < 5.0 x ULN 
5.0 to < 10.0 x ULN 
≥ 10.0 x ULN 
Alkalosis 
NA 
pH > ULN to ≤ 7.5 
pH > 7.5 without life-
threatening 
consequences 
pH > 7.5 with life-
threatening 
consequences 
ALT or SGPT, High 
Report only one 
1.25 to < 2.5 x 
ULN 
2.5 to < 5.0 x ULN 
5.0 to < 10.0 x ULN 
≥ 10.0 x ULN 
Amylase 
(Pancreatic) or 
Amylase (Total), 
High 
Report only one 
1.1 to < 1.5 x ULN 
1.5 to < 3.0 x ULN 
3.0 to < 5.0 x ULN 
≥ 5.0 x ULN 
AST or SGOT, High 
Report only one 
1.25 to < 2.5 x 
ULN 
2.5 to < 5.0 x ULN 
5.0 to < 10.0 x ULN 
≥ 10.0 x ULN 
Bicarbonate, Low
(mEq/L; mmol/L) 
16.0 to < LLN 
16.0 to < LLN 
11.0 to < 16.0 
11.0 to < 16.0 
8.0 to < 11.0 
8.0 to < 11.0 
< 8.0 
< 8.0 
Bilirubin Direct 
Bilirubin14, High 
> 28 days of age 
NA 
NA 
> ULN 
> ULN with life-
threatening 
consequences (e.g., 
signs and symptoms of 
liver failure) 
≤ 28 days of age 
ULN to ≤ 1 mg/dL 
> 1 to ≤ 1.5 mg/dL 
> 1.5 to ≤ 2 mg/dL 
> 2 mg/dL 
Total Bilirubin, High 
> 28 days of age 
1.1 to < 1.6 x ULN 
1.6 to < 2.6 x ULN 
2.6 to < 5.0 x ULN 
≥ 5.0 x ULN 
≤ 28 days of age 
Total Bilirubin for 
Term and Preterm 
Neonates 
Total Bilirubin for 
Term and Preterm 
Neonates 
Total Bilirubin for 
Term and Preterm 
Neonates 
Total Bilirubin for Term 
and Preterm Neonates 
Calcium, High 
(mg/dL; mmol/L) 
≥ 7 days of age 
10.6 to < 11.5 
2.65 to < 2.88 
11.5 to < 12.5 
2.88 to < 3.13 
12.5 to < 13.5 
3.13 to < 3.38 
≥ 13.5 
≥ 3.38 
< 7 days of age 
11.5 to < 12.4 
2.88 to < 3.10 
12.4 to < 12.9 
3.10 to < 3.23 
12.9 to < 13.5 
3.23 to < 3.38 
≥ 13.5 
≥ 3.38 
Calcium (Ionized), 
High (mg/dL; 
mmol/L) 
> ULN to < 6.0
> ULN to < 1.5 
6.0 to < 6.4 
1.5 to < 1.6 
6.4 to < 7.2 
1.6 to < 1.8 
≥ 7.2 
≥ 1.8 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Calcium, Low 
(mg/dL; mmol/L) 
≥ 7 days of age 
7.8 to < 8.4 
1.95 to < 2.10 
7.0 to < 7.8 
1.75 to < 1.95 
6.1 to < 7.0 
1.53 to < 1.75 
< 6.1 
< 1.53 
< 7 days of age 
6.5 to < 7.5 
1.63 to < 1.88 
6.0 to < 6.5 
1.50 to < 1.63 
5.50 to < 6.0 
1.38 to < 1.50 
< 5.50 
< 1.38 
Calcium (Ionized), 
Low (mg/dL; mmol/L) 
< LLN to 4.0 
< LLN to 1.0 
3.6 to < 4.0 
0.9 to < 1.0 
3.2 to < 3.6 
0.8 to < 0.9 
< 3.2 
< 0.8 
Cardiac Troponin I, 
High 
NA 
NA 
NA 
Levels consistent with 
myocardial infarction or 
unstable angina as 
defined by the local 
laboratory 
Creatine Kinase, 
High 
3 to < 6 x ULN 
6 to < 10 x ULN 
10 to < 20 x ULN 
≥ 20 x ULN 
Creatinine, High 
1.1 to 1.3 x ULN 
> 1.3 to 1.8 x ULN 
OR Increase of > 
0.3 mg/dL above 
baseline 
> 1.8 to < 3.5 x ULN 
OR Increase of 1.5 to 
< 2.0 x above 
baseline 
≥ 3.5 x ULN OR 
Increase of ≥ 2.0 x 
above baseline 
Creatinine 
Clearance15 or
Estimated 
glomerular filtration 
rate (eGFR), Low 
Report only one 
NA 
< 90 to 60 mL/min 
or mL/min/1.73 m2 
OR 10 to < 30% 
decrease from 
baseline 
< 60 to 30 mL/min or 
mL/min/1.73 m2 OR 
≥ 30 to < 50% 
decrease from 
baseline 
< 30 mL/min or 
mL/min/1.73 m2 OR ≥ 
50% decrease from 
baseline or dialysis 
needed 
Glucose 
(mg/dL; mmol/L) 
Fasting, High 
110 to 125 
6.11 to < 6.95 
> 125 to 250 
6.95 to < 13.89 
> 250 to 500 
13.89 to < 27.75 
> 500 
≥ 27.75 
Nonfasting, High 
116 to 160 
6.44 to < 8.89 
> 160 to 250 
8.89 to < 13.89 
> 250 to 500 
13.89 to < 27.75 
> 500 
≥ 27.75 
Glucose, Low 
(mg/dL; mmol/L) 
≥ 1 month of age 
55 to 64 
3.05 to 3.55 
40 to < 55 
2.22 to < 3.05 
30 to < 40 
1.67 to < 2.22 
< 30 
< 1.67 
Lactate, High 
ULN to < 2.0 x 
ULN without 
acidosis 
≥ 2.0 x ULN without 
acidosis 
Increased lactate with 
pH < 7.3 without life-
threatening 
consequences 
Increased lactate with 
pH < 7.3 with life-
threatening 
consequences 
Lipase, High 
1.1 to < 1.5 x ULN 
1.5 to < 3.0 x ULN 
3.0 to < 5.0 x ULN 
≥ 5.0 x ULN 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Lipid Disorders 
(mg/dL; mmol/L) 
Cholesterol, 
Fasting, High 
≥ 18 years of age 
200 to < 240 
5.18 to < 6.19 
240 to < 300 
6.19 to < 7.77 
≥ 300 
≥ 7.77 
NA 
< 18 years of age 
170 to < 200 4.40 
to < 5.15 
200 to < 300 5.15 to 
< 7.77 
≥ 300 ≥7.77 
NA 
Low Density 
Lipoprotein (LDL),
Fasting, High 
≥ 18 years of age 
130 to < 160 3.37 
to < 4.12 
160 to < 190 4.12 to 
< 4.90 
≥ 190 ≥ 4.90 
NA 
> 2 to < 18 years of 
age 
110 to < 130 2.85 
to < 3.34 
130 to < 190 3.34 to 
< 4.90 
≥ 190 ≥ 4.90 
NA 
Triglycerides, 
Fasting, High 
150 to 300 
1.71 to 3.42 
>300 to 500 
>3.42 to 5.7 
>500 to < 1,000 
>5.7 to 11.4 
> 1,000 
> 11.4 
Magnesium16, Low 
(mEq/L; mmol/L) 
1.2 to < 1.4 
0.60 to < 0.70 
0.9 to < 1.2 
0.45 to < 0.60 
0.6 to < 0.9 
0.30 to < 0.45 
< 0.6 
< 0.30 
Phosphate, Low 
(mg/dL; mmol/L) 
> 14 years of age 
2.0 to < LLN 
0.81 to < LLN 
1.4 to < 2.0 
0.65 to < 0.81 
1.0 to < 1.4 
0.32 to < 0.65 
< 1.0 
< 0.32 
1 to 14 years of age 
3.0 to < 3.5 
0.97 to < 1.13 
2.5 to < 3.0 
0.81 to < 0.97 
1.5 to < 2.5 
0.48 to < 0.81 
< 1.5 
< 0.48 
< 1 year of age 
3.5 to < 4.5 
1.13 to < 1.45 
2.5 to < 3.5 
0.81 to < 1.13 
1.5 to < 2.5 
0.48 to < 0.81 
< 1.5 
< 0.48 
Potassium, High 
(mEq/L; mmol/L) 
5.6 to < 6.0 
5.6 to < 6.0 
6.0 to < 6.5 
6.0 to < 6.5 
6.5 to < 7.0 
6.5 to < 7.0 
≥ 7.0 
≥ 7.0 
Potassium, Low 
(mEq/L; mmol/L) 
3.0 to < 3.4 
3.0 to < 3.4 
2.5 to < 3.0 
2.5 to < 3.0 
2.0 to < 2.5 
2.0 to < 2.5 
< 2.0 
< 2.0 
Sodium, High 
(mEq/L; mmol/L) 
146 to < 150 
146 to < 150 
150 to < 154 
150 to < 154 
154 to < 160 
154 to < 160 
≥ 160 
≥ 160 
Sodium, Low 
(mEq/L; mmol/L) 
130 to < 135 
130 to < 135 
125 to < 130 
125 to < 135 
121 to < 125 
121 to < 125 
≤ 120 
≤ 120 
Uric Acid, High 
(mg/dL; mmol/L) 
7.5 to < 10.0 
0.45 to < 0.59 
10.0 to < 12.0 
0.59 to < 0.71 
12.0 to < 15.0 
0.71 to < 0.89 
≥ 15.0 
≥ 0.89 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
HEMATOLOGY
Absolute cluster of 
differentiation 4 
(CD4+) Count, Low 
(cell/mm3; cells/L) 
> 5 years of age (not 
HIV infected) 
300 to < 400 
300 to < 400 
200 to < 300 
200 to < 300 
100 to < 200 
100 to < 200 
< 100 
< 100 
Absolute 
Lymphocyte Count, 
Low 
(cell/mm3; cells/L) 
> 5 years of age 
(not HIV infected) 
600 to < 650 
0.600 x 109 to < 
0.650 x 109
500 to < 600 
0.500 x 109 to < 
0.600 x 109
350 to < 500 
0.350 x 109 to < 
0.500 x 109
< 350 
< 0.350 x 109
Absolute Neutrophil 
Count (ANC), Low 
(cells/mm3; cells/L) 
> 7 days of age 
800 to 1,000 
0.800 x 109 to 
1.000 x 109
600 to 799 
0.600 x 109 to 0.799 
x 109
400 to 599 
0.400 x 109 to 0.599 
x 109
< 400 
< 0.400 x 109
2 to 7 days of age 
1,250 to 1,500 
1.250 x 109 to 
1.500 x 109
1,000 to 1,249 
1.000 x 109 to 1.249 
x 109
750 to 999 
0.750 x 109 to 0.999 
x 109
< 750 
< 0.750 x 109
≤ 1 day of age 
4,000 to 5,000 
4.000 x 109 to 
5.000 x 109 
3,000 to 3,999 
3.000 x 109 to 3.999 
x 109
1,500 to 2,999 
1.500 x 109 to 2.999 
x 109
< 1,500 
< 1.500 x 109
Fibrinogen, 
Decreased (mg/dL; 
g/L) 
100 to < 200 
1.00 to < 2.00 OR 
0.75 to < 1.00 x 
LLN 
75 to < 100 
0.75 to < 1.00 OR ≥ 
0.50 to < 0.75 x 
LLN 
50 to < 75 
0.50 to < 0.75 OR 
0.25 to < 0.50 x LLN 
< 50 
< 0.50 OR < 0.25 x LLN 
OR Associated with 
gross bleeding 
Hemoglobin17, Low 
(g/dL; mmol/L)18 
≥ 13 years of age 
(male only) 
10.0 to 10.9 
6.19 to 6.76 
9.0 to < 10.0 
5.57 to < 6.19 
7.0 to < 9.0 
4.34 to < 5.57 
< 7.0 
< 4.34 
≥ 13 years of age 
(female only) 
9.5 to 10.4 
5.88 to 6.48 
8.5 to < 9.5 
5.25 to < 5.88 
6.5 to < 8.5 
4.03 to < 5.25 
< 6.5 
< 4.03 
57 days of age to < 
13 years of age 
(male and female) 
9.5 to 10.4 
5.88 to 6.48 
8.5 to < 9.5 
5.25 to < 5.88 
6.5 to < 8.5 
4.03 to < 5.25 
< 6.5 
< 4.03 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
36 to 56 days of age 
(male and female) 
8.5 to 9.6 
5.26 to 5.99 
7.0 to < 8.5 
4.32 to < 5.26 
6.0 to < 7.0 
3.72 to < 4.32 
< 6.0 
< 3.72 
22 to 35 days of age 
(male and female) 
9.5 to 11.0 
5.88 to 6.86 
8.0 to < 9.5 
4.94 to < 5.88 
6.7 to < 8.0 
4.15 to < 4.94 
< 6.7 
< 4.15 
8 to ≤ 21 days of age 
(male and female) 
11.0 to 13.0 
6.81 to 8.10 
9.0 to < 11.0 
5.57 to < 6.81 
8.0 to < 9.0 
4.96 to < 5.57 
< 8.0 
< 4.96 
≤ 7 days of age 
(male and female) 
13.0 to 14.0 
8.05 to 8.72 
10.0 to < 13.0 
6.19 to < 8.05 
9.0 to < 10.0 
5.59 to < 6.19 
< 9.0 
< 5.59 
INR, High 
(not on 
anticoagulation 
therapy) 
1.1 to < 1.5 x ULN 
1.5 to < 2.0 x ULN 
2.0 to < 3.0 x ULN 
≥ 3.0 x ULN 
Methemoglobin (% 
hemoglobin) 
5.0 to < 10.0% 
10.0 to < 15.0% 
15.0 to < 20.0% 
≥ 20.0% 
PTT, High 
(not on 
anticoagulation 
therapy) 
1.1 to < 1.66 x 
ULN 
1.66 to < 2.33 x 
ULN 
2.33 to < 3.00 x ULN 
≥ 3.00 x ULN 
Platelets, 
Decreased 
(cells/mm3; cells/L) 
100,000 to < 
124,999 100.000 
x 109 to < 124.999 
x 109
50,000 to < 100,000 
50.000 x 109 to < 
100.000 x 109 
25,000 to < 50,000 
25.000 x 109 to < 
50.000 x 109
< 25,000 < 25.000 x 109
PT, High 
(not on 
anticoagulation 
therapy 
1.1 to < 1.25 x 
ULN 
1.25 to < 1.50 x 
ULN 
1.50 to < 3.00 x ULN 
≥ 3.00 x ULN 
WBC, Decreased
(cells/mm3; cells/L) 
> 7 days of age 
2,000 to 2,499 
2.000 x 109 to 
2.499 x 109
1,500 to 1,999 
1.500 x 109 to 1.999 
x 109
1,000 to 1,499 
1.000 x 109 to 1.499 
x 109
< 1,000 
< 1.000 x 109
≤ 7 days of age 
5,500 to 6,999 
5.500 x 109 to 
6.999 x 109 
4,000 to 5,499 
4.000 x 109 to 5.499 
x 109
2,500 to 3,999 
2.500 x 109 to 3.999 
x 109
< 2,500 
< 2.500 x 109
URINALYSIS
Glycosuria (random 
collection tested by 
dipstick) 
Trace to 1+ or 
≤ 250 mg 
2+ or ˃ 250 to 
≤ 500 mg 
> 2+ or > 500 mg 
NA 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Hematuria (not to be 
reported based on 
dipstick findings or 
on blood believed to 
be of menstrual 
origin) 
6 to < 10 RBCs 
per high power 
field 
≥ 10 RBCs per high 
power field 
Gross, with or without 
clots OR With RBC 
casts OR Intervention 
indicated 
Life-threatening 
consequences 
Proteinuria (random 
collection tested by 
dipstick) 
1+ 
2+ 
3+ or higher 
NA 
1.
Blood pressure norms for children <18 years of age can be found in: Expert Panel on Integrated Guidelines for 
Cardiovascular Health and Risk Reduction in Children and Adolescents. Pediatrics 2011;128;S213; originally 
published online November 14, 2011; DOI: 10.1542/peds.2009-2107C.  
2.
As per Bazett’s formula.  
3.
For pruritus associated with injections or infusions, see the Site Reactions to Injections and Infusions section.  
4.
Definition: A disorder characterized by fat loss in the face, extremities, and buttocks. 
5.
Definition: A disorder characterized by abnormal fat accumulation on the back of the neck, breasts, and abdomen.  
6.
Bone mineral density (BMD) t and z scores can be found in: Kanis JA on behalf of the World Health Organization 
Scientific Group (2007). Assessment of osteoporosis at the primary health-care level. Technical Report. World 
Health Organization Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, UK. 2007: Printed 
by the University of Sheffield.  
7.
Definition: A delivery of a live-born neonate occurring at ≥20 to <37 weeks gestational age. 
8.
Definition: A clinically recognized pregnancy occurring at <20 weeks gestational age.  
9.
Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and/or shortness of 
breath. 
10. For pain associated with injections or infusions, see the Site Reactions to Injections and Infusions section.
11. Definition: A disorder characterized by fever, arthralgia, myalgia, skin eruptions, lymphadenopathy, marked 
discomfort, and/or dyspnea.
12. WHO reference tables may be accesed by clicking the desired age range or by accessing the following URLs: 
http://www.who.int/growthref/who2007_bmi_for_age/en/ for participants >5 to 19 years of age and 
http://www.who.int/childgrowth/standards/chart_catalogue/en/ for those ≤ 5 years of age.  
13. Injection Site Erythema or Redness should be evaluated and graded using the greatest single diameter or
measured surface area. 
14. Direct bilirubin >1.5 mg/dL in a participant <28 days of age should be graded as Grade 2, if <10% of the total 
bilirubin.  
15. Use the applicable formula (i.e., Cockroft-Gault in mL/min or Schwatrz in mL/min/1.73m2).  
16. To convert a magnesium value from mg/dL to mmol/L, laboratories should multiply by 0.4114.  
17. Male and female sexes are defined as sex at birth. 
18. The conversion factor used to convert g/dL to mmol/L is 0.6206 and is the most commonly used conversion factor. 
For grading hemoglobin results obtained by an analytic method with a conversion factor other than 0.6206, the 
result must be converted to g/dL using the appropriate conversion factor for the particular laboratory.  
 
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12.9.
Appendix 9: Toxicity Management
ANEMIA
Grade 1 (mild) hemoglobin decrease:
Any hemoglobin decrease meeting the definition of Grade 1 must be repeated with the 
following additional tests:
3.
peripheral blood smear
4.
indirect bilirubin
(abnormal if increased >50% from baseline)
5.
haptoglobin
(abnormal if 25 mg/dL)
6.
reticulocyte count
(abnormal if 4%) 
If the additional tests are within the normal range, subjects may continue study 
medication.  If one or more of the additional tests is abnormal or suggestive of hemolytic 
anemia as specified above, subjects will permanently discontinue study medication and 
be withdrawn from the trial.  Subjects should be followed up until resolution of anemia.
Grade 2 (moderate) hemoglobin decrease:
Any hemoglobin decrease meeting the definition of Grade 2 must be repeated with the 
following additional tests:
7.
peripheral blood smear
8.
indirect bilirubin
(abnormal if increased > 50% from baseline)
9.
haptoglobin
(abnormal if 25 mg/dL)
10. reticulocyte count
(abnormal if 4%) 
If the additional tests are within the normal range, subjects may continue study 
medication.  If one or more of the additional tests is abnormal or suggestive of hemolytic 
anemia as specified above, subjects will permanently discontinue study medication and 
be withdrawn from the trial.  Consultation with a Hematologist should be considered.  
Subjects should be followed up until resolution of anemia.
Grade 3 (severe) or Grade 4 (potentially life threatening) hemoglobin decrease:
Any hemoglobin decrease meeting the definition of Grade 3 or 4 must be repeated with 
the following additional tests:
11. peripheral blood smear
12. indirect bilirubin
13. haptoglobin
14. reticulocyte count 
 
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Subjects will permanently discontinue study medication and be withdrawn from the trial.  
Consultation with a Hematologist should be considered.  Subjects should be followed up 
until resolution of anemia.
TOTAL BILIRUBIN ELEVATION
Grade 1 (mild) bilirubin elevation (1.1 - 1.5 times ULN) or Grade 2 (moderate 
- 1.6-2.5 times ULN):
Any bilirubin value above the upper limit of normal must be repeated and fractionated 
(direct and indirect bilirubin).  Subjects may continue study medication.  Subjects should 
be followed up until resolution (return to baseline) of elevation.
Grade 3 (severe – 2.6-5.0 times ULN) or 4 (life-threatening - > 5.0 times ULN) 
bilirubin elevation:
Any bilirubin value above the upper limit of normal must be repeated and fractionated 
(direct and indirect bilirubin).  Subjects will permanently discontinue study medication 
and be withdrawn from the trial.  Subjects should be followed up until resolution (return 
to baseline) of bilirubin elevation.
AST AND ALT ELEVATION
See Appendix 9.
RASH
Grade 1 rash (Localized macular rash):
Subjects with Grade 1 rash should be evaluated by the Investigator immediately.  A 
dermatologist may be consulted and a biopsy may be obtained if recommended by the 
dermatologist.  The study drug should be permanently discontinued if the following signs 
or symptoms are noted at any time:
15. Temperature > 38.5°C
16. Lymphadenopathy
17. Pharyngitis
18. Any indication of internal organ involvement (hepatitis, nephritis)
In the absence of the above signs or symptoms, subjects with Grade 1 rash may continue 
the study drug at the discretion of the Investigator.  The subject should be advised to 
contact the Investigator immediately if there is any worsening of the rash, if any systemic 
signs or symptoms worsen, or if mucosal ulceration develops. If the rash is considered to 
be most likely due to concomitant illness or non-study medication, standard management, 
including discontinuation of the likely causative agent, should be undertaken. If no other 
causative factor is found after clinical evaluation, the subject may be treated 
symptomatically until the rash resolves. Antihistamines, topical corticosteroids or 
antipruritic agents may be prescribed.  The subject should remain on the study to be 
followed for safety and PK as outlined in Section 10.5.
 
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Grade 2 rash (Diffuse macular, maculopapular, or morbilliform rash OR Target
lesions):
Subjects with Grade 2 rash should be evaluated by the Investigator immediately.  Digital 
photographs should be obtained.  A dermatologist may be consulted and a biopsy may be 
obtained if recommended by the dermatologist.  The study drug should be permanently 
discontinued if the following signs or symptoms are noted at any time:
19. Temperature > 38.5°C
20. Lymphadenopathy
21. Pharyngitis
22. Any indication of internal organ involvement (hepatitis, nephritis)
In the absence of the above signs or symptoms, subjects with Grade 2 rash may continue 
the study drug at the discretion of the Investigator.  It should be noted that oral mucosal 
erosions may be part of a Grade 2 rash.  Any mucosal ulceration increases the severity 
of the rash to at least Grade 3.  The subject should be advised to contact the Investigator 
immediately if there is any worsening of the rash, if any systemic signs or symptoms 
worsen, or if mucosal ulceration develops. If the rash is considered to be most likely due 
to concomitant illness or non-study medication, standard management, including 
discontinuation of the likely causative agent, should be undertaken. If no other causative 
factor is found after clinical evaluation, the subject may be treated symptomatically until 
the rash resolves. Antihistamines, topical corticosteroids or antipruritic agents may be 
prescribed.  The subject should remain on the study to be followed for safety and PK as 
outlined in Section 10.5.
Grade 3 rash (Diffuse macular, maculopapular, or morbilliform rash with vesicles 
or limited number of bullae OR Superficial ulcerations of mucous membrane 
limited to one site):
Subjects with a Grade 3 rash will permanently discontinue the study medication.  The 
subject should be evaluated in the physician’s office immediately and should be seen in 
the physician’s office or contacted by phone every 2 days until the rash resolves.  A 
dermatologist should be consulted and digital photographs and a biopsy should be 
obtained.  Antihistamines, topical corticosteroids or antipruritic agents may be prescribed 
at the discretion of the Investigator.  The subject should be advised to contact the 
Investigator immediately if there is any worsening of the rash, if any systemic signs or 
symptoms appear, or if mucosal involvement develops.  The subject should remain on the 
study to be followed for safety and PK as outlined in Section 10.5.
Grade 4 rash (Extensive or generalized bullous lesions OR Stevens-Johnson 
syndrome OR Ulceration of mucous membrane involving two or more distinct 
mucosal sites OR Toxic epidermal necrolysis (TEN)):
Subjects with a Grade 4 rash will permanently discontinue the study medication.  A 
dermatologist should be consulted and digital photographs and a biopsy should be 
obtained.  Sponsor and GSK Medical Monitor should be notified of this serious adverse 
event within 24 hours via phone or fax.  The subject should be closely followed everyday 
until resolution of the reaction.  The subject should remain on the study to be followed 
for safety and PK as outlined in Section 10.5.
 
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ALLERGIC REACTION
Grade 1 allergic reaction (Pruritis without rash):
Subjects with Grade 1 allergic reaction should be evaluated by the Investigator 
immediately.  The study drug should be permanently discontinued if the following signs 
or symptoms are noted at any time:
23. Temperature > 38.5°C
24. Eosinophilia
25. Respiratory involvement including bronchospasm, laryngospasm, or 
angioedema
26. Any indication of internal organ involvement (hepatitis, nephritis)
In the absence of the above signs or symptoms, subjects with Grade 1 allergic reaction 
may continue the study drug at the discretion of the Investigator.  The subject should be 
advised to contact the Investigator immediately if there is any worsening of the allergic 
reaction and/or if any systemic signs or symptoms worsen.  If the allergic reaction is 
considered to be most likely due to concomitant illness or non-study medication, standard
management, including discontinuation of the likely causative agent, should be 
undertaken.  If no other causative factor is found after clinical evaluation, the subject may 
be treated symptomatically until the rash resolves. Antihistamines, topical corticosteroids 
or antipruritic agents may be prescribed.  The subject should remain on the study to be 
followed for safety and PK as outlined.
Grade 2 allergic reaction (Localized urticaria):
Subjects with Grade 2 allergic reaction should be evaluated by the Investigator 
immediately.  The study drug should be permanently discontinued if the following signs 
or symptoms are noted at any time:
27. Temperature > 38.5°C
28. Eosinophilia
29. Respiratory involvement including bronchospasm, laryngospasm, or 
angioedema
30. Any indication of internal organ involvement (hepatitis, nephritis)
In the absence of the above signs or symptoms, subjects with Grade 2 allergic reaction 
may continue the study drug at the discretion of the Investigator.  The subject should be 
advised to contact the Investigator immediately if there is any worsening of the allergic 
reaction and/or if any systemic signs or symptoms worsen.  If the allergic reaction is 
considered to be most likely due to concomitant illness or non-study medication, standard 
management, including discontinuation of the likely causative agent, should be 
undertaken.  If no other causative factor is found after clinical evaluation, the subject may 
be treated symptomatically until the rash resolves. Antihistamines, topical corticosteroids 
or antipruritic agents may be prescribed.  The subject should remain on the study to be 
followed for safety and PK as outlined in Section 7.
 
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Grade 3 allergic reaction (Generalized urticaria or angioedema):
Subjects will permanently discontinue the study medication and be withdrawn from the 
trial.  Subjects will be treated as clinically appropriate.  Subjects should be followed up 
until resolution of the adverse event and standard management should be undertaken.
Grade 4 allergic reaction (Anaphylaxis):
Subjects will permanently discontinue the study medication and be withdrawn from the 
trial.  Subjects will be treated as clinically appropriate.  Subjects should be followed up 
until resolution of the adverse event and standard management should be undertaken.
Revised ACTG Toxicity Grade
Definitions
Investigator Action
Grade 1
Pruritus without rash
May continue therapy
Grade 2
Localized urticaria
May continue therapy
Grade 3
Generalized urticaria
Angioedema
Discontinue Therapy
Grade 4
Anaphylaxis
Discontinue Therapy
 
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SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
200911
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for A Phase 2a, Multicenter, 
Randomized, Adaptive, Open-label, Dose Ranging Study to 
Evaluate the Antiviral Effect, Safety, Tolerability and 
Pharmacokinetics of Cobicistat-boosted GSK2838232 
Monotherapy Over 10 Days in HIV-1 Infected Adults
Compound Number
:
GSK2838232
Effective Date 
:
11-May-2018
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Study 200911.

This RAP is intended to describe the safety, tolerability, pharmacokinetic, and 
antiviral analyses required for the study. 

This RAP will be provided to the study team members and CRO (PPD) to convey the 
content of the Statistical Analysis Complete (SAC) deliverable.
Author’s Name and Functional Area: 
11-May-2018
Senior Reviewer, PPD
11-May-2018
Lead Statistician, PPD
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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RAP Team Approvals: 
Approver
Date
Approval 
Method
30-APR-2018
Email Approval
Director (Clinical Pharmacology), GSK
01-MAY-2018
eSignature
Director (Clinical Development), GSK
30-APR-2018
Email Approval
Executive Medical Director (SM), GSK
30-APR-2018
Email Approval
Director (Clinical Pharmacology Modelling and 
Simulation), GSK
30-APR-2018
Email Approval
Medical Director (SERM), GSK
03-MAY-2018
Email Approval
Manager (Clinical Data Management), GSK
02-MAY-2018
Email Approval
Manager (Clinical Development), GSK
Clinical Statistics and Clinical Programming Line Approvals:
Approver
Date
Approval Method
30-APR-2018
Signature
Data Analyst Statistician (Clinical Statistics)
30-APR-2018
Signature
Statistics Leader (Clinical Programming)
30-APR-2018
Signature
Senior Statistics Director (Clinical Statistics), GSK
01-MAY-2018
Signature
Programming Manager, GSK
03-MAY-2018
Signature
Programming Manager, GSK
 
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PPD
PPD
PPD
PPD
PPD
PPD
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TABLE OF CONTENTS
PAGE
1.
REPORTING & ANALYSIS PLAN SYNOPSIS.........................................................6
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................9
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................9
2.2.
Study Design ................................................................................................9
2.3.
Statistical Hypotheses.................................................................................10
3.
PLANNED ANALYSES ..........................................................................................10
3.1.
Interim Analyses .........................................................................................10
3.2.
Final Analyses ............................................................................................10
4.
ANALYSIS POPULATIONS ...................................................................................10
4.1.
Protocol Deviations.....................................................................................11
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................13
6.
STUDY POPULATION ANALYSES .......................................................................14
6.1.
Overview of Planned Analyses ...................................................................14
6.2.
Display Details............................................................................................15
6.2.1.
Subject Disposition ......................................................................15
6.2.2.
Protocol Deviations......................................................................15
6.2.3.
Populations analysed...................................................................16
6.2.4.
Demography................................................................................16
6.2.5.
Medical Conditions and Medications............................................16
6.2.5.1.
Medical Conditions .....................................................16
6.2.5.2.
Medications ................................................................17
6.2.6.
Exposure and Treatment Compliance..........................................17
7.
PRIMARY STATISTICAL ANALYSES....................................................................19
7.1.
Efficacy Analyses........................................................................................19
7.1.1.
Overview of Planned Efficacy Analyses .......................................19
7.1.1.1.
Viral Load...................................................................20
7.1.2.
Planned Efficacy Statistical Analyses...........................................21
7.2.
Safety Analyses..........................................................................................22
7.2.1.
Overview of Planned Safety Analyses .........................................22
7.2.2.
Display Details.............................................................................25
7.2.2.1.
Adverse Event Safety Analyses..................................25
7.2.2.2.
Clinical Laboratory Safety Analyses ...........................26
7.2.2.3.
Other Safety Analyses................................................26
7.2.2.3.1.
Electrocardiograms.................................26
7.2.2.3.2.
Vital Signs ..............................................26
7.2.2.3.3.
Hepatobiliary (Liver)................................27
7.3.
Pharmacokinetic Analyses..........................................................................28
7.3.1.
Overview of Planned Pharmacokinetic Analyses .........................28
7.3.2.
Drug Concentration Measures .....................................................28
7.3.3.
Pharmacokinetic Parameters.......................................................28
7.3.3.1.
Deriving Pharmacokinetic Parameters........................28
 
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7.3.3.2.
Statistical Analysis of Pharmacokinetic 
Parameters.................................................................29
8.
PHARMACODYNAMIC ANALYSES.......................................................................31
9.
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES ...................................33
9.1.
PK/PD Analyses of HIV-1 RNA...................................................................33
9.2.
Concentration-QTcF Analyses....................................................................35
10. SECONDARY STATISTICAL ANALYSES .............................................................36
10.1.
Efficacy Analyses........................................................................................36
10.1.1.
Overview of Planned Efficacy Analyses .......................................36
10.1.1.1.
Immunology................................................................36
10.1.1.2.
Clinical Virology..........................................................36
11. REFERENCES.......................................................................................................37
12. APPENDICES........................................................................................................39
12.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................40
12.1.1.
Exclusions from Per Protocol Population .....................................40
12.2.
Appendix 2: Time & Events.........................................................................41
12.2.1.
Protocol Defined Time & Events ..................................................41
12.3.
Appendix 3: Assessment Windows .............................................................44
12.3.1.
Definitions of Assessment Windows for Analyses........................44
12.4.
Appendix 4: Treatment States and Phases.................................................45
12.4.1.
Treatment Phases .......................................................................45
12.4.2.
Treatment States .........................................................................45
12.4.2.1.
Treatment States for Laboratory Data.........................45
12.4.2.2.
Treatment States for AE Data.....................................45
12.4.2.3.
Classification of cardiovascular adverse events 
of special interest .......................................................45
12.4.2.4.
Classification of prior, concomitant, or post-
therapy medications ...................................................46
12.5.
Appendix 5: Data Display Standards & Handling Conventions....................47
12.5.1.
Study Treatment & Sub-group Display Descriptors......................47
12.5.2.
Baseline Definition & Derivations .................................................47
12.5.2.1.
Baseline Definitions....................................................47
12.5.2.2.
Derivations and Handling of Missing Baseline 
Data ...........................................................................47
12.5.3.
Reporting Process & Standards...................................................47
12.6.
Appendix 6: Derived and Transformed Data ...............................................50
12.6.1.
General........................................................................................50
12.6.2.
Study Population..........................................................................51
12.6.3.
Safety ..........................................................................................51
12.7.
Appendix 7: Premature Withdrawals & Handling of Missing Data ...............53
12.7.1.
Premature Withdrawals................................................................53
12.7.2.
Handling of Missing Data.............................................................53
12.7.2.1.
Handling of Missing Dates..........................................53
12.7.2.2.
Handling of Partial Dates............................................54
12.8.
Appendix 8: Values of Potential Clinical Importance ...................................55
12.8.1.
Laboratory Values........................................................................55
 
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12.8.2.
ECG.............................................................................................56
12.8.3.
Vital Signs....................................................................................56
12.8.4.
Methods for Handling Centres .....................................................56
12.9.
Appendix 9: Population Pharmacokinetic Analyses.....................................57
12.9.1.
Blood Sample Collection..............................................................57
12.9.2.
Sample Analysis ..........................................................................57
12.10. Appendix 10: Pharmacodynamic / Biomarker Analyses ..............................58
12.10.1. Viral Genotyping and Phenotyping...............................................58
12.10.2. Genetics ......................................................................................58
12.10.3. Value Evidence and Outcomes....................................................58
12.11. Appendix 11 – Abbreviations & Trade Marks ..............................................59
12.11.1. Abbreviations...............................................................................59
12.11.2. Trademarks .................................................................................60
12.12. Appendix 12: List of Data Displays..............................................................61
12.12.1. Data Display Numbering..............................................................61
12.12.2. Deliverable [Priority].....................................................................61
12.12.3. Study Population Tables..............................................................62
12.12.4. Efficacy Tables ............................................................................66
12.12.5. Efficacy Figures ...........................................................................68
12.12.6. Safety Tables...............................................................................68
12.12.7. Safety Figures .............................................................................71
12.12.8. Pharmacokinetic Tables...............................................................72
12.12.9. Pharmacokinetic Figures .............................................................73
12.12.10.Pharmacodynamic Tables ...........................................................74
12.12.11.Pharmacodynamic Figures ..........................................................74
12.12.12.Pharmacokinetic / Pharmacodynamic Tables ..............................75
12.12.13.Pharmacokinetic / Pharmacodynamic Figures .............................75
12.12.14.ICH Listings .................................................................................76
12.12.15.Non-ICH Listings..........................................................................78
12.13. Appendix 13: Model Checking and Diagnostics for Statistical 
Analyses.....................................................................................................82
12.13.1. Statistical Analysis Assumptions..................................................82
 
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1.
REPORTING & ANALYSIS PLAN SYNOPSIS
Overview
Key Elements of the RAP
Purpose

The purpose of this RAP is to describe the planned analyses and output to 
be included in the Clinical Study Report for Study 200911.
Protocol

This RAP is based on the protocol amendment 3 (Dated: 15Jun2017) of 
Study 200911 (GSK Document No.: 2015N227852_03) and eCRF Version 
1.0.
Primary 
Objectives

To evaluate antiviral activity of GSK2838232/Tybost (cobicistat,cobi) in HIV-1 
infected patients during 10 days of monotherapy.

To assess safety and tolerability of GSK2838232/cobi when administered as 
monotherapy over 10 days.

To characterize the pharmacokinetics of GSK2838232 in HIV-1 infected 
patients following GSK2838232/cobi dosing for 10 days.
Primary 
Endpoints

Maximum decline from baseline and change from baseline (Day 1) in plasma 
HIV-1 RNA.

Safety and tolerability parameters, including adverse event, concurrent 
medication, clinical laboratory, electrocardiogram (ECG) and vital signs 
assessments.

GSK2838232 PK parameters following dose administration, as follows:
Day 1: area under the plasma concentration time curve AUC(0-24), 
maximum observed concentration (Cmax), time to maximum observed 
concentration (tmax), concentration at 24 hours post dose (C24), absorption 
lag time (tlag); 
Following last repeat administration on Day 10:  AUC(0-), pre-dose 
concentration (C0), concentration at end of dosing interval (C), Cmax, tmax, 
t½, and apparent oral clearance (CL/F), if data permit
Study 
Design

This is a Phase 2a, multicenter, open-label, adaptive, dose ranging study.
Planned 
Analyses

The final analysis will be performed after the completion of the study and final 
datasets authorization.
Analysis 
Populations

Intent to Treat Exposed Population (ITT): defined as all subjects who meet 
study criteria and are enrolled into the study with documented evidence of 
having received at least 1 dose of treatment and at least one post-baseline 
HIV-1 RNA measurement. This will be the primary population for the final 
efficacy analysis for all active treatment groups.

Per Protocol Population (PP): defined as all subjects who meet study criteria 
and are enrolled into the study with documented evidence of having received 
all doses and all post-baseline HIV-1 RNA measurement, with exceptions of
major protocol deviation. 
 
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Overview
Key Elements of the RAP

Safety Population: defined as all subjects who are enrolled into the study with 
documented evidence of having received at least 1 dose of study treatment.

Pharmacokinetic Population: includes all subjects who receive GSK2838232 
and undergo plasma PK sampling during the study. Subjects for whom a 
plasma PK sample is obtained and assayed will be included in the listing of 
plasma GSK2838232 concentration-time data.  Results from samples 
collected from a subject with emesis occurring within 4 hours of the dose will 
not be considered as evaluable.

Pharmacokinetic/ Pharmacodynamic Population: Subjects who meet criteria 
for Per-Protocol and Pharmacokinetic Population analysis sets and who 
undergo PD sampling during the study.
Hypothesis

No formal hypothesis will be tested.
Primary 
Analyses

Both the PP and ITT Populations will be used for all efficacy analyses if there 
are exclusions from the Per Protocol population. Plasma HIV-1 RNA 
maximum decline and change from baseline during the study will be 
calculated for each subject on each assessment day.
Plasma HIV-1 RNA will be listed by treatment, subject, and assessment day 
and summarized by treatment and assessment day along with change from 
baseline.  Plots of mean and median plasma HIV-1 RNA actual and change 
from baseline data will be generated by treatment and assessment day.
Plasma HIV-1 RNA maximum decline from baseline will be calculated for 
each subject and summarized by treatment.
Together, the data from Parts A and B will be used to investigate the 
complete dose-response curve and the impact of lower doses on potential 
development of resistance. A dose-response curve will be fit to the data from 
Parts A & B.

Safety data will be presented in tabular format and summarized descriptively 
according to GSK’s Integrated Data Standards Library standards and data 
will be in CDISC format. No formal statistical analysis of the safety data will 
be conducted.

Plasma GSK2838232 concentration-time data will be analysed by non-
compartmental methods with WinNonlin Version 6.4 or higher. Calculations 
will be based on the actual sampling times recorded during the study.
Results based on samples collected from a subject with emesis within 4 
hours of the dose will not be considered as evaluable.
All PK data will be stored in the R&D archives, GlaxoSmithKline.
Pharmacokinetic data will be presented in graphical and tabular form and will 
be summarized descriptively. Plasma GSK2838232 PK parameters, with the 
exception of tmax and tlag, will be log-transformed prior to analysis.
Dose proportionality of plasma GSK2838232 PK parameters from Day 1 
[AUC(0-24) and Cmax] and Day 10 [AUC(0-) and Cmax] will be assessed 
 
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Overview
Key Elements of the RAP
using a power model if multiple dose levels are assessed. The power model 
will be fitted by restricted maximum likelihood (REML) using SAS Proc 
Mixed. A fixed effects power model will be used.  The mean slope will be 
estimated from the power model with the corresponding 90% CI.  The 
accumulation ratio (R) and steady-state assessments will be performed, if 
quality of the data permits. Comparisons of Day 10 with Day 1 PK for each 
dose will be used for the accumulation ratio (R) evaluation. Pre-dose 
concentrations between Days 7-10 will be used for steady-state assessment.
Secondary 
Analyses

Relationships between various pharmacokinetic parameters (e.g., AUC, 
Cmax, C, etc.) and pharmacodynamic measures (e.g., log10 reduction from 
baseline in plasma HIV-1 RNA on Day 11) or safety parameters will be 
explored using various models including Emax and linear models. The 
relationship between dose and pharmacodynamic measures will also be 
explored.

Viral genotypic/phenotypic data will be listed and descriptive summaries will 
be provided. Details of the analyses will be provided in the clinical virology 
report.
 
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2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
In protocol amendment 3 (Dated: 15/JUN/2017), the Safety Population is defined as all 
subjects who are enrolled into the study with documented evidence of having received at 
least 1 dose of assigned treatment.  The Safety Population is defined in the RAP as all 
subjects who are enrolled into the study with documented evidence of having received at 
least 1 dose of study treatment.
2.2.
Study Design
Overview of Study Design and Key Features
Part A: GSK2838232/cobi
Once Daily x 10 days1
Part B: GSK2838232/cobi
Once Daily x 10 days1,2
Cohort
N
GSK2838232 Dose
(mg)
Cohort
N
GSK2838232 Dose 
(mg)
1
103
100
2
8
200
3
8
50
4
8
20
1. 
Part A Cohort 1 safety/PK/virology data was evaluated at interim, prior to initiating other cohorts in Part B, which 
are planned to run in a sequential fashion. All doses will be given with 150 mg cobicistat.
2. 
More doses/cohorts (including potential removal of cobi co-dosing) may be added (the maximum dose in Part B 
would not exceed 200 mg with cobicistat unless overall plasma exposure [as AUC and Cmax] was lower in HIV 
infected subjects than in healthy subjects at the same dose level).
3.
Two subjects who were enrolled in Cohort 1 were mis-dosed at 50 mg GSK2838232 for 10 days. These 2 
subjects will be included in and analysed with Cohort 3.
Design 
Features

This is a Phase 2a, multicenter, open label, adaptive dose ranging, study to 
evaluate the antiviral effect, safety, tolerability, and PK of GSK2838232/cobi 
monotherapy over 10 days in HIV-1 infected adults who are not currently 
receiving ART therapy. To minimize the number of subjects exposed to 
suboptimal doses, an adaptive and dose ranging design is applied in this study.

This study consists of a screening visit, a 10-day treatment period, and follow-
up evaluations for 2 weeks following last dose.

Screening will be performed as the patients are identified, within 30 days of the 
first dose of study drug.  Eligible HIV-1 infected subjects will receive study 
treatments for 10 days.
Dosing

All subjects enrolled in Part A will receive 100 mg GSK2838232 and 150 mg 
cobicistat daily for 10 days.

Following the interim analysis of safety, virology and PK data from the first 
cohort of subjects in Part A, the dose levels for Part B were determined to be 
200 mg, 50 mg, and 20 mg GSK2838232 and 150 mg cobicistat.
Treatment 
Assignment

Subjects will be assigned to treatment (active), prior to the start of the study, 
using validated internal software.
Interim 
Analysis

An interim analysis of preliminary safety, tolerability, PK and antiviral activity 
occurred after subjects of Part A Cohort 1 completed their Day 13 visit and is 
described in a separate reporting and analysis plan.
 
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2.3.
Statistical Hypotheses
The primary objectives of this study are to investigate the safety, tolerability, and 
antiviral activity of GSK2838232 administered as monotherapy in combination with 
cobicistat in HIV-1 infected subjects, over a 10-day treatment period. The antiviral 
activity will be assessed by estimating plasma HIV-1 RNA max change from baseline 
during the study.  No formal hypotheses will be tested.
3.
PLANNED ANALYSES
3.1.
Interim Analyses
An interim analysis of preliminary safety, tolerability, PK and antiviral activity occurred
after subjects of Part A Cohort 1 completed their Day 13 visit. Full details of the interim 
analysis are described in a separate reporting and analysis plan. Based on the results of 
the interim analysis, the dose levels for Part B were determined to be 200 mg, 50 mg, and 
20 mg GSK2838232 with 150 mg cobicistat.
3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All subjects have completed the study as defined in the protocol.
2.
All required database cleaning activities have been completed and final database 
release and database freeze has been declared by Data Management.
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), median, minimum, 
and maximum, whereas n and percent will be used as summary statistics for categorical 
variables.  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
All Screened

Comprise all subjects who consented to 
participate in the clinical trial and were 
screened.

Summarize the 
screen failure 
subjects
Safety

Comprise of all subjects who receive at least 
one dose of study treatment.

This population will be based on the treatment 
the subject actually received.

Study Population

Safety
 
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Population
Definition / Criteria
Analyses Evaluated
Intent-To-Treat 
Exposed 

Comprise of all subjects who meet study 
criteria and are enrolled into the study with 
documented evidence of having received at 
least 1 dose of treatment and at least one 
post-baseline HIV-1 RNA measurement.

This population will be based on the treatment 
which the subject actually received.

Efficacy
Per-Protocol

Comprise of all subjects who meet study 
criteria and are enrolled into the study with 
documented evidence of having received all 
doses and all post-baseline HIV-1 RNA 
measurement, with exceptions of those who 
have at least one major protocol deviation.

Protocol deviations that would exclude 
subjects from the PP population are defined in 
Section 4.1 (Protocol Deviations) and 
Appendix 1 (Protocol Deviation Management 
and Definition for Per-Protocol Population).

Efficacy
Pharmacokinetic

Subjects who receive GSK2838232 and 
undergo plasma PK sampling during the study. 
Subjects for whom a plasma PK sample is 
obtained and assayed will be included in the 
listing of plasma GSK2838232 concentration-
time data.  Results from samples collected 
from a subject with emesis occurring within 4 
hours of the dose will not be considered as 
evaluable.

Pharmacokinetic
Pharmacokinetic/ 
Pharmacodynamic

Subjects who meet criteria for Per-Protocol 
and Pharmacokinetic Population analysis sets 
and who undergo PD sampling during the 
study.

Pharmacokinetic/ 
Pharmacodynamic
NOTES: 

Please refer to Appendix 12: List of Data Displays which details the population to be used for each display being 
generated.
4.1.
Protocol Deviations

Important protocol deviations including deviations related to study 
inclusion/exclusion criteria, conduct of the trial, patient management or patient 
assessment) will be summarised and listed.

Important deviations which result in exclusion from the analysis population will also 
be summarised and listed. (Please refer to Appendix 1: Protocol Deviation 
Management and Definitions for Per Protocol Population).
 
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12

Protocol deviations will be tracked by the study team throughout the conduct of the 
study in accordance with the Protocol Deviation Management Plan.
o
Data will be reviewed prior to freezing the database to ensure all important 
deviations and deviations which may lead to exclusion from the analysis are 
captured and categorised on the protocol deviations dataset.
o
This dataset will be the basis for the summaries and listings of protocol 
deviations.

A separate summary and listing of all inclusion/exclusion criteria deviations will also 
be provided. This summary will be based on data as recorded on the 
inclusion/exclusion page of the eCRF.
 
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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS
Table 1 provides an overview of appendices within the RAP for outlining general 
considerations for data analyses and data handling conventions. 
Table 1
Overview of Appendices
Section
Component
12.1
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population
12.2
Appendix 2: Time & Events
12.3
Appendix 3: Assessment Windows
12.4
Appendix 4: Treatment States and Phases
12.5
Appendix 5: Data Display Standards & Handling Conventions
12.6
Appendix 6: Derived and Transformed Data
12.7
Appendix 7: Premature Withdrawals & Handling of Missing Data
12.8
Appendix 8: Values of Potential Clinical Importance
12.9
Appendix 9: Population Pharmacokinetic Analyses
12.10
Appendix 10: Pharmacodynamic / Biomarker Analysis
12.11
Appendix 11: Abbreviations & Trade Marks
12.12
Appendix 12: List of Data Displays
12.13
Appendix 13: Model Checking and Diagnostics for Statistical Analyses
 
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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Analyses
The study population analyses will be based on the Safety population, unless otherwise 
specified.
Table 2 provides an overview of the planned study population analyses, with full details 
of data displays being presented in Appendix 12 List of Data Displays.
Table 2
Overview of Planned Study Population Analyses
Data Displays Generated
Table
Figure
Listing
Subject Disposition
Subject Disposition
Y
Reasons for Screening Failure
Y
Y
Study Treatment Discontinuation
Y
Y
Reasons for Study Withdrawal
Y
Planned and Actual Treatment Assignment
Y
Subjects at Each Visit
Y
Protocol Deviations
Summary of Protocol Deviations
Y
Y
Deviations Leading to Exclusions from Per Protocol 
Population
Y
[1]
Inclusion/Exclusion Criteria Deviations
Y
Y
Populations analysed 
Study Populations
Y
Y
Number of Subjects by Centre
Y
Subjects Excluded from Any Population
Y
Demography & Disease Characteristics at Screening
Demographic Characteristics
Y
Y
Race & Racial Combinations
Y
Y
Race & Racial Combination Details
Y
Cardiovascular Risk Assessment
Y
Family History of Cardiovascular Risk
Y
HIV Risk Factors
Y
Substance Use
Y
Medical Condition & Prior and Concomitant 
Medications
Cardiovascular Medical Conditions
Y
Y
Medical Conditions (Current/Past)
Y
Y
Medication (Concomitant/Prior)
Y
Y
 
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Data Displays Generated
Table
Figure
Listing
Relationship Between ATC Level 1, Ingredients and 
Verbatim Text
Y
HIV Associated Conditions
Y
Exposure and Treatment Compliance
Study Treatment Overall Compliance
Y
Exposure to Study Treatment
Y
Y
[1] Subjects with protocol deviations leading to exclusions from Per Protocol population will be listed in Listing of 
Subjects Excluded from Any Population
6.2.
Display Details
6.2.1.
Subject Disposition
The disposition table will consist of all intent-to-treat subjects  
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, a by-subject listing of 
reasons for study treatment discontinuation, and a by-subject listing of planned and actual 
treatment received will be produced.
The number and percentage of subjects at each visit will be summarized for each 
treatment group and overall. 
6.2.2.
Protocol Deviations
The number and percentage of subjects who had important protocol deviations defined in 
Section 12.1 will be summarized overall and by treatment group.
A listing of important protocol deviations will be produced.
Protocol deviations leading to exclusion from Per Protocol population will be 
summarized (see Section 12.1 for protocol deviations, which may lead to the exclusion of 
a subject from the Per Protocol population).
Subjects excluded from the Per Protocol population can be found in the listing of subjects 
excluded from any populations (see below). 
Inclusion and exclusion criteria deviations will be summarized and listed. 
 
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6.2.3.
Populations analysed
The number of subjects who were enrolled into the study, and the number of subjects 
within each analysis population (ITT, Per Protocol, Safety and PK) will be summarized 
for each treatment group and overall. A by-subject listing showing inclusion within each 
study population will be produced.
The number and percentage of subjects will be summarized by centre for each treatment 
group and overall. 
Subjects excluded from any population, including subjects excluded from the Per 
Protocol population, will be listed.
6.2.4.
Demography
The demographic and baseline characteristics age, sex, race, ethnicity, height, weight, 
BMI, and baseline CDC HIV-1 classification will be summarized by treatment group and 
overall for the ITT 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 family history of cardiovascular risk and substance use history will be 
provided by treatment group and overall. Cardiovascular risk assessment by subject will 
be listed.  
A listing of HIV risk factors and mode of transmission by subject will be produced.
6.2.5.
Medical Conditions and Medications
6.2.5.1.
Medical Conditions
The number and percentage of subjects with each past and current medical condition will 
be reported for each treatment group and overall. Past conditions are those reported as 
‘past’ and current conditions are those reported as ‘current’ at screening.  Past and current 
conditions will be reported separately. Medical conditions will be coded using the 
Medical Dictionary for Regulatory Activities (current MedDRA version at the time of 
DBR) and reported by system organ class (SOC) and preferred term (PT). By-subject 
listings of past and current medical conditions will also be produced.
A summary of cardiovascular medical conditions will be provided by treatment group 
and overall, and a by-subject listing will be produced.
A by-subject listing for HIV associated conditions will be produced.
 
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6.2.5.2.
Medications
For reporting purposes, medications will be classified as prior, concomitant, and/or post-
treatment using the associated start and stop dates recorded in the eCRF and relative to 
the first and last dose dates of investigational product (IP) (see Appendix 4). Medications 
will be coded using the GSK Drug coding dictionary (current version at the time of 
DBR).
Concomitant and prior medications will be summarised by GSK-Drug Anatomical 
Therapeutic Chemical (ATC) classification level 1 (body system) and ingredient. Drugs 
that are composed of a combination of ingredients will be displayed according to the 
ATC classifications of the ingredients, not of the combination. 
The relationship between ATC level 1, ingredients and verbatim text for all medications 
in the study will be listed.
6.2.6.
Exposure and Treatment Compliance
The complete dosing experience will be listed for all subjects. The total duration of 
exposure (number of days on study drug), average daily dose, and cumulative dose will 
be summarized by treatment group.
For subjects who completed the 10-day treatment period in Part A and in Part B of the 
study, the expected number of doses during each treatment period is 10.  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: 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 10-day treatment period in either Part A or Part B, the 
expected cumulative dose of GSK2838232 taken during the treatment period is as 
follows:
Part A

For subjects who received 100 mg GSK2838232, the expected cumulative dose is 
1,000 mg GSK2838232 (the 100 mg of IP is comprised of two 50 mg capsules of 
GSK2838232 administered daily over the 10-day treatment period)
Part B

For subjects who received 200 mg GSK2838232, the expected cumulative dose is 
2,000 mg GSK2838232 (the 200 mg of IP is comprised of four 50mg capsules of 
GSK2838232 administered daily over the 10-day treatment period)
 
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
For subjects who received 50 mg GSK2838232, the expected cumulative dose is
500 mg GSK2838232 (the 50 mg of IP is comprised of one 50 mg capsules of 
GSK2838232 administered daily over the 10-day treatment period)

For subjects who received 20 mg GSK2838232, the expected cumulative dose is 
200 mg GSK2838232 (the 20 mg of IP is comprised of one 20 mg capsule 
administered daily over the 10-day treatment period). 
Each daily dose of GSK2838232 is taken with 150 mg cobicistat.  The expected 
cumulative dose of cobicistat taken during the 10-day treatment period is 1,500 mg.  
For subjects who permanently discontinued study treatment or withdrew early from the 
study, the expected cumulative dose of GSK2838232 taken during the treatment period
will be calculated as follows:
Part A

For subjects who received 100 mg GSK2838232, the expected cumulative dose is 
100 mg*(Last Dose Date – First Dose Date +1)
Part B

For subjects who received 200 mg GSK2838232, the expected cumulative dose is 
200 mg*(Last Dose Date – First Dose Date +1)

For subjects who received 50 mg GSK2838232, the expected cumulative dose is 
50 mg*(Last Dose Date – First Dose Date +1)

For subjects who received 20 mg GSK2838232, the expected cumulative dose is 
20 mg*(Last Dose Date – First Dose Date +1)
For subjects who permanently discontinued study treatment or withdrew early from the 
study, the expected cumulative dose of cobicistat taken during the treatment period is 150 
mg*(Last Dose Date – First Dose Date + 1).
The actual cumulative dose of GSK2838232 for all subjects is the sum of all doses, in 
mg, of study drug consumed for the duration of the study.  Similarly, the actual 
cumulative dose of cobicistat for all subjects is the sum of all doses, in mg, of study drug 
consumed for the duration of the study.  
 
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7.
PRIMARY STATISTICAL ANALYSES
7.1.
Efficacy Analyses
7.1.1.
Overview of Planned Efficacy Analyses
Both the Per Protocol and Intent-To-Treat populations will be used for all efficacy 
analyses if there are subjects excluded from the Per Protocol population.  If there are no 
exclusions (i.e., if the Per Protocol and Intent-To-Treat population do not differ), then the 
Intent-To-Treat population will be used for all efficacy analyses.
Table 3 provides an overview of the planned efficacy analyses, with full details of data 
displays being presented in Appendix 12 List of Data Displays.
Table 3
Overview of Planned Efficacy Analyses
Absolute
Change from Baseline
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Viral Load
Plasma HIV-1 RNA
Y
Y
Change from baseline 
(Day 1) to Day 11 and 
maximum decline from 
baseline in plasma 
HIV-1 RNA
Y
Y
Proportion of subjects 
with plasma HIV-1 
RNA <400 and < 50 
copies/mL 
Y
Proportion of subjects 
with plasma HIV-1 
RNA change from 
baseline >1.5 log10 
copies/mL decrease
Y
Summary of modelled 
Plasma HIV-1 RNA 
mean rate of decline
and maximum decline
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes 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.
 
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7.1.1.1.
Viral Load
Plasma HIV-1 RNA will be listed by treatment, subject, and assessment day and 
summarized by treatment and assessment day along with change from baseline.
A plot of mean plasma HIV-1 RNA actual and change from baseline data will be 
generated by treatment and assessment day. 
Plasma HIV-1 RNA maximum decline from baseline and time to nadir will be calculated 
for each subject and summarized by treatment.
Plasma HIV-1 RNA values will be averaged on the days that it is collected twice (Days 1, 
10, and 11) for baseline and corresponding post-baseline assessments. 
Plasma HIV-1 RNA values below LLOD or above ULOD will be imputed as: <400 
copied/mL to 399, <50 copies/mL to 49, and >75000 copies/mL as 75001.
 
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7.1.2.
Planned Efficacy Statistical Analyses
Plasma HIV-1 RNA change from baseline to Day 11, and also maximum decline from 
baseline will be fitted in a mixed-effects linear model by treatment, with baseline plasma 
HIV-1 RNA and day fitted as fixed effects and subject fitted as a random effect.  
Estimated mean rate of decline (i.e., slope of day) with corresponding 90% CI will be 
provided for each treatment.
Proportion of subjects with plasma HIV-1 RNA <400 and < 50 copies/mL and proportion 
of subjects with plasma HIV-1 RNA change from baseline >1.5 log10 copies/mL decrease 
will be summarized by treatment and visit for ITT and PP Population.
Primary Statistical Analyses
Endpoints

Change from baseline to Day 11 in Plasma HIV-1 RNA

Maximum decline from baseline in Plasma HIV-1 RNA
Model Specification

Plasma HIV-1 RNA change from baseline to Day 11, and also maximum decline from baseline 
will be fitted in a mixed-effects linear model by treatment, with baseline plasma HIV-1 RNA and 
day fitted as fixed effects and subject fitted as a random effect.  
Model Results Presentation

Statistical analysis for change from baseline and maximum decline from baseline will be 
presented in tabular format. The linear model will be used to provide slope, intercept and a 
90% CI of the slope.
Example SAS Code: 
proc mixed data=dataset
class dose day subjid;
model plasma = baseplas day dose;
random subjid / type=un solution; 
run;
 
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7.2.
Safety Analyses
7.2.1.
Overview of Planned Safety Analyses
The primary safety analyses will be based on the Safety population, unless otherwise 
specified.
Table 4 provides an overview of the planned safety analyses, with full details of data 
displays being presented in Appendix 12 List of Data Displays.
Table 4
Overview of Planned Safety Analyses
Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
Adverse Events
Adverse Events 
Overview
Y
All Adverse Events 
Y
Y
Subject Numbers for 
Individual AEs
Y
Summary of All 
Adverse Events by 
Maximum Grade and
SOC and PT
Y
Summary of Drug-
Related Adverse 
Events by Maximum 
Grade and SOC and 
PT
Y
Drug Related Adverse 
Events 
Y
Y
Serious Adverse 
Events 
Y
Y
Drug Related Serious 
Adverse Events 
Y
Adverse Events 
Leading to Withdrawal 
from Study/Permanent 
Discontinuation of 
Study Treatment
Y
Y
Common Adverse 
Events and Common 
Non-Serious Adverse 
Events By Overall 
Frequency
Y
Fatal AEs
Y
Non-Fatal SAEs
Y
AEs of Special Interest
Y
Y
 
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Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
Laboratory Values
Clinical Chemistry by 
Visit
Y
Y
Y
Haematology by Visit
Y
Y
Y
Liver Function by Visit
Y
Y
Y
Treatment Emergent 
Clinical Chemistry 
Toxicities
Y
On-Treatment Lab 
Abnormalities 
Worsened from 
Baseline by Maximum 
Grade - Chemistry 
Y
Treatment Emergent 
Haematology Toxicities
Y
On-Treatment Lab 
Abnormalities 
Worsened from 
Baseline by Maximum 
Grade - Haematology 
Y
Treatment Emergent 
Liver Toxicities
Y
On-Treatment Lab 
Abnormalities 
Worsened from 
Baseline by Maximum 
Grade – Liver Events
Y
Liver Function Lab 
Abnormalities of 
Potential Clinical 
Importance
Y
Y
Chemistry Lab 
Abnormalities of 
Potential Clinical 
Importance 
Y
Y
Haematology Lab 
Abnormalities of 
Potential Clinical 
Importance
Y
Y
Urinalysis Data by Visit
Y
 
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Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
Hepatobiliary (Liver)
Liver Monitoring/ 
Stopping Event 
Reporting
Y
Time on Treatment 
before Liver Stopping 
Event
Y
Summary of Liver 
Biopsy Details
Y
Summary of Liver 
Imaging Results
Y
Medical Conditions for 
Subjects with Liver 
Stopping Events
Y
ECG’s
ECG Findings
Y
Change from Baseline 
in ECG Values
Y
Maximum QTc Values 
Post-Baseline Relative 
to Baseline by 
Category
Y
Maximum Increase in 
QTc Values Post-
Baseline Relative to 
Baseline by Category
Y
All ECG Values for 
Subjects with a Value 
of Potential Clinical 
Importance
Y
Mean (95% CI) 
Change from Baseline 
in QTc interval by Time 
and Treatment
Y
Vital Signs
Vital Signs
Y
Y
Y
Vital Sign Data Outside 
Clinical Concern 
Range
Y
Vital Sign Results by 
Maximum Grade 
Increase Post Baseline 
Relative to Baseline
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes 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.     
 
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7.2.2.
Display Details
7.2.2.1.
Adverse Event Safety Analyses
All adverse event (AE) data will be summarized, sorted by the system organ class and 
preferred term assigned by MedDRA version 20.0, and presented by treatment group.  
The following summaries will be provided:

Adverse events overview

All adverse events by SOC and PT and all adverse events by maximum grade and 
SOC and PT

Drug related adverse events by SOC and PT and drug related adverse events by 
maximum grade and SOC and PT

Serious adverse events

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

Cardiovascular adverse events of special interest
Cardiovascular AEs are defined as myocardial infarction/unstable angina, congestive 
heart failure, arrhythmias, valvulopathy, pulmonary hypertension, cerebrovascular 
events/stroke and transient ischemic attack, peripheral arterial thromboembolism, deep 
venous thrombosis/pulmonary embolism, and revascularization.
The following listings will be provided:

All adverse events

Subject numbers for individual AEs

Drug related adverse events

Serious adverse events

Drug related serious adverse events

Adverse events leading to withdrawal from study/permanent discontinuation of study 
treatment

Fatal adverse events

Non-fatal serious adverse events

Cardiovascular adverse events of special interest
 
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7.2.2.2.
Clinical Laboratory Safety Analyses
Haematology and clinical chemistry parameters collected are listed below.  
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
WBC Count with 
Differential:
RBC Count
MCV
Neutrophils
Haemoglobin
MCH
Lymphocytes with T-cell 
subsets
Haematocrit
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry
BUN
Potassium
AST (SGOT)
Creatinine
Sodium
ALT (SGPT)
Glucose 
Bicarbonates
Alkaline phosphatise
Troponin
Total and direct bilirubin
Total Protein
Albumin
Laboratory values, treatment emergent toxicities, and change from baseline for 
haematology, clinical chemistry, and liver function parameters will be summarized by 
visit and by treatment group.  Laboratory values for haematology, clinical chemistry, 
liver function, and urinalysis will also be listed by subject.  In addition, the number and 
percentage of subjects with on-treatment laboratory abnormalities worsened from 
baseline by maximum grade will be reported for haematology, clinical chemistry, and 
liver function parameters. The number and percentage of subjects with laboratory values 
of potential clinical importance will be summarized and listed (potential clinical 
importance criteria are specified in Section 12.8). 
7.2.2.3.
Other Safety Analyses
7.2.2.3.1.
Electrocardiograms
A summary of the number and percentage of subjects who had abnormal and/or clinically 
significant ECG findings will be displayed by treatment.  Additionally, summary 
statistics of 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 QTcB-interval and QTcF interval 
will be plotted by time and treatment. 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).  
7.2.2.3.2.
Vital Signs
Each vital sign parameter (systolic blood pressure, diastolic blood pressure, and heart 
rate) at every assessed time point will be summarised (n, mean, standard deviation, 
 
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median, minimum, and maximum).  A summary of the number and percentages of vital 
sign changes by category (low, normal/no change, high) from baseline compared to those 
collected on Day 10 will be tabulated, and a summary of vital sign results by maximum 
grade increase post-baseline relative to baseline will be generated.  A by-subject listing of 
vital signs for all subjects will be produced. A summary of the number and percentage of 
subjects who had vital signs outside the clinical concern range will be displayed by day, 
category, and treatment (potential clinical importance criteria are specified in Section 
12.8).
7.2.2.3.3.
Hepatobiliary (Liver)
Liver monitoring/stopping event reporting will be summarized by treatment group.  A 
summary of time on treatment before liver stopping will be displayed.  Listings of 
medical conditions for subjects with liver stopping events and of function lab 
abnormalities of potential clinical importance will also be produced.
 
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7.3.
Pharmacokinetic Analyses
7.3.1.
Overview of Planned Pharmacokinetic Analyses
The pharmacokinetic (PK) analyses will be based on the PK Population for plasma PK 
concentrations, and PK Parameter Population for plasma PK parameters, unless otherwise 
specified.
Table 5 provides an overview of the planned analyses, with full details being presented in 
Appendix 12 List of Data Displays. 
Table 5
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
Plasma PK 
Concentrations
Y
Y[1] 
[2]
Y[1]
Y
Y
Y
Y
Plasma PK 
Parameters
Y
Y
Y
Y
Y[3]
Y
Y
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes 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.
[1]
Linear and Semi-Log plots will be created on the same display.
[2]
Separate mean and median plots will be generated.
[3]
Create as table using GSK listing standard.
7.3.2.
Drug Concentration Measures
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 12.5.3
Reporting Process & Standards).
7.3.3.
Pharmacokinetic Parameters
7.3.3.1.
Deriving Pharmacokinetic Parameters

Refer to Appendix 5: Data Display Standards & Handling Conventions
(Section 12.5.3 Reporting Process & Standards).

The pharmacokinetic parameters will be calculated by standard non-compartmental 
analysis according to current working practices and using Phoenix WinNonlin 
Version 6.4 or higher.

All calculations of non-compartmental parameters will be based on actual sampling 
times.

Pharmacokinetic parameters described in Table 6 will be determined from the plasma 
concentration-time data, as data permit.
 
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Table 6
Derived Pharmacokinetic Parameters
Parameter
Parameter Description
Day 1
AUC(0-24)
Area under the concentration-time curve from time zero to the concentration at 24 hour post 
dose. AUC will be calculated using the linear trapezoidal rule for each incremental trapezoid 
and the log trapezoidal rule for each decremental trapezoid.
Cmax
Maximum observed concentration, determined directly from the concentration-time data.
C24
Concentration at 24 hours post dose
tmax
Time to reach Cmax, determined directly from the concentration-time data.
tlag
absorption lag time
Day 10
AUC(0-)
Area under the concentration-time curve over the dosing interval. AUC will be calculated 
using the linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule 
for each decremental trapezoid.
C0
Concentration at pre-dose
C
Concentration at the end of the dosing interval
C-avg
Defined as average of Days 8 -10 pre-dose concentration and Day 10 concentration at 24 
hours
Cmax
Maximum observed concentration, determined directly from the concentration-time data.
tmax
Time to reach Cmax, determined directly from the concentration-time data.
λz
The slope of the apparent terminal phase
Rsq
The correlation coefficient of the slope of the terminal phase
t½
Apparent terminal half-life will be calculated as: 
t½ = ln2 / λz
CL/F
Apparent oral clearance will be calculated as:
CL/F = Dose / AUC(0- )
R_AUC
The accumulation ratio of AUC will be calculated as: will be calculated as: 
R_AUC = AUC(0-) Day 10 / AUC(0-24) Day 1
R_Cmax
The accumulation ratio of Cmax will be calculated as: will be calculated as: 
R_Cmax = Cmax Day 10 / Cmax Day 1
R_C
The accumulation ratio of Cwill be calculated as: will be calculated as: 
R_C= CDay 10 / C24 Day 1
NOTES:

Additional parameters may be included as required.

Lambda_z is the terminal phase rate constant.
7.3.3.2.
Statistical Analysis of Pharmacokinetic Parameters
All the derived parameters described in Table 6 will be listed.  For each of these 
parameters, except tmax, tmin, and tlag, the following summary statistics will be 
calculated for each active treatment group: median, maximum, minimum, arithmetic 
mean, standard deviation, coefficient of variation on arithmetic mean, geometric mean, 
 
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coefficient of variation on geometric mean, 95% confidence interval for the geometric 
mean and standard deviation of logarithmically transformed data.  For tmax, tmin, and 
tlag, median, maximum, minimum, arithmetic mean and standard deviation will be 
calculated.
The following pharmacokinetic statistical analyses will only be performed, if sufficient 
data is available (i.e. if subjects have well defined plasma profiles). 
Pharmacokinetic Statistical Analyses
Endpoint(s)

Plasma primary PK endpoints include 
Day 1: area under the plasma concentration time curve AUC(0-24), maximum observed 
concentration (Cmax), time to maximum observed concentration (tmax), concentration at 24 
hours post dose (C24), absorption lag time (tlag);
Day 10:  AUC(0-), pre-dose concentration (C0), concentration at end of dosing interval (C), 
Cmax, tmax, t½, and apparent oral clearance (CL/F), if data permit
Model Specification

To assess the dose proportionality of plasma GSK2838232, PK parameters from Day 1 
[AUC(0-24), Cmax and C24] and Day 10 [AUC(0-), Cmax, and C] will be assessed using a 
power model if multiple dose levels are assessed. The power model will be fitted by restricted 
maximum likelihood (REML) using SAS Proc Mixed. A fixed effects power model will be used. 
The mean slope will be estimated from the power model with the corresponding 90% CI, 
separately for Day 1 and Day 10.

To assess the achievement of steady state, pre-dose concentrations between Days 7-10 for 
each treatment. A linear mixed model using Day, Treatment, and Day by Treatment interaction 
as fixed effects and subject as a random effect on the ln-transformed pre-dose values will be 
performed evaluating whether steady state was achieved using Helmert transformation 
approach. The comparison will begin with Day 7 vs the average of Days 8, 9 and 10. The ratio 
of Geometric LS means and its 95% CI will be presented for the comparison(s). 
Model Checking & Diagnostics

Refer to Appendix 13: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

Statistical analysis for dose proportionality from Day 1 [AUC(0-24), Cmax and C24], and Day 
10 [AUC(0-), Cmax, and C] will be presented in tabular format, respectively. The linear 
model will be used to provide a slope, intercept and a 90% CI of the slope.
Example SAS Code:
PROC MIXED;
MODEL LNPKPARM=LNDOSE /SOLUTION CL ALPHA=0.1;
ODS OUTPUT SOLUTIONF=SOLUTION1(RENAME=(ESTIMATE=EST STDERR=SE));
RUN;

Statistical analysis of steady state will be analyze using Helmert transformation approach 
Example SAS Code:
 
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Pharmacokinetic Statistical Analyses
PROC MIXED DATA=PKPARM;
CLASS TREATMENT DAY SUBJECT;
MODEL LNPKPARM = TREATMENT DAY 
TREATMENT*DAY/DDFM=KR;
RANDOM SUBJECT;
LSMEANS TREATMENT*DAY;
ESTIMATE "Treatment A: DAY 7 VS AVERAGE OF DAYS 8 TO 10" 
DAY 2 -1 -1 TREATMENT*DAY 2 -1 -1 0 0 0 0 0 0 0 0 0 /DIVISOR=2 CL ALPHA=.1; 
ESTIMATE "Treatment B: DAY 7 VS AVERAGE OF DAYS 8 TO 10" 
DAY 2 -1 -1 TREATMENT*DAY 0 0 0 2 -1 -1 0 0 0 0 0 0  /DIVISOR=2 CL ALPHA=.1; 
ESTIMATE "Treatment C: DAY 7 VS AVERAGE OF DAYS 8 TO 10" 
DAY 2 -1 -1 TREATMENT*DAY 0 0 0 0 0 0 2 -1 -1 0 0 0 /DIVISOR=2 CL ALPHA=.1; 
ESTIMATE "Treatment D: DAY 7 VS AVERAGE OF DAYS 8 TO 10" 
DAY 2 -1 -1 TREATMENT*DAY 0 0 0 0 0 0 0 0 0  2 -1 -1/DIVISOR=2 CL ALPHA=.1; 
RUN;
8.
PHARMACODYNAMIC ANALYSES
The dose-response model will be generated using subjects from the Per Protocol
population. Relationships between dose and PD measures (e.g., Log10 reduction in 
plasma HIV-1 RNA to Day 11 from baseline, or maximum reduction in log10 plasma 
HIV-1 RNA from baseline) measures will be explored with an Emax and linear models.  
Model selection will be based on Akaike Information Criteria (AIC) value, where model 
with the lowest AIC value will be considered the best model.  
Table 7 provides an overview of the planned analyses, with full details being presented in 
Appendix 12 List of Data Displays. 
Table 7
Overview of Planned PD Analyses
Absolute
Change from Baseline
Stats 
Analysis
Summary
Individual
Stats 
Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Pharmacodynamic Analyses
Dose-Response Model 
Y
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes 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.
 
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Primary Statistical Analyses: Dose Response Model
Endpoint

Maximum decline in plasma HIV-1 RNA and CD4+ with Doses
Model Specification

To model the dose-response relationship, a frequentist simplified Emax model is planned.  
This model assumes the following form: 
Where:

ΔBL is the maximum change from baseline, defined as the viral load decline in Plasma 
HIV-1 RNA and the Day 11 change from baseline for CD4+

Emax is the maximum response

ED50 is the dose that attains the 50% of the maximal effect ε is a random error assumed 
to be normally distributed with mean zero and constant variance (σ2)
The observed decline in Plasma HIV-1 RNA will be used as the response variable in the Emax 
model.  
The derived data from this Emax model (estimates Emax, ED50 and Variance along with their 
standard error, and 95% CI) will be tabulated and a dose-response curve will also be produced.
If problems are encountered Emax model or if the Emax shape is a poor fit for the data and a linear 
relationship looks plausible across the dose range, then a linear model will be considered of the 
form: 
Model Checking & Diagnostics

Refer to Appendix 13: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

The derived data from this Emax model (estimates Emax, EC50 and Variance along with their 
standard error, and 95% CI) will be tabulated and an exposure-response curve will also be 
produced. 
Example SAS Code:
PROC NLMIXED;
PARMS E0 = EST EMAX = EST ED50 = EST S2E = SE;
BOUNDS E0>0 EMAX>0 ED50>0 S2E>0;
PRED = E0 +(EMAX-E0)/(1+(ED50/DOSE));
 
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Primary Statistical Analyses: Dose Response Model
MODEL RESPONSE ~ NORMAL (PRED, S2E);
PREDICT PRED OUT=DOSE;
RUN;
9.
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES
9.1.
PK/PD Analyses of HIV-1 RNA
Scatter plots of plasma HIV-1 RNA change from baseline to Day 11 and maximum 
change from baseline vs. plasma GSK2838232 PK parameters on Day 10 [AUC(0-24), 
Cmax, C0, C, and Cτ-avg [defined as average for Days 8 -10 pre-dose concentration, 
and Day 10 concentration at 24 hours] will be generated separately for each active 
treatment and overall.  The Pearson’s correlations between plasma HIV-1 RNA change 
from baseline to Day 11 and maximum change from baseline and plasma GSK2838232
PK parameters on Day 10 will be summarized by treatment and overall.
Relationships between various PK parameters (Day 10 AUC(0-τ), Day 10 Cmax, Day 10 
C0, Cτ and Cτ-avg) and PD measures (Log10 reduction in plasma HIV-1 RNA to Day 11 
from baseline, or maximum reduction in log10 plasma HIV-1 RNA from baseline) will 
be explored with various Emax models and graphically with Emax model results overlaid 
with the observed PK/PD values.  Model selection will be based on Akaike Information 
Criteria (AIC) value, where model with the lowest AIC value will be considered the best 
model.  
Table 8
Overview of Planned PK/PD Analyses
Absolute
Change from Baseline
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
PK/PD
Emax Exposure-
Response Model
Y
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes 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.
 
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Primary Statistical Analyses: Exposure Response Model
Endpoint

Change from baseline to Day 11 and maximum decline in plasma HIV-1 RNA and CD4+ 
relative to the Day 10 PK parameters (AUC(0-τ), C0, Cmax, Cτ and Cτ-avg)
Model Specification

To model the exposure-response relationship, a frequentist three-parameter Emax model 
is planned.  This model assumes the following form
Where:

ΔVL is the maximum viral load decline or decline to Day 11 in plasma HIV-1 RNA 

E0 is the baseline response

Emax is the maximum response

EC50 is the corresponding exposure/PK parameter value that attains the 50% of the 
maximal effect

C is the PK parameter

ε is a random error assumed to be normally distributed with mean zero and constant 
variance (σ2)
Model Checking & Diagnostics

Refer to Appendix 13: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

The derived data from this Emax model (estimates E0, Emax, EC50 and Variance along with 
their standard error, and 95% CI) will be tabulated and an exposure-response curve will also 
be produced. If E0 turns out as not significant, the reduced Emax model without baseline E0 
will be selected as the final model.
Example SAS Code:
PROC NLMIXED;
PARMS E0 = EST EMAX = EST ED50 = EST S2E = SE;
BOUNDS E0>0 EMAX>0 ED50>0 S2E>0;
PRED = E0 +(EMAX-E0)/(1+(ED50/PARAM));
MODEL RESPONSE ~ NORMAL (PRED, S2E);
PREDICT PRED OUT=DOSE;
RUN;
 
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9.2.
Concentration-QTcF Analyses
For each ECG assessment, the individual subject’s QTcF change from baseline will be 
calculated and will be merged with time-matched PK concentration values, when 
available. QTcF change from baseline (y-axis) will be plotted against the PK 
concentration data (x-axis) with a linear regression overlay.
Table 9
Overview of Concentration-QTcF Analyses
Absolute
Change from Baseline
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
PK/PD
PK Concentration-
QTcF Individual Plot
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes 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.
 
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10.
SECONDARY STATISTICAL ANALYSES
10.1.
Efficacy Analyses
10.1.1.
Overview of Planned Efficacy Analyses
Both the Per Protocol and Intent-To-Treat populations will be used for all efficacy 
analyses if there are subjects excluded from the Per Protocol population.  If there are no 
exclusions, then the Intent-To-Treat population will be used for all efficacy analyses.
To assess the development of viral resistance over 10 days, genotypic and phenotypic 
analyses will be carried out.  Details of the analyses will be provided in a separate clinical 
virology report.  
Table 10 provides an overview of the planned efficacy analyses, with further details of 
data displays being presented in Appendix 12 List of Data Displays.
Table 10
Overview of Planned Efficacy Analyses
Absolute
Change from Baseline
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Immunology
Change from baseline 
(Day 1) in CD4+ cell 
count to Day 11
Y
Y
Clinical Virology
Viral genotypic data
Y
Viral phenotypic data
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes 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.
10.1.1.1.
Immunology
Change from baseline (Day 1) in CD4+ cell count to Day 11 will be listed by treatment 
group, subject, and assessment day and summarized by treatment and assessment day.  
10.1.1.2.
Clinical Virology
Viral genotypic and phenotypic data will be listed by treatment group, subject, and 
assessment day. 
 
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11.
REFERENCES
Bloch M, Bodsworth N, Fidler M, Workman C, Balach A, Byakagwa H, et al. Efficacy, 
safety and pharmacokinetics of MPC-4326 (bevirimat dimeglumine) 200mg BID and 
300mg BID monotherapy administered for 14 days in subjects with HIV-1 infection. 
ICAAC. 2009; Abstract H-1230.
Bornkamp B, Practical considerations for using functional uniform prior distributions for 
dose-response estimation in clinical trials. Biometrical Journal 56 (2014) 6, 947-962
Cockcroft DW, Gault MH. Prediction of creatinine clearance form serum creatinine. 
Nephron. 1976;16:31-41.
Dang Z, Huang L, Chen C. HIV-1 maturation inhibitors:  An update. Drugs of the Future. 
2009;34 (10):797-802.
Elion R, Cohen C, Gathe J, Shalit P, Hawkins T, Liu HC, Mathias AA, Chuck SL, 
Kearney BP, Warren DR.  Phase 2 study of cobicistat versus ritonavir each with once-
daily atazanavir and fixed-dose emtricitabine.tenofovir df in the initial treatment of HIV 
infection.  AIDS.  2011; 25:1881-1886.
Food and Drug Administration (FDA). Guidance for industry: Estimating the maximum 
safe starting dose in initial clinical trials for therapeutics in adult healthy subjects. CDER, 
Rockville, MD; 2005. UCM078932.
Food and Drug Administration (FDA). Guidance for Industry: Human Immunodeficiency 
Virus-1 Infection: Developing Antiretroviral Drugs for Treatment. CDER, Rockville, 
MD; 2015. UCM355128.
Gallant JE, Koenig E, Andrade-Villaneuva J, Chetchotisakd P, deJesus E, Antunes F, 
Arastéh K, Moyle G, Rizzardini G, Fehr J, Liu Y, Zhong L, Callebaut C, Scwarcberg J, 
Rhee MS, Cheng AK.  Cobicistat versus ritonavir as a pharmacoenhancer of atazanavir 
plus emtricitabine/tenofovir disoproxil fumarate in treatment-naïve HIV type 1-infected 
patients:  week 48 results.  J. Infect. Dis.  2013; 208-:32-39.
GlaxoSmithKline Document Number 2012N151889_03 Compound GSK2838232. 
Investigator’s Brochure.  Effective November 2016.
GlaxoSmithKline Non-Clinical Research report. Document Number 2013N163221_00.
Hatcher RA, Trussel J, Nelson AL, Cates W, Stewart F, Kowal D, editors. Contraceptive 
Technology. 19th ed. New York:Ardent Media; 2007. 
Kakuda TN, Opsomer M, Timmers M, Iterbeke K, Van De Casteele T, Hillewaert V, 
Petrovic R, Hoetelmans RMW.  Pharmacokinetics of darunavir in fixed-dose 
combination with cobicistat compared with coadministration of darunavir and ritonavir as 
single agents in healthy volunteers.  J. Clin. Pharmacol.  2009; 54:949-957.
 
2018N360917_00


CONFIDENTIAL
200911
38
Lalezari J, McCallister S, Gigliotti M, Cohen C, Elion R, et al. Safety and efficacy study 
of bevirimat (BVM) in heavily treatment experienced HIV+ patients identifies the target 
phase 3 study profile. ICAAC. 2008; Abstract: H891. 
Mahmood I. Prediction of human drug clearance from animal data. Application of the 
rule of exponent and fu corrected intercept method (FCIM). J Pharm Sci. 
2006;95:1810-21. 
Martin D, Galbraith H, Ellis C, Schettler J and Doto J. Minimal effect of ritonavir (RTV) 
on the pharmacokinetics of bevirimat in healthy volunteers [abstract]. IAS Conference on 
HIV Pathogenesis, Treatment and Prevention. 2007; Abstract no. WEPEB015:Poster 
discussion.
Martin DE, Blum R, Doto J, Galbraith H, Ballow C. Multiple-dose pharmacokinetics and 
safety of bevirimat, a novel inhibitor of HIV maturation, in healthy volunteers. Clin 
Pharmacokinet. 2007(a);46(7):589-98.
Martin DE, Blum R, Wilton J, Doto J, Galbraith H, et al. Safety and pharmacokinetics of 
bevirimat (PA-457), a novel inhibitor of human immunodeficiency virus maturation, in 
healthy volunteers. Antimicrobial Agents and Chemotherapy. 2007(b);Sep:3063-6.
Martin DE, Galbraith H, Schettier J, Ellis C, Doto J. Pharmacokinetic properties and 
tolerability of bevirimat and atazanavir in healthy volunteers:  An open-label, parallel-
group study. Clinical Therapeutics. 2008;30(10):1794-1805.
NORVIR (ritonavir) Product Information. January, 2013.
Nowicka-Sans B, Protack T, Lin Z, Li Z, Zhang S, Meanwell N, et al. BMS-955176: 
Characterization of a second-generation HIV-1 maturation inhibitor. 8th IAS Conference 
on HIV Pathogenesis, Treatment and Prevention, July 19-22, 2015, Vancouver, Canada.
Qian K, Morris-Natschke SL, Lee KH. HIV entry inhibitors and their potential in HIV 
therapy. Medicinal Research Reviews. 2009;29(2):369-93.
Saxena SK, Gupta A, Bhagyashree K, Saxena R, Arora N, Banerjee AK, et al. Targeting 
strategies for human immunodeficiency virus: A combinatorial approach. Min Rev Med 
Chem. 2012;12(3):236-54.
TYBOST (cobicistat) Product Information. 2012
Wainburg MA, Albert J. Can the further clinical development of bevirimat be justified?. 
AIDS. 2010;24:773-4.
 
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12.
APPENDICES
Section
Appendix
RAP Section 4: Analysis Populations
Section 12.1
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population
RAP Section 5: General Considerations for Data Analyses & Data Handling Conventions
Section 12.2
Appendix 2: Time and Events
Section 12.3
Appendix 3: Assessment Windows
Section 12.4
Appendix 4: Treatment States & Phases
Section 12.5
Appendix 5: Data Display Standards & Handling Conventions

Study Treatment & Sub-group Display Descriptors

Baseline Definitions & Derivations

Reporting Process & Standards
Section 12.6
Appendix 6: Derived and Transformed Data

General

Study Population

Safety
Section 12.7
Appendix 7: Premature Withdrawals & Handling of Missing Data

Premature Withdrawals

Handling of Missing Data
Section 12.8
Appendix 8: Values of Potential Clinical Importance

Laboratory Values

ECG

Vital Signs
Section 12.9
Appendix 9: Population Pharmacokinetic Analyses
Section 12.10
Appendix 10: Pharmacodynamic / Biomarker Analyses
Other RAP Appendices
Section 12.11
Appendix 11: Abbreviations & Trade Marks
Section 12.12
Appendix 12: List of Data Displays
Section 12.13
Appendix 13: Model Checking and Diagnostics for Statistical Analyses
 
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12.1.
Appendix 1: Protocol Deviation Management and Definitions
for Per Protocol Population
12.1.1.
Exclusions from Per Protocol Population
The following criteria define the major protocol deviations, which may lead to the 
exclusion of a subject from the per protocol (PP) population (refer to Section 4for 
population definitions).  These are major deviations that are considered to affect 
interpretation of the primary endpoints (change from baseline in plasma HIV-1 RNA, 
safety and tolerability parameters, and PK parameters).  Protocol deviations will be 
recorded in the eCRF.  Potential protocol deviations listed below will be reviewed by the 
clinical team to establish whether subjects meeting these criteria should be excluded from 
the PP population.  This review will occur before the clinical database has been locked 
for the final analysis.
Number
Exclusion Description
01
Inclusion/Exclusion criteria not met.

Subjects who deviate from any inclusion/exclusion criteria, as recorded in the 
eCRF.
02
Not withdrawn after meeting the following stopping criteria

Liver chemistry stopping criteria

QTc stopping criteria

Stopping criteria based on Adverse Event
03
Use of prohibited concomitant medications
04
Informed Consent

Study-specific assessments conducted prior to obtaining proper consent.
05
Study visits performed out of window 

Consecutive subject study visits performed out of window

Multiple study visits performed out of window by various subjects (Trending)
06
Assessments performed out of window

ECGs not performed at protocol timepoint

PK samples completed out of window

Samples for HIV-1 RNA PCR out of window
07
Safety assessments not performed

Central safety lab samples not collected and/or not properly sent to Q2
08
Incorrect study treatment or non-compliance

Unresolved IP accountability discrepancy

IP storage guidelines not followed

IP incorrectly administered

IP accountability not done
09
Lack of PI oversight
 
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12.2.
Appendix 2: Time & Events
12.2.1.
Protocol Defined Time & Events
Day:
Screen1
Random
1
2
3
4
5
62
7
8
9
10
11
12
141
211 
(FU)
ET
Informed Consent
X
Review inclusion/exclusion
X
X
Demography including height, 
weight and BMI
X
Brief physical
X
Medical/medication/
drug/alcohol history
X
X
CDC Classification
X
X
X
X
Prior antiretroviral therapy
X
12-lead ECG3
X
X
X
X
X
X
X
X
X
Holter (24 hr)
X
Vital signs4
X
X
X
X
X
X
X
X
X
Drug screen
X
X
X
X
X
Hepatitis B Surface antigen and 
hepatitis C antibody testing
X
Serum or urine -hCG (WoCBP 
only)
X
X
X
Clinical lab tests (inc troponin)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Fasting lipid panel
X
X
AE assessment5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Con Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HIV-1 RNA PCR6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lymphocyte subsets7
X
X
X
Plasma for genotype/phenotype8
X
X
X
X
X
X
X
 
 
 
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Day:
Screen1
Random
1
2
3
4
5
62
7
8
9
10
11
12
141
211 
(FU)
ET
HIV-associated conditions 
assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK blood sample9
X
X
X
X
X
X
X
X
X
X
X
X14
Plasma samples10
X
X
X
Dosing11
X
X
X
X
X
X
X
X
X
X
PGx12
X
Telephone call to IVRS14
X
X
Plasma for storage15
X
X
X
X
X
X
X
X
X
X
X
X
X
Outpatient visit
X
X
X
X
X
X
X
X
X
X
X
X
1.
Screening will occur within 14 - 30 days prior to the first dose of study drug.
2.
Table is set up for the weekend during dosing to occur on Days 6 and 7.  If the weekend occurs on Days 5 and 6, perform all “Day 5” assessments on Day 7.
3.
On Day 1, ECGs will be performed pre-dose, and then 1, 1.5, 2, 3, 4 and 6 hours post dose.  The ECGs should be performed at least 5 minutes apart and preferably within 1 hour 
prior to dose.  On Days 4 and 8, ECGs will be obtained prior to morning dosing and at 2, 4 and 6 hours post-dose. To accommodate scheduling, serial ECGs collected on Days 4 
and 8 may be performed 1 day. On Day 10, ECGs will be performed pre-dose, and then 1, 1.5, 2, 3, 4 and 6 hours post dose.  On Day 11, an ECG will be obtained prior to the
24-hour PK sample. ECGs will be performed in triplicate at all timepoints. 
4.
BP, RR, HR and temperature will be obtained at Screening (x1) and Day 1 pre-dose (x2).  BP and HR will be obtained on Day 1 at 2 hours post-morning dose and on Days 4, 5 
and 8 pre-dose.  BP and HR will be obtained on Day 10 at pre-dose and 2 hours post-morning dose, and at day 12 and Follow-up (Day 21).
5.
Only SAEs related to study participation will be collected between screening and Day 1. An AE enquiry will be made at each visit, subjects will be asked if they have experienced 
any neuropsychiatric adverse events, including psychosis or altered mental status
6.
On Days 1-5 and 8-10 samples for HIV-1 RNA PCR collected before morning dose.  On Days 1, 10 and 11 two samples for HIV-1 RNA PCR will be collected 5-30 minutes apart.  
HIV-1 RNA PCR samples will also be collected on days 12, 14 & Follow-up (Day 21).
7.
Lymphocyte subsets by flow cytometry (total lymphocyte counts, percentage, and absolute CD4+and CD8+counts).
8.
Blood samples for phenotype and genotype will be collected at pre-dose on Days 1, 4, 5 and 8 in the morning on Day 11 and at follow-up. 
9.
Serial plasma samples (2 mL) for determination of GSK2838232 will be collected on Day 1 and Day 10 at pre dose (within 15 minutes prior to dose) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 
12 (optional), and 24 hours (to occur on morning of Day 2) post-am dose.  Pre-dose PK samples (within 15 minutes prior to dose) will be taken on the mornings of Days 3, 4, 5, 8 
and 9 and a single sample will be taken on Days 12 and 14.
10. Samples (2 x 0.5mL) of plasma for assessment of immunological markers at screen, baseline (pre-dose) and day 11 
11. Subjects will receive a single dose of GSK2838232 and cobicistat each morning with a light breakfast meal and 240 mL of water from Day 1 to Day 10.  Doses taken in the clinic 
will be administered after an overnight fast of at least 10 hours. On Days 6 and 7, doses will be self-administered but confirmed by phone 
12. PGx sample should be collected on Day 1.
 
 
 
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13. A screening/registration call should be made to the IVRS to register the subject at screening.   An additional call will be made to document a screen failure.   A randomization call 
should be made to the IVRS system approximately one week prior to scheduled Day 1.  Note: The randomization call must be made in order to have study drug on site for Day 1. 
Additional calls will be made every day that the subject has a scheduled study visit to the clinic.  If a subject terminates the study prematurely a call should be made to the IVRS
14. Only if early termination visits occur during the treatment period.
15. Plasma samples for storage will be collected at each visit starting at Day 1, including unscheduled visits (e.g. for HIV-1 RNA levels and immunological parameters).  Additionally, 
these samples will be used when needed, such as when samples are lost or arrive at the laboratory unevaluable.
AE = Adverse event; CDC= Center for Disease Control and Prevention; ECG = Electrocardiogram; ET = Early termination; hCG = Human chorionic gonadotrophin; HIV = Human 
immunodeficiency virus; IVRS= Interactive Voice Response System; PCR = Polymerase chain reaction; PK=Pharmacokinetic.
 
 
 
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12.3.
Appendix 3: Assessment Windows
12.3.1.
Definitions of Assessment Windows for Analyses
Analyses will be presented by scheduled visits as collected in the CRF.  The following 
table presents protocol defined assessment windows.
Analysis Set 
/ Domain
Parameter (if 
applicable)
Target 
Analysis Window
Analysis 
Timepoint
Beginning 
Timepoint
Ending 
Timepoint
Safety and 
Efficacy
All
14 - 21 days prior to first 
dose
21 days prior 
to first dose
14 days prior 
to first dose
SCREEN
Safety and 
Efficacy
All
Day 14
Day 13
Day 15
DAY14FUP
Safety
ECG
Day 4
Day 3
Day 5
DAY4
Safety
ECG
Day 8
Day 7
Day 9
DAY8
NOTES:
Screening visit window may be extended to 30 days upon discussion with the Medical Monitor (i.e., subject has 
scheduling conflicts or any screening assessment needs to be repeated).
 
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12.4.
Appendix 4: Treatment States and Phases
12.4.1.
Treatment Phases
Assessments and events will be classified according to the time of occurrence relative to 
the start and/or stop date of the study treatment.
Treatment Phase
Definition
Screening Period 
Day -30 to Day -1
Treatment Period
Day 1 to Day 10 / study treatment stop date
Follow-up Period
Study treatment stop date + 1 to Day 21 (±1 day)
12.4.2.
Treatment States
Assessments and events will be classified according to time of occurrence relative to the 
start and/or stop date of the study treatment.
12.4.2.1.
Treatment States for Laboratory Data
Treatment State
Definition
Pre-Treatment
Date ≤ Study Treatment Start Date
On-Treatment
Study Treatment Start Date < Date ≤ Study Treatment Stop Date + 1
Post-Treatment
Date > Study Treatment Stop Date +1
NOTES: 

If the study treatment stop date is missing then the assessment will be considered to be On-Treatment
12.4.2.2.
Treatment States for AE Data
Treatment State
Definition
On-treatment
Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment Stop Date + 12
Onset Time Since 
1st Dose (Days)
If Treatment Start Date ˃  AE Onset Date = AE Onset Date - Treatment Start Date
If Treatment Start Date ≤ AE Onset Date = AE Onset Date - Treatment Start Date +1
Missing otherwise.
Duration (Days) 
AE Resolution Date – AE Onset Date + 1
Drug-related
If relationship is marked ‘YES’ on CRF
NOTES: 

If the study treatment stop date is missing then the AE will be considered On-Treatment.  
12.4.2.3.
Classification of cardiovascular adverse events of special interest
Cardiovascular AEs of special interest will be determined through clinical team review of 
preferred terms for all captured adverse events.
 
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12.4.2.4.
Classification of prior, concomitant, or post-therapy medications
Prior medications are those taken (i.e., started) before the start date of study treatment. 
Concomitant medications are those taken (i.e., started or continued) at any time between 
the start date and stop date of study treatment, inclusive. Prior medications that were 
continued during the study treatment period are also considered as concomitant 
medications. Post-treatment medications are those started after the stop date of study 
treatment. Concomitant medications that were continued after the stop date of the study 
treatment are also considered as post-treatment medications.
It will be assumed that medication has been taken on the date in which it is reported as 
started or stopped.  Also, for any medication starting on the same date as study treatment, 
it will be assumed that the medication was taken after the subject started taking the study 
treatment.
 
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12.5.
Appendix 5: Data Display Standards & Handling 
Conventions
12.5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting[1]
Description
Description
Order [2]
GSK2838232 20 mg
20 mg GSK2838232/150 mg Cobicistat
1
Low-Dose 3
50 mg GSK2838232/150 mg Cobicistat
2
Mid-Dose 2
100 mg GSK2838232/150 mg Cobicistat
3
High-Dose 1
200 mg GSK2838232/150 mg Cobicistat
4
NOTES:
1.
Unless otherwise indicated in data displays.
2.
Order represents treatments being presented in TFL, as appropriate.
12.5.2.
Baseline Definition & Derivations
12.5.2.1.
Baseline Definitions
For all endpoints the baseline value will be the latest pre-dose assessment. 
12.5.2.2.
Derivations and Handling of Missing Baseline Data
Definition
Reporting Details
Change from Baseline
= Post-Dose Visit Value – Baseline
% Change from Baseline
= 100 x [(Post-Dose Visit Value – Baseline) / Baseline]
Maximum Decline from Baseline
= Calculate the change from baseline at each given timepoint 
   and determine the maximum decline
NOTES:

Unless otherwise specified, the baseline definitions specified in Section 12.5.2.1 Baseline Definitions will be used 
for derivations for endpoints / parameters and indicated on summaries and listings.

Unless otherwise stated, if baseline data is missing no derivation will be performed and will be set to missing.

The baseline definition will be footnoted on all change from baseline displays.
12.5.3.
Reporting Process & Standards
Reporting Process
Software

The currently supported versions of SAS software, version 9.2 or higher, will be used.
Analysis Datasets 

Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2 & 
 
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Reporting Process
ADaM IG Version 1.1.)

For creation of ADaM datasets (ADCM/ADAE), the same version of dictionary datasets will be 
implemented for SDTM.
Generation of RTF Files

RTF files will be generated for Final Analysis TLFs.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated:
o
4.03 to 4.23: General Principles
o
5.01 to 5.08: Principles Related to Data Listings
o
6.01 to 6.11: Principles Related to Summary Tables
o
7.01 to 7.13: Principles Related to Graphics 
Formats

All data will be reported according to the actual treatment the subject received unless 
otherwise stated.

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for 
reporting of data based on the raw data collected.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but 
may be adjusted to a clinically interpretable number of DP’s.
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled 
visit days on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to 
IDSL Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Reporting of Pharmacokinetic Concentration Data
Descriptive 
Summary Statistics
Refer to IDSL Statistical Principle 6.06.1
Assign zero to NQ values (Refer to GUI_51487 for further details)
Reporting of Pharmacokinetic Parameters
Descriptive 
Summary Statistics 
(Log Transformed)
N, n, geometric mean, 95% CI of geometric mean, standard deviation (SD) 
of logged data and [between and or within] geometric coefficient of variation 
(CVb/w (%)) will be reported.
 
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Reporting Standards
[1] CVb (%) = √ (exp(SD2) - 1) * 100
(SD = SD of log transformed data) 
[2] CVw (%) = √ (exp(MSE) - 1) * 100 
(MSE = mean square error from mixed effect model of loge-transformed data).
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.
 
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12.6.
Appendix 6: Derived and Transformed Data
12.6.1.
General
Multiple Measurements at One Time Point

Triplicate 12-lead ECGs will be recorded at each study-specified visit. Mean of the 
measurements will be calculated and used in any derivation of summary statistics but if 
listed, all data will be presented.

If there are two or more values within a time window the value closest to the target day for
that window will be used. If values are the same distance from the target then the mean will 
be taken.

Subjects having both High and Low values for Normal Ranges at any post-baseline visits for 
safety parameters will be counted in both the High and Low categories of “Any visit post-
baseline” row of related summary tables. This will also be applicable to relevant Potential 
Clinical Importance summary tables.
Study Day

Calculated as the number of days from treatment start date:

Ref Date = Missing                       → Study Day = Missing 

Ref Date < Treatment Start Date   → Study Day = Ref Date – Treatment Start Date    

Ref Data ≥ Treatment Start Date   → Study Day = Ref Date – (Treatment Start Date) + 
1    
Treatment Start Date

The date of first dose of study treatment
Treatment Stop Date

Calculated as the date of final dose of study treatment received. If treatment stop date is 
missing, then, for purposes of calculating exposure, it will be imputed using the date of last 
visit or the recorded date of withdrawal/completion, whichever is earlier. Note that the follow-
up visit date must not be used as the date of last visit or recorded date of 
withdrawal/completion because this date will be off-treatment. 
Study Completion/Withdrawal Date

Date of withdrawal for subjects withdrawing (i.e., subjects who actively withdraw or are 
deemed lost to follow-up) from study or date of completion of study for subjects who 
complete the study, as documented in the eCRF.
Time Definitions (per GSK standard principles)

1 week = 7 days

1 month = 30.4375 days

1 year = 365.25 days
 
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12.6.2.
Study Population
Demographics
Age
Due to local privacy regulations, only the year of birth is recorded in the eCRF. The following 
algorithm will be used for imputation:

All dates of birth will be imputed using the 30th day of June.
Completely missing dates of birth will remain as missing, with no imputation applied.  Consequently, 
the age of the subject will not be calculated and will remain missing. In listings of demographic data, 
the year of birth as entered will be displayed.
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 enrolled 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.
12.6.3.
Safety
ECG Parameters
RR Interval

IF RR interval (msec) is not provided directly, then RR can be derived as:
[1] If QTcB is machine read & QTcF is not provided, then:
[2] If QTcF is machine read and QTcB is not provided, then: 

If ECGs are manually read, the RR value preceding the measurement QT interval should be a 
collected value THEN do not derive.
 
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ECG Parameters
Corrected QT Intervals

When not entered directly in the eCRF, corrected QT intervals by Bazett’s (QTcB) and 
Fredericia’s (QTcF) formulas will be calculated, in msec, depending on the availability of other 
measurements.

IF RR interval (msec) is provided then missing QTcB and/or QTcF will be derived as:
Laboratory Parameters

If a laboratory value which is expected to have a numeric value for summary purposes, has a 
non-detectable level reported in the database, where the numeric value is missing, but typically 
a character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the 
comment field) is present, the number of significant digits in the observed values will be used to 
determine how much to add or subtract in order to impute the corresponding numeric value. 
o
Example 1: 2 Significant Digits =  ‘< x ‘ becomes x – 0.01
o
Example 2: 1 Significant Digit   =  ‘> x’ becomes x + 0.1
o
Example 3: 0 Significant Digits = ‘< x’ becomes x – 1    
 
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12.7.
Appendix 7: Premature Withdrawals & Handling of Missing 
Data
12.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) is defined as a 
subject who has completed all phases of the study including the follow-up visit.

Withdrawn subjects may be replaced in the study.

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.
12.7.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank 
fields on the collection instrument:
o
These data will be indicated by the use of a “blank” in subject listing 
displays. Unless all data for a specific visit are missing in which case the 
data is excluded from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to 
be missing data and should be displayed as such.
Outliers

Any subjects excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
12.7.2.1.
Handling of Missing Dates
Element
Reporting Detail
General
Partial dates will be displayed as captured in subject listing displays.
Adverse 
Events

The eCRF allows for the possibility of partial dates (i.e., only month and year) to 
be recorded for AE start and end dates; that is, the day of the month may be 
missing. In such a case, the following conventions will be applied for calculating 
the time to onset and the duration of the event:
o
Missing Start Day and Non-missing End Date: If the day in a start date is 
missing, e.g. - -JUN2006, and the month is the one in which treatment 
started, assign the day to the day treatment started (i.e. the event is 
considered on-treatment as per Section 12.4.2) if treatment start date <= AE 
end date).  Otherwise, set to the first of the month, 01JUN2006.
o
Missing Stop Day and Non-missing Start Date: Last day of the month (28th, 
29th, 30th, or 31st as appropriate for the month and year) will be used. If the 
last day of the month is after the stop date of study treatment in the same 
month and treatment stop date >= AE start date, then study treatment stop 
date will be used.
o
Missing Start Day and Missing End Day: If both the day in a start date and 
 
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Element
Reporting Detail
the day in an end date are missing, set them to the first day of the month 
and the last day of the month, respectively. 

Completely missing start or end dates will remain missing, with no imputation 
applied. Consequently, time to onset and duration of such events will be 
missing.

The recorded partial date will be displayed in listings. Start or end dates which 
are completely missing (i.e. no year specified) will remain missing, with no 
imputation applied.
12.7.2.2.
Handling of Partial Dates
Element
Reporting Detail
Concomitant 
Medications

Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention:

If the partial date is a start date, a '01' will be used for the day and 'Jan' will 
be used for the month

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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12.8.
Appendix 8: Values of Potential Clinical Importance
12.8.1.
Laboratory Values
Haematology
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Hematocrit 
Ratio of 1
Male
0.54
Female
0.54
∆from BL
↓0.075
Hemoglobin 
g/L
Male
180
Female
180
∆from BL
↓25
Lymphocytes 
x109/ L
0.8
Neutrophil Count 
x109/ L
1.5
Platelet Count 
x109/ L
100
550
White Blood Cell Count (WBC)
x109/ L
3
20
Clinical Chemistry
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Albumin 
g/L
30
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 Protein
g/L
∆from ref. 
range
<15
>15
Troponin
ng/mL
0.01
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
Direct Bilirubin
µmol/L
High
>0.3x ULN
 
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12.8.2.
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
PR Interval
msec
< 120
> 200
QRS Duration
msec
< 60
> 109
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
12.8.3.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Clinical Concern Range
Lower
Upper
Systolic Blood Pressure
mmHg
< 85
> 160
Diastolic Blood Pressure
mmHg
< 45
> 100
Heart Rate
bpm
< 40
> 110
Vital Sign Parameter
(Change from Baseline)
Units
Clinical Concern Range
Decrease
Increase
Lower
Upper
Lower
Upper
Systolic Blood Pressure
mmHg
≥ 20
≥ 40
≥ 20
≥ 40
Diastolic Blood Pressure
mmHg
≥ 10
≥ 20
≥ 10
≥ 20
Heart Rate
bpm
≥ 15
≥ 30
≥ 15
≥ 30
12.8.4.
Methods for Handling Centres
This study will be conducted in the United States and Canada.  Data will be summarized 
for all centres combined. Statistical analyses will not be adjusted for centre. 
 
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12.9.
Appendix 9: Population Pharmacokinetic Analyses
12.9.1.
Blood Sample Collection
Blood samples for analysis of GSK2838232 concentrations will be collected at the time 
points indicated in Time and Events Tables (Appendix 2).  
The actual date and time of each blood sample collection will be recorded.  The timing of 
PK samples may be altered and/or PK samples may be obtained at additional time points 
to ensure thorough PK monitoring.  
Details of PK blood sample collection (including volume to be collected), processing, 
storage and shipping procedures are provided in the Study Reference Manual (SRM).
12.9.2.
Sample Analysis
Plasma analysis will be performed by Covance, Madison under the control of 
Bioanalysis, Immunogenicity and Biomarkers (BIB), PTS, GlaxoSmithKline.
Concentrations of GSK2838232 will be determined in plasma using the currently 
approved bioanalytical methodology. 
Once the plasma has been analysed for GSK2838232 any remaining plasma may be 
analysed qualitatively for other circulating metabolites and these results would be 
reported under a separate PTS protocol.
Raw data will be archived at the Covance, Madison facility.
 
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12.10.
Appendix 10: Pharmacodynamic / Biomarker Analyses
12.10.1.
Viral Genotyping and Phenotyping
Whole venous blood samples will be obtained from each subject to provide plasma for 
viral genotype and phenotype analysis, at the times listed in the Time and Events Table in 
Appendix 2. Details concerning the handling, labelling and shipping of these samples will 
be supplied separately.
Genotypic and phenotypic analyses will be carried out by Monogram Biosciences using 
their GAG/PR and PR/RT formats, in which PCR amplification is used to generate HIV 
cDNA products including the Gag and the PR and RT coding regions, respectively. 
Phenotypic analyses of the GAG/PR region will include susceptibility to GSK2838232. 
Analysis will be done on Day 1 and Day 11 samples.  In the case of rebound HIV-1 viral 
load, analysis will be completed on samples corresponding to time point of rebound 
occurrence. 
12.10.2.
Genetics
Information regarding genetic research is included in Appendix 4, Section 12.4 of 
protocol amendment 3 (Dated: 15/JUN/2017).
12.10.3.
Value Evidence and Outcomes
Not required.
 
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12.11.
Appendix 11 – Abbreviations & Trade Marks
12.11.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
AIC
Akaike's Information Criteria
AIDS
Auto immunodeficiency syndrome
ALT
Alanine aminotransferase
ART
Antiretroviral therapy
AST
Aspartate aminotransferase
AUC
Area under the plasma concentration time curve
AUC(0-τ)
Area under the plasma concentration time curve over the dosing interval
AUC(0-24)
Area under the plasma concentration time curve from time zero to the 
concentration at 24 hours post dose
A&R
Analysis and Reporting 
Bpm
beats per minute
BIL
Bilirubin
C0
Concentration at pre-dose
Cτ
Concentration at the end of the dosing interval
Cτ-avg
Defined as average of Days 8 -10 pre-dose concentration, and Day 10 
concentration at 24 hours
C24
Concentration at 24 hours post dose
CDISC
Clinical Data Interchange Standards Consortium
CL/F
Apparent oral clearance
CI
Confidence Interval
Cmax
Maximum observed concentration
CS
Clinical Statistics
CSR
Clinical Study Report
CTR
Clinical Trial Register
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
DOB
Date of Birth
DP
Decimal Places
ECG
Electrocardiogram
eCRF
Electronic Case Record Form
IA
Interim Analysis
ICH
International Conference on Harmonisation
IDSL
Integrated Data Standards Library
IP
Investigational Product
ITT
Intent-To-Treat
g
gram
GSK
GlaxoSmithKline
GUI
Guidance
H
Hour(s)
HIV
Human Immunodeficiency Virus
 
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Abbreviation
Description
Kg
Kilogram
λz
The slope of the apparent terminal phase
L
Litre
LOC
Last Observation Carries Forward
MedDRA
Medical Dictionary for Regulatory Activities
mL
Milliliter
mg
milligrams
MMRM
Mixed Model Repeated Measures
ng/mL
Nanogram per millilitre
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PK
Pharmacokinetic
PP
Per Protocol
PT
Preferred Term
QC
Quality Control
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
R_AUC
The accumulation ratio of AUC from Day 10 to Day 1
R_Cmax
The accumulation ratio of Cmax from Day 10 to Day 1
R_Cτ
The accumulation ratio of Cτ from Day 10 to Day 1
RAP
Reporting & Analysis Plan
Rsq
The correlation coefficient of the slope of the terminal phase
SAC
Statistical Analysis Complete
SAE
Serious Adverse Event
SDTM
Study Data Tabulation Model
SOC
System Organ Class
SOP
Standard Operation Procedure
t½
Apparent terminal half-life
tlag
Absorption lag time
tmax
Time to reach Cmax
TFL
Tables, Figures & Listings 
U
Units
12.11.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
None
Phoenix WinNonlin
SAS
Tybost (cobicistat)
 
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12.12.
Appendix 12: List of Data Displays
12.12.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.22
Efficacy
2.1 to 2.12
2.1 to 2.2
Safety
3.1 to 3.37
3.1
Pharmacokinetic
4.1 to 4.7
4.1 to 4.7
Pharmacodynamic
5.1
5.1 to 5.2
Pharmacokinetic / Pharmacodynamic
6.1
6.1 to 6.5
Section
Listings
ICH Listings
1 to 20
Non-ICH Listings
21 to 51
12.12.2.
Deliverable [Priority]
Delivery [Priority] [1]
Description
IB
Investigator’s Brochure
SAC 
Final Statistical Analysis Complete
NOTES: 
1.
Indicates priority (i.e. order) in which displays will be generated for the reporting effort.
 
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12.12.3.
Study Population Tables
Study Population Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Populations Analysed
1.1.
All Screened
SP1
Summary of Study Populations
SAC
1.2.
ITT
NS1
Summary of Number of Subjects by Centre
SAC
Subject Disposition
1.3.
ITT
ES1
Summary of Subject Disposition
IB, SAC 
1.4.
All Screened
ES6
Summary of Reasons Screening Status and for Screen Failure
SAC
1.5.
Safety
SD1
Summary of Study Treatment Discontinuation
Use the primary reasons and the 
sub-reasons for IP discontinuation 
collected from the eCRF.
SAC
1.6.
ITT
Summary of Subjects at Each Visit
SAC
 
 
 
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Study Population Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Demography & Disease Characteristics at Screening
1.7.
ITT
DM1
Summary of Demographic Characteristics
Age, sex, child-bearing potential, 
race, ethnicity, height, weight, 
Baseline CDC HIV-1 Classification, 
and BMI.
For details on Race categories 
shown in this table, please see GSK 
IDSL Demography Statistical 
Display Standards, Section 1.1.1 
Summary of Demographic 
Characteristics
IB, SAC
1.8.
ITT
DM11
Summary of Age Ranges
SAC
1.9.
ITT
DM5
Summary of Race & Racial Combinations
For details on Race categories 
shown in this table, please see GSK 
IDSL Demography Statistical 
Display Standards, Section 1.1.2 
Summary of Race and Racial 
Combinations
SAC 
1.10.
ITT
DM6
Summary of Race & Racial Combinations Details
For details on Race categories 
shown in this table, please see GSK 
IDSL Demography Statistical 
Display Standards, Section 1.1.2 
Summary of Race and Racial 
Combinations
SAC 
1.11.
Safety
FH1
Summary of Family History of Cardiovascular Risk
SAC 
1.12.
Safety 
SU1
Summary of Substance Use
SAC 
 
 
 
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64
Study Population Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Protocol Deviations
1.13.
ITT
DV1A
Summary of Protocol Deviations
See RAP Section 12.1.1 for 
categories of protocol deviations.
SAC
1.14.
ITT
DV1A
Summary of Deviations Leading to Exclusions from Per Protocol 
Population
See RAP Section 12.1.1 for 
categories of protocol deviations.
SAC
1.15.
ITT
IE1
Summary of Inclusion/Exclusion Criteria Deviations
SAC
Medical Condition & Concomitant Medications
1.16.
Safety
MH1
Summary of Cardiovascular Medical Conditions
SAC 
1.17.
Safety
MH1
Summary of Past Medical Conditions
Categories of medical conditions 
will be sorted in descending order of 
“Total” incidence, and medical 
conditions within each category will 
be sorted in descending order of 
“Total” incidence. If the “Total” 
incidence for any two or more 
medical conditions is equal, then 
they will be presented in 
alphabetical order.
SAC 
 
 
 
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65
Study Population Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.18.
Safety
MH1
Summary of Current Medical Conditions
Categories of medical conditions 
will be sorted in descending order of 
“Total” incidence, and medical 
conditions within each category will 
be sorted in descending order of 
“Total” incidence. If the “Total” 
incidence for any two or more 
medical conditions is equal, then 
they will be presented in 
alphabetical order.
SAC 
1.19.
Safety
CM1
Summary of Concomitant Medication ATC Level 1 by Ingredient
Medications will be sorted in 
descending order of “Total”
incidence for the ATC level 1 and in 
descending order of total incidence 
for the ingredient within each ATC 
level. If the total incidence of for any 
two or more ingredients is equal, 
the events will be presented in 
alphabetical order.
See GSK IDSL “CONCOMITANT 
MEDICATIONS STATISTICAL 
DISPLAY STANDARDS” (Version 
12), Section 1.1.1  
SAC 
1.20.
Safety
CM1
Summary of Prior Medication ATC Level 1 by Ingredient
SAC
 
 
 
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66
Study Population Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Exposure and Treatment Compliance
1.21.
Safety
COMP1
Summary of Study Treatment Overall Compliance
SAC
1.22.
Safety
EX1
Summary of Exposure to Study Treatment
IB, SAC
12.12.4.
Efficacy Tables
Efficacy: Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Viral Load
2.1.
ITT
Summary of Plasma HIV-1 RNA
SAC 
2.2.
ITT
Summary of Change from Baseline to Day 11 and Maximum 
Decline from Baseline in Plasma HIV-1 RNA
SAC 
2.3.
ITT
Summary of Modelled Plasma HIV-1 RNA Mean Rate of Decline
and Maximum Decline by Treatment
SAC 
2.4.
ITT
Summary of Proportion of Subjects with Plasma HIV-1 RNA 
<400 and < 50 copies/mL
SAC 
2.5.
ITT
Summary of Proportion of Subjects with Plasma HIV-1 RNA 
Change from Baseline >1.5 log10 copies/mL Decrease
SAC 
2.6.
PP
Summary of Plasma HIV-1 RNA
To be generated if there are subjects 
excluded from the Per Protocol 
population
SAC 
2.7.
PP
Summary of Change from Baseline to Day 11 and Maximum 
Decline from Baseline in plasma HIV-1 RNA
To be generated if there are subjects 
excluded from the Per Protocol 
population
SAC 
 
 
 
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67
Efficacy: Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.8.
PP
Summary of Modelled Plasma HIV-1 RNA Mean Rate of Decline 
and Maximum Decline by Treatment
To be generated if there are subjects 
excluded from the Per Protocol 
population
SAC 
2.9.
PP
Summary of Proportion of Subjects with Plasma HIV-1 RNA 
<400 and < 50 copies/mL
To be generated if there are subjects 
excluded from the Per Protocol 
population
SAC 
2.10.
PP
Summary of Proportion of Subjects with Plasma HIV-1 RNA 
Change from Baseline >1.5 log10 copies/mL Decrease
To be generated if there are subjects 
excluded from the Per Protocol 
population
SAC 
Immunology
2.11.
ITT
Summary of Change from Baseline (Day 1) in CD4+ Cell Count 
to Day 11
SAC 
2.12.
PP
Summary of Change from Baseline (Day 1) in CD4+ Cell Count 
to Day 11
To be generated if there are subjects 
excluded from the Per Protocol 
population
SAC
 
 
 
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12.12.5.
Efficacy Figures
Efficacy: Figures
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Viral Load
2.1.
ITT
Plot of Mean and Median Change from Baseline (Day 1) in 
Plasma HIV-1 RNA by Treatment
SAC 
2.2.
PP
Plot of Mean and Median Change from Baseline (Day 1) in 
Plasma HIV-1 RNA by Treatment
To be generated if there are subjects 
excluded from the Per Protocol 
population
SAC 
12.12.6.
Safety Tables
Safety: Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events
3.1.
Safety
AE13
Adverse Events Overview
SAC
3.2.
Safety
AE1
Summary of All Adverse Events by System Organ Class and 
Preferred Term
IB, SAC
3.3.
Safety
AE5B
Summary of All Adverse Events by System Organ Class and 
Preferred Term and Maximum Grade
SAC
3.4.
Safety
AE5B
Summary of Drug-Related Adverse Events by System Organ 
Class and Preferred Term and Maximum Grade
SAC
3.5.
Safety
AE1
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term
SAC
 
 
 
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69
Safety: Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.6.
Safety
AE1
Summary of Drug Related Adverse Events by System Organ 
Class and Preferred Term
IB, SAC
3.7.
Safety
AE1
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Drug or Withdrawal from Study
SAC
3.8.
Safety
AE1
Summary of Common (>=5%) Adverse Events By Overall 
Frequency
SAC 
3.9.
Safety
AE1
Summary of Common (>=5%) Non-Serious Adverse Events By 
Overall Frequency
SAC 
3.10.
Safety
AE1
Summary of Cardiovascular Adverse Events of Special Interest
SAC 
Laboratory Values
3.11.
Safety
LB1
Summary of Clinical Chemistry Data by Visit
SAC 
3.12.
Safety
LB1
Summary of Change from Baseline in Clinical Chemistry Data by 
Visit
SAC 
3.13.
Safety
LB1
Summary of Haematology Data by Visit
SAC 
3.14.
Safety
LB1
Summary of Change from Baseline in Haematology Data by 
Visit 
SAC 
3.15.
Safety
LB1
Summary of Liver Function Data by Visit
SAC 
3.16.
Safety
LB1
Summary of Change from Baseline in Liver Function by Visit
SAC 
3.17.
Safety
Summary of Treatment Emergent Clinical Chemistry Toxicities
SAC 
3.18.
Safety
LB2
Summary of On-Treatment Laboratory Abnormalities Worsened 
from Baseline by Maximum Grade – Chemistry
IB, SAC
3.19.
Safety
Summary of Treatment Emergent Haematology Toxicities
SAC
3.20.
Safety
LB2
Summary of On-Treatment Laboratory Abnormalities Worsened 
from Baseline by Maximum Grade – Haematology
IB, SAC
 
 
 
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70
Safety: Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.21.
Safety
Summary of Treatment Emergent Liver Toxicities
SAC
3.22.
Safety
LB2
Summary of On-Treatment Laboratory Abnormalities Worsened 
from Baseline by Maximum Grade – Liver Function
IB, SAC
3.23.
Safety
LB2
Summary of Chemistry Laboratory Abnormalities of Potential 
Clinical Importance
SAC
3.24.
Safety
LB2
Summary of Haematology Laboratory Abnormalities of Potential 
Clinical Importance
SAC
3.25.
Safety
LB2
Summary of Liver Function Laboratory Abnormalities of Potential 
Clinical Importance
SAC
Hepatobiliary (Liver)
3.26.
Safety
Liver1
Summary of Liver Monitoring/Stopping Event Reporting
IB, SAC
3.27.
Safety
Liver2
Summary of Time on Treatment Before Liver Stopping Event
IB, SAC 
3.28.
Safety
Liver3
Summary of Liver Biopsy Details
SAC
3.29.
Safety
Liver4
Summary of Liver Imaging Details
SAC
ECGs
3.30.
Safety
EG1
Summary of ECG Findings
IB, SAC
3.31.
Safety
EG2
Summary of Change from Baseline in ECG Values
SAC
3.32.
Safety
EG10
Summary of Maximum QTc Values Post-Baseline Relative to 
Baseline by Category
SAC
3.33.
Safety
EG11
Summary of Maximum Increase in QTc Values Post-Baseline 
Relative to Baseline by Category
SAC
 
 
 
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71
Safety: Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Vital Signs
3.34.
Safety
VS1
Summary of Vital Sign Values by Visit
SAC
3.35.
Safety
VS3
Summary of Worst Case Vital Sign Results Relative to Normal 
Range Post-Baseline Relative to Baseline
SAC
3.36.
Safety
VS2
Summary of Vital Sign Data Outside Clinical Concern Range
SAC
3.37.
Safety
VS6
Summary of Vital Sign Results by Maximum Grade Increase 
Post Baseline Relative to Baseline
SAC
12.12.7.
Safety Figures
Safety: Figures
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
ECG
3.1.
Safety
Mean (95% CI) Change from Baseline in QTc interval by Time 
and Treatment
SAC
 
 
 
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72
12.12.8.
Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PK Concentration Data
4.1.
PK
PK01
Summary of Plasma GSK2838232 Pharmacokinetic 
Concentration-Time Data
SAC
PK Derived Parameters
4.2.
PK
PKPL1P
Listing of Derived Plasma GSK2838232 Pharmacokinetic 
Parameters by Treatment - Day 1
Parameters with units 
SAC
4.3.
PK
PKPL1P
Listing of Derived Plasma GSK2838232 Pharmacokinetic 
Parameters by Treatment – Day 10
Parameters with units 
SAC
4.4.
PK
PKPT2
Summary Statistics of Derived Plasma GSK2838232
Pharmacokinetic Parameters by Treatment and Day
Parameters with units 
SAC
4.5.
PK
PKPT4
Summary Statistics of Log-Transformed Derived Plasma 
GSK2838232 Pharmacokinetic Parameters and Day
Parameters with units 
SAC
4.6.
PK
Assessment of Dose Proportionality of GSK2838232 by Day
Day 1 parameters: AUC(0-24) and 
Cmax
Day 10 parameters: AUC(0-τ) and 
Cmax
SAC
4.7.
PK
Assessment of Plasma GSK2838232 Steady State 
Concentrations
Pre-dose concentration values for 
Day 7, 8, 9 and 10
SAC
 
 
 
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12.12.9.
Pharmacokinetic Figures
Pharmacokinetic: Figures
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Individual Concentration Plots
4.1.
PK
PKCF1P
Individual Plasma GSK2838232 Concentration-Time Plot by Day 
(Linear and Semi-Log)
Present individual Day 1 and Day 
10 profile on same plot. Paginate by 
Subject
SAC
4.2.
PK
PK26
Individual Plasma GSK2838232 Trough Concentration-Time Plot 
(Linear and Semi-Log)
Present Pre-dose and 24 hr time 
points only. Paginate by Subject
SAC
Mean/Median Concentration Plots
4.3.
PK
PKCF2
Mean Plasma GSK2838232 Concentration-Time Plots by 
Treatment and Day (Linear and Semi-Log)
Paginate by Day
SAC
4.4.
PK
PK27
Mean Plasma GSK2838232 Trough Concentration-Time Plots
by Treatment (Linear and Semi-Log)
Pre-dose and 24 hr time points only. 
Time scale by Day
SAC
4.5.
PK
PKCF3
Median Plasma GSK2838232 Concentration-Time Plots by 
Treatment and Day (Linear and Semi-Log)
Paginate by Day
SAC
4.6.
PK
PK27
Median Plasma GSK2838232 Trough Concentration-Time Plots
by Treatment (Linear and Semi-Log)
Pre-dose and 24 hr time points only. 
Time scale by Day
SAC
PK Parameter Plots
4.7.
PK
PK28
Individual and Geometric Mean (95% CI) of Plasma PK 
Parameters versus Dose by Day
Paginate by Parameter and Day. 
Present overlay of individual 
parameters with Geometric mean 
and 95%CI for parameters and 
results for Table 4.4 for regression 
line
SAC
 
 
 
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12.12.10. Pharmacodynamic Tables
Pharmacodynamic: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PD Linear and Emax Models
5.1
PP
Summary of Estimates from Dose-Response Model 
Note that max decline from baseline 
is the endpoint for this analysis. To 
be generated using those subjects 
in the PP population
SAC
12.12.11. Pharmacodynamic Figures
Pharmacodynamic: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PK/PD – RNA Change from Baseline
5.1
PP
Scatter Plot of HIV RNA Maximum Decline from Baseline versus 
Dose
SAC
5.2
PP
PK28
Scatter Plot of Day 11 CD4+ Change from Baseline versus Dose
SAC
 
 
 
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12.12.12. Pharmacokinetic / Pharmacodynamic Tables
Pharmacokinetic/Pharmacodynamic: Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PK Concentration Data
6.1
PK/PD
PK28
Summary of Estimates from Exposure Response Model
Note that max decline from baseline 
is the endpoint for this analysis. To 
be generated using those subjects 
in the PK/PD population
SAC
12.12.13. Pharmacokinetic / Pharmacodynamic Figures
Pharmacokinetic / Pharmacodynamic: Figures
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PK/PD – RNA Change from Baseline
6.1.
PK/PD
PK28
Scatter Plot of Day 11 HIV RNA Change from Baseline versus 
Day 10 Plasma PK Parameters
Present Day 11 CFB HIV RNA vs 
Day 10 AUC(0-τ) and Cmax
SAC
6.2.
PK/PD
PK28
Scatter Plot of HIV RNA Maximum Change from Baseline versus 
Day 10 Plasma PK Parameters
Maximum CFB HIV RNA vs Day 10 
AUC(0-τ) and Cmax
SAC
PK/PD – CD4+ Change from Baseline
6.3.
PK/PD
PK28
Scatter Plot of Day 11 CD4+ Change from Baseline versus Day 
10 Plasma PK Parameters
Present Day 11 CFB CD4+ vs Day 
10 AUC(0-τ) and Cmax
SAC
6.4.
PK/PD
PK28
Scatter Plot of CD4+ Maximum Change from Baseline versus 
Day 10 Plasma PK Parameters
Maximum CFB CD4+ vs Day 10 
AUC(0-τ) and Cmax
SAC
 
 
 
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Pharmacokinetic / Pharmacodynamic: Figures
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PK/PD – QTcF Change from Baseline
6.5.
PK/PD
PK28
Scatter Plot of QTcF Change from Baseline versus Time-
matched PK Concentration
SAC
12.12.14. ICH Listings
ICH: Listings
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Populations Analysed
1.
ITT
Listing of Subjects Excluded from Any Population
SAC
Subject Disposition
2.
Safety
SD2
Listing of Reasons for Study Treatment Discontinuation
SAC
3.
ITT
ES2
Listing of Reasons for Study Withdrawal
IB, SAC
4.
ITT
Listing of Planned and Actual Treatment Assignment
SAC
 
 
 
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ICH: Listings
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Demography & Disease Characteristics at Screening
5.
ITT
DM2
Listing of Demographic Characteristics
Age, sex, race, ethnicity, height, 
weight, and BMI.
For details on Race categories 
shown in this table, please see GSK 
IDSL Demography Statistical 
Display Standards, Section 1.1.1 
Summary of Demographic 
Characteristics
SAC 
6.
ITT
DM9
Listing of Race & Racial Combinations
For details on Race categories 
shown in this table, please see GSK 
IDSL Demography Statistical 
Display Standards, Section 1.1.2 
Summary of Race and Racial 
Combinations
SAC 
Protocol Deviations
7.
ITT
Listing of Protocol Deviations
See RAP Section 12.1.1 for 
categories of protocol deviations.
SAC
8.
ITT
IE3
Listing of Inclusion/Exclusion Criteria Deviations
SAC
Exposure and Treatment Compliance
9.
Safety
OEX8B
Listing of Extent of Exposure to Study Treatment
IB, SAC
Adverse Events
10.
Safety
AE8
Listing of All Adverse Events
IB, SAC
11.
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events
SAC
12.
Safety
AE8
Listing of Serious Adverse Events
IB, SAC
 
 
 
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ICH: Listings
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
13.
Safety
AE8
Listing of Drug Related Serious Adverse Events
IB, SAC
14.
Safety
AE8
Listing of Adverse Events Leading to Withdrawal from 
Study/Permanent Discontinuation of Study Treatment
IB, SAC
15.
Safety
AE8
Listing of Fatal Adverse Events
IB, SAC
16.
Safety
AE8
Listing of Non-Fatal Serious Adverse Events
SAC
17.
Safety
AE8
Listing of Cardiovascular Adverse Events of Special Interest
SAC
Laboratory Values
18.
Safety
LB5
Listing of Chemistry Laboratory Abnormalities of Potential 
Clinical Importance
SAC 
19.
Safety
LB5
Listing of Haematology Laboratory Abnormalities of Potential 
Clinical Importance
SAC 
20.
Safety
LB5
Listing of Liver Function Laboratory Abnormalities of Potential 
Clinical Importance
SAC 
12.12.15. Non-ICH Listings
Non-ICH:: Listings
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Populations Analysed
21.
All Screened
Listing of Study Populations
SAC
 
 
 
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Non-ICH:: Listings
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
22.
All Screened
ES7
Listing of Reasons for Screen Failure
SAC
Demography & Disease Characteristics at Screening
23.
ITT
Listing of Cardiovascular Risk Assessment
SAC 
24.
ITT
Listing of HIV Risk Factors
SAC 
Medical Condition & Concomitant Medications
25.
Safety
Listing of Cardiovascular Events
SAC 
26.
ITT
MH2
Listing of Medical Conditions (Current/Past)
SAC 
27.
ITT
CM2
Listing of Concomitant Medication ATC Level 1 by Ingredient
See GSK IDSL “CONCOMITANT 
MEDICATIONS STATISTICAL 
DISPLAY STANDARDS” (Version 
12), Section 1.1.1  
SAC 
28.
ITT
CM2
Listing of Prior Medication ATC Level 1 by Ingredient
SAC 
29.
ITT
CM6
Listing Relationship Between ATC Level 1, Ingredients And 
Verbatim Text
SAC 
30.
ITT
Listing of HIV Associated Conditions
SAC 
Efficacy
31.
ITT
Listing of Plasma HIV-1 RNA
SAC 
32.
ITT
Listing of Change from baseline (Day 1) in CD4+ cell count to 
Day 11
SAC 
33.
ITT
Listing of Viral Genotypic Data
SAC 
34.
ITT
Listing of Viral Phenotypic Data
SAC 
 
 
 
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Non-ICH:: Listings
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events
35.
Safety
AE8
Listing of Drug Related Adverse Events
IB, SAC
Laboratory Values
36.
Safety
LB5
Listing of Clinical Chemistry Data
IB, SAC 
37.
Safety
LB5
Listing of Haematology Data
IB, SAC 
38.
Safety
LB5
Listing of Liver Function Data
IB, SAC 
39.
Safety
LB5
Listing of Urinalysis Data
SAC
Hepatobiliary (Liver)
40.
Safety
MH2
Listing of Medical Conditions for Subjects with Liver Stopping 
Events
SAC 
ECGs
41.
Safety
EG3
Listing of All ECG Values for Subjects with a Value of Potential 
Clinical Importance
IB, SAC 
Vital Signs
42.
Safety
VS4
Listing of Vital Sign Values by Visit
SAC 
Pharmacokinetic
43.
PK
PKCL1P
Listing of Plasma GSK2838232 Concentrations (ng/mL) by 
Treatment
List all the concentration data 
including unscheduled. Repeat for
all treatments.
SAC
 
 
 
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Non-ICH:: Listings
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Statistical Output
44.
ITT
Statistical Output Listing of Modelled Plasma HIV-1 RNA Mean 
Rate of Decline by Treatment
SAC
45.
ITT
Statistical Output Listing of Modelled Plasma HIV-1 RNA 
Maximum Decline by Treatment
SAC
46.
PP
Statistical Output Listing of Modelled Plasma HIV-1 RNA Mean 
Rate of Decline by Treatment
SAC
47.
PP
Statistical Output Listing of Modelled Plasma HIV-1 RNA 
Maximum Decline by Treatment
SAC
48.
PK
Statistical Output Listing of Assessment of Dose Proportionality 
of GSK2838232 by Day
SAC
49.
PK
Statistical Output Listing of Assessment of Plasma GSK2838232 
Steady State Concentrations
SAC
50.
PP
Statistical Output Listing of Summary of Estimates from Dose-
Response Model
SAC
51.
PK/PD
Statistical Output Listing of Summary of Estimates from 
Exposure Response Model
SAC
 
 
 
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82
12.13.
Appendix 13: Model Checking and Diagnostics for Statistical 
Analyses
12.13.1.
Statistical Analysis Assumptions
Endpoint(s)

PK endpoints AUC(0-∞), AUC(0-τ) and Cmax
Analysis

Mixed Effects
Assumptions:

Model assumptions will be applied, but appropriate adjustments may be made based on the 
data.

The Kenward and Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used.
Endpoint(s)

PD dose response endpoints Emax, E0, ED50
Analysis

Nonlinear Mixed Effects
Assumptions:

Model assumptions will be applied, but appropriate adjustments may be made based on the 
data.
Endpoint(s)

PKPD exposure response endpoints Emax, E0, EC50
Analysis

Nonlinear Mixed Effects
Assumptions:

Model assumptions will be applied, but appropriate adjustments may be made based on the 
data.
 
2018N360917_00