A Phase IIb Study Evaluating a Long-Acting Intramuscular Regimen of GSK1265744 Plus TMC278 For The Maintenance of Virologic Suppression Following an Induction of Virologic Suppression on an Oral Regimen of GSK1265744 Plus Abacavir/Lamivudine in HIV-1 Infected, Antiretroviral Therapy-Naive Adult Subjects
Phase: PHASE2
Conditions: Infection, Human Immunodeficiency Virus, HIV Infections
Sponsor: ViiV Healthcare

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TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A Phase IIb Study Evaluating a Long-Acting Intramuscular 
Regimen of GSK1265744 plus TMC278 For the Maintenance of 
Virologic Suppression Following an Induction of Virologic 
Suppression on an Oral regimen of GSK1265744 plus 
Abacavir/Lamivudine in HIV-1 Infected, Antiretroviral Therapy-
Naive Adult Subjects
Compound Number:
GSK1265744
Development Phase:
IIB
Effective Date:
16-NOV-2017
Protocol Amendment Number:  07
Authors:
 
Copyright 2017 the ViiV Healthcare and 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
2013N168152_00
2013-JUL-12
Original
2013N168152_01
2013-OCT-08
Amendment No.:01 
Updated protocol summary, clarified study drug naming conventions, updated T&E 
tables, clarified study drug descriptions, clarified IDMC, clarified health outcomes 
timings and questionnaires, additional miscellaneous changes
2013N168152_01
2013-OCT-11
Amendment No.:01
Republished for administrative formatting change, however, incorrect signature page 
used.
2013N168152_02
2013-OCT-16
Amendment No.:01
Republished for corrected signature page.
2013N168152_03
2013-OCT-28
Amendment No.:01
Republished to clarify revision chronology; corrected Section 6.3 treatment 
administration
2013N168152_04
2014-JAN-23
Amendment No.: 02
Primary modifications:  Study design adapted to consolidate the Induction Period into a 
single 20 Week arm and for the addition of an every 8 week IM regimen into the 
Maintenance Period.  Increased sample size to 265 subjects.  Primary endpoint changed 
from Week 24 to Week 32.  Dose rationale updated.
2013N168152_05
2014-JUN-13
Amendment No.: 03:  
Primary modifications:  Epzicom / Kivexa added as Investigational Product beginning at 
Day 1 of the Maintenance Period; clarification that alternative background therapy (if 
positive for HLA-B*5701) is not counted as the protocol permitted switch for NRTI; 
clarification regarding provision of alternative NRTI therapy; change in visit window for 
subjects on the oral dosing arm; excursion temperatures added for Epzicom / Kivexa and 
Edurant; text added for Epzicom / Kivexa overdose; deleted option for subject informed 
consent by legal representative; Time and Events Table clarifications. Additional 
clarifications and typographical corrections throughout.
2013N168152_06
2015-APR-22
Amendment No. 4
Primary modifications:  Addition of a 2-hour post dose pharmacokinetic samples and 
ECG at Week 32 and Week 48 for subjects receiving intramuscular GSK744 LA and 
 
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TMC278 LA.  Addition of LAI116482 Week 96 data.  Addition of maladministration of 
injection risk.  Additional clarifications for injection site reaction collection.  Clarified 
visit windows.
2013N168152_07
2016-JUN-21
Amendment No. 5
Primary modifications:  Allowed subjects to remain on their randomized IM regimens 
during the extension period (rather than switching to a single selected IM regimen as 
originally planned).  Allowed subjects randomized to the oral arm to switch to one of the 
optimized Q8W/Q4W regimens (using proposed phase 3 dosing schedules, see Section 
5.1.6), based on subject preference.  Added Dose Rationale for optimized IM dosing 
based off new modelling.  New exploratory objectives and endpoints added for 
evaluation of maintenance and optimized Q8W/Q4W regimens at Week 128 and 152.  
Updated study design schematic for extension phase.  Dosage and Administration Table 
updated to include details on optimized IM regimens. Time and Events tables updated to 
reflect updated Extension Period IM dosing schedule.  Added Extension Period PK 
assessments for subjects switching to the optimized IM regimens.  Added new study 
‘Extension Switch Population’ for the ‘Week 128 analysis’.  Added IDMC monitoring of 
number of PDVFs for subjects switching from oral treatment to optimized IM regimens.  
Added Week 128 Extension Switch Analysis and a Week 152 Analysis
2013N168152_08
2017-AUG-14
Amendment No. 6 (United 
States Specific 
Amendment)
This United States specific amendment has been developed to assess the amount of peak 
drug concentrations (both cabotegravir [CAB] and rilpivirine [RPV] long acting 
injectables [LAI]) that enters the Central Nervous System and more specifically, the 
cerebrospinal fluid (CSF) after subjects receive an injection of the LAI CAB and RPV in 
the LATTE-2 study. This amendment will also characterize the plasma concentration of 
CAB/RPV LAI obtained at the same time point as the CSF analysis and will also assess 
the relationship between the peak concentration of CAB/RPV in the CSF with the amount 
of HIVRNA in the CSF using a sensitive HIVRNA assay called single copy assay  
2013N168152_09
2017-NOV-16
Amendment No. 7
This amendment is to update a planned interim analysis from Week 152 to Week 160.
 
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SPONSOR INFORMATION PAGE
Clinical Study Identifier:
200056
This study is sponsored by ViiV Healthcare.  GlaxoSmithKline is responsible for
implementing and managing all aspects of this study.
Sponsor Legal Registered Address:
ViiV Healthcare
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Telephone:  
Sponsor Contact Address
ViiV Healthcare
Five Moore Drive 
P.O. 13398
Research Triangle Park, NC 27709-3398, USA
Telephone: 
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate
company (or designee). Where applicable, the details of the Sponsor and contact person 
will be provided to the relevant regulatory authority as part of the clinical trial 
submission.
Sponsor Medical Monitor Contact Information: 
 MD, MPH
ViiV Healthcare
Research Triangle Park
Five Moore Drive, Research Triangle Park, NC 27709 (USA)
Mobile: 
Office Telephone: 
Fax: 
e-mail: 
 
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Sponsor Serious Adverse Events (SAE) Contact Information:
 MD, MPH
ViiV Healthcare
Research Triangle Park
Five Moore Drive, Research Triangle Park, NC 27709 (USA)
Mobile: 
Office Telephone: 
Fax: 
e-mail: 
Regulatory Agency Identifying Number(s):
US IND 109,678
EudraCT # 2013-000783-29
 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol 200056
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
LIST OF ABBREVIATIONS...........................................................................................13
PROTOCOL SUMMARY...............................................................................................16
1.
INTRODUCTION....................................................................................................27
1.1.
Background ................................................................................................27
1.2.
List of Study Terms.....................................................................................27
1.3.
Cabotegravir (GSK1265744) – Oral (CAB) .................................................28
1.4.
Cabotegravir – Long Acting Injectable (CAB LA).........................................28
1.5.
Rilpivirine – Oral (RPV)...............................................................................29
1.6.
Rilpivirine – Long Acting Injectable (RPV LA) .............................................29
1.7.
Study LAI116482 ........................................................................................30
1.8.
200056 .......................................................................................................32
1.9.
Study Rationale ..........................................................................................34
1.10.
Dose Rationale ...........................................................................................37
1.10.1.
CAB.............................................................................................37
1.10.2.
CAB LA........................................................................................37
1.10.3.
RPV.............................................................................................46
1.10.4.
RPV LA........................................................................................47
1.11.
Benefit: Risk Assessment ...........................................................................54
1.11.1.
Risk Assessment .........................................................................55
1.11.1.1.
CAB and CAB LA .......................................................55
1.11.1.2.
RPV and RPV LA .......................................................58
1.11.1.3.
Abacavir/Lamivudine (ABC/3TC)................................60
1.11.1.4.
Study Procedures.......................................................61
1.11.1.5.
Risk of Treatment Failure ...........................................61
1.11.2.
Other Clinically Relevant Information...........................................61
1.11.3.
Benefit Assessment.....................................................................62
1.11.4.
Overall Benefit: Risk Conclusion..................................................62
2.
OBJECTIVES AND ENDPOINTS...........................................................................63
3.
INVESTIGATIONAL PLAN.....................................................................................65
3.1.
Study Design Schematic.............................................................................65
3.2.
Study Design ..............................................................................................66
3.2.1.
Screening Period .........................................................................66
3.2.2.
Induction Period...........................................................................67
3.2.3.
Eligibility for the Maintenance Period ...........................................67
3.2.4.
Maintenance Period.....................................................................68
3.2.5.
Extension Period..........................................................................70
3.2.5.1.
Entering from the CAB LA + RPV LA Arm ..................70
3.2.5.2.
Eligibility for the Extension Period for Subjects 
Entering From the CAB 30 mg + ABC/3TC Arm .........70
3.2.5.3.
Entering from the CAB 30 mg + ABC/3TC Arm ..........71
3.2.6.
Long-term Follow-Up Period – IM Regimens only........................73
3.2.7.
Follow Up Visit.............................................................................73
3.2.8.
Independent Data Monitoring Committee.....................................74
3.2.9.
Primary Analysis..........................................................................74
 
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3.3.
Discussion of Design ..................................................................................75
4.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA.......................................77
4.1.
Number of Subjects ....................................................................................77
4.2.
Inclusion Criteria.........................................................................................77
4.3.
Exclusion Criteria........................................................................................79
4.4.
Additional Eligibility Criteria.........................................................................81
4.5.
Withdrawal Criteria .....................................................................................81
4.5.1.
Subjects Receiving CAB LA and / or RPV LA ..............................84
4.6.
Virologic Failure..........................................................................................84
4.6.1.
Definition of Virologic Failure .......................................................84
4.6.2.
Managing Virologic Failure ..........................................................85
4.6.2.1.
Suspected Virologic Failure........................................85
4.6.2.2.
Confirmed Virologic Failure ........................................85
4.7.
Screening Failures......................................................................................86
5.
STUDY TREATMENTS..........................................................................................86
5.1.
Investigational Product and Other Study Treatment....................................86
5.1.1.
Cabotegravir (GSK1265744) – Tablet (CAB) ...............................86
5.1.2.
Rilpivirine - Tablet (RPV) .............................................................87
5.1.3.
Epzicom / Kivexa .........................................................................87
5.1.4.
Cabotegravir (GSK1265744) – Injectable Suspension 
(CAB LA) .....................................................................................87
5.1.5.
Rilpivirine – Injectable Suspension (RPV LA)...............................87
5.1.6.
Dosage and Administration..........................................................88
5.1.7.
Dosing Considerations for CAB LA + RPV LA..............................90
5.2.
Treatment Assignment................................................................................91
5.3.
Blinding.......................................................................................................91
5.4.
Product Accountability ................................................................................91
5.5.
Treatment Compliance................................................................................91
5.6.
Protocol Permitted Substitutions.................................................................92
5.6.1.
Oral Bridging................................................................................92
5.7.
Interruption of Study Treatment and Visit/Dosing Windows.........................93
5.7.1.
Oral Dosing Including Long Term Follow Up................................93
5.7.2.
IM Dosing ....................................................................................93
5.8.
Discontinuation of Study Treatment ............................................................94
5.8.1.
Discontinuation of ABC/3TC ........................................................94
5.8.2.
Discontinuation of CAB LA or RPV LA.........................................94
5.9.
Concomitant Medications and Non-Drug Therapies....................................95
5.9.1.
Permitted Medications and Non-Drug Therapies..........................95
5.9.2.
Prohibited Medications and Non-Drug Therapies.........................95
5.9.2.1.
Concurrent with CAB and/or RPV...............................96
5.9.2.2.
Concurrent with RPV..................................................96
5.9.2.3.
Concurrent with either CAB LA or RPV LA .................96
5.10.
Treatment after the End of the Study ..........................................................97
5.10.1.
Long-Term Follow-Up Period.......................................................97
5.11.
Treatment of Study Treatment Overdose....................................................97
6.
STUDY ASSESSMENTS AND PROCEDURES .....................................................98
6.1.
Time and Events Table – Induction Period..................................................98
6.2.
Time and Events Table – Maintenance Period for IM Regimen (CAB 
LA+RPV LA Q8W)....................................................................................101
 
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6.3.
Time and Events Table – Maintenance Period for IM Regimen (CAB 
LA+RPV LA Q4W)....................................................................................104
6.4.
Time and Events Table – Maintenance Period for Oral Regimen 
(CAB 30 mg+ABC/3TC)............................................................................107
6.5.
Time and Events Table – Extension Period for IM Regimen (CAB 
LA + RPV LA-Q8W)..................................................................................111
6.6.
Time and Events Table – Extension Period for IM Regimen (CAB 
LA + RPV LA - Q4W)................................................................................114
6.7.
Time and Events Table – Long-Term Follow Up Period............................117
6.8.
Critical Screening and Baseline Assessments ..........................................118
6.8.1.
Screening ..................................................................................118
6.8.2.
Baseline.....................................................................................119
6.9.
Efficacy.....................................................................................................119
6.9.1.
Plasma HIV-1 RNA....................................................................119
6.9.2.
Lymphocyte Subsets, CD4+ and CD8+ .....................................119
6.9.3.
HIV Associated Conditions ........................................................120
6.10.
Safety .......................................................................................................120
6.10.1.
Clinical evaluations ....................................................................120
6.10.2.
Laboratory Assessments ...........................................................121
6.10.3.
Liver Chemistry Stopping and Follow up Criteria........................122
6.10.3.1.
Liver Chemistry Stopping Criteria .............................122
6.10.3.2.
Liver Chemistry Stopping Criteria, Subject 
Management ............................................................123
6.10.3.3.
Liver Chemistry Stopping Criteria -
Rechallenge .............................................................124
6.10.4.
Adverse Events..........................................................................126
6.10.4.1.
Definition of an AE....................................................126
6.10.4.2.
Definition of an SAE .................................................127
6.10.5.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs.......................................................128
6.10.6.
Specific Toxicities / Adverse Event Management.......................128
6.10.6.1.
Treatment Interruption Due to an Adverse 
Event........................................................................128
6.10.6.2.
Grade 1 or Grade 2 Toxicity/Adverse Event .............129
6.10.6.3.
Grade 3 Toxicity/Adverse Event ...............................129
6.10.6.4.
Grade 4 Toxicity/Adverse Event ...............................130
6.10.6.5.
Diarrhea ...................................................................131
6.10.6.6.
Hypertriglyceridemia/ Hypercholesterolemia.............131
6.10.6.7.
Creatine Phosphokinase (CPK) Elevation ................132
6.10.6.8.
Lipase Elevations and Pancreatitis...........................132
6.10.6.9.
Decline in Renal Function.........................................132
6.10.6.10. Proteinuria................................................................133
6.10.6.11. QTc Prolongation .....................................................134
6.10.6.12. Injection Site Reactions (ISRs) .................................134
6.10.6.13. Allergic Reaction ......................................................134
6.10.6.14. Abacavir Hypersensitivity Reaction (ABC HSR)........135
6.10.6.14.1. Essential Patient Information ................135
6.10.6.14.2. Reporting of Hypersensitivity 
Reactions .............................................136
6.10.6.15. Rash Without ABC HSR Symptoms .........................136
6.10.6.16. Seizures ...................................................................137
6.10.7.
Cardiovascular Events...............................................................138
 
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6.10.8.
Death Events.............................................................................138
6.10.9.
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as SAEs.............................................138
6.10.10. Monitoring Suicidal Ideation and Behavior .................................139
6.10.11. Pregnancy .................................................................................140
6.10.11.1. Pregnancy Testing....................................................140
6.10.11.2. Time Period for Collecting Pregnancy 
Information ...............................................................140
6.10.11.3. Action to be Taken if Pregnancy Occurs...................140
6.10.12. Time Period and Frequency of Detecting AEs and SAEs...........141
6.10.13. Method of Detecting AEs and SAEs...........................................141
6.10.14. Prompt Reporting of Serious Adverse Events and Other 
Events to GSK...........................................................................142
6.10.14.1. Regulatory Reporting Requirements for SAEs..........143
6.11.
Pharmacokinetics .....................................................................................143
6.11.1.
PK Sample Collection ................................................................144
6.11.2.
Rationale of PK Sampling Strategy............................................146
6.11.3.
Bioanalysis of CAB and RPV .....................................................146
6.12.
Viral Genotyping and Phenotyping............................................................147
6.12.1.
HIV-1 pol Viral Genotyping and Phenotyping .............................147
6.12.2.
HIV-1 Exploratory Analysis ........................................................147
6.13.
Pharmacogenetic Research......................................................................147
6.14.
Health Outcomes......................................................................................148
7.
DATA MANAGEMENT .........................................................................................149
8.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS.................................149
8.1.
Hypotheses...............................................................................................149
8.2.
Study Design Considerations....................................................................149
8.2.1.
Sample Size Assumptions .........................................................149
8.2.2.
Sample Size Sensitivity..............................................................151
8.2.3.
Sample Size Re-estimation........................................................152
8.3.
Data Analysis Considerations ...................................................................152
8.3.1.
Analysis Populations..................................................................152
8.3.1.1.
Intent-to-Treat Exposed Population (ITT-E)..............152
8.3.1.2.
Intent-to-Treat Maintenance Exposed 
Population (ITT-ME) .................................................153
8.3.1.3.
Per Protocol Maintenance Exposed Population 
(PP-ME) ...................................................................153
8.3.1.4.
PK Population...........................................................153
8.3.1.5.
Safety Population .....................................................153
8.3.1.6.
Extension Switch Population ....................................153
8.3.2.
Analysis Data Sets.....................................................................153
8.3.3.
Treatment Comparisons ............................................................154
8.3.3.1.
Primary Comparisons of Interest ..............................154
8.3.3.2.
Other Comparisons of Interest..................................154
8.3.4.
Planned Analysis .......................................................................154
8.3.4.1.
IDMC Interim Analyses.............................................155
8.3.4.2.
Futility Interim Monitoring..........................................155
8.3.4.3.
Day 1 Interim Analysis..............................................158
8.3.4.4.
Week 32 Primary Analysis........................................158
8.3.4.5.
Week 48 Analysis.....................................................158
 
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8.3.4.6.
Week 96 Analysis.....................................................158
8.3.4.7.
Week 128 Extension Switch Analysis .......................158
8.3.4.8.
Week 160 Analysis...................................................158
8.3.5.
Key Elements of Analysis Plan ..................................................159
8.3.5.1.
Efficacy Analyses .....................................................159
8.3.5.2.
Safety Analyses........................................................160
8.3.5.3.
Treatment Compliance .............................................161
8.3.5.4.
Health Outcomes Analyses ......................................161
8.3.5.5.
Pharmacokinetic Analyses........................................161
8.3.5.6.
Pharmacokinetic/Pharmacodynamic Analyses .........162
8.3.5.7.
Viral Genotyping/Phenotyping Analyses...................162
8.3.5.8.
Pharmacogenetic Analyses ......................................162
9.
STUDY CONDUCT CONSIDERATIONS .............................................................162
9.1.
Posting of Information on Publicly Available Clinical Trial Registers..........162
9.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ......................................................................................162
9.3.
Quality Control (Study Monitoring) ............................................................163
9.4.
Quality Assurance.....................................................................................163
9.5.
Study and Site Closure .............................................................................164
9.6.
Records Retention....................................................................................164
9.7.
Provision of Study Results to Investigators, Posting of Information 
on Publicly Available Clinical Trials Registers and Publication..................165
9.8.
Independent Data Monitoring Committee (IDMC) .....................................165
10. REFERENCES.....................................................................................................166
11. APPENDICES......................................................................................................169
11.1.
Appendix 1: CDC Classification System for HIV-1 Infections (1993) .........169
11.2.
Appendix 2: Division of AIDS Table for Grading the Severity of Adult 
and Pediatric Adverse Events...................................................................172
11.3.
Appendix 3: Pharmacogenetic Research ..................................................191
11.4.
Appendix 4: Liver Safety Drug Restart or Rechallenge Guidelines............196
11.5.
Appendix 5: Country Specific Requirements.............................................203
11.6.
Appendix 6: Changes to the Protocol........................................................204
 
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LIST OF ABBREVIATIONS

Dosing interval, time between consecutive doses
3TC
Lamivudine, EPIVIR
ABC
Abacavir, ZIAGEN
AE
Adverse Event
AIDS
Acquired immunodeficiency syndrome
ALT
Alanine Aminotransferase
ART
Antiretroviral Therapy
AST
Aspartate Aminotransferase
AUC
Area Under the Curve
AUC(0-)
Area under the plasma drug concentration-time curve from predose to the 
end of the dosing interval at steady state
BMI
Body Mass Index
BP
Blood Pressure
BUN
Blood urea nitrogen
C
Concentration at the end of a dosing interval
c/mL
Copies/millilitre
CAB
Cabotegravir, Oral
CAB LA
Cabotegravir, Long Acting Injectable
CDC
Centers for Disease Control and Prevention
CI
Confidence Interval
Cmax
Maximum plasma drug concentration
CPK
Creatine Phosphokinase
CV
Coefficient of variation
DAIDS
Division of Acquired Immunodeficiency Syndrome
ECG
Electrocardiograph
eCRF
Electronic case report form
eC-SSRS
Electronic Columbia Suicidality Severity Rating Scale
EFV
Efavirenz
FC
Fold Change
FDA
Food and Drug Administration
FDC
Fixed dose combination
FTC
Emtricitibine
GCP
Good Clinical Practices
GI
Gastrointestinal
GSK
GlaxoSmithKline
HAART
Highly Active Antiretroviral Therapy
HbsAg
Hepatitis B Virus surface Antigen
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
HDPE
High Density Polyethylene
HIV-1
Human Immunodeficiency Virus Type 1
HIVMQ
HIV medication questionnaire
HIVTSQ
HIV treatment satisfaction questionnaire
HIVTSQc
HIV Treatment Satisfaction Questionnaire change version
 
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HIVTSQs
HIV Treatment Satisfaction Questionnaire status version
HSR
Hypersensitivity reactions
IAS
International AIDS Society
IB
Investigator’s Brochure
IC90
90% Inhibitory Concentration
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee
IEC
Institutional Ethics Committee
IM
Intramuscular
INI
Integrase Inhibitor
INR
International Normalized Ratio
IP
Investigational Product, both formulations of cabotegravir and rilpivirine
IRB
Institutional Review Board
ISR
Injection Site Reaction
ITT
Intent-to-Treat
ITT-ME
Intent-to-Treat Maintenance Exposed
IUD
Intrauterine Device
IV
Intravenous
LA
Long acting
LLOD
Lower limit of detection
LSLV
Last Subject Last Visit
mg
Milligram
mL
Milliliter
MSDF
Missing, Switch or Discontinuation = Failure
MSDS
Material Safety Data Sheet 
ng
Nanogram
NNRTI
Non-nucleoside reverse transcriptase inhibitor
NRTI
Nucleoside reverse transcriptase inhibitor
OC
Observed case
PD
Pharmacodynamic
PDVF
Protocol Defined Virologic Failure
PGx
Pharmacogenetics
PI
Protease Inhibitor
PK
Pharmacokinetic
Pol
Polymerase
PopPK
Population Pharmacokinetics
PP
Per Protocol population
PRO
Patient Reported Outcomes
PSRAE
Possible Sucidiality Related Adverse Event
PT
Prothrombin Time
Q4W
Every 4 Weeks
Q8W
Every 8 Weeks
QTC
Corrected QT interval
RAP
Reporting analysis plan
RBC
Red blood cell
RNA
Ribonucleic acid
 
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RPV
Rilpivirine, Edurant, oral formulation of TMC278
RPV LA
Rilpivirine, Long Acting Injectable
RT
Reverse transcriptase
SAE
Serious adverse event
SPM
Study Procedure Manual
SVF
Suspected Virologic Failure
t1/2
Estimated terminal phase half-life
TDF
Tenofovir disoproxyl fumarate, Viread
TLOVR
Time to Loss of Virologic Response
ULN
Upper limit of normal
US
United States
VSLC
ViiV Safety and Labeling Committee
WBC
White blood cells
WD
Withdrawal
Trademark Information
Trademarks of ViiV Healthcare
Trademarks not owned by 
ViiV Healthcare
EPZICOM
Edurant
KIVEXA
GeneSeq
ZIAGEN
GenoSure
Isentress (raltegravir)
Monogram Biosciences
PhenoSense
Truvada
 
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PROTOCOL SUMMARY
Study Terms
For the ease of the reader, the following terms will be useful to understand:

Cabotegravir (GSK1265744) – the ViiV compound under study.  When written 
as shown, this refers to either the oral or long acting formulation.
o
CAB – the oral formulation of cabotegravir; 
o
CAB LA – the long acting injectable formulation of cabotegravir; LA stands 
for “long acting”;

Rilpivirine – the Janssen / partner compound under study.  When written as 
shown, this refers to either the oral or long acting formulation.
o
RPV – rilpivirine or the oral formulation of rilpivirine, also known as Edurant;
o
RPV LA - the long acting injectable formulation of rilpivirine; LA stands for 
“long acting”;

Induction – the induction of virologic suppression of Human Immunodeficiency 
Virus Type 1 (HIV-1) infection in anti-retroviral naive subjects prior to the 
initiation of the CAB LA + RPV LA regimen.  This period will be represented in 
text, schema and Time and Events as negative weeks.  The length of induction is 
20 weeks.  Baseline is the first day of the Induction Period (i.e. this is not Day 1). 

Maintenance – the maintenance of virologic suppression of HIV-1 infection; the 
length of maintenance being evaluated is 96 weeks.  Day 1 is the first day of the 
Maintenance Period.  

Dosing Regimen - Two intramuscular (IM) dosing regimens are being evaluated:  
every 4 weeks (Q4W) and every 8 weeks (Q8W). One oral dosing is being 
evaluated (oral).

Extension – extending study treatment past the key study analysis points; length 
of extension being evaluated is until investigational product (IP) is either locally 
approved and commercially available, a subject no longer derives clinical 
benefit, a subject meets a protocol-defined reason for discontinuation or until 
development of IP is terminated.

Long-Term Follow-Up – follow up period for subjects receiving at least one dose 
of CAB LA and/or RPV LA who have discontinued treatment or have been 
withdrawn; length of follow up being evaluated is 52 weeks.
 
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
IP = Investigational product; both formulations of CAB and RPV.  Epizcom / 
Kivexa (ABC/3TC) will also be considered IP beginning at Day 1 of the 
Maintenance Period.
Study Objective
The overall objective of this study is to select an intramuscular dosing regimen of CAB 
LA plus RPV LA based on a comparison of the Week 32 antiviral activity, tolerability, 
and safety of the two IM dosing regimens, relative to CAB 30 mg plus abacavir 
(ABC)/lamivudine (3TC) orally once daily.
Study Schematic
Induction Period
 
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Maintenance and Extension Period
Notable Inclusion Criteria

Male or female subjects at least 18 years old that are HIV-1 positive (HIV-1 
ribonucleic acid (RNA) 1000 copies/millilitre [c/mL])

Women of childbearing potential may be enrolled if they agree to use adequate 
contraception for the life of the study and at least 52 weeks after withdrawal from 
an IM regimen.

CD4+ cell count 200 cells/mm3 (or higher as local guidelines dictate).

Antiretroviral therapy (ART) naive (no more than 10 days of prior therapy with 
any antiretroviral agent following a diagnosis of HIV-1 infection.  Any previous 
exposure to an HIV integrase inhibitor or non-nucleoside reverse transcriptase
inhibitor will be exclusionary).
Notable Exclusion Criteria

Any evidence of primary resistance based on the presence of any major 
resistance-associated mutation (International AIDS Society [IAS]-USA, 2013) in 
the Screening result or, if known, any historical resistance test result.

Subjects with known moderate to severe hepatic impairment.  
 
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
History of ongoing or clinically relevant hepatitis within the previous 6 months, 
including chronic hepatitis B virus (HBV) infection (Hepatitis B Virus Surface
Antigen [HBsAg] positive). Asymptomatic individuals with chronic hepatitis C 
virus (HCV) infection will not be excluded, however Investigators must carefully 
assess if therapy specific for HCV infection is required; subjects who are 
anticipated to require such therapy must be excluded.

History of liver cirrhosis with or without hepatitis viral co-infection.

Current or anticipated need for chronic anti-coagulation.

Any verified Grade 4 laboratory abnormality.

Any acute laboratory abnormality at Screening, which, in the opinion of the 
Investigator, would preclude the subject’s participation in the study of an 
investigational compound.

Subject has estimated creatinine clearance <50 mL/min via Cockcroft-Gault 
method.

Alanine aminotransferase (ALT) 5 times upper limit of normal (ULN).  Subjects 
with ALT > 2xULN but <5xULN may participate in the study, if in the opinion of 
the Investigator and GlaxoSmithKline (GSK) medical monitor the lab 
abnormality will not interfere with the study procedures or compromise subject 
safety.

ALT 3xULN and bilirubin 1.5xULN (with >35% direct bilirubin).

Subjects who are HLA-B*5701 positive and unable to use an alternative 
nucleoside reverse transcriptase inhibitor (NRTI) backbone (subjects who are 
HLA-B*5701positive may be enrolled if they use an alternative NRTI backbone 
that does not contain abacavir).

Any clinically significant finding on screening or Baseline electrocardiograph 
(ECG).

Tattoo or other dermatologic condition over gluteus region.

Need for chronic anticoagulants.
Study Design
Study 200056 is a Phase IIb, randomized, multicentre, parallel group, open-label, three-
part study to be conducted in approximately 265 HIV-1 infected ART-naive adults. This 
study will consist of a Screening Period, Induction Period, Maintenance Period, 
Extension Period and a Long-term Follow-up Period (withdrawn IM dosing regimen
subjects only). 
Induction Period
Following the 28-day Screening Period, eligible subjects will be enrolled into the study 
and begin a 20-week Induction Period utilizing an oral regimen of CAB 30 mg once daily 
plus ABC/3TC 600/300 mg once daily.  
 
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Subjects will initiate treatment on their first day on study and will be seen every 4 weeks 
for study treatment dispensing and safety and efficacy assessments.  
At Week (-4) the treatment regimen is modified to add RPV 25 mg once daily for the 
remainder of the Induction Period.
Eligibility for the Maintenance Period
Subjects who have demonstrated tolerability to the Induction Period regimen and with an 
undetectable HIV-1 RNA (<50 c/mL) at the Week (-4) visit are eligible to enter the 
Maintenance Period. A single repeat to determine eligibility may be allowed ONLY after 
consultation with the medical monitor.  Subjects with HIV-1 RNA 400 c/mL at 
Week (-4) are not eligible to enter the Maintenance Period, will not be allowed a repeat to 
determine eligibility and will therefore be withdrawn from the study. 
Maintenance Period
At Day 1, the Maintenance Period begins.  Eligible subjects will be randomized 2:2:1 to 
receive an IM regimen of CAB LA 400 mg + RPV LA 600 mg every 4 weeks for 96 
weeks, an IM regimen of CAB LA 600 mg + RPV LA 900 mg every 8 weeks for 96 
weeks, or to continue on the oral Induction Period regimen of CAB 30 mg + ABC/3TC 
once daily for 96 weeks (or 100 weeks if continuing on to the Extension Period).  Subject 
randomization will be stratified by subjects’ HIV-1 RNA prior to Week (-8) (<50 c/mL, 
yes or no).
On the first day of the Maintenance Period (Day 1), subjects will receive their last dose of 
the Induction regimen (CAB 30 mg+ABC/3TC+RPV 25 mg) in the clinic and initiate 
either IM injections or be dispensed the oral regimen depending on the randomization 
arm.  Add-on RPV treatment will be discontinued for all subjects after Day 1.  
Dosing for each arm is as follows (all injections are single injections per drug unless 
otherwise noted):
IM injections every 8 weeks (Q8W)

Day 1 only – CAB LA 800 mg (loading dose delivered as two 400 mg IM 
injections) + RPV LA 900 mg IM

Week 4 only - CAB LA 600 mg IM (second loading dose, no RPV LA)

Week 8 - CAB LA 600 mg IM + RPV LA 900 mg IM every 8 weeks for 96 
weeks
IM injections every 4 weeks (Q4W)

Day 1 only - CAB LA 800 mg (loading dose delivered as two 400 mg IM 
injections) + RPV LA 600 mg IM

Week 4 - CAB LA 400 mg IM + RPV LA 600 mg IM every 4 weeks for 96 
weeks
Oral Control Arm
 
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
CAB 30 mg + ABC/3TC once daily for 96 weeks (or 100 weeks if going on to the 
Extension period)
It is important to note that keeping to the subject’s dosing / visit schedule is a very 
important component to the study.  IM dosing is expected to occur during the week in 
which the subject’s projected visit falls (as according to the Day 1 visit).  A (+ or -) 7-day
window, from the projected visit date, is allowable for IM dosing but not preferred.  At 
one-week post dose visits (Week 1, Week 25, and Week 41), there is no defined visit 
window, rather visits should occur approximately 1 week from the last injection.
Visits for subjects on the oral dosing arm are expected to occur as projected according to 
the Baseline visit.  There is a (+ or -) 3-day visit window, from the projected visit date.  
However, the number of tablets dispensed should be considered when scheduling the next 
visit.  Visits in Long Term Follow Up are to occur as projected from the last injection 
with a (+ or -) 3-day visit window, from the projected visit date.
All subjects are seen approximately every 4 weeks for safety, efficacy and PK 
assessments through Week 32.  After Week 32, subjects will continue to be seen as per 
the Time and Events Schedule (see Section 6) for dosing, safety, efficacy and PK 
assessments through Week 96 (or Week 100 for the oral arm if continuing on to the 
Extension Period).
Some visits that are not aligned with dosing will be conducted by telephone interview.  
This allows for safety assessments to be conducted at all visits, but limits clinic visits for 
non-dosing visits.
See the Time and Events Schedule Section 6.2 and Section 6.3 for more information.  See 
Section 3.2.5.3 for additional information regarding special requirements from Week 96 
to Week 104 for subjects on the oral arm entering the Extension Period.
Eligibility for the Extension Period
Subjects who have demonstrated tolerability to their Maintenance Period regimen and 
with an undetectable HIV-1 RNA (<50 c/mL) at the Week 96 visit are eligible to enter 
the Extension Period. A single repeat to determine eligibility may be allowed ONLY
after consultation with the medical monitor.  Subjects with HIV-1 RNA 400 c/mL at 
Week 96 are not eligible to enter the Extension Period, will not be allowed a repeat to 
determine eligibility and will therefore be withdrawn from the study.
Extension Period
Both IM dosing regimen (Q8W and Q4W) will continue to be evaluated in the Extension 
period.
Entering from the CAB LA + RPV LA Arms
All subjects who successfully complete 96 weeks of CAB LA + RPV LA treatment in the 
Maintenance Period as described in Section 3.2.5.1, will continue with their current IM 
dosing regimen of CAB LA and RPV LA in the Extension Period until:
 
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
study treatment is locally approved and commercially available, 

the subject no longer derives clinical benefit, 

the subject meets a protocol-defined reason for discontinuation  

until development of either CAB LA or RPV LA is terminated.  
Subjects will remain on their current regimen after Week 96 and will continue to receive 
their Maintenance Period IM dosing regimen for the remainder of study participation.  
Safety and efficacy assessments will be conducted every 16 weeks. Dosing visits will 
occur according to the selected dosing regimen.  See the Time and Events Schedule 
Section 6.5 and Section 6.6 for more information.  
Entering from the CAB 30 mg + ABC/3TC Arm
All subjects who successfully complete 96 weeks of CAB 30 mg + ABC/3TC treatment 
in the Maintenance Period will have the option to continue study participation by 
switching to an optimized IM dosing regimen of their choice (either Q8W or Q4W) of 
CAB LA + RPV LA in the Extension Period.  Subjects not choosing to switch to an 
optimized long acting regimen will complete their study participation at Week 96.
Subjects who choose to continue on to the Extension Period will be assessed for 
eligibility to begin their selected CAB LA + RPV LA regimen.  Subjects will continue on 
their Maintenance regimen (CAB 30 mg + ABC/3TC) while eligibility is being 
confirmed.  RPV will not be added to their Maintenance regimen prior to the switch to 
optimized IM dosing.  Subjects were given RPV during the last 4 weeks of the Induction 
Period to evaluate safety and tolerability before being randomized to continue in the 
Maintenance Period and thus further evaluation is not necessary.  
Participants with a Week 96 HIV-1 RNA <50 c/mL, will continue their oral regimen 
(CAB 30 mg + ABC/3TC) until Week 100.  In order to qualify to receive CAB LA + 
RPV LA injections at Week 100, the HIV-1 RNA results from the Week 96 visit must be
undetectable (<50 c/mL; a single repeat HIV-1 RNA test may be allowed prior to Week 
100 following consultation with the Medical Monitor).  
If the Optimized Q4W IM Dosing Regimen is Selected by the Subject
At visit Week 100, participants will return to the clinic, take the last dose of their oral 
regimen (CAB 30 mg + ABC/3TC), and receive the first CAB LA (600 mg) + RPV LA 
(900 mg) injections (within 2 hours of the final oral dose of CAB + ABC/3TC).  The 
second and third injections (CAB LA 400 mg + RPV LA 600 mg) will be administered at 
Week 104 and Week 108.  There will be a one week dosing window for the second and 
third IM injections such that the second injections occur within the window of Week 103 
to Week 104, but not later than Week 104, and the third injections occur within the 
window of Week 107 to Week 108, but no later than Week 108.  Subsequent injections 
(CAB LA 400 mg + RPV LA 600 mg) will occur every 4 weeks thereafter, from the 
projected visit date, with a (+ or -) 7 day dosing window being allowed (but not 
preferred).  Following the Week 108 injection, the interval between injection visits 
 
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should be limited to a maximum of 5 weeks.  The Medical Monitor must be contacted if 
the length of time between injections exceeds, or is projected to exceed, 5 weeks.
If the Optimized Q8W IM Dosing Regimen is Selected by the Subject
At visit Week 100, subjects will return to the clinic, take the last dose of their oral (CAB 
30 mg + ABC/3TC), and receive the first CAB LA (600 mg) + RPV LA (900 mg) 
injections (within 2 hours of the final oral dose of CAB + ABC/3TC).  The second 
loading injections will be administered at Week 104 (CAB LA 600 mg + RPV LA 
900 mg, with subsequent injections (CAB LA 600 mg + RPV LA 900 mg) occurring 
every 8 weeks thereafter.  The dosing window for the second injection allows 
administration between Week 103 and Week 104, but preferably not later than Week 104.  
Starting at the Week 112 injection, the interval between injection visits should be limited 
to a maximum of 9 weeks.  If the length of time between injections exceeds, or is 
projected to exceed 9 weeks, the Medical Monitor must be contacted to discuss individual 
subject case management.  After Week 112, a dosing window (7 days) for injections is 
allowed, but not preferred.
Subjects will continue study treatment until CAB LA and RPV LA are either locally 
approved and commercially available, the subject no longer derives clinical benefit, the 
subject meets a protocol-defined reason for discontinuation or until development of either 
CAB LA or RPV LA is terminated. 
Safety and efficacy assessments will be conducted as per the Time and Events Schedule
(See the Time and Events Schedule Section 6.5 and Section 6.6 for more information.)
Subjects not eligible to enter the Extension Period will end their study participation and 
will complete the Withdrawal Visit.  Sites may be reimbursed for up to a one month 
supply of antiretroviral medication to facilitate transition to non-study ART for subjects 
that do not qualify for the Extension Period.
Long-term Follow-Up Period IM Regimens
Any subject who receives at least a single dose of CAB LA and/or RPV LA and 
discontinues the CAB LA + RPV LA regimen for any reason must remain on suppressive 
Highly Active Antiretroviral Treatment (HAART) for at least 52 weeks after the last dose 
of CAB LA and/or RPV LA in order to prevent selective pressure on HIV and the 
potential for selection of resistant mutants.  This period is considered study participation 
and subjects will be followed on study during this time.
In the Long-Term Follow-Up Period, subjects will receive oral HAART and be followed 
for 52 weeks after the last dose of CAB LA and/or RPV LA. In order to assure that 
subjects have access to HAART during the Long-Term Follow-Up Period, GSK may
supply HAART regionally or reimbursement will be provided during this period.
 
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Follow Up Visit
A Follow up visit may be conducted approximately 4 weeks after the last dose of IP and 
is required only if the subject has ongoing adverse events (AEs) or lab abnormalities at 
the last on-study visit.
Key Study Assessments

HIV-1 RNA and CD4+ cell counts

Laboratory assessments including hematology, blood chemistry, urinalysis and 
fasting glucose, lipids and pregnancy testing

PK assessments including 2-hour post dose samples at Day 1, Weeks 32, 48, 100 
and 128.

Monitoring and recording of all AEs and serious adverse events (SAEs)

Physical exams and vitals

Past medical history, family history, social history, medication history.  Targeted 
history on cardiovascular risk (smoking history, family and personal history)

HIV-associated conditions

Exercise habits utilizing a subject diary

Electrocardiograms

Assessment of Injection Site Reactions (ISRs) clinically and utilizing a subject 
diary

Columbia Suicide Severity Rating Scale (eC-SSRS)

Health Outcomes questionnaires for treatment satisfaction and medication 
adherence
Definition of Virologic Failure

Non-response as indicated by a less than a 1.0 log10 copies/mL decrease in plasma 
HIV-1 RNA after 4 weeks of starting the Induction Period, which is subsequently 
confirmed, unless the plasma HIV-1 RNA is < 400 c/mL.

Rebound as indicated by two consecutive plasma HIV-1 RNA levels 200 c/mL 
after prior suppression to < 200 c/mL. 
 
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
Rebound as indicated by two consecutive plasma HIV-1 RNA that are 
> 0.5 log10 c/mL increase in plasma HIV-1 RNA from the nadir value on study, 
where the lowest HIV-1 RNA value is 200 c/mL.
Permitted Treatment Substitutions
Subjects who are HLA-B*5701 positive at the Screening visit are allowed to enter the 
study on an approved dual-NRTI backbone that does not contain abacavir (e.g. 
tenofovir/emtricitibine [TDF/FTC]).  This regimen may be supplied regionally by GSK 
or reimbursement will be provided.
Switch of background NRTI therapy to an alternative approved NRTI therapy for toxicity 
or tolerability management is allowed once during the study.  Switches of a background 
NRTI for any other reason are not permitted in the study. 
In exceptional circumstances, the medical monitor may authorize the use of CAB and/or 
RPV (oral regimen) as a short-term “bridging” strategy for subjects who have begun 
CAB LA + RPV LA.  This strategy would only be employed to address any potential gap 
in CAB LA + RPV LA dosing as a result of scheduling conflicts which would prevent 
planned dosing.
Independent Data Monitoring Committee
An Independent Data Monitoring Committee (IDMC) will evaluate the efficacy, 
tolerability, and safety of CAB and RPV before all eligible subjects have transitioned 
from the Induction Period to the Maintenance Period. This IDMC review may be 
conducted after approximately 45 subjects have reached Week 8 of the Maintenance 
Period, depending on IDMC agreement. In addition, futility guidance is included to 
monitor the performance of all treatment arms when 50% of subjects have completed 
Week 24 of the Maintenance Period in order to prevent subjects from continuing on a 
dosing regimen if existing data indicates that subjects are at unacceptable risk of 
inadequate maintenance of virologic suppression.
As subjects enter the Maintenance Period of the study, if the number of protocol defined 
virologic failures meets or exceeds the pre-specified thresholds specified in the IDMC 
Charter, this will be considered strong evidence of an inadequate response and will 
trigger a comprehensive data review by the IDMC.  Similar thresholds will be used by the 
IDMC to monitor the number of protocol defined virologic failures for subjects switching 
from oral CAB 30 mg +ABC/3TC to an optimized IM dosing regimen during the 
Extension Period.  The IDMC charter will contain details of this continual monitoring of 
the protocol defined virologic failure rates, the specifics around what will trigger a data 
review, and the safety summaries and efficacy analyses that will be provided should a 
data review be required.
If one of the IM dosing regimens (Q8W or Q4W) is discontinued as a result of an IDMC 
review or any subsequent analysis (as detailed in the IDMC Charter), those subjects who 
have not met any clinical management criteria for discontinuation and who were 
randomized to the discontinued IM dosing regimen, or selected a discontinued optimized 
 
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IM dosing regimen, may be given the option to discontinue permanently from the study 
or to continue on the remaining IM dosing regimen at the next scheduled visit. 
Primary Analysis
The Week 32 primary analysis will be conducted once the last randomized subject has 
completed the Week 32 study visit and the database has been cleaned and released for 
analysis.  The results of this analysis will be used to characterize safety, tolerability and 
durability of antiviral response of both IM dosing regimens of CAB LA + RPV LA and 
to select a regimen for further development.
 
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1.
INTRODUCTION
1.1.
Background
It is estimated that 34 million people are currently living with HIV/ acquired 
immunodeficiency syndrome (AIDS) and that the worldwide epidemic continues to grow 
at a rate of 2.5 million new infections and cause 1.7 million deaths per year [UNAIDS, 
2012]. While advances in the development of new antiretroviral therapies (ART) provide 
extensive insights into the management of HIV-infected individuals, chronic HIV 
infection in adults continues to be characterized by increased development of resistant 
virus, increasing transmission of resistant virus and issues associated with long term 
toxicity of ART. The current paradigm in the treatment of HIV involves life-long 
therapy with multiple antiretrovirals. This dependency on medical therapy requires that 
we continue to improve on the durability, tolerability and convenience of all antiretroviral 
classes. There is an enduring need to develop new agents with improved safety and 
resistance profiles and convenient dosing for both antiretroviral treatment-naïve and 
treatment-experienced patients.
1.2.
List of Study Terms
For the ease of the reader, the following terms will be useful to understand:

Cabotegravir (GSK1265744) – the ViiV compound under study.  When written 
as shown, this refers to either the oral or long acting formulation.
o
CAB – the oral formulation of cabotegravir;
o
CAB LA – the long acting injectable formulation of cabotegravir; LA
stands for “long acting”;

Rilpivirine (TMC278) – the Janssen / partner compound under study.  When 
written as shown, this refers to either the oral or long acting formulation.
o
RPV – rilpivirine or the oral formulation of rilpivirine, also known as 
Edurant;
o
RPV LA - the long acting injectable formulation of rilpivirine; LA stands 
for “long acting”;

Induction – the induction of virologic suppression of Human Immunodeficiency 
Virus Type 1 (HIV-1) infection in anti-retroviral naive subjects prior to the 
initiation of the CAB LA + RPV LA regimen.  This period will be represented in 
text, schema and Time and Events as negative weeks.  The length of induction is 
20 weeks.  Baseline is the first day of the Induction Period (i.e. this is not Day 
1).

Maintenance – the maintenance of virologic suppression of HIV-1 infection; the 
length of maintenance being evaluated is 96 weeks.  Day 1 is the first day of the 
Maintenance Period.  
 
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
Dosing Regimen - Two intramuscular (IM) dosing regimens are being 
evaluated:  every 4 weeks (Q4W) and every 8 weeks (Q8W).  One oral dosing is 
being evaluated (oral).

Extension – extending study treatment past the key study analysis points; length 
of extension being evaluated is until investigational product (IP) is either locally 
approved and commercially available, a subject no longer derives clinical 
benefit, a subject meets a protocol-defined reason for discontinuation or until 
development of IP is terminated.

Long-Term Follow-Up – follow up period for subjects receiving at least one 
dose of CAB LA and/or RPV LA who have discontinued treatment or have been 
withdrawn; length of follow up being evaluated is 52 weeks.

IP = Investigational product; both formulations of CAB and RPV. Epzicom / 
Kivexa will also be considered IP beginning at Day 1 of the Maintenance 
Period.
1.3.
Cabotegravir (GSK1265744) – Oral (CAB)
CAB is an integrase inhibitor with potent in vitro and in vivo inhibition of HIV-1. CAB
shows low nanomolar activity against a broad range of HIV-1 strains, including clinical 
isolates with documented raltegravir resistance. Human pharmacokinetics (PK) data with 
the oral formulation support once daily dosing without the use of a pharmacokinetic 
enhancer. Potent short-term antiviral activity of once daily dosing of CAB was 
demonstrated during 10-day monotherapy in integrase-naïve HIV-1 infected subjects. 
Mean reductions from Baseline on Day 11 plasma HIV-1 ribonucleic acid (RNA) were 
2.14 and 2.55 log10 copies/millilitre (c/mL) at the CAB doses of 5 mg and 30 mg once 
daily, respectively [GlaxoSmithKline Document Number RM2009/00485/00 and 
GlaxoSmithKline Document Number RM2008/00633/00]. 
Data from the non-clinical toxicology evaluations conducted to date with CAB have not 
identified any progression-limiting toxicity. CAB has been administered in early phase 
clinical studies at doses between 5-50 mg in single or repeat doses or for up to 10 days.
Of 187 subjects participating across all Phase I and IIa oral studies, the most frequent 
adverse events (AEs) (>3 subjects) observed during CAB dosing were headache (13.9%), 
nausea (4.3%), and dizziness (3.8%) [Lou, 2013].  
Through Phase I and Phase IIa studies conducted to date, there have been no CAB related 
Grade 2-4 AEs or serious serious adverse events (SAEs) reported. No CAB laboratory 
trends have been identified.  An ongoing Phase IIb study of CAB, LAI116482 is 
described below (see Section 1.7).
1.4.
Cabotegravir – Long Acting Injectable (CAB LA)
CAB LA, a long acting injectable formulation of cabotegravir, has been dosed in 136
healthy subjects.  Subjects have received single or repeat doses of CAB LA at doses 
between 100 to 800 mg, either intramuscularly (IM) or subcutaneously (SC) and either 
alone or in combination with RPV LA (study LAI114433 [single dose LA, n=58], study 
 
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LAI115428 [repeat dose LA, n=40], and study LAI116815 [single dose LA, n=38]). The
adverse event (AE) profile has been similar to those of CAB (oral).  To date, no studies in 
HIV-1 infected subjects have been conducted with CAB LA.  
CAB LA has been generally well-tolerated as either an IM or SC dose.  Intramuscular 
injection site reactions (ISRs) have been predominantly mild or Grade 1 (85%), self-
limited, and have not led to study discontinuation in any subject to date. Erythema, 
nodules, induration, and warmth at the injection site were most commonly reported in 
healthy subjects.  Painless nodules were more common following SC injections than IM 
injections.  No treatment emergent serious AEs have been reported in any of the healthy 
volunteer studies involving CAB LA.  [LAI115428 GlaxoSmithKline Document Number 
2011N112455_03 and GlaxoSmithKline Document Number RM2010/00170/04: 
LAI114433]. 
All of the above characteristics make cabotegraivir an attractive compound for continued 
HIV drug development.
1.5.
Rilpivirine – Oral (RPV)
RPV, the oral formulation of rilpivirine (Edurant), is a diarylpyrimidine derivative and a 
potent non-nucleoside reverse transcriptase inhibitor (NNRTI) with in vitro activity 
against wild type HIV-1 and select NNRTI-resistant mutants.  RPV is currently approved 
as a 25 mg oral tablet formulation in multiple countries such as the United States (US), 
EU and Canada for use in antiretroviral (ARV) treatment-naïve patients as per the 
approved label in each country / region. Review and approval in other countries is 
ongoing. RPV combines once daily dosing with potent antiviral activity and a good 
tolerability/safety profile. The approval of RPV is based on Week 96 safety and efficacy 
analyses from 2 randomized, double blind, active controlled Phase III trials in ART 
treatment-naive subjects.
The Phase III trials (TMC278-C209 [Molina, 2011] and TMC278-C215 [Cohen, 2011]) 
compared RPV to efavirenz (EFV) each with a background regimen of 2 NRTIs, in 
antiretroviral-naïve HIV-1 infected subjects with HIV-1 RNA 5000 c/mL and no 
NNRTI resistance. Both trials were identical in design, with the exception of the 
background regimen. The Week 48 efficacy outcome for the pooled data from TMC278-
C209 and TMC278-C215 (N=1368) showed that the proportion of subjects with HIV-1
RNA < 50 c/mL was 83% for RPV based regimen compared to 80% for the EFV based 
regimen (Snapshot algorithm). The overall virologic failure rate was 13% for the RPV 
compared to 9% for EFV. The proportion of patients who discontinued study due to an 
adverse event or death was 2% for RPV and 7% for EFV [Cohen, 2012]. 
1.6.
Rilpivirine – Long Acting Injectable (RPV LA)
Rilpivirine is also formulated as a long acting injectable (RPV LA) with PK that could 
support IM dosing every 4 or 8 weeks. Results from 3 completed Phase I trials 
(TMC278-TiDP15-C146 [C146] and TMC278-TiDP15-C158 [C158]) have provided an 
understanding of the safety and tolerability after parenteral RPV LA dosing, as well as its 
pharmacokinetic characteristics. Seventy subjects have received RPV LA injectable 
 
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suspension in these trials.  To date, no studies in HIV-1 infected subjects have been 
completed with RPV LA.
The results of study C146 demonstrated that RPV LA was generally well tolerated at all 
doses (200, 400, or 600 mg) and with all injection routes (IM and SC). Overall, there 
were no RPV LA signs of systemic intolerance. The incidence of ISRs was dependent on 
the type of administration and dose volume: better tolerability was observed for doses of 
1 or 2 mL vs 3 mL in volume. No clinically relevant safety issues were identified with 
respect to laboratory parameters, vital signs, and electrocardiograph (ECGs).
In C158 (N=20), RPV LA injectable suspension in the current formulation after single 
IM injection of 300 mg or of 600 mg, or after multiple dosing regimens of 3 successive 
IM doses was generally safe and well tolerated. Successive monthly IM administration 
(1200, 600, and 600 mg) of RPV LA was also well tolerated with few AEs and ISRs. No 
deaths or SAEs related to the trial medication were reported.  The most frequently 
reported AEs were headache (4 subjects [23.5%]) and mild injection site reactions (5 
subjects [29.4%]). There were no clinically relevant effects on laboratory parameters, 
ECGs, and vital signs (TMC278 [Rilpivirine, oral and parenteral] Integrated 
Investigator’s Brochure, 2013).
In LAI115428, RPV LA was administered as successive monthly IM injections as 
1200/900 mg or 1200/600 mg along with CAB LA.  As noted in Section 1.4, the 
injections were generally well tolerated, no subject discontinued due to an ISR, and no 
treatment emergent serious AEs were reported [GlaxoSmithKline Document Number 
2011N112455_03].
1.7.
Study LAI116482
LAI116482 is an ongoing Phase IIb dose-ranging study (CAB 10 mg, 30 mg, 60 mg) 
evaluating the utility of a two-drug, two-class combination (CAB + RPV) when both are 
given as a once daily oral regimen following induction of virologic suppression using 
CAB plus 2 investigator selected NRTIs. Eligible subjects enter Maintenance at Week 24 
where they begin the CAB + RPV regimen.  
To date, the study has enrolled 244 subjects, 181 of whom received one of three oral dose 
regimens of CAB (10 mg, 30 mg or 60 mg) plus 2 NRTIs. A planned Week 96 (24 weeks 
on Induction and 72 weeks on two-drug Maintenance) analysis is complete and 
demonstrated similar antiviral activity across the three dosing arms of CAB in 
combination with RPV, which compared favorably to the control regimen of 
EFV 600 mg once daily plus 2 NRTIs.  
Rates of protocol defined virologic failure (PDVF) through Week 96 were low across all 
study arms. Three subjects receiving CAB (one at each dose) and three subjects 
receiving EFV were characterized as PDVFs during Induction.  During Maintenance, 
three subjects receiving CAB (10 mg, n=2; and 30 mg, n=1) and two subjects receiving 
EFV were characterized as PDVF.   
 
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During Maintenance, treatment emergent integrase inhibitor (INI) (Q148R) and NNRTI 
(E138Q) resistance mutations were identified in one subject on CAB (10 mg). The 
subject experienced suspected virologic failure (SVF) at Week 48, which was 
subsequently confirmed.  There was no change in RPV susceptibility, and a 3.08 fold 
change in susceptibility to CAB.  The subject reported starting an extreme low calorie 
diet prior to SVF.  Week 26 and Week 36 RPV pre-dose concentrations for the subject 
were lower than concentrations seen in the Phase III RPV studies.  The subject also had 
lower CAB predose concentrations in Maintenance compared to Induction.  The Week 40 
and Week 48 PK for this subject was consistent with Maintenance Phase Individual 
Average pre-dose values determined prior to the reported dates of calorie restriction. 
One subject on CAB (10 mg) developed treatment emergent NNRTI resistance 
(K101K/E and E138E/A).  The subject experienced virologic failure at Week 72 which 
was subsequently confirmed.  There was no change to CAB susceptibility, and a 4.6 fold 
change in susceptibility to RPV. There was no treatment-emergent integrase resistance.
By Week 16 or at time of IP discontinuation if before Week 16, 63% of subjects were 
treated with Truvada (tenofovir/emtricitibine, TDF/FTC) as their background dual NRTI 
and 37% of the subjects were treated with EPZICOM/KIVEXA™ (abacavir/lamivudine, 
ABC/3TC).  Similar virologic response rates (HIV-1 RNA < 50 c/mL) through 24 weeks 
were seen in subjects taking CAB + ABC/3TC (87%) and in subjects taking CAB + 
TDF/FTC (86%). 
Following induction therapy, CAB + RPV (86%) maintained virologic suppression at a 
rate similar to EFV + NRTIs (83%) through 96 weeks.  There was a numerically lower 
response rate of CAB 10 mg and CAB 30 mg, relative to CAB 60 mg, but this was 
largely due to non-virologic discontinuations, with a low PDVF rate across all arms.
The most common treatment-emergent AEs reported for subjects on any of the CAB
doses, were upper respiratory tract infections, diarrhea, nausea, and headache.  One 
subject receiving CAB 60 mg and one subject receiving CAB 30 mg had a Grade 3 
headache.  The Grade 3 headache for the CAB 60 mg subject occurred very early, study 
day 3, while the Grade 3 headache for the CAB 30 mg subject occurred on study day 343.  
The majority of AEs were Grade 1 (29%) or Grade 2 (49%) severity.  Seven subjects on 
CAB versus nine on EFV withdrew due to an AE, one receiving 10 mg (ECG abnormal 
and palpitations), two receiving 30 mg (panic attack, Burkitt’s lymphoma) and four 
receiving 60 mg (hepatitis, transaminases increased, anxiety disorder and musculoskeletal 
pain).  The majority of CAB related AEs were Grade 1 and few of those AEs led to 
withdrawal through Week 96 (n=4 [2%]).  There have been no CAB drug related SAEs to 
date.  
Two of the subjects that withdrew due to AE met liver stopping criteria with an alanine 
aminotransferase (ALT)>10x upper limit of normal (ULN) at approximately Week 4 and 
Week 8 after initiating study drug.  Both had pre-existing steatohepatitis and were dosed 
with CAB 60 mg + ABC/3TC.  Both subjects remained asymptomatic, had normal serum 
bilirubin levels and had resolution of the ALT values after drug discontinuation.  These 2 
subjects accounted for the only Grade 3-4 ALT abnormalities in this study to date.  
Overall, the rates of any graded ALT or aspartate aminotransferase (AST) abnormality 
 
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were similar between CAB and EFV dosed subjects through Week 96: ALT:  20% and 
21% respectively; AST:  25% and 21% respectively.
These data from LAI116482 support the conduct of study 200056 by demonstrating the 
antiviral activity of CAB when used initially as part of a HAART regimen to induce 
virologic suppression.  In addition, this data confirmed antiviral activity of CAB + RPV 
as a two-drug oral Maintenance regimen and provides proof of principle for CAB LA + 
RPV LA as a maintenance regimen.  
Based upon the results through Week 96 of the LAI116482 study [Margolis, 2015], and 
in accordance with the pre-specified dose selection criteria at Week 48, a 30 mg oral dose 
of CAB has been selected to be used in combination with ABC/3TC for induction of 
virologic suppression in study 200056.
All ongoing subjects in the LAI116482 study have entered the Open Label Extension 
phase to continue to receive the two drug regimen of CAB 30 mg + RPV 25 mg.  All 
subjects had completed 48 weeks of the Maintenance regimen by the time study 200056 
began dosing any IM regimen, permitting a robust evaluation of the virologic efficacy of 
the oral two drug regimen of CAB and RPV, prior to initiating the long acting injectable 
regimen.  These data will be made available to Investigators.
1.8.
200056
The 200056 study (LATTE-2) evaluated a 20 week induction of HIV-1 RNA suppression 
with a three drug oral antiretroviral regimen consisting of CAB + ABC / 3TC Fixed Dose 
Combination (FDC) followed by randomization to a two-drug regimen consisting of 
intramuscular (IM) long-acting (LA) CAB LA + RPV LA compared to continuation of 
oral CAB + ABC / 3TC for the maintenance of HIV-1 RNA suppression.  A total of 309 
participants were enrolled and treated.
During the Induction Period there was a rapid and sustained decline in HIV-1 RNA, with 
91% of participants (282/309) achieving HIV-1 RNA <50 c/mL through 20 weeks of 
therapy.  There was a single participant (with known compliance issues) with confirmed 
virologic failure during the Induction Period.  Virologic testing revealed no treatment 
emergent phenotypic or genotypic resistance in this participant.
The primary endpoint for 200056 was the Week 32 proportion of participants with HIV-1 
RNA < 50 c/mL (Snapshot, Intent-to-Treat Maintenance Exposed population [ITT-ME]). 
Following virologic suppression on three drug oral therapy in the Induction Period, 
286 participants qualified to enter randomization at the Day 1 visit, and were 
subsequently randomized 2:2:1 onto every 4 week intramuscular (IM) injections with 
CAB LA + RPV LA (Q4W), every 8 week IM injections with CAB LA + RPV LA 
(Q8W) or continuation of oral CAB + NRTIs, respectively.  At the time of randomization 
at Day 1, participants entering one of the IM arms discontinued all oral ART. Through 
32 weeks of two-drug maintenance therapy, 95% (Q8W) and 94% (Q4W) of participants 
on injectable dosing were virologic successes, compared to 91% of participants 
continuing three drug oral CAB + NRTIs, meeting pre-specified criteria for comparability 
between the dosing arms. Through 32 weeks of Maintenance therapy, there was one 
 
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participant each on Q8W and oral dosing with confirmed virologic failure (CVF), without 
any evolution of viral resistance. The CVF on Q8W dosing occurred following an 
aberrant RPV injection, without measurable plasma RPV concentrations 4 weeks post 
dosing.  
Week 48 data was a secondary endpoint for 200056, and permitted the evaluation of the 
two-drug long-acting combinations’ ability to maintain the virologic suppression 
demonstrated at Week 32.  At Week 48, 92% (Q8W) and 91% (Q4W) of participants 
receiving injectable dosing had a sustained virologic response (HIV-1 RNA <50 c/mL) 
compared to 89% of participants continuing oral CAB + 2 NRTIs.  Although the 
proportion of participants with virologic success was similar for Q8W and Q4W dosing, 
the reason for Snapshot failure was different between the arms.  There were more 
Snapshot failures for virologic reasons on the Q8W arm (n=8, 7%) than in the Q4W arm 
(n=1, <1%), and more participants with no virologic data (discontinued due to AE or 
other reasons) on the Q4W arm (n=9, 8%) compared to the Q8W arm (n=1, <1%).  
Between Week 32 and Week 48, one additional participant (Q8W) had confirmed 
virologic failure.  This participant had a Baseline HIV-1 RNA of 444,489 c/mL.  At 
Week 48, the participant was a suspected virologic failure with HIV-1 RNA = 463 c/mL.  
Upon retest, ten days later, the virologic failure was confirmed with HIV-1 RNA of 
205 c/mL.  At the time of CVF, this participant had treatment emergent NNRTI 
resistance K103N, E138G, and K238T, with high level phenotypic resistance to 
delaviridine (>MAX), efavirenz (48 fold change [FC]), nevirapine (>Max), and 
rilpivirine (3.34 FC). The fold change to etravirine (1.91) was below the lower cutoff.
Week 48 integrase genotype had the treatment emergent integrase resistance mutation 
Q148R, with accompanying resistance to raltegravir (29 FC), elvitegravir (138 FC), and 
cabotegravir (6.06 FC). The Week 48 sample was not resistant to dolutegravir (1.38 FC).
Overall, AEs and clinical chemistries were similar to those observed in prior studies with 
CAB, without discernible trends between Q8W, Q4W, and oral. Injections were well 
tolerated with two participants discontinuing due to injection tolerability through 48 
weeks (both on Q8W dosing). The vast majority of injection site reactions were due to 
pain/discomfort with nearly all injection site reactions classified as mild (82%) or 
moderate (17%), with <1% of reactions classified as severe. There was no discernible 
tolerability difference between Q4W (2 mL) dosing and Q8W (3 mL dosing).  The most 
common non-ISR AEs during the Maintenance Phase were nasopharyngitis (24%), 
headache (16%), and diarrhea (13%) on IM arms and nasopharyngitis (30%), headache 
(11%), and diarrhea (5%) on oral CAB.  Through Week 48, SAEs during the 
Maintenance Period occurred in 7% of participants randomized to CAB LA + RPV LA 
and 5% of participants randomized to remain on oral treatment, none were drug related.  
Based on the data from the Week 48 endpoint, Q4W dosing was chosen to progress for 
further clinical development in Phase 3 studies, however, due to continued interest in 
evaluating the potential of Q8W dosing, subjects entering the Extension Period from the 
oral CAB 30 mg + ABC/3TC arm in this study will be given the option to switch to either 
an optimized Q8W or Q4W regimen.  Subjects originally randomized to the IM regimen 
and entering the extension phase will remain on their randomized regimen.  
 
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1.9.
Study Rationale
While advances in the development of new anti-retroviral therapies (ART) provide 
extensive insights into the management of HIV-infected individuals, chronic HIV 
infection in adults continues to be characterized by increased development of resistant 
virus, increasing transmission of resistant virus and issues associated with the long-term 
toxicity of ART. The current paradigm in the treatment of HIV involves life-long 
therapy with multiple antiretrovirals. There is an enduring need to develop new agents 
with improved safety and resistance profiles with convenient dosing for both 
antiretroviral treatment-naive and treatment-experienced patients. 
Various approaches to simplify a patient's antiretroviral therapy (ART) regimen, after 
achieving virologic suppression, have been studied. Previous studies have evaluated 
switches to ritonavir-boosted PI monotherapy therapy in virologically suppressed patients 
[Bierman, 2009 and Arribas, 2012]. While the data from these studies have shown both 
long-term non-inferiority and inferiority to continual Highly Active Antiretroviral 
Therapy (HAART), they suggest that simplifying from a three drug dual class regimen to 
a single boosted protease inhibitor may be a safe and effective option for the majority of 
subjects studied who have effectively maintained virologic suppression. 
This clinical trial, 200056, will evaluate a different simplification approach (see 
Section 3.1 for study schematic).  In this study, subjects will induce HIV-1 RNA 
suppression with a three drug antiretroviral regimen consisting of CAB + ABC/3TC FDC 
and then switch to a two-drug two-class regimen consisting of CAB LA + RPV LA for 
the maintenance of HIV-1 RNA suppression. 
The overall objective of this study is to select an intramuscular dosing regimen of CAB
LA plus RPV LA based on a comparison of the Week 32 antiviral activity, tolerability, 
and safety of two IM dosing regimens, relative to CAB 30 mg plus ABC/3TC orally once 
daily, in HIV-1 infected antiretroviral-naïve subjects.  
This study consists of three parts: an Induction Period, Maintenance Period and 
Extension Period.  There is also a Long-Term Follow Up Period for subjects who 
withdraw and have received at least one dose of CAB LA and / or RPV LA. 
Induction Period
The objective of the Induction Period is to induce virologic suppression prior to the 
initiation of the CAB LA + RPV LA regimen.  In addition, the Induction Period will 
evaluate the safety, tolerability and efficacy of CAB in combination with ABC/3TC in 
HIV-1-infected, ART-naive adults. The Induction Period consists of an evaluation of 
CAB 30 mg once daily plus ABC/3TC through 20 weeks.  Virologic suppression in the 
LAI116482 study was rapid, with 83% of CAB 30 mg treated subjects achieving an HIV-
1 RNA <50 c/mL by Week 8 suggesting that the majority of subjects in the 200056 study 
will be virologically suppressed for at least 12 weeks prior to randomization into the 
Maintenance Period.  A review of the virology data from LAI116482 suggests that few 
subjects required greater than 16 weeks of therapy to achieve virologic suppression 
 
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(HIV-1 RNA <50 c/mL), including subjects who entered the study with HIV-1 
RNA >100,000 c/mL.  
Unless subjects meet a study withdrawal criterion, their regimen will be modified during 
Induction at Week (-4) by adding on RPV 25 mg orally once daily.  RPV is being added 
to the ART regimen for all subjects at Week (-4) to establish safety and tolerability of 
RPV in individual subjects prior to initiating treatment with CAB LA + RPV LA during 
the Maintenance Period.  Subjects who do not or cannot tolerate CAB or RPV during this 
period should not enter the Maintenance Period.  At the majority of time points, the 
incidence of (treatment related) AEs in the Phase III RPV studies were comparable 
between the RPV and control group and highest during the first 4 weeks of treatment. 
Median time to onset of first rash events was 10.5 days.  No grade 4 rash events were 
reported.  In addition, this RPV add on will serve as a pharmacokinetic lead in, achieving 
steady state levels of RPV, prior to the administration of RPV LA [Rashbaum, 2011a and 
Rashbaum, 2011b].
The selection of CAB 30 mg + ABC/3TC as an induction regimen is validated by clinical 
efficacy results from LAI116482.  In addition, utilizing the same regimen, across all 
subjects, during the Induction Period will minimize the variability of responses between 
subjects, study complexity, and the impact of differential response rates during the 
Induction Period which could impact the interpretation of Maintenance Period results.
Maintenance Period
All subjects with an undetectable HIV-1 RNA (<50 c/mL) at the Week (-4) visit are 
eligible to enter the Maintenance Period. 
The objective of the Maintenance Period of this study is to assess the ability of a two-
drug regimen of CAB LA and RPV LA to maintain virologic suppression for 96 weeks 
with the primary endpoint occurring after 32 weeks.  Two injectable IM dosing regimens 
(Q8W and Q4W) and one oral control dosing regimen will be evaluated.  
Subjects eligible to enter the Maintenance Period will be randomized 2:2:1 at Day 1 to 
one of the dosing regimens described below:

CAB LA 600 mg + RPV LA 900 mg IM every 8 Weeks (Q8W)

+ Loading Dose of CAB 800 mg at Day 1

+ Loading Dose of CAB 600 mg at Week 4

CAB LA 400 mg + RPV LA 600 mg IM every 4 Weeks (Q4W)

+ Loading Dose of CAB 800 mg at Day 1

CAB 30 mg + ABC/3TC once daily
Randomization will be stratified by HIV-1 RNA <50 c/mL before Week (-8) (yes or no).
 
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Subjects on either IM regimen will discontinue the Induction regimen (including the add-
on of RPV) after a final dose in the clinic on Day 1.  Subjects on the oral regimen will 
discontinue the add-on of RPV after a final dose in the clinic on Day 1.  
While both drugs, CAB LA and RPV LA, have been studied with both SC and IM 
administration, the IM administration is being progressed into study 200056 to best 
accommodate the required injection volumes of both drugs and to ensure good 
tolerability.  
The selection of CAB 30 mg + ABC/3TC as an oral comparator regimen in this study, 
will allow for a direct comparison of subjects who either i) continue their existing 
regimen or ii) simplify their regimen to one of the IM regimens.  The chosen comparator 
will also allow for a direct comparison of oral daily pill taking vs. Q4W and Q8W IM 
administration, as it relates to efficacy, tolerability, safety, and acceptability.  
Normalizing the comparator populations by randomizing only suppressed subjects at 
Day 1 will also serve to strengthen this comparison.
Long-term maintenance of HIV virologic suppression will be assessed.  
Extension Period
The Extension Period of this study will allow for a collection of longer term efficacy and 
safety and tolerability data from subjects receiving CAB LA and RPV LA.  Both of the 
current IM dosing regimens, Q8W and Q4W, will be taken into the Extension Period of 
the study based on similar efficacy results across each arm (see Section 1.8).
Unless subjects meet a study withdrawal criterion, subjects on the oral regimen may elect 
to continue on the Extension Period by switching to an optimized IM dosing regimen of 
their choice of CAB LA + RPV LA (either Q8W or Q4W). 
Long-Term Follow-Up Period
Subjects who have received at least one dose of CAB LA and/or RPV LA are anticipated 
to be at high risk for development of virologic resistance if ART is interrupted. The time 
period during which subjects may be at greatest risk for developing virologic resistance 
may be the period between when drug levels fall below therapeutic exposures and when 
they fall below levels which exert selective pressure on HIV. This time period will vary 
by ART agent and may be dependent upon effective concentration, inhibitory 
concentration and half-life.  Plasma concentrations of both drugs may be measurable for 
approximately 52 weeks following IM injections.
Therefore, any subject who receives at least a single dose of CAB LA and/or RPV LA 
and who discontinue the CAB LA + RPV LA regimen for any reason must remain on 
suppressive HAART for at least 52 weeks after the last dose of CAB LA and/or RPV LA 
in order to prevent selective pressure on HIV and the potential for selection of resistant 
mutants.  In this study, this will be accomplished through the Long-Term Follow-Up 
Period. 
 
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1.10.
Dose Rationale
1.10.1.
CAB
CAB 10 mg, 30 mg and 60 mg oral once daily achieved similar efficacy at Week 24 of 
Induction when coadministered with 2 NRTIs and at Week 48 of Maintenance (24 weeks 
on Maintenance) when coadministered with RPV 25 mg once daily (Table 1).  Rates of 
virologic suppression through Week 48 (Maintenance) on the two drug regimen remained 
similar to that attained through Week 24 (Induction) on three-drug ART.  
The oral dosing period intended for induction of virologic suppression also serves as a 
lead-in period required to confirm tolerability in each subject prior to initiating the 
prolonged exposure following CAB LA injection, which has been observed to be up to 52 
weeks following a single injection in some subjects [GlaxoSmithKline Document 
Number RM2010/00170/04: LAI114433].  Although all doses provided similar induction 
and maintenance of viral suppression, CAB 30 mg once daily was selected as the oral 
dose to be used in combination with ABC/3TC for induction of virologic suppression in 
this study.  CAB 30 mg achieves higher plasma exposures than the 10 mg oral dose, 
providing higher toxicity coverage prior to initiating IM dosing.  
Based upon the results through Week 48 of the LAI116482 study, and in accordance with 
the pre-specified dose selection criteria at Week 24, a 30 mg oral dose of CAB has been 
selected to be used in combination with ABC/3TC for induction of virologic suppression 
in this study.
1.10.2.
CAB LA
CAB 10 mg, 30 mg and 60 mg orally once daily achieved similar efficacy at Week 24 of 
Induction when coadministered with 2 NRTIs and at Week 48 of Maintenance (24 weeks 
on Maintenance) when coadministered with RPV 25 mg once daily (Table 1).  Rates of 
virologic suppression through Week 48 (Maintenance) on the two drug regimen remained 
similar to that attained through Week 24 (Induction) on three-drug ART.  The similar 
efficacy in all three treatment arms in LAI116482 suggests that maintaining target 
concentration at the end of a dosing interval (C) following IM administration of CAB 
LA with RPV LA at approximately the level of the 10 mg oral dose (geometric mean 
1.35 g/mL, 8.1-fold above PA-90% inhibitory concentration [IC90]) should also 
maintain suppression of HIV infection.  Once safety and tolerability are confirmed with 
oral dosing, maintaining target Cfollowing IM administration of CAB LA with RPV
LA at approximately the level of the 10 mg oral dose (geometric mean 1.35 g/mL, 8.1-
fold above PA-IC90) should be sufficient to maintain suppression of HIV infection.  
Maintaining a target at approximately the level of the 30 mg oral dose is not needed in 
Maintenance, as viral suppression and short-term tolerability have been established
during Induction.  
Using population pharmacokinetic (PK) modelling and simulations, CAB Cvalues for 
several IM dosing regimens were calculated and two regimens were selected based upon:

ability to reach target concentration early in treatment,
 
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
ability to maintain mean Cabove that obtained with oral CAB 10 mg once daily 
during treatment (CAB trough concentrations 1.35 g/mL), and

minimizing the total number of injections per visit.
Table 1
Proportion of Subjects with Plasma HIV-1 RNA <50 c/mL at Key 
Visits - Snapshot (MSDF) Analysis (ITT-E Population)
Visit
GSK744
10 mg
N=60
n (%)
GSK744
30 mg
N=60
n (%)
GSK744
60 mg
N=61
n (%)
GSK744 
Subtotal
N=181
n (%)
EFV 
600 mg
N=62
n (%)
Week 16 – Induction
54 (90)
50 (83)
53 (87)
157 (87)
46 (74)
Week 24 – Induction
52 (87)
51 (85)
53 (87)
156 (86)
46 (74)
Week 48 - Maintenance
48 (80)
48 (80)
53 (87)
149 (82)
44 (71)
CAB LA– Maintenance Period
Q8W
Subjects randomized to CAB LA Q8W will receive a CAB 800 mg IM Loading Dose on 
Day 1 (within 2 hours of final oral dosing), a 600 mg IM Second Loading Dose at Week 
4, and 600 mg IM Q8W starting at Week 8. 
The first 800 mg IM loading dose and second 600 mg IM loading dose were selected so 
that 80% of subjects will be above 1.35 g/mL throughout treatment.  Mean (90% 
confidence interval [CI]) simulated CAB Cvalues versus time across doses for CAB LA 
Q8W are presented graphically in Figure 1.
 
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Figure 1
Simulated Mean (90% CI) CABTrough Concentrations versus Time 
for CAB LA Q8W
At Week 56 (approximately one year of dosing), CAB LA Q8W is predicted to achieve 
CAB trough concentrations 1.35 g/mL (target) in 84% of subjects. Although the lower 
bound of the 90% CI falls below 1.35 g/mL, Cfor all subjects remains above 4PA-
IC90 (0.166 g/mL).  At Week 56, geometric mean CAB Cfor CAB LA Q8W is 
predicted to be 2.02 g/mL, 1.5-fold above target and 12.2-fold above PA-IC90 (Table 2).  
A one week delay in dosing at steady state the Q8W regimen is predicted to result in a 
geometric mean Cthat is 9% lower than for dosing that is administered on schedule 
while remaining above the 1.35 g/mL target associated with the 10mg oral dose.  
Q4W Subjects randomized to the Q4W dosing arm will first receive CAB 800 mg IM as 
a loading dose on Day 1 (within 2 hours of final oral dosing) and then, starting at Week 4, 
will receive CAB 400 mg IM Q4W. 
The 800 mg loading dose was selected so that 80% of subjects will be above
1.35 µg/mL throughout treatment, including the end of the first dosing interval.  Mean 
(90% CI) simulated CAB Cvalues versus time across Q4W doses for CAB LA are 
presented graphically in Figure 2.
 
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Figure 2
Simulated Mean (90% CI) GSK744 Trough Concentrations versus 
Time for CAB LA Q4W
At Week 56 (approximately one year of dosing), CAB LA Q4W is predicted to achieve 
CAB trough concentrations 1.35 g/mL (target) in 99.6% of subjects.  Geometric mean 
CAB Cfor CAB LA Q4W at Week 56 is predicted to be 3.35 g/mL, 2.5-fold above 
target, 20.2-fold above the PA-IC90 (0.166 g/mL), and similar to the observed mean C
after 16 weeks of this regimen in healthy subjects (Table 2).
A one week delay in dosing at steady state for the Q4W regimen is predicted to result in a 
geometric mean Cthat is 8% lower than for dosing that is administered on schedule 
while remaining above the 1.35g/mL target associated with the 10 mg oral dose.
 
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Table 2
Summary of Cabotegravir PK Parameters following oral 
administration in HIV infected subjects, CAB LA administration in 
healthy subjects, and following Simulations
Route
Study
Population
CAB Regimen
CAB PK Parameter
C  or C0
(g/mL)a
Cmax
(g/mL)b
AUC(0-)
(gh/mL)c
IQ
(C0:IC90
ratio)d
Oral
LAI116482
HIV
10 mg orally every day
1.35
[45%]
2.77
[33%]
45.7
[32%]
8.13
30 mg orally every day
4.20
[40%]
7.49
[28%]
134
[32%]
25.3
60 mg orally every day
7.93
[39%]
13.1
[44%]
195
[48%]
47.8
IM
LAI115428 
HVs
800 mg IM LD
400 mg IM Q4W x3
3.22
[28%]
4.37
[33%]
2362
[27%]
19.4
IM 
PopPK 
simulation
HIV
LA Regimen #1 (200056):
800mg IM LD
400mg IM Q4W from W4
3.35
[35%]
ND
ND
20.2
IM
PopPK 
simulation
HIV
LA Regimen #2 (200056):
800mg IM LD 1
600mg IM LD 2 (Week 4)
600mg IM Q8W from W8
2.02
[52%]
ND
ND
12.2
Data presented as Geometric mean [CVb%], HIV = HIV infected subjects, HV = Healthy Volunteers, ND=Not 
determined, LD = Loading Dose
a.
C0:  n=57 (10 mg orally), 53 (30 mg orally), 55 (60 mg orally), 9 (800 mg/400 mg IM), 
b.
Cmax:  n=14 (10 mg orally), 12 (30 mg orally), 11 (60 mg orally), 9 (800 mg/400 mg IM)
c.
AUC(0-):  n=14 (10 mg orally), 12 (30 mg orally), 11 (60 mg orally), 9 (800 mg/400 mg IM)
d.
PA-IC90 determined in vitro 0.166 g/mL.
CAB LA – Extension Period
CAB concentrations following administration of CAB LA Q8W and Q4W during the 
Maintenance Period of LATTE-2 were lower than predicted by the modelling and 
simulation in the original protocol. Observed data for both CAB LA regimens in 
LATTE-2 are presented in Figure 3.  The CAB LA population PK model has been 
updated to include data from Phase 2a/b studies, specifically Study 201120 (CAB LA 
PrEP) and Study 200056.  The current model has increased from 93 subjects to 416 
subjects receiving CAB LA single or repeat IM injections. The rationales for the new
CAB LA IM dosing regimens are described below.
 
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Figure 3
Observed Mean (SD) Concentration-Time Data following CAB LA 
Q8W and Q4W and Cfollowing 30 mg PO QD through Week 48 
(200056, LATTE-2)
Week
0 1
4
8
12
16
20
2425
28
32
32
36
4041
44
48
48
Plasma CAB (g/mL)
0.1
1
10
800mg IM LD, 600mg IM W4, W8 and Q8W
800mg IM LD, 400mg IM Q4W
30mg PO QD
PA-IC90 (0.166g/mL)
10mg PO QD C (LATTE, 1.35g/mL)
Both predose and 2h post injection concentrations are shown at Time Zero, Week 32, and Week 48.
Extension Phase Rationale for CAB LA Q8W
After the Maintenance Period oral regimen, the first and second CAB LA 600 mg IM 
dose at study visit Week 100 (1st injection day) and Week 104 (2nd injection) of the 
Extension Period of this study was selected so that 50% of subjects are anticipated to be 
above 1.35 g/mL, the geometric mean Cfollowing oral CAB 10 mg once daily, 
throughout treatment which was shown to be efficacious in the LATTE study.  The lower 
bound of the 90% prediction interval is approximately 0.166 g/mL, indicating that 95% 
of subjects on this regimen should remain above the PA-IC90 throughout dosing (Figure 
4).
 
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Figure 4
Simulated* Median (90% Prediction Interval [PI]) CAB Plasma 
Concentrations versus Time for the Optimized CAB LA Q8W
Regimen (600 mg IM Day 1, Week 4, Q8W thereafter)^
*Note: current simulations based on interim plasma concentration dataset
^Study Time and Events include a 4 week oral lead in.  Therefore, Day 1 = date of first injections (Week 100 study 
visit); Week 4 = second injections (Week 104 study visit)
Model based predicted steady-state CAB concentrations were consistent with observed 
data in this study, where CAB LA 600 mg IM Q8W was given, albeit with a loading dose 
of 800 mg IM on Day 1 and a third dose of 600 mg IM at Week 8 prior to initiating Q8W.  
The mean CAB plasma concentration at Week 32 was 1.53 g/mL (Figure 3). 
At steady state, a one week delay in dosing of the Q8W regimen is predicted to result in a 
median steady state Cthat is 15% lower than for dosing that is administered on 
schedule, with 92% remaining above the PA-IC90 (Figure 5).
 
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Figure 5
Impact of 1-week Delay in Dosing at Steady State (Week 44) on 
Simulated* Median (90% PI) CAB Plasma Concentrations versus 
Time for the Optimized CAB LA 600 mg IM Q8W regimen (Day 1, 
Week 4, and Q8W thereafter^)
*Note: current simulations based on interim plasma concentration dataset
^Study Time and Events include a 4 week oral lead in.  Therefore, Day 1 = date of first injections (Week 100 study 
visit); Week 4 = second injections (Week 104 study visit)
Extension Phase Dose Rationale for CAB LA Q4W
The simulation of the predicted median (90% prediction interval [PI]) CAB 
concentration-time profile based on the population PK model is shown in Figure 6.  The 
lower bound of the PI remains approximately at or above 4x PA-IC90 throughout dosing.  
At steady state, 98% of the population is predicted to achieve trough concentrations 
above 4x PA-IC90, and 88% is predicted to achieve trough concentrations above the 
geometric mean trough following the 10 mg oral dose in LATTE of 1.35 g/mL (8x PA-
IC90).  
 
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Figure 6
Simulated* Median (90% Prediction Interval [PI]) CAB Plasma 
Concentrations versus Time for the Optimized CAB LA Q4W 
Regimen (600 mg IM Day 1, then 400 mg IM Q4W thereafter^)
* Note: current simulations based on interim plasma concentration dataset
^Study Time and Events include a 4 week oral lead in.  Therefore, Day 1 = day of first injections (Week 100 study visit); 
Week 4 = second injections (Week 104 study visit)
Medium dashed line at 1.35 g/mL corresponds to the geometric mean Ctrough concentration following oral CAB 10 
mg once daily  (LATTE) and is equivalent to 8x PA-IC90
Dotted line at 0.664 g/mL corresponds to 4x PA-IC90
Long dashed line at 0.166 g/mL corresponds to the PA-IC90.
At steady state, a one week delay in dosing of the Q4W regimen results in approximately 
15% reduction in median CAB trough. With this delay, 95% are predicted to remain 
above 4x PA-IC90, and 79% are predicted to remain above the 10 mg oral target (Figure 
7).  Simulations including delays greater than one week have been explored (not shown), 
with <70% of subjects remaining above the 10 mg oral target.  Therefore, a 1-week delay 
is the maximum allowed per the protocol.  
 
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Figure 7
Impact of 1-week Delay in Dosing at Steady State (Week 40 delayed 
to Week 41) on Simulated* Median (90% PI) CAB Plasma 
Concentrations versus Time for the Optimized CAB LA Q4W regimen 
(600 mg IM Day 1, then 400 mg IM Q4W thereafter^)
* Note: current simulations based on interim plasma concentration dataset
^Study Time and Events include a 4 week oral lead in.  Therefore, Day 1 = day of first injections (Week 100 study visit); 
Week 4 = second injections (Week 104 study visit)
Medium dashed line at 1.35 g/mL corresponds to the geometric mean Cfollowing oral CAB 10 mg once daily  
(LATTE) and is equivalent to 8x PA-IC90
Dotted line at 0.664 g/mL corresponds to 4x PA-IC90
Long dashed line at 0.166 g/mL corresponds to the PA-IC90.
1.10.3.
RPV
All subjects will receive 4 weeks of RPV 25 mg once daily, co-administered with 
CAB+ABC/3TC, from Week (-4) through Day 1 to confirm tolerability in each subject 
prior to possible IM dosing with RPV LA. Data from study LAI116182 
[GlaxoSmithKline Document Number 2012N134026_02:  LAI116482] have 
demonstrated that there is no clinically relevant drug-drug interaction following repeat 
oral administration of CAB with RPV. With this oral RPV add-on, subjects will also 
have steady-state RPV plasma concentrations prior to starting CAB LA dosing during the 
Maintenance Period.
 
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1.10.4.
RPV LA
During the Maintenance Period, subjects will receive either IM injections of CAB LA 
600 mg every 4 weeks (Q4W) or RPV LA 900 mg every 8 weeks (Q8W). The selection 
of the RPV LA dosing regimens is based on achieving RPV plasma concentrations in the 
range of those observed with oral RPV 25 mg once daily in HIV-infected patients (mean 
(SD) Ctrough of 80 (36) ng/mL in pooled Phase III studies (RPV + 2 NRTIs); and 77 (34) 
ng/mL in the Maintenance Phase of LAI116482 (RPV + CAB), as well as constructing a 
regimen that is most practical for patients, i.e. by reducing the number of dosing/clinic 
visits while maintaining an acceptable injection volume.
Figure 8 and Figure 9 show the model-predicted RPV plasma concentrations over a 
dosing interval at steady-state with the respective Q4W and Q8W RPV LA dosing 
regimens. The graphs show the mean profile (red curve) with the 90% prediction interval 
(shaded area). Also indicated are the mean Ctrough for oral RPV 25 mg once daily in HIV-
infected patients (Phase III, 80 ng/mL) and the protein-binding adjusted IC90 for RPV 
(12 ng/mL), as well as a scatter of the individual Ctrough values (plotted both at the 
beginning and at the end of the RPV LA dosing interval) in HIV-infected patients (Phase 
III).
For the simulations, a pharmacokinetic model was used based on all available data from 
studies with the current RPV LA formulation (TMC278-C158, SSAT040, LAI115428) 
and the population PK model of RPV. With this model, the RPV LA dosing regimen (i.e., 
4 weeks RPV 25 mg every day followed by IM injections every 4 weeks of RPV LA 600 
mg) was simulated for 100 subjects. For each of these individuals, the median Ct between 
day 168 (i.e. after injection 5) and day 336 (i.e., after injection 11) was determined, and 
from these median values, the mean across subjects was calculated [GlaxoSmithKline 
Document Number 2011N112455_03: LAI115428].
 
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Figure 8
Model-Predicted Mean (90% prediction interval) RPV Plasma 
Concentration-Time Profile at steady-state after Q4W IM injections of 
RPV LA 600 mg (immediately following 4 weeks oral RPV 25 mg 
once daily)
Red line represents the predicted mean steady state Ctrough concentration.
Blue dotted line represents mean Ctrough for oral RPV 25 mg once daily; 
Green dotted line represents protein-binding adjusted IC90 for RPV; 
Black open circles represent individual Ctrough values with oral RPV 25 mg once daily 
 
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Figure 9
Model-Predicted Mean (90% prediction interval) RPV Plasma 
Concentration-Time Profile at steady-state after Q8W IM injections of 
RPV LA 900 mg (immediately following 4 weeks oral RPV 25 mg 
once daily)
Red line represents the predicted mean steady state Ctrough concentration.
Blue dotted line represents mean Ctrough for oral RPV 25 mg once daily; 
Green dotted line represents protein-binding adjusted IC90 for RPV; 
Black open circles represent individual Ctrough values with oral RPV 25 mg once daily
RPV LA – Maintenance Period
Q8W
For the Q8W RPV LA dosing regimen, the mean steady-state Ctrough is predicted to be 
around 65 ng/mL, as of the 1st injection. Though this is below the mean RPV Ctrough with 
oral RPV 25 mg once daily, the range of model-predicted Ctrough is similar to the range of 
Ctrough with oral RPV 25 mg once daily in the RPV Phase III studies (Figure 9) and in 
LAI116482 (Maintenance). The RPV plasma concentrations are also higher during the 
larger part of the RPV LA dosing interval. Furthermore, all patients are virologically 
suppressed before switching to the RPV LA regimen. In LAI116482, there were 58/160 
HIV-infected patients with a RPV Ctrough (based on population PK modeling) below 65 
ng/mL.  These 58 patients all maintained virologic suppression.
Q4W
The mean steady-state Ctrough with the Q4W RPV LA dosing regimen is predicted to be 
around 115 ng/mL. This is above the mean RPV Ctrough (80 ng/mL) and the mean Cavg
(100 ng/mL) for RPV 25 mg once daily (Phase III). Furthermore, the mean RPV plasma 
concentrations are already above the mean Ctrough for RPV as of the 1st injection with 
RPV LA 600 mg.
 
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RPV LA – Extension Period
Similar to CAB, RPV concentrations following RPV LA in LATTE-2 were lower than 
predicted by the modelling and simulation in the original protocol.  Observed data for 
both RPV LA regimens in LATTE-2 are presented in Figure 10.  The RPV LA 
population PK model has been updated to include data from LATTE-2.
Figure 10
Observed Mean (SD) Concentration-Time Data following RPV LA 
Q8W and Q4W through Week 48 and Day 1 Cfollowing RPV 25 mg 
PO QD (LATTE-2)
Week
0 1
4
8
12
16
20
2425
28
32
32
36
4041
44
48
48
Plasma RPV (ng/mL)
10
100
1000
900mg IM Q8W
600mg IM Q4W
25mg PO QD
PA-IC90 (12ng/mL)
25mg PO QD (LATTE, 70ng/mL)
Extension Phase Rationale for RPV LA Q8W
The new optimized RPV LA Q8W regimen for this study was selected based on safety 
and efficacy data from this study, 200056 (LATTE-2) and supported by modelling and 
simulation of pharmacokinetic and response data obtained following administration RPV 
LA administration in healthy subjects (Phase 1 studies C158 and LAI115428 
[GlaxoSmithKline Document Number 2011N112455_03]) and in HIV-infected subjects 
(Phase 2 study LATTE-2), the majority of the data coming from 200056 (LATTE-2). 
The predicted median (90% PI) steady-state Cfor the optimized RPV LA Q8W regimen 
is 54 ng/mL (25 – 109 ng/mL) (Figure 11).  With this regimen, 100% of subjects remain 
above the RPV PA-IC90 during the whole dose interval at steady-state.  These data are 
similar to the observed Week 32 median steady-state Cwhich was also 54 ng/mL and 
the mean Cwas 58 ng/mL (Figure 10).  With the 2nd RPV LA dose at Week 104, the 
anticipated median RPV Cat Week 104 is 42 ng/mL (versus 30 ng/mL observed prior to 
 
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second injection at Week 8 in LATTE-2), with >98% of subjects above the RPV PA-
IC90.
Figure 11
Simulated* Median (90% PI) RPV Plasma Concentrations versus 
Time Profile for the Optimized RPV LA Q8W regimen (900 mg IM Day 
1, Week 4, and Q8W thereafter^)
* Note: current simulations based on interim plasma concentration dataset
^Study Time and Events include a 4 week oral lead in.  Therefore, Day 1 = date of first injections (Week 100 study 
visit); Week 4 = second injections (Week 104 study visit)
At steady-state, a one week delay in dosing for the Q8W regimen is predicted to result in 
a median steady-state Cthat is approximately 13% lower (47 ng/mL) than for dosing 
that is administered on schedule, with >99% of subjects still remaining above the RPV 
PA-IC90 (Figure 12).  This supports allowance of some flexibility in the dosing regimen 
in this study, similar to what is currently practiced in this study.
 
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Figure 12
Simulated* Median (90% PI) RPV Plasma Concentrations versus 
Time Profile for Optimized RPV LA Q8W dosing regimen, impact of 
1-week visit window (injection at Week 45 instead of Week 44)^
* Note: current simulations based on interim plasma concentration dataset
^Study Time and Events include a 4 week oral lead in.  Therefore, Day 1 = date of first injections (Week 100 study 
visit); Week 4 = second injections (Week 104 study visit)
Extension Phase Rationale for RPV LA Q4W
The optimized RPV LA Q4W regimen for this study was selected based on LATTE-2 
safety and efficacy data as described above and supported by modeling and simulation of 
pharmacokinetic data obtained following administration of RPV LA in healthy 
participants (Phase 1 studies C158 and LAI115428 [GlaxoSmithKline Document Number 
2011N112455_03]) and in HIV-infected participants (Phase 2 study LATTE-2), with the 
majority of the data coming from 200056 (LATTE-2). 
The predicted median (90% PI) steady-state Cfor the proposed regimen is 86.8 ng/mL 
(45.6 – 168 ng/mL) (Figure 13).  With this regimen, >99% of participants remain above 
the 5th percentile of steady state trough values following oral RPV 25 mg (corresponding 
to 2x the PA-IC90).  With a loading dose of 900 mg RPV LA on Day 1, the anticipated 
 
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median RPV Cat Week 4 is 42 ng/mL, with >98% of participants above the RPV PA-
IC90.
Figure 13
Simulated* Median (90% PI) RPV Plasma Concentrations versus 
Time Profile for the Optimized RPV LA Q4W regimen (900 mg IM Day 
1, then 600 mg IM Q4W thereafter^)
* Note: current simulations based on interim plasma concentration dataset
^Study Time and Events include a 4 week oral lead in.  Therefore, Day 1 = day of first injections (Week 100 study visit); 
Week 4 = second injections (Week 104 study visit) 
Horizontal line at 72 ng/mL corresponds to median Cfollowing oral RPV 25mg once daily in LATTE-2 (oral lead-in) 
and is similar to median RPV Cin other studies in HIV-infected patients (LATTE, ECHO/THRIVE)
At steady-state, a one week delay in dosing for the Q4W regimen is predicted to result in 
a median steady-state Cthat remains above the median trough for RPV 25 mg (Figure 
14).  This supports allowance of some flexibility in the dosing regimen.
 
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Figure 14
Impact of 1-week Delay in Dosing at Steady State (Week 40 delayed 
to Week 41) on Simulated* Median (90% PI) RPV Plasma 
Concentrations versus Time for Optimized RPV LA Q4W dosing 
regimen (900 mg IM Day 1 and then 600 mg IM Q4W thereafter^)
*Note: current simulations based on interim plasma concentration dataset
^Study Time and Events include a 4 week oral lead in.  Therefore, Day 1 = day of first injections (Week 100 study visit); 
Week 4 = second injections (Week 104 study visit)
Horizontal line at 72 ng/mL corresponds to median Cfollowing oral RPV 25 mg once daily in LATTE-2 (oral lead-in) 
and is similar to median RPV Cin other studies in HIV-infected patients (LATTE, ECHO/THRIVE)
1.11.
Benefit: Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with CAB
and CAB LA can be found in the Investigator’s Brochure.  RPV is a recently authorized 
medicinal product and detailed information on its benefit/risk profile together with any 
risk mitigation measures are described in product labeling.  Summaries of findings from 
both clinical and non-clinical studies conducted with RPV LA can be found in the 
Investigator’s Brochure.  Other medicinal products including ABC/3TC that are 
administered in this protocol have been in clinical use for at least 10 years and have well 
established benefit/risk profiles described in detail in their respective product labels.  
 
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Relevant mitigation measures are also incorporated in to this protocol. The following 
sections outline the risk assessment and mitigation strategies specific to this protocol: 
1.11.1.
Risk Assessment
1.11.1.1.
CAB and CAB LA
Since CAB is at an early stage of clinical development, and exposure in humans with or 
without HIV infection is limited, the clinical safety profile in humans has yet to be fully 
elucidated. The following risks have primarily been identified during routine preclinical 
testing and/or in the clinical trial experience to date and are considered of potential 
relevance to clinical usage in the context of this protocol.  Additional information about 
the clinical experience to date and possible risks associated with treatment using CAB 
can be found in the Summary of Data and Guidance for the Investigator section of the IB.
Elevated Liver Transaminases
A small proportion of participants in the CAB program to date (total exposure 
approximately 1198 to 01 April 2016) have developed transaminitis (elevated liver 
transaminases characterised by predominant ALT elevation).  In some of these 
participants’ transient transaminitis were explained by acute hepatitis C infection and 
whilst a small number of others did not have alternative explanations, suggesting a mild 
form of DILI (drug induced liver injury) without hepatic dysfunction which resolved 
upon withdrawal of treatment with CAB. 
Of the five participants with possible or probable cases of DILI identified in Phase 2
studies, four participants were receiving oral CAB and one participant developed 
probable DILI following CAB LA or Placebo LA administration.
Mitigation: Liver transaminases will be closely monitored throughout this study (refer to 
Time & Events Table) and the liver chemistry stopping criteria will be adopted as 
described in Section 6.10.3.1 of this protocol. All instances of liver transaminase 
elevations of Grade 2 and above will be followed to resolution. This risk will also be 
mitigated by exclusion criteria as described in Section 4.3.  In addition, an oral lead in 
period is being implemented in this study, where all subjects will receive CAB oral 
during the Induction Period, to determine individual safety and tolerability, prior to the 
possible administration of CAB LA.
Elevated Serum Creatinine
This risk was identified from placebo controlled studies which demonstrated slightly 
more pronounced changes from Baseline associated with CAB exposure compared to 
placebo. Changes were generally small with a maximum change from Baseline observed 
at a dose of 30 mg given to 12 healthy subjects for 24 days (~ 0.19 mg/dL at Day 24), 
Levels returned to Baseline after cessation of CAB dosing. Further Phase I and Phase II 
clinical studies have not demonstrated an increase in creatinine levels with CAB
administration. No pre-clinical signal for renal toxicity has been demonstrated and 
 
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findings in humans have not been associated with clinically evident renal dysfunction or 
proteinuria.
Mitigation: Standard renal toxicity monitoring procedures and treatment stopping 
guidelines for CAB are incorporated in to this protocol as described in Section 6.10.6.9. 
Creatine Phosphokinase (CPK) elevations
Occurrences of asymptomatic, transient instances of elevations of CPK levels have been 
observed in Phase I studies and an ongoing Phase IIb studies with CAB at dose levels of 
10, 30 and 60 mg (LAI116482) and with CAB LA (200056). These generally appeared 
to be related to physical activity, were not associated with clinical symptoms and returned 
to pre-treatment levels in all cases.  No subject has required a discontinuation of CAB as 
a result of a CPK elevation. Rhabdomyolysis of uncertain cause has been included in 
labeling for a currently available integrase inhibitor (raltegravir) but has not been seen in 
any subject receiving CAB to date.
Mitigation: standard laboratory monitoring as detailed in Section 6.10.6.7.  Occurrences 
of elevated CPK levels will be reported and managed as described in Section 6.10.6.7.
Bone Marrow depletion
This risk was demonstrated in high dose (1000 mg/kg/day) CAB monkey study but was 
not apparent from studies conducted in rats or at lower dose levels in monkeys. Blood 
disorders such as anemia and leucopenia are labeled for other drugs of the integrase 
inhibitor class.  No signal for bone marrow depletion has been identified for CAB to date 
through Phase IIb.
Mitigation: Doses used within this study will result in many fold lower level exposure 
compared to the effect level in primates. Careful monitoring of adverse hematological 
events (including laboratory monitoring as in Section 6.10.2) will occur during study 
conduct. Serious/severe events will be managed appropriately including, but not limited 
to, withdrawal of CAB, and will be followed to resolution as per Sponsor’s standard 
medical monitoring practices. 
Gastrointestinal intolerability 
The risk identified in a monkey toxicity study at the highest administered dose of CAB
and considered related to local irritation (rather than a systemic effect) leading to 
morbidity associated with clinical signs of intolerance.
Mitigation: Careful monitoring of adverse GI events will occur throughout the study. 
Serious/severe events will be managed appropriately including, but not limited to, 
withdrawal of CAB, and will be followed to resolution as per Sponsor’s standard medical 
monitoring practices.   
 
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Injection Site Reactions
The occurrence of ISRs was identified in rats and monkeys at all dose levels of CAB LA 
and associated with both the IM and SC route of administration. In humans, experience 
to date has demonstrated ISRs occur in the majority of exposed subjects but are generally 
mild (Grade 1) or moderate (Grade 2) and include tenderness, erythema, or nodule 
formation of several days duration. Reactions have been well tolerated and have only 
rarely led to subject withdrawal.
Mitigation: Subjects will be closely monitored for ISRs particularly for signs of pain, 
tenderness, infections, erythema, swelling, induration, or nodules (granulomas or cysts) 
throughout the study. Specialist dermatology consultation will be sought if warranted for 
individual subjects.
Hypersensitivity Reactions (HSR)
While there have been no clinical cases of hypersensitivity to CAB, there is a theoretical 
risk of systemic or severe hypersensitivity reactions with or without hepatic symptoms 
associated with use of CAB LA. The long exposures anticipated after a CAB LA 
injection may complicate the management of a drug hypersensitivity reaction, were it to 
occur.
Mitigation:  This risk of developing a hypersensitivity reaction post administration of 
CAB LA will be minimized by the use of an oral lead-in of CAB to determine individual 
safety and tolerability prior to the introduction of CAB LA.  Any reactions would be 
managed supportively. 
Development of Resistance
Residual concentrations of CAB would remain in the systemic circulation of participants 
for prolonged periods (up to 1 year) despite stopping treatment (e.g. for tolerability issues 
or treatment failure). Participants discontinuing CAB LA regimen may be at risk for 
developing HIV-1 resistance to CAB many weeks after discontinuing injectable therapy.
Mitigation:  Alternative oral HAART regimens will be prescribed within four weeks 
after participants stop CAB LA.  This would be anticipated to result in rapid 
resuppression of HIV-1 RNA thus minimizing of the risk of emergent resistance.  The 
participants in this study who discontinue CAB LA for any reason will be monitored for a 
minimum of 52 weeks from the time of the last CAB LA injection.
Drug-Drug Interactions (DDIs)
Residual concentrations of CAB would remain in the systemic circulation of subjects 
who stopped treatment (e.g. for tolerability issues or treatment failure) for prolonged 
periods (months). Subjects discontinuing a LA regimen may be at risk for developing 
DDIs many weeks after discontinuing injectable therapy.  Of note, evidence to date 
indicates that significant DDIs with CAB and other antiretrovirals are unlikely to occur.
 
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Mitigation: None needed at this time.  All subjects will be informed of prohibited 
medications throughout the study and updates provided as needed via informed consent.
Inadvertent Intravenous Injection (Accidental Maladministration)
As with any intramuscular injection, it is possible that CAB LA can be inadvertently 
administered intravenously instead of intramuscularly resulting in higher than expected 
concentrations of CAB.  This could be due to administrator error, improper injection 
technique and / or improper needle length used based on body type.    The clinical 
consequences of overdose with CAB are currently unknown. HIV-1 viral suppression 
may not be effective following accidental maladministration.
Mitigation:  Training will be provided to all sites on proper injection technique.  Should 
IM maladministration be suspected at any time (e.g. suspected under or overdose or 
inadvertent IV dosing), a PK sample, post dose ECG, vital signs or any other supportive 
testing may be obtained at the discretion of the investigator, and the Medical Monitor 
notified.  Laboratory samples for safety parameters and HIV-1 RNA will be closely 
monitored in all subjects.  Additionally, 2 hour post dose PK samples will be obtained at 
a few early timepoints (Day 1, Week 32 and Week 48) for determination of CAB
concentration and possible pharmacokinetic correlation with safety parameters such as 
ECG changes and virologic response.  Should IM maladministration be suspected at any 
time (e.g. suspected under or overdose or inadvertent IV dosing), a post dose ECG or any 
other supportive testing may be obtained at the discretion of the investigator, and the 
medical monitor notified.  Additionally, an unscheduled PK sample may be drawn 
approximately 2 hours post dosing for future evaluation of CAB and RPV concentrations.
1.11.1.2.
RPV and RPV LA
For safety and risk mitigation for RPV, refer to the rilpivirine prescribing information 
[Edurant Product Information, 2015].  Information about the clinical experience to date 
and possible risks associated with treatment using RPV LA can be found in the Summary 
of Data and Guidance for the Investigator section of the IB.  Beyond what has already 
been identified with oral RPV, no new systemic adverse reactions to RPV LA (same 
active moiety) have been observed.  The following risks are considered to be of specific 
clinical relevance in the context of IM use:
Injection Site Reactions
Injection site pain (upon touch) mild to moderate and injection site induration have 
occurred with RPV LA injection. Incidences vary with dose (volume of administration) 
and site of injection. Any recurrence may be linked to the formulation used and any 
recurrence will be monitored in future repeated dose clinical studies with RPV LA. 
Mitigation: Local tolerance will be closely monitored.
Rash
Some observations of rash with RPV have been reported in clinical studies executed to 
date (the majority are Grade 1 or 2).
 
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Mitigation:  In this study, RPV LA administration will be preceded by a one month RPV 
lead in to evaluate safety and tolerability in individual participants.
Development of Resistance
Residual concentrations of RPV LA would remain in the systemic circulation of subjects 
who stopped treatment (e.g. for tolerability issues or treatment failure) for prolonged 
periods (months). Participants discontinuing a LA regimen may be at risk for developing 
resistance to RPV many weeks after discontinuing injectable therapy.
Mitigation:  Alternative oral HAART regimens will be constructed for subjects stopping 
long acting therapy which would be anticipated to result in rapid resuppression of HIV-1 
RNA thus minimization of the risk of emergent resistance. The Sponsor will continue to 
monitor subjects in this study who discontinue a LA regimen for any reason for a 
minimum of 52 weeks from the time of the last LA administration.
Drug-Drug Interactions (DDIs)
Residual concentrations of RPV would remain in the systemic circulation of subjects who 
stopped treatment (e.g. for tolerability issues or treatment failure) for prolonged periods 
(months). Subjects discontinuing a LA regimen may be at risk for developing DDIs 
many weeks after discontinuing injectable therapy.  Of note, evidence to date indicates 
that significant DDIs with RPV LA and other antiretrovirals are unlikely to occur.
Mitigation: None needed at this time.  All subjects will be informed of prohibited 
medications throughout the study and updates provided as needed via informed consent.
Refer to the Investigator Brochure for RPV LA for detailed descriptions of the clinical 
experience to date [TMC278 LA [Rilpivirine, oral and parenteral] Integrated 
Investigator’s Brochure, 2016].
 
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Inadvertent Intravenous Injection (Accidental Maladministration)
As with any intramuscular injection, it is possible that RPV LA can be inadvertently 
administered intravenously instead of intramuscularly resulting in higher than expected 
concentrations of RPV LA.  This could be due to administrator error, improper injection 
technique and / or improper needle length used based on body type.  The clinical 
consequences of overdose with RPV LA are currently unknown. HIV-1 viral suppression 
may not be effective following accidental maladministration.
Mitigation:  Training will be provided to all sites on proper injection technique.  Should 
IM maladministration be suspected at any time (e.g. suspected under or overdose or 
inadvertent IV dosing), a PK sample, post dose ECG monitoring and vital signs or any 
other supportive testing may be obtained at the discretion of the investigator, and the 
Medical Monitor notified.  Laboratory samples for safety parameters and HIV-1 RNA 
will be closely monitored in all subjects.  Additionally, 2 hour post dose PK samples will 
be obtained at a few early timepoints (Day 1, Week 32 and Week 48) for determination 
of RPV concentration and possible pharmacokinetic correlation with safety parameters 
such as ECG changes and virologic response.  Should IM maladministration be suspected 
at any time (e.g. suspected under or overdose or inadvertent IV dosing), a post dose ECG 
or any other supportive testing may be obtained at the discretion of the investigator, and 
the medical monitor notified.  Additionally, an unscheduled PK sample may be drawn 
approximately 2 hours post dosing for future evaluation of CAB and RPV concentrations.
1.11.1.3.
Abacavir/Lamivudine (ABC/3TC)
The most significant toxicity associated with ABC is the well-characterized drug-related 
hypersensitivity reaction (HSR). Studies have shown that carriage of the HLA-B*5701 
allele is associated with a significantly increased risk of a HSR to ABC. In the 
prospective study CNA106030 (PREDICT-1), the use of pre-therapy screening for the 
presence of HLA-B*5701 and subsequently avoiding ABC in HLA-B*5701 positive 
patients, significantly reduced the incidence of clinically suspected ABC HSR from 7.8% 
(66 of 847) to 3.4% (27 of 803) (p<0.0001). In clinical studies EPZ108859 (ARIES) and 
CNA109586 (ASSERT), 0.8% (4/515) and 3.1% (6/192) of subjects who were HLA-
B*5701 negative and who received ABC developed a clinically suspected ABC HSR, 
respectively.
In any subject treated with ABC, the clinical diagnosis of suspected HSR (as detailed in 
the Local Country Prescribing Information) must remain the basis of clinical decision 
making. Regardless of HLA-B*5701 status, it is important to permanently discontinue 
ABC and not re-challenge with ABC (i.e., ZIAGEN™, EPZICOM/KIVEXA or 
TRIZIVIR) if a HSR cannot be ruled out on clinical grounds, due to the potential for a 
severe or even fatal reaction.
A detailed clinical description of this reaction (including the type and severity of events 
that can occur on re-challenge or reintroduction following ABC interruption for non-HSR 
reasons) and guidance regarding its management are included in the Local Country
Prescribing Information for EPZICOM.  
 
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Mitigation:  Every potential subject will be screened for the carriage of the HLA-
B*5701 allele.  Subjects who are HLA-B*5701 positive at the Screening visit are allowed 
to enter the study on a dual-NRTI backbone that does not contain abacavir (see 
Section 5.6).
1.11.1.4.
Study Procedures
Risks associated with study procedures include swelling, bleeding, bruising and infection 
from venipuncture required for blood sampling.  These risks will be minimized using 
current standard of care techniques for venipuncture.  Additionally, subjects will be 
required to have ECGs conducted periodically throughout the study; some discomfort and 
rash may occur where the ECG pads are removed.
1.11.1.5.
Risk of Treatment Failure
This study employs an induction / maintenance approach to the treatment of HIV-1 
infection.  Following virologic suppression, subjects will be transitioned off of a 3 drug 
ART regimen to a 2 drug ART regimen.  CAB and RPV have demonstrated antiviral 
activity in the Phase 2b studies LAI116482 (oral two drug treatment) and 200056 
(through 48 weeks LA treatment).  Viral loads will be closely monitored throughout the 
study.
Doses of the CAB LA and RPV LA have been selected to achieve exposures that are 
expected to maintain virologic efficacy on the basis of available data with the oral 
formulations.  Neither CAB LA nor RPV LA, at any dose, has been used in HIV-1 
infected subjects.  Plasma samples will be collected throughout the Maintenance Period 
for determination of CAB and RPV concentration and possible pharmacokinetic 
correlation with virologic response.  
Due to administration error, it is possible that a subject could receive an inadequate dose 
of CAB LA or RPV LA.  Sub-therapeutic concentrations of either CAB LA or RPV LA 
could lead to virologic failure and possibly the development of resistance.  HIV-1 RNA 
viral loads will be closely monitored throughout the injection period of the study.
Mitigation:  HIV-1 RNA will be closely monitored throughout the study.  Plasma 
samples will be collected throughout the Maintenance Phase for determination of CAB 
and RPV concentration and possible pharmacokinetic correlation with virologic response.
1.11.2.
Other Clinically Relevant Information
Additional details concerning safety observations from clinical studies and for which a 
causal association has not been established or which are of minimal clinical significance 
may be found in the Investigator’s Brochure.  Please refer to Section 6: ‘Summary of 
Data and Guidance for the Investigator’
 
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Adverse Events of Special Interest:
Seizure:
Four cases of possible or definitive seizures have occurred in the CAB program 
cumulatively through 7 June 2016. Two of the cases occurred in HIV uninfected subjects 
with a prior history of seizure. Two cases occurred in HIV infected subjects, one case 
involved a subject in this study, 200056, and another case in the LAI116482 study, both 
cases displayed circumstantial and anecdotal evidence of illicit drug use which may have 
contributed to the event, and each case was determined by the Sponsor to not be 
reasonably likely related to CAB or RPV. Overall, there is insufficient evidence that 
CAB exposure may be causally associated with seizure or with reduction of seizure 
threshold, due to the low frequency of reports, the confounders present in the cases 
received to date and lack of any pre-clinical signal or identified plausible mechanism.
However, seizure and seizure-like events will be closely monitored in clinical studies, 
including this study (200056).  Any case of seizure or possible seizure must be reported 
to the Sponsor within 24 hours of notification, as detailed in Section 6.10.14.
1.11.3.
Benefit Assessment
The antiviral activity of CAB has been well established through Phase IIa and Phase IIb 
studies and subjects receiving 30 mg of CAB + ABC/3TC are anticipated to benefit from 
attainment of virological suppression. RPV is an established antiviral agent in treatment 
naive patients, with long term durability (>96 weeks in Phase III and >240 weeks in 
Phase IIb). Subjects who achieve virologic suppression will be randomized to either a 
two-drug, two-class ART regimen containing CAB LA + RPV LA or to continue a 
suppressive oral regimen. Subjects randomized to an arm containing CAB LA + RPV
LA will have infrequent, monthly or every other month dosing without the need to take 
concomitant daily oral therapy.  The reduction in ART, and the discontinuation of NRTIs, 
may offer long term safety and tolerability benefits in these subjects.
Efficacy of the two-drug regimen, as oral agents, has been demonstrated through 
Week 96 of the ongoing LAI116482 study.  Efficacy of the two-drug regimen, as LA 
agents, has been demonstrated through Week 48 of the ongoing 200056 study.  
1.11.4.
Overall Benefit: Risk Conclusion
Taking into account the measures taken to minimize risk to subjects participating in this 
study, the potential risks identified in association with CAB, RPV and the study as a 
whole are justified by the anticipated benefits that may be afforded to treatment-naïve 
patients with HIV infection.
 
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2.
OBJECTIVES AND ENDPOINTS
Objective
Endpoint
Primary
To select an intramuscular dosing regimen of 
CAB LA plus RPV LA based on a comparison of 
the Week 32 antiviral activity, tolerability, and 
safety of two IM dosing regimens, relative to 
CAB 30 mg plus ABC/3TC orally once daily.
The proportion of subjects with HIV-1 RNA 
<50 c/mL at Maintenance Week 32 based on 
intent to treat-maintenance exposed (ITT-ME) 
population using the Missing, Switch, or 
Discontinuation = Failure (MSDF) algorithm.
Proportion of subjects with protocol defined 
virologic failures over time
Incidence and severity of AEs and laboratory 
abnormalities over time.
Secondary
To evaluate the antiviral activity, tolerability, and 
safety of CAB 30 mg plus ABC/3TC orally once 
daily through the Induction and Maintenance 
Periods.
Proportion of subjects with plasma HIV-1 RNA 
<200 c/mL and <50 c/mL over time.
Absolute values and change from Baseline in 
plasma HIV-1 RNA.
Absolute values and changes from Baseline in 
CD4+ cell counts.
Incidence of disease progression (HIV-
associated conditions, acquired 
immunodeficiency syndrome [AIDS] and death).
Incidence and severity of AEs and laboratory 
abnormalities over time.
Absolute values and changes in laboratory 
parameters over time.
To evaluate the efficacy, tolerability, and safety 
of CAB LA 400 mg IM plus RPV LA 600 mg IM 
every 4 weeks and CAB LA 600 mg IM plus 
RPV LA 900 mg every 8 weeks, relative to CAB
30 mg plus ABC/3TC orally once daily, through 
Week 96 of the Maintenance Period.
Proportion of subjects with plasma HIV-1 RNA 
<200 c/mL and <50 c/mL over time.
Proportion of subjects with protocol defined 
virologic failures over time.
Absolute values and change from Baseline in 
plasma HIV-1 RNA.
Absolute values and changes from Baseline in 
CD4+ cell counts.
Incidence of disease progression (HIV-
associated conditions, acquired 
immunodeficiency syndrome [AIDS] and death.
 
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Objective
Endpoint
Incidence and severity of AEs and laboratory 
abnormalities over time.
Absolute values and changes in laboratory 
parameters over time.
To characterize CAB LA and RPV LA PK and to 
explore PK-PD relationships.  
Plasma PK parameters for CAB LA and RPV LA
(Ctrough and concentrations post dose [~Cmax]) 
during the Maintenance Period.  
Plasma CAB and RPV trough concentrations
will be used to determine when steady state is 
achieved for each CAB LA and RPV LA
regimen.
Relationship between plasma PK parameters 
and plasma HIV-1 RNA, CD4+ cell counts 
and/or occurrence of adverse events [AEs] 
through Week 48 of the Maintenance Period will 
be explored.
To assess the development of viral resistance in 
subjects experiencing protocol defined virologic 
failure.
Incidence of treatment emergent genotypic and 
phenotypic resistance to CAB, RPV, and other 
on-study ART.
To explore the effect of various demographic 
Baseline characteristics and adherence on 
virologic response of CAB and RPV over time.
Proportion of subjects with plasma HIV-1 RNA 
<50 c/mL over time.
To evaluate the treatment satisfaction for 
subjects on the long-acting injectable regimens
with those on the oral regimen through Week 96 
of the Maintenance Period.
Summarize treatment satisfaction using the HIV 
Treatment Satisfaction Questionnaire Status 
(HIVTSQ(s)) over time. 
To evaluate the change in treatment satisfaction 
for subjects in both the long-acting injectable 
and oral regimens through Week 32 of the 
Maintenance Period.
Measure change in treatment satisfaction using 
the HIV Treatment Satisfaction Questionnaire 
Change (HIVTSQ(c)) over time.
To evaluate medication adherence over time.
Summarize subject reported medication 
adherence using the HIV Medication 
Questionnaire (HIVMQ) over time.
Exploratory
To evaluate the efficacy, tolerability, and safety 
of optimized IM dosing regimens CAB LA 400 
mg IM plus RPV LA 600 mg IM every 4 weeks
and CAB LA 600 mg IM plus RPV LA 900 mg 
every 8 weeks at Weeks 128 and 160 for 
subjects switching from the oral regimen 
therapy at the end of the Maintenace Period.
Proportion of subjects with a ‘virologic failure’ 
endpoint as per FDA Snapshot algorithm at 
Week 128 and 160 (Missing, Switch or 
Discontinuation = Failure, Extension Switch 
population)
Proportion of subjects with Plasma HIV-1 RNA 
<50 copies/mL (c/mL) at Week 128 and 160 
 
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Objective
Endpoint
To evaluate the long term efficacy, tolerability, 
and safety of IM dosing regimens CAB LA 400 
mg IM plus RPV LA 600 mg IM every 4 weeks
and CAB LA 600 mg IM plus RPV LA 900 mg 
every 8 weeks at Week 160 for subjects who 
continued randomized IM dosing in the 
Extension Period.
using the FDA Snapshot algorithm (Extension 
Switch population)
Proportion of subjects with protocol defined 
virologic failures over time
Proportion of subjects with plasma HIV-1 RNA 
<200 c/mL and <50 c/mL over time. Absolute
values and changes in CD4+ cell counts over 
time
Incidence of disease progression (HIV-
associated conditions, acquired 
immunodeficiency syndrome [AIDS] and death).
Incidence and severity of AEs and laboratory 
abnormalities over time.
Absolute values and changes in laboratory 
parameters over time.
3.
INVESTIGATIONAL PLAN
3.1.
Study Design Schematic
Induction Period
 
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Maintenance and Extension Period
3.2.
Study Design
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct. 
Study 200056 is a Phase IIb, randomized, multicentre, parallel group, open-label, three-
part study in HIV-1 infected ART-naive adults.  The study will enroll approximately 
265 subjects in order to randomize approximately 225 subjects at Day 1.
This study will consist of a Screening Period, Induction Period, Maintenance Period, 
Extension Period and a Long-term Follow-up Period (withdrawn subjects only). 
A subject is considered to have completed the study if they complete the Induction and 
Maintenance Period through Week 96.
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM).  The SPM will provide 
the site personnel with administrative and detailed technical information that does not 
impact subject safety.
3.2.1.
Screening Period
Informed consent must be obtained prior to any study procedures, including any 
Screening assessment.
 
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Subjects will participate in a screening period of up to 28 days. Subjects may be re-
screened once. Subjects who are randomized into the trial and subsequently withdrawn 
from the study, for any reason, may not be re-screened. Subjects may be randomized as 
soon as all eligibility requirements have been met.
Subjects who are HLA-B*5701 positive at the Screening visit are allowed to enter the 
study on a dual-NRTI backbone that does not contain abacavir.  The selected dual-NRTI 
backbone may be supplied regionally by GlaxoSmithKline (GSK) or reimbursement will 
be provided.
3.2.2.
Induction Period
Following the Screening Period, eligible subjects will be enrolled into the study and 
begin a 20 week Induction Period utilizing an oral regimen of CAB 30 mg once daily 
plus ABC/3TC 600/300 mg once daily.  
Week -20 is considered the Baseline visit and is the first day on study treatment.  Further 
weeks of treatment throughout the Induction Period will be counted up to Day 1 (Day 1 
initiates the Maintenance Period).
Example:  First day on study Week (-20)
Next visit Week (-16)
Next visit Week (-12), etc
Subjects will initiate treatment at Baseline (Week -20) and will be seen every 4 weeks for 
study treatment dispensing and safety and efficacy assessments (see Time and Events 
Section 6.1).  
Unless subjects meet a study withdrawal criteria, their regimen will be modified at 
Week (-4) with the addition of RPV 25 mg once daily for the remainder of the Induction 
Period. 
3.2.3.
Eligibility for the Maintenance Period
All subjects with an undetectable HIV-1 RNA (<50 c/mL) at the Week (-4) visit are 
eligible to enter the Maintenance Period. A single repeat to determine eligibility may be 
allowed ONLY after consultation with the medical monitor.  Subjects with HIV-1 
RNA 400 c/mL at Week (-4) are not eligible to enter the Maintenance Period and will 
not be allowed a repeat to determine eligibility.
 
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Result of HIV-1 RNA at Week (-4)
Action
<50 c/mL
Begin Maintenance Period
50 c/mL but <400 c/mL
Single repeat allowed only after consultation 
and approval from medical monitor
Single repeat <50 c/mL
Begin Maintenance Period
Single repeat 50 c/mL
Cannot begin Maintenance Period and must be 
withdrawn from study; Complete withdrawal visit 
instead of Day 1.  
400 c/mL
Cannot begin Maintenance Period and must be 
withdrawn from study; Complete withdrawal visit 
instead of Day 1
Should a subject be allowed a repeat, results of this repeat must be available prior to 
Day 1, therefore the time needed for scheduling the visit, lab draws and lab analysis 
should be considered.  
The medical monitor may advise the site to withdraw a subject from the study prior to 
Week (-4) to avoid initiating RPV in a subject who is unlikely to be eligible for the 
Maintenance Period.
In addition to the viral load criteria above, if in the opinion of the Investigator, a subject 
experiences a significant safety event while taking either CAB or RPV, Maintenance 
eligibility will be determined ONLY in consultation with the medical monitor.  Any rash 
that is possibly related to study drug, and is present between Week (-4) and Day 1, 
must be discussed with the Medical Monitor prior to initiation of CAB LA or RPV
LA (See Section 6.10.6.15).
Subjects ineligible for the Maintenance Period will be withdrawn.  
If the subject is ineligible for the Maintenance Period, samples will be sent to a central 
laboratory for resistance testing and results provided to the Investigator once available.
Sites may be reimbursed for up to a one month supply of antiretroviral medication to 
facilitate transition to non-study ART for subjects that do not qualify for the Maintenance 
Period.
3.2.4.
Maintenance Period
At Day 1, the Maintenance Period begins.  Eligible subjects will be randomized 2:2:1 to 
receive an IM regimen of CAB LA 400 mg + RPV LA 600 mg every 4 weeks for 96 
weeks, an IM regimen of CAB LA 600 mg + RPV LA 900 mg every 8 weeks for 96 
weeks, or to continue on the oral Induction Period regimen of CAB 30 mg + ABC/3TC 
 
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once daily for 96 weeks (or 100 weeks if continuing on to the Extension Period).  Subject 
randomization will be stratified by subjects’ HIV-1 RNA prior to Week (-8) (<50 c/mL, 
yes or no).
On the first day of the Maintenance Period (Day 1), subjects will receive their last dose of
the Induction regimen (CAB+ABC/3TC+RPV) in the clinic and initiate either IM 
injections or be dispensed the oral regimen depending on the randomization arm.  Add-on 
RPV treatment will be discontinued for all subjects after Day 1.  
Dosing for each arm is as follows (all injections are single injections per drug unless 
otherwise noted):

IM injections every 8 weeks (Q8W)
Day 1 only – CAB LA 800 mg (loading dose delivered as two 400 mg IM 
injections) + RPV LA 900 mg IM
Week 4 only - CAB LA 600 mg IM (second loading dose, no RPV)
Week 8 - CAB LA 600 mg IM + RPV LA 900 mg IM every 8 weeks for 96 
weeks

IM injections every 4 weeks (Q4W)
Day 1 only - CAB LA 800 mg (loading dose delivered as two 400 mg IM 
injections) + RPV LA 600 mg IM
Week 4 - CAB LA 400 mg IM + RPV LA 600 mg IM every 4 weeks for 96 
weeks

Oral Control Arm
CAB 30 mg + ABC/3TC once daily for 96 weeks (or 100 weeks if continuing on 
to the Extension period)
It is important to note that keeping to the subject’s visit schedule is a very important 
component to the study.  IM dosing is expected to occur during the week in which 
the subject’s projected visit falls (as according to the Day 1 visit).  A (+ or -) 7 day 
window, from the projected visit date, is allowable for IM dosing but not preferred.  
Visits for subjects on the oral dosing arm are expected to occur as projected 
according to the Baseline visit.  There is a (+ or -) 3 day visit window, from the 
projected visit date.  However, the number of tablets dispensed should be considered 
when scheduling the next visit.
All subjects are seen approximately every 4 weeks for safety, efficacy and PK 
assessments through Week 32.  After Week 32, subjects will continue to be seen as per 
the Time and Events Schedule (see Section 6) for dosing, safety, efficacy and PK 
assessments through Week 96 (or Week 100 for the oral arm if subject is continuing on to 
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Some visits that are not aligned with dosing will be conducted by telephone interview.  
This allows for safety assessments to be conducted at all visits, but limits clinic visits for 
non-dosing visits.  Telephone safety assessments will include interviewing the subject for 
adverse events, concomitant medications, HIV associated conditions and any other issues 
including injection site reactions or oral compliance issues.  Telephone visits will be 
clearly noted in the Time and Events Schedule.  
See the Time and Events Schedule Section 6.2 and Section 6.3 for more information.  See 
Section 3.2.5.3 for additional information regarding special requirements from Week 96 
to Week 104 for subjects on the oral arm entering the Extension Period.
If one of the IM dosing regimens (Q8W or Q4W) is discontinued as a result of an IDMC 
review or any subsequent analysis, those subjects who have not met any clinical 
management criteria for discontinuation and who were randomized to the discontinued 
dosing regimen may be given the option to discontinue permanently from the study or to 
continue on the remaining IM dosing regimen at the next scheduled visit. 
3.2.5.
Extension Period
Both IM dosing regimens (Q8W and Q4W) will continue evaluation in the Extension 
period.  Subjects who successfully complete 96 weeks of CAB 30 mg + ABC/3TC 
treatment in the Maintenance Period will have the option of continuing study 
participation by switching to an optimized IM dosing regimen of their choice (either 
Q8W or Q4W).
3.2.5.1.
Entering from the CAB LA + RPV LA Arm
All subjects who successfully complete 96 weeks of CAB LA + RPV LA treatment in the 
Maintenance Period will continue with their current IM dosing regimen of CAB LA and 
RPV LA in the Extension Period until:

study treatment is locally approved and commercially available, 

the subject no longer derives clinical benefit, 

the subject meets a protocol-defined reason for discontinuation  

the development of either CAB LA or RPV LA is terminated.  
Subjects will remain on their current regimen after Week 96 and will continue to receive 
their Maintenance Period IM dosing regimen for the remainder of study participation.  
Safety and efficacy assessments will be conducted every 16 weeks. Dosing visits will 
occur according to the selected dosing regimen.  See the Time and Events Schedule 
Section 6.5 and Section 6.6 for more information.
3.2.5.2.
Eligibility for the Extension Period for Subjects Entering From the CAB 
30 mg + ABC/3TC Arm
All subjects with an undetectable HIV-1 RNA (<50 c/mL) at the Week 96 visit are 
eligible to enter the Extension Period. A single repeat to determine eligibility may be 
allowed ONLY after consultation with the medical monitor.  Subjects with HIV-1 
 
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RNA 400 c/mL at Week 96 are not eligible to enter the Extension Period and will not be 
allowed a repeat to determine eligibility.
Result of HIV-1 RNA at Week 96
Action
<50 c/mL
Begin Extension Period
50 c/mL but <400 c/mL
Single repeat allowed only after consultation 
and approval from medical monitor
Single repeat <50 c/mL
Begin Extension Period
Single repeat 50 c/mL
Cannot begin Extension Period and must be 
withdrawn from study; Complete withdrawal 
visit.  
400 c/mL
Cannot begin Extension Period and must be 
withdrawn from study; Complete withdrawal 
visit.
Should a subject be allowed a repeat, results of this repeat must be available prior to next 
visit, therefore the time needed for scheduling the visit, lab draws and lab analysis should 
be considered.  
In addition to the viral load criteria above, if in the opinion of the Investigator, a subject 
experiences a significant safety event while taking either CAB or RPV, Extension 
eligibility will be determined ONLY in consultation with the medical monitor.  
Subjects ineligible for the Extension Period will be withdrawn.  
If the subject is ineligible for the Extension Period, samples will be sent to a central 
laboratory for resistance testing and results provided to the Investigator once available.
Sites may be reimbursed for up to a one month supply of antiretroviral medication to 
facilitate transition to non-study ART for subjects that do not qualify for the Extension
Period.
3.2.5.3.
Entering from the CAB 30 mg + ABC/3TC Arm
All subjects who successfully complete 96 weeks of CAB 30 mg + ABC/3TC treatment 
in the Maintenance Period will have the option to continue study participation by 
switching to the optimized IM dosing regimen of their choice (either Q8W or Q4W) of 
CAB LA + RPV LA in the Extension Period.  Subjects not choosing to switch to an 
optimized long acting regimen will complete their study participation at Week 96.
Subjects who choose to continue on to the Extension Period will be assessed for 
eligibility to begin their selected CAB LA + RPV LA regimen as described in Section 
 
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3.2.5.2. Subjects will continue on their oral Maintenance regimen (CAB 30 mg + 
ABC/3TC) until Week 100 while eligibility is being confirmed.  RPV will not be added 
to their Maintenance regimen prior to the switch to optimized IM dosing.  Subjects were 
given RPV during the last 4 weeks of the Induction Period to evaluate safety and 
tolerability before being randomized to continue in the Maintenance Period and thus 
further evaluation is not necessary.
In order to qualify to receive CAB LA + RPV LA injections at Week 100, the HIV-1 
RNA results from the Week 96 visit must be undetectable (<50 c/mL; a single repeat 
HIV-1 RNA test may be allowed prior to Week 100 following consultation with the 
Medical Monitor). 
If the Optimized Q4W IM Dosing Regimen is selected by the Subject:
At visit Week 100, participants will return to the clinic, take the last dose of their oral 
regimen (CAB 30 mg + ABC/3TC), and receive the first CAB LA (600 mg) + RPV LA 
(900 mg) injections (within 2 hours of the final oral dose of CAB + ABC/3TC).  The 
second and third injections (CAB LA 400 mg + RPV LA 600 mg) will be administered at 
Week 104 and Week 108.  There will be a one week dosing window for the second and 
third IM injections such that the second injections occur within the window of Week 103 
to Week 104, but not later than Week 104, and the third injections occur within the 
window of Week 107 to Week 108, but no later than Week 108.  Subsequent injections 
(CAB LA 400 mg + RPV LA 600 mg) will occur every 4 weeks thereafter, from the 
projected visit date, with a (+ or -) 7 day dosing window being allowed (but not 
preferred).  Following the Week 108 injection, the interval between injection visits 
should be limited to a maximum of 5 weeks.  The Medical Monitor must be contacted if 
the length of time between injections exceeds, or is projected to exceed, 5 weeks from the 
previous injection.
If the Optimized Q8W IM Dosing Regimen is selected by the Subject:
At visit Week 100, subjects will return to the clinic, take the last dose of their oral (CAB 
30 mg + ABC/3TC), and receive the first CAB LA (600 mg) + RPV LA (900 mg) 
injections (within 2 hours of the final oral dose of CAB + ABC/3TC).  The second 
loading injections will be administered at Week 104 (CAB LA 600 mg + RPV LA 
900 mg), with subsequent injections (CAB LA 600 mg + RPV LA 900 mg) occurring 
every 8 weeks thereafter.  The dosing window for the second injection allows 
administration between Week 103 and Week 104, but preferably not later than Week 104.
Starting at the Week 112 injection, the interval between injection visits should be limited 
to a maximum of 9 weeks.  If the length of time between injections exceeds, or is 
projected to exceed 9 weeks, the Medical Monitor must be contacted to discuss individual 
subject case management.  After Week 112, a dosing window (7 days) for injections is 
allowed, but not preferred.
Subjects will continue study treatment until:

study treatment is locally approved and commercially available, 

the subject no longer derives clinical benefit, 

the subject meets a protocol-defined reason for discontinuation  
 
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
the development of either CAB LA or RPV LA is terminated.
Safety and efficacy assessments will be conducted as per the Time and Events schedule 
(Section 6.5 and Section 6.6 for more information).  Dosing will occur according to the 
selected regimen. 
Subjects not eligible to enter the Extension Period will end their study participation.  
Sites may be reimbursed for up to a one month supply of antiretroviral medication to 
facilitate transition to non-study ART for subjects that do not qualify for the Extension
Period.
If one of the optimized IM dosing regimens (Q8W or Q4W) is discontinued as a result of 
an IDMC review or any subsequent analysis, those subjects who have not met any 
clinical management criteria for discontinuation and who selected a discontinued 
optimized IM dosing regimen may be given the option to discontinue permanently from 
the study or to continue on the remaining IM dosing regimen at the next scheduled visit.
3.2.6.
Long-term Follow-Up Period – IM Regimens only
Any subject who receives at least a single dose of CAB LA and/or RPV LA and 
discontinues the CAB LA + RPV LA regimen for any reason must remain on suppressive
Highly Active Antiretroviral Treatment (HAART) for at least 52 weeks after the last dose 
of CAB LA and/or RPV LA in order to prevent selective pressure on HIV and the 
potential for selection of resistant mutants.  This period is considered study participation 
and subjects will be followed on study during this time.
In the Long-Term Follow-Up Period, subjects will receive oral HAART and will be 
followed for 52 weeks after the last dose of CAB LA and/or RPV LA. Investigators 
must discuss the choice of HAART regimen and timing of initiation with the medical 
monitor before initiating. The 52 weeks follow up period will begin the day of the last 
CAB LA and/or RPV LA dose.  These subjects will not complete a Withdrawal visit, but 
will instead move directly into the Long-Term Follow Up Period as per the Time and 
Events Schedule (see Section 6.7). 
Subjects will be assessed with clinic visits at months 1, 3, 6, 9 and 12. Female subjects of 
child bearing potential must continue to use adequate contraception methods (see Study 
Procedures Manual for list of accepted forms of contraception) for the entire year of 
follow up.  
In order to assure that subjects have access to HAART during the Long-Term Follow-Up 
Period, GSK may supply HAART regionally or reimbursement will be provided during 
this period.
3.2.7.
Follow Up Visit
A Follow up visit may be conducted approximately 4 weeks after the last dose of IP and 
is required only if the subject has ongoing AEs or lab abnormalities at the last on-study 
visit. The assessments performed should reflect what is considered medically necessary 
 
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to assess the event(s).  The Follow-up visit may be conducted via telephone if the subject 
has no ongoing adverse events or other issues that would require a clinic visit.
This visit is not required for subjects in the Long-Term Follow Up Period.
3.2.8.
Independent Data Monitoring Committee
An IDMC will evaluate the efficacy, tolerability, and safety of CAB and RPV before all 
eligible subjects have transitioned from the Induction Period to the Maintenance Period.  
This IDMC review may be conducted after approximately 45 subjects have reached 
Week 8 of the Maintenance Period, depending on IDMC agreement.  The intent of this 
analysis is to identify any early safety or tolerability signals from the long acting 
regimen.  In addition, futility guidance (e.g., a Bayesian posterior probability approach
when 50% of subjects have completed Week 24 of the Maintenance Period) is included to 
monitor the performance of all treatment arms in order to prevent subjects from 
continuing on a dosing regimen if existing data indicates that subjects are at unacceptable 
risk of inadequate maintenance of virologic suppression.
If one of the IM dosing regimens (Q8W or Q4W) is discontinued as a result of an IDMC 
review or any subsequent analysis, those subjects who have not met any clinical 
management criteria for discontinuation and who were randomized to the discontinued 
dosing regimen, or selected a discontinued optimized IM dosing regimen, may be given 
the option to discontinue permanently from the study or to continue on the remaining IM 
dosing regimen at the next scheduled visit. 
As subjects enter the Maintenance Period of the study, if the number of protocol defined 
virologic failures meets or exceeds the pre-specified thresholds specified in the IDMC 
Charter, this will be considered strong evidence of an inadequate response and will 
trigger a comprehensive data review by the IDMC.  Similar thresholds will be used by the 
IDMC to monitor the number of protocol defined virologic failures for subjects switching 
from oral CAB 30 mg + ABC/3TC to an optimized IM dosing regimen during the 
Extension Period.  The IDMC charter will contain details of this continual monitoring of 
the protocol defined virologic failure rates, the specifics around what will trigger a data 
review, and the safety summaries and efficacy analyses that will be provided should a 
data review be required.
Full details of the analyses, estimated timing and the decision criteria that will be used to 
determine regimen performance will be pre-specified in the IDMC Charter.
3.2.9.
Primary Analysis
The primary analysis will be conducted when all subjects have completed their 
Maintenance Period Week 32 visit. This analysis will characterize the safety, tolerability 
and durability of antiviral response from both the Induction Period and the Maintenance 
Period. Planned analyses will also be conducted at Week 48, Week 96, Week 128 and 
Week 160. Follow-up analyses of data collected after subjects have entered into the 
Extension Period may be conducted to more fully characterize the long-term safety and
efficacy profile of CAB and RPV.
 
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3.3.
Discussion of Design
Study 200056 is a Phase IIb assessment of a regimen consisting of the long-acting 
injectable forms of CAB and RPV to maintain virologic suppression in previously 
untreated HIV-infected subjects without evidence of transmitted resistance who achieve 
virologic suppression on CAB plus ABC/3TC.  The ongoing study LAI116482 provides 
support for this unique approach of a two-class, two-drug regimen. Results from planned 
analyses of LAI116482 support the choice of 30 mg CAB for use in the Induction Period 
of this study.  Exposure and efficacy data from LAI116482 as well as exposure data from 
the repeat dose studies with CAB LA and RPV LA defined the target doses and 
exposures for CAB LA and RPV LA during the Maintenance Period. Systemic exposure 
of RPV obtained with RPV LA is aimed to be comparable to that obtained with RPV, for 
which the antiviral activity and safety has been well established through Phase III studies.  
Long acting CAB has been investigated in 136 healthy subjects to date as both SC and 
IM injections. This study will be the first evaluation of CAB LA or RPV LA in HIV-
infected subjects.  The results to date support CAB LA and RPV LA for continued 
clinical development.  Injection site reactions (ISR) of both agents have been generally 
mild, self-limited, and well-tolerated in single and multiple dose studies.  
The results of LAI116482 support the use of oral CAB plus NRTIs as a reference 
regimen to the investigational two-drug long-acting regimen. At the primary endpoint of 
Week 48, the response rates (HIV-1 RNA <50 c/mL; ITT, MSDF, Table 1) for the three 
doses of CAB in the LAI116482 study were 80%, 80% and 87% for the 10 mg, 30 mg, 
and 60 mg arms, respectively.  These rates compare favorably to the control regimen of 
EFV plus NRTIs in this study where 71% of subjects achieved HIV-1 RNA <50 c/mL at 
Week 48. 
These data indicate continued viral suppression after 24 weeks of the two drug CAB and 
RPV regimen.
The ITT-Maintenance Exposed (ITT-ME) Population consists of all randomized subjects 
who received at least one dose of investigational product during the Maintenance Phase 
of the study.  Of the subjects who entered the Maintenance Phase of the study, the 
majority remained suppressed through Week 48 (24 weeks of two drug therapy) (Table 
3).
Table 3
LAI116482 Proportion of Subjects with Plasma HIV-1 RNA <50 c/mL 
at Key Visits - Snapshot (MSDF) Analysis (ITT-ME Population)
Visit
GSK744
10 mg
N=52
n (%)
GSK744
30 mg
N=53
n (%)
GSK744
60 mg
N=55
n (%)
GSK744 
Subtotal
N=160
n (%)
EFV 
600 mg
N=47
n (%)
Week 16 - Induction
50 (96)
49 (92)
52 (95)
151 (94)
43 (91)
Week 24 - Induction
50 (96)
50 (94)
53 (96)
153 (96)
45 (96)
Week 48 - Maintenance
48 (92)
48 (91)
53 (96)
149 (93)
44 (94)
The background NRTIs (ABC/3TC) are accepted agents for initiation of antiretroviral 
therapy in treatment guidelines [EACS, 2012; DHHS, 2013] and as such are considered 
appropriate for this trial.  RPV is approved as Edurant for use in combination ART at an 
 
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oral dose of 25 mg, once daily with a meal in treatment naive patients [Edurant Product 
Information, 2015].
This trial is designed to evaluate two distinct periods.  First, to evaluate the ability of 
CAB + background NRTIs to induce virologic suppression during the Induction Period.  
Second, during the Maintenance Period, two different dosing strategies of a long-acting, 
two-drug, two-class regimen will be evaluated on their ability to maintain virologic 
efficacy for 96 weeks compared to a control regimen of oral CAB + ABC/3TC.  
The primary endpoint, proportion of subjects with plasma HIV-1 RNA < 50 c/mL, is a 
well-established surrogate endpoint for prognosis of HIV-1 infection and disease 
progression [CDER, 2002]. The primary endpoint for this study is proportion of subjects 
with plasma HIV-1 RNA < 50 c/mL at Week 32 and will be used to select an IM dosing 
regimen (Q8W or Q4W).  Week 32 has been selected to allow a comparable evaluation 
among the dosing regimens.  Q8W begins dosing at Week 8, following a loading dose at 
Day 1 and Week 4.  Therefore, choosing Week 32 as an endpoint allows for a 24 week 
evaluation of the Q8W arm at steady state.  
The Week 48 analysis will permit an evaluation of the ability of the investigational two-
drug long-acting combinations to maintain virologic suppression over time, and will 
serve as the dose confirmation of the dosing regimen selected at Week 32. Longer term 
durability of virologic suppression for these long-acting two-drug regimens will also be 
evaluated through a formal Week 96 analysis.
The Extension Period will allow participants on the oral Maintenance Period regimen 
who successfully complete Week 96 with an HIV-1 RNA viral load <50 c/mL the 
opportunity to choose an optimized IM dosing regimen (Q8W or Q4W).  This will permit 
an evaluation of the ability of the optimized investigational two-drug long acting 
combinations (see Section 5.1.6) to maintain virologic suppression over time.  This 
period will also allow participants currently on a IM Maintenance Period regimen who 
successfully complete Week 96 with an HIV-1 RNA viral load <50 c/mL the ability to
continue to receive their current IM dosing regimen and to generate additional long-term 
safety and efficacy data for randomized IM dosing regimens.
A planned Week 128 analysis will primarly evaluate the efficacy, tolerability, and safety 
of the optimized IM dosing regimens through 28 weeks of optimized IM treatment in 
subjects switching from oral Maintenance therapy. Long term durability of virologic 
suppression of the randomized long-acting two-drug regimens through Week 128 may 
also be evaluated.
A Week 160 analysis will permit an evaluation of the ability of the randomized and 
optimized investigational two-drug long-acting combinations to showcase long-term 
durability of virologic suppression. Additional long-term safety and efficacy data for all 
IM dosing regimens will be generated.
 
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4.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA
4.1.
Number of Subjects
Sufficient subjects will be screened (approximately 350) in order to ensure that a total of 
approximately 265 subjects are enrolled at the beginning of the Induction Period and to 
ensure approximately 225 subjects are randomized into the Maintenance Period.  Subjects 
will be enrolled from multiple sites which may include sites in the US, Canada, France, 
Germany, and/or Spain.
4.2.
Inclusion Criteria
Deviations from inclusion criteria are not allowed because they can potentially jeopardise 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.
In general, subjects screened for this study must:

be able to understand and comply with protocol requirements, instructions, and 
restrictions, 

be likely to complete the study as planned, 

understand the long term commitment to the study,

be considered appropriate candidates for participation in an investigative clinical 
trial with oral and intramuscularly injectable medications (e.g., no active 
substance abuse, acute major organ disease).
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the investigational regimen or other study treatment 
that may impact subject eligibility is provided in the current Investigator’s Brochure (IB) 
for CAB and RPV and in the current prescribing information for ABC/3TC.  
A single repeat of a procedure / lab parameter is allowed to determine eligibility (unless 
otherwise specified).
Subjects are allowed to re-screen for this study one time.  This will require a new subject 
number.
The following are study specific eligibility criteria unless stated otherwise.  In addition 
to these criteria, Investigators must exercise clinical discretion regarding selection of 
appropriate study subjects, taking into consideration any local treatment practices 
or guidelines and good clinical practice (GCP).  All subjects must be considered 
appropriate candidates for initiation of antiretroviral therapy in accordance with 
local treatment guidelines.
Laboratory results from the central laboratory services provided by this trial will be used 
to assess eligibility.
 
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Subjects eligible for enrollment in the study must meet all of the following criteria:
1.
HIV-1 infected subjects 18 years of age.
2.
A female subject is eligible to enter and participate in the study if she:
a. is of non-child-bearing potential defined as either post-menopausal (12 months of 
spontaneous amenorrhea and 45 years of age) or physically incapable of 
becoming pregnant with documented tubal ligation, hysterectomy or bilateral 
oophorectomy or
b. is of child-bearing potential with a negative pregnancy test at both Screening and 
first day of the Induction Period and agrees to use one of the following methods 
of contraception to avoid pregnancy 2 weeks prior to administration of IP, 
throughout the study, and for at least 2 weeks after discontinuation of all oral 
study medications and for at least 52 weeks after discontinuation of CAB LA 
and RPV LA:

Complete abstinence from intercourse (where this is the subject’s preferred 
and usual lifestyle).

Double barrier method (male condom/spermicide, male condom/diaphragm, 
diaphragm/spermicide).

Approved hormonal contraception (see the SPM for a listing of examples of 
approved hormonal contraception).

Any intrauterine device (IUD) with published data showing that the expected 
failure rate is <1% per year (not all IUDs meet this criterion, see the study 
procedures manual [SPM] for specifics).

Male partner sterilization prior to the female subject’s entry into the study, 
and this male is the sole partner for that subject.

Any other method with published data showing that the lowest expected 
failure rate is <1% per year.

Any contraception method must be used consistently and in accordance with 
the approved product label.
ALL subjects participating in the study must be counseled on safer sexual practices 
including the use of effective barrier methods to minimize risk of HIV transmission.

HIV-1 infection as documented by Screening plasma HIV-1 RNA 1000 c/mL.

CD4+ cell count 200 cells/mm3 (or higher as local guidelines dictate).

ART-naive defined as having no more than 10 days of prior therapy with any 
antiretroviral agent following a diagnosis of HIV-1 infection.  Any previous 
exposure to an HIV integrase inhibitor or non-nucleoside reverse transcriptase 
inhibitor will be exclusionary.
French subjects: In France, a subject will be eligible for inclusion in this study only if 
either affiliated to or a beneficiary of a social security category.
 
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4.3.
Exclusion Criteria
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardise the scientific integrity of the study, regulatory acceptability or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential. 
Subjects meeting any of the following criteria must not be enrolled in the study:
Exclusionary Medical Conditions
1.
Women who are breastfeeding.
2.
Any evidence at screening of an active Centers for Disease and Prevention Control 
(CDC) Category C disease [Centers for Disease Control and Prevention 
(CDC), 1993], except cutaneous Kaposi’s sarcoma not requiring systemic therapy.
3.
Subjects with known moderate to severe hepatic impairment.
4.
Any pre-existing physical or mental condition (including substance abuse disorder) 
which, in the opinion of the Investigator, may interfere with the subject’s ability to 
comply with the dosing schedule and/or protocol evaluations or which may 
compromise the safety of the subject.
5.
Subject who, in the investigator's judgment, poses a significant suicide risk.  Recent 
history of suicidal behavior and/or suicidal ideation may be considered as evidence 
of serious suicide risk.
6.
The subject has a tattoo or other dermatological condition overlying the gluteus 
region which may interfere with interpretation of injection site reactions.
7.
History of ongoing or clinically relevant hepatitis within the previous 6 months, 
including chronic hepatitis B virus (HBV) infection (Hepatitis B Virus surface 
Antigen [HBsAg] positive). 
8.
Asymptomatic individuals with chronic hepatitis C virus (HCV) infection will not be 
excluded, however Investigators must carefully assess if therapy specific for HCV 
infection is required; subjects who are anticipated to require such therapy must be 
excluded.  
9.
History of liver cirrhosis with or without hepatitis viral co-infection.
10. Ongoing or clinically relevant pancreatitis.
11. History of the following cardiac diseases: myocardial infarction, congestive heart 
failure, documented hypertrophic cardiomyopathy, sustained ventricular tachycardia.
12. Personal or known family history of prolonged QT syndrome.
13. Any condition which, in the opinion of the Investigator, may interfere with the 
absorption, distribution, metabolism or excretion of the drug or render the subject 
unable to receive study medication.
14. History or presence of allergy or intolerance to the study drugs or their components 
or drugs of their class.  In addition, if heparin is used during PK sampling, subjects 
with a history of sensitivity to heparin or heparin-induced thrombocytopenia must 
not be enrolled.
 
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15. Current or anticipated need for chronic anti-coagulation.
Exclusionary Laboratory Values or Clinical Assessments at Screening (a single repeat to 
determine eligibility is allowed)
16. Any evidence of primary resistance based on the presence of any major resistance-
associated mutation (International AIDS Society [IAS]-USA, 2013) in the Screening 
result or, if known, any historical resistance test result.  Note:  re-tests of Screening 
genotypes are allowed only at the discretion of the study virologist.
17. Any verified Grade 4 laboratory abnormality.
18. Any acute laboratory abnormality at Screening, which, in the opinion of the 
Investigator, would preclude the subject’s participation in the study of an 
investigational compound.
19. Subject has estimated creatinine clearance <50 mL/min via Cockcroft-Gault 
[Cockcroft, 1976] method.
20. Alanine aminotransferase (ALT) 5 times ULN.  Subjects with ALT > 2xULN but 
<5xULN may participate in the study, if in the opinion of the Investigator and GSK 
medical monitor the lab abnormality will not interfere with the study procedures or 
compromise subject safety.
21. Alanine aminotransferase (ALT) 3xULN and bilirubin 1.5xULN (with >35% 
direct bilirubin).
22. Any clinically significant finding on screening or Baseline electrocardiograph 
(ECG), specifically:
Males
Females
Heart rate*
<45 and >100 bpm
<50 and >100 bpm
QRS duration
>120 msec
QTc interval (B or F)
>450 msec
*A heart rate from 100 to 110 bpm can be rechecked within 30 minutes to verify eligibility.

Non-sustained (3 consecutive beats) or sustained ventricular tachycardia.

Sinus pauses >2.5 seconds.

2nd degree (Type II) or higher atrioventricular (AV) block.

Evidence of WPW (Wolff- Parkinson-White) syndrome (ventricular 
preexcitation).

Pathologic Q waves (defined as Q wave > 40msec OR depth >0.4 mV.

Any significant arrhythmia (either on ECG or by history) which, in the opinion 
of the Investigator and GSK medical monitor, will interfere with the safety for 
the individual subject.
23. Subjects who are HLA-B*5701 positive and unable to use an alternative NRTI 
backbone (subjects who are HLA-B*5701 positive may be enrolled if they use an 
alternative NRTI backbone that does not contain abacavir).
 
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Exclusionary Treatments prior to Screening or First Day of Induction Period
24. Exposure to an experimental drug and/or experimental vaccine within 28 days or 5 
half-lives of the test agent, or twice the duration of the biological effect of the test 
agent, whichever is longer, prior to the first dose of IP.
25. Treatment with any of the following agents within 28 days of Screening:

radiation therapy

cytotoxic chemotherapeutic agents

tuberculosis therapy

Immunomodulators that alter immune responses (such as systemic 
corticosteroids, interleukins, or interferons) Note: Subjects using short-term 
(<10 day) steroid tapers, topical, inhaled and intranasal corticosteroids are 
eligible for enrollment.
26. Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening.
27. Treatment with any agent, except recognized ART as allowed above, with 
documented activity against HIV-1 within 28 days of the first dose of IP.
Notwithstanding these minimum inclusion and exclusion criteria, investigators must 
also follow country specific guidelines where they exist when making decisions about 
subjects who are eligible for study participation.
4.4.
Additional Eligibility Criteria
To assess any potential impact on subject eligibility with regard to safety, the Investigator 
must refer to the current IB and supplements, approved product labels, and/or local 
prescribing information for detailed information regarding warnings, precautions, 
contraindications, AEs, drug interactions, and other significant data pertaining to the IP 
and the dual NRTI background drugs being used in this study.
4.5.
Withdrawal Criteria
Subjects permanently discontinuing study treatments prior to Week 96 are considered to 
be withdrawn from the study treatments and also from the study.  Similarly, subjects 
permanently discontinuing participation from the Extension and Long-Term Follow-Up 
Period prior to commercially available drug supply are considered to be withdrawn from 
the study treatments and also from the study.
A subject may voluntarily discontinue participation in this study at any time.  The 
investigator may also, at their discretion, discontinue the subject from participating in this 
study at any time.  Subjects who are withdrawn from the study will not be replaced.
Should a subject fail to attend the clinic for a required study visit, the site should attempt 
to contact the subject and re-schedule the missed visit as soon as possible.  The site 
should also 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 
 
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study based on previous non-compliance.  In cases where the subject does not return for 
the rescheduled visit or cannot be reached to reschedule the missed visit, the site should 
make every effort to regain contact with the subject (3 telephone calls and if necessary a 
certified letter to the subject’s last known mailing address) so that they can appropriately 
be withdrawn from the study.  These contact attempts should be documented in the 
subject’s medical record.  Should the subject continue to be unreachable, then and only 
then will he/she be considered to have withdrawn from the study with a primary reason of 
“Lost to Follow-up”.  For all other subjects withdrawing from the study, an alternative 
reason for discontinuation should be recorded in the electronic case report form (eCRF).
Subjects are not obligated to state the reason for withdrawal but the Investigator must 
make every attempt to elucidate a reason.  The efforts must be documented in the source 
including efforts to locate a subject that has been deemed lost to follow up. The reasons 
for withdrawal, or failure to provide a reason, must be documented in the eCRF.
The investigator must make every effort to perform a Withdrawal visit as well as a 
Follow-Up visit (as needed) as per the Time and Events Table (see Section 6).  Follow-up 
for AEs and SAEs must occur as specified in Section 6.10.12.
Subjects with an HIV-1 RNA > 200 c/mL at the time of Withdrawal will have samples 
sent to a central laboratory for resistance testing and results provided to the Investigator 
once available.
All subjects who discontinue prematurely from the study, irrespective of arm, will be 
asked for additional information to establish the reason for withdrawal.
Reasons for study withdrawal may include:

Adverse event/Serious adverse event

Protocol deviation

Intolerability of injections

Subject lost to follow-up

Subject withdrew consent

Investigator discretion

Subject or investigator non-compliance

Termination of the study by the Sponsor

At the request of the subject, Investigator, or GSK

The subject requires concurrent prohibited medications during the course of the 
study.  If, in the opinion of the Investigator and the study medical monitor, such 
medication will not interfere with the conduct or interpretation of the study or 
compromise the safety of the subject, then the subject may remain in the study.
 
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Subjects must be withdrawn from the study for any of the following reasons:

Subjects who are not eligible to continue into the Maintenance Period as per 
Section 3.2.3.

Subjects who do not wish to continue on the remaining dosing regimen if one dosing 
regimen is discontinued further to an IDMC decision (see Section 3.2.8).

Subjects who are not eligible, or do not wish to continue on to the Extension Period 
(see Section 3.2.5.3).

Subjects who cannot or do not wish to continue on to the Long-Term Follow Up 
Period (see Section 3.2.6).

Confirmed virologic failure as described in Section 4.6.

Pregnancy (intrauterine).

Subject requires a switch of background NRTI therapy (except as allowed in 
Section 5.6).

Subject requires substitution or dose reduction of CAB or RPV.

Grade 4 AE or toxicity in the absence of compelling evidence that the AE is not 
causally related to the IP (See Section 6.10.6.4).

Liver toxicity where Stopping Criteria as described in Section 6.10.3 are met and no 
compelling alternative cause is identified.

Renal toxicity as specified in Section 6.10.6.9 and Section 6.10.6.10 is met and no 
compelling alternate cause is identified. 

Subject has a Grade 3 or higher rash or Grade 2 rash with evidence of systemic 
involvement as described in Section 6.10.6.15.

The following QT criteria:

Corrected QT interval (QTc) >500 msec

Uncorrected QT >600 msec
These criteria must be based on the average QTc value of triplicate ECGs. For 
example, if an ECG demonstrates a prolonged QT interval, obtain two more ECGs 
over a brief period, and then use the averaged QTc values of the three ECGs to 
determine whether the patient should be discontinued from the study.  
For subjects with underlying Bundle Branch Block: 
Baseline QTc with Bundle Branch Block
Discontinuation QTc with Bundle Branch Block
<450 msec
>500 msec
450-480 msec
530 msec
Efficacy data for subjects withdrawing from the study will be considered evaluable up to 
the point at which they are withdrawn using the same criteria for evaluability as for 
subjects who complete the study.
 
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Safety data for all subjects who receive any amount of study drug, including subjects who 
withdraw from the study, will be included in evaluations of safety.
4.5.1.
Subjects Receiving CAB LA and / or RPV LA
Subjects who have received at least one dose of CAB LA or RPV LA and choose to 
withdraw or are required to withdraw, will be asked to participate in the Long-Term 
Follow Up Period of the study (See Section 3.2.6).  The investigator must make every 
effort to conduct visits as per the Time and Events Table (see Section 6.7).
The Investigator must discuss choice of follow-up HAART regimen and timing of 
initiation with the medical monitor prior to initiating the new regimen with the 
subject.
4.6.
Virologic Failure
Following study entry, no changes, or intensification of ART will be permitted prior to 
protocol-defined virologic failure, with the exception of the planned addition of RPV at 
Week (-4), the change to the Maintenance Period regimen, and one allowed alternative 
approved NRTI change for management of drug toxicity. 
Only plasma HIV-1 RNA values determined by the central laboratory will be used to 
assess virologic failure. Baseline plasma HIV-1 RNA is the assessment completed on the 
first day of the Induction Period.
The definition of protocol defined virologic failure does not apply to subjects in the 
Long-Term Follow-Up Period.  These subjects will be followed for the emergence of 
potential virologic resistance only.  If the HIV-1 RNA > 200 c/mL, a confirmation 
sample must be obtained.  If the repeat HIV-1 RNA is > 200 c/mL samples will be sent to 
a central laboratory for resistance testing and results provided to the Investigator once 
available.
4.6.1.
Definition of Virologic Failure
For the purposes of clinical management in this study, virologic failure is defined as any
of the following:

Non-response as indicated by a less than a 1.0 log10 copies/mL decrease in 
plasma HIV-1 RNA after 4 weeks of starting the Induction Period, which is 
subsequently confirmed, unless the plasma HIV-1 RNA is < 400 c/mL.

Rebound as indicated by two consecutive plasma HIV-1 RNA levels 200 c/mL 
after prior suppression to < 200 c/mL. 

Rebound as indicated by two consecutive plasma HIV-1 RNA that are 
> 0.5 log10 c/mL increase in plasma HIV-1 RNA from the nadir value on study, 
where the lowest HIV-1 RNA value is 200 c/mL.
 
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4.6.2.
Managing Virologic Failure
Inadequate adherence is a common cause for virologic failure, and should be explored as 
a first step in the management of study subjects (e.g., at the first indication of inadequate 
virologic response or rebound).
4.6.2.1.
Suspected Virologic Failure
Upon notification that a subject’s HIV-1 RNA plasma level meets any of the definitions 
of virologic failure, the Investigator should confirm the definition is met by initiating a 
repeat of the HIV-1 RNA assessment.  
The following guidelines should be followed for scheduling confirmatory HIV-1 RNA 
testing in an effort to avoid false-positive results: 

Confirmatory testing should be scheduled 2 to 4 weeks following resolution of 
any intercurrent illness, during which time the subject should receive full dose 
of all IP.

Confirmatory testing should be scheduled at least 4 weeks following any 
immunization, during which time the subject should receive full dose of all IP.

If therapy is interrupted* due to toxicity management, non-compliance, or other 
reasons, confirmatory testing should be scheduled 2 to 4 weeks following 
resumption of full dose of all IP.

The subject should have received full dose of IP for at least 2 weeks at the time 
confirmatory plasma HIV-1 RNA testing is done.
*Note:  treatment interruption guidelines above may not apply for subjects on CAB LA + 
RPV LA treatment.  The study team should be contacted to discuss any treatment 
interruptions for subjects meeting the definition of virologic failure.
In addition, the Investigator should query the subject regarding intercurrent illness, recent 
immunization, or interruption of therapy.  
Sites should contact the study medical monitor to discuss individual subjects, 
whenever necessary.
4.6.2.2.
Confirmed Virologic Failure
Subjects who confirm virologic failure must be discontinued from the study.  However, 
subjects who have received at least one dose of CAB LA or RPV LA prior to confirming 
virologic failure will remain in the study on oral HAART in the Long-Term Follow Up 
Period (see Section 3.2.6).
A plasma sample from the suspected virologic failure visit as well as the first day of the 
Induction Period (Baseline) will be sent for genotypic and phenotypic resistance testing 
and the result made known to the Investigator when available.  A plasma sample from the 
confirmation visit will be obtained for storage.  This sample may be used for possible 
 
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future analyses, e.g. for genotypic and phenotypic analyses of subjects who experience 
virologic failure.
4.7.
Screening Failures
Subjects who do not meet ALL Inclusion, Exclusion and any other eligibility criteria will 
be considered Screen Failures.  Basic study data will be collected for all screened 
subjects including the reason for screen failure.  Subjects are allowed to rescreen once but 
the subject will be assigned a new subject number.  Subjects who are randomized into the 
trial and subsequently withdrawn from the study, for any reason, may not be re-screened.
5.
STUDY TREATMENTS
5.1.
Investigational Product and Other Study Treatment
In this study, investigational product (IP) refers to CAB, CAB LA, RPV and RPV LA.  
These will be supplied by GlaxoSmithKline and Janssen Pharmaceuticals, respectively.  
Epzicom / Kivexa will also be considered IP from Day 1 of the Maintenance Period and 
will be provided by GSK.  
Other antiretrovirals administered in the study as dual background NRTIs (e.g. for 
subjects who are HLA-B*5701 positive or switch due to toxicity) are not considered IP.  
These may be supplied regionally by GSK or reimbursement will be provided.
The contents of the labels will be in accordance with all applicable regulatory 
requirements.
Under normal conditions of handling and administration, investigational product is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to avoid 
direct eye or skin contact and the generation of aerosols or mists. Notify the monitor of 
any unintentional occupational exposure.  A Material Safety Data Sheet (MSDS) 
describing the occupational hazards and recommended handling precautions will be 
provided to site staff if required by local laws or will otherwise be available from GSK 
upon request.
Investigational product and background NRTIs must be stored in a secure area under the 
appropriate physical conditions for the product.  Access to and administration of the 
investigational product and background NRTIs will be limited to the investigator and 
authorised site staff.  Investigational product and background NRTIs must be dispensed 
or administered only to subjects enrolled in the study and in accordance with the 
protocol.
5.1.1.
Cabotegravir (GSK1265744) – Tablet (CAB)
CAB is manufactured by GlaxoSmithKline and is formulated as white to almost white 
oval shaped film coated 30 mg tablets for oral administration, packaged in high density 
polyethylene (HDPE) bottles with desiccant and child-resistant closure that include an 
 
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induction seal. CAB tablets will be packaged in bottles of 30 tablets. Subjects must keep 
all IP in its original pack container. GSK will notify sites if and when data are available 
to support the use of pill boxes.  CAB tablets are to be stored up to 30°C and protected 
from moisture.
5.1.2.
Rilpivirine - Tablet (RPV)
RPV [Edurant Product Information, 2015] is provided by Janssen Research & 
Development, a division of Janssen Pharmaceuticals as 25 mg tablets that are off-white, 
round, biconvex, film-coated and debossed on one side with “TMC” and the other side 
with “25”. RPV is manufactured by Janssen -Cilag S.p.A, Latina, Italy. RPV will be 
provided as globally marketed product, including US and the European Union, and 
overlabeled, packaged in bottles of 30 tablets.  RPV tablets are to be stored at 25°C 
(excursions permitted to 15°-30°C [59°-86°F]) and protected from light.
5.1.3.
Epzicom / Kivexa
ABC/3TC [Epzicom Product Information, 2012] is manufactured by GlaxoSmithKline 
and is supplied as the ABC/3TC fixed dose combination (FDC) oral tablet, which 
contains 600 mg of ABC (as abacavir sulfate) and 300 mg of 3TC. The tablets are 
orange, film-coated, modified capsule-shaped and debossed with GS FC2 on one side 
with no markings on the reverse side. ABC/3TC is packaged in bottles of 30 tablets. 
ABC/3TC will be supplied by GSK as commercial product. ABC/3TC tablets are to be 
stored at 25°C (excursions permitted to 15°-30°C [59°-86°F]).
5.1.4.
Cabotegravir (GSK1265744) – Injectable Suspension (CAB LA)
CAB LA is manufactured by GlaxoSmithKline and is a sterile white to slightly colored 
suspension containing 200 mg/mL of CAB as free acid for administration by 
intramuscular (IM) injection.  The product is packaged in a 3 mL USP Type I glass vial 
with a 13 mm gray stopper and aluminium seal.  Each vial is for single use containing a 
withdrawable volume of 2.0 mL, and does not require dilution prior to administration.  
CAB LA injectable suspension is to be stored at up to 30°C, do not freeze.
CAB LA is composed of cabotegravir free acid, polysorbate 20, polyethylene glycol 
3350, mannitol, and water for injection.
5.1.5.
Rilpivirine – Injectable Suspension (RPV LA)
RPV LA, also named JNJ-16150108-AAA 300 mg/mL Extended Release Suspension for 
Injection (G001), is provided by Janssen Research & Development, a division of Janssen 
Pharmaceuticals as a sterile white suspension containing 300 mg/mL of RPV as free base 
for administration by intramuscular (IM) injection.  The product is packaged in a single 
use 4 mL USP Type I glass vial with a 13 mm grey stopper and aluminium seal. Each 
vial is for single use containing a nominal fill of 2.0 mL, and does not require dilution 
prior to administration but requires refrigeration.  RPV LA injectable suspension is to be 
stored 2-8°C, do not freeze, protected from light and kept in the outer package.
 
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RPV LA is composed of RPV free base, poloxamer 338, sodium dihydrogen phosphate 
monohydrate, citric acid monohydrate, glucose monohydrate, sodium hydroxide, water 
for injection.
5.1.6.
Dosage and Administration
Following is a table of dosing and administration for all treatment arms:
Induction Period (Week -20 through Day 1)
Week -20 to Week (-4)
(2 tablets once daily)
Take 1 X ABC 600 mg / 3TC 300 mg tablet once daily 
Take 1 X CAB 30 mg tablet once daily
Week (-4) to Day 1
(3 tablets once daily)
Take 1 X ABC 600 mg / 3TC 300 mg tablet once daily 
Take 1 X CAB 30 mg tablet once daily
Take 1 X RPV 25 mg tablet once daily

Take with a meal

Take Day 1 doses in the clinic
Maintenance Period (Day 1 to Week 96*)
CAB LA 600 mg + RPV LA 900 mg IM every 8 Weeks (Q8W)
Day 1 – loading dose
(3 injections once)
Receive last dose of Induction regimen
Receive CAB LA 800 mg given as 2 X 2 mL IM injections 
Receive RPV LA 900 mg given as 1 X 3 mL IM injection 
Week 4 – 2nd loading dose
(1 injection once)
Receive CAB LA 600 mg given as 1 X 3 mL IM injections 
(No RPV LA)
Week 8 to Week 88
(2 injections every 8 weeks)
Receive CAB LA 600 mg given as 1 X 3 mL IM injection 
Receive RPV LA 900 mg given as 1 X 3 mL IM injection
CAB LA 400 mg + RPV LA 600 mg IM every 4 Weeks (Q4W)
Day 1 – loading dose
(3 injections once)
Receive last dose of Induction regimen
Receive CAB LA 800 mg given as 2 X 2 mL IM injections 
Receive RPV LA 600 mg given as 1 X 2 mL IM injection 
 
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Week 4 to Week 92
(2 injections every 4 weeks)
Receive CAB LA 400 mg given as 1 X 2 mL IM injection
Receive RPV LA 600 mg given as 1 X 2 mL IM injection
CAB 30 mg + ABC/3TC once daily
Day 1
Receive last dose of Induction regimen
Day 2 to Week 96
(2 tablets once daily)
Take 1 X ABC 600 mg / 3TC 300 mg tablet once daily 
Take 1 X CAB 30 mg tablet once daily
If continuing to Extension Period:
Week 96 to Week 100
(2 tablets once daily)
Take 1 X ABC 600 mg / 3TC 300 mg tablet once daily 
Take 1 X CAB 30 mg tablet once daily
Extension Period (Week 96 +) 
If subject was randomized to the Q8W regimen during the Maintenance Period:
Week 96 plus+
(2 injections every 8 weeks)
Receive CAB LA 600 mg given as 1 X 3 mL IM injection 
Receive RPV LA 900 mg given as 1 X 3 mL IM injection
If switching from Oral Arm and the Optimized Q8W regimen is selected by subject:
Week 100 – 1st loading dose
(2 injections once)
Receive last dose of Maintenance regimen
Receive CAB LA 600 mg given as 1 X 3 mL IM injections 
Receive RPV LA 900 mg given as 1 X 3 mL IM injection
Week 104 – 2nd loading dose
(2 injection once)
Receive CAB LA 600 mg given as 1 X 3 mL IM injections 
Receive RPV LA 900 mg given as 1 X 3 mL IM injection
Week 112 plus+
(2 injections every 8 weeks)
Receive CAB LA 600 mg given as 1 X 3 mL IM injection 
Receive RPV LA 900 mg given as 1 X 3 mL IM injection
 
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If Subject was Randomized to the Q4W regimen during the Maintenance Period:
Week 96 plus+
(2 injections every 4 weeks)
Receive CAB LA 400 mg given as 1 X 2 mL IM injection 
Receive RPV LA 600 mg given as 1 X 2 mL IM injection
If switching from Oral Arm and the Optimized Q4W regimen is selected by subject:
Week 100 – 1st loading dose
(2 injections once)
Receive last dose of Maintenance regimen
Receive CAB LA 600 mg given as 1 X 3 mL IM injections 
Receive RPV LA 900 mg given as 1 X 3 mL IM injection 
Week 104 – 2nd loading dose
(2 injections once)
Receive CAB LA 400 mg given as 1 X 2 mL IM injection 
Receive RPV LA 600 mg given as 1 X 2 mL IM injection
Week 108 plus+
(2 injections every 4 weeks)
Receive CAB LA 400 mg given as 1 X 2 mL IM injection 
Receive RPV LA 600 mg given as 1 X 2 mL IM injection
*Or through Week 100 if eligible to enter the Extension Period.
+until locally approved and commercially available, the subject no longer derives clinical benefit, the subject meets a 
protocol-defined reason for discontinuation or until development of CAB or RPV is terminated
5.1.7.
Dosing Considerations for CAB LA + RPV LA
Vials of CAB LA and RPV LA are each supplied as a suspension and need no further 
dilution or reconstitution.  However, sites should gently invert the vials a few times to re-
suspend sediments and allow bubbles to subside, and then use a syringe to withdraw the 
required volume of suspension for IM injection. Since RPV LA requires refrigeration 
sites should allow the vial to come to approximately room temperature prior to injecting.
All injections must be given intramuscularly in the gluteus medius.  Sites may use their 
discretion as to where in the gluteus muscle each injection is given according to 
individual subject circumstance.  If possible, injections should be spaced approximately 
2 cm from one another, from the site of any previous injection or any injection site 
reaction.  The time and location of injection will be captured in the eCRF.  
IM injections should be administered at a 90 degree angle into the gluteus medius muscle 
using a 1.5” 25 gauge needle for CAB LA and a 1.5” 21 gauge needle for RPV LA in 
most subjects.  The needle should be long enough to reach the muscle mass and prevent 
study drug from seeping into subcutaneous tissue, but not so long as to involve 
underlying nerves, blood vessels, or bone. Variable needle lengths may need to be used 
to accommodate individual body type.  For example, longer needle lengths may be 
required for subjects with higher body mass indexes (BMIs, example > 30), to ensure that 
injections are administered intramuscularly as opposed to subcutaneously.  BMI and 
needle length used will be collected in the eCRF.
On Day 1, subject should be dosed with the IM regimen within 2 hours of taking the last 
Induction regimen dose where possible.  The same should apply to subjects switching 
from the oral regimen to an IM regimen at Week 100.
 
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Should the subject have intolerance to the single 3 mL injection, the injection may be 
administered as 2 separate 1.5 mL injections with the assent of the medical monitor.  If 
the injection is split, this will be noted in the eCRF and the intolerance captured as an 
AE.
Should IM maladministration be suspected at any time (e.g. suspected under or overdose 
or inadvertent IV dosing), the investigator may consider requesting the subject stay onsite 
for up to 2 hours post dose for safety monitoring and notifying the medical monitor.  An 
ECG or any other supportive testing may be obtained at the discretion of the investigator.
Additionally, a PK sample may be drawn approximately 2 hours post dosing for future 
evaluation of CAB and RPV concentrations.
Additional dosing instructions and considerations can be found in the SPM.
5.2.
Treatment Assignment
Subjects will be assigned to study treatment in accordance with the randomization 
schedule.
Following completion of the Induction Period, subjects eligible to enter the Maintenance 
Period will be randomized 2:2:1 to Q8W or Q4W of CAB LA + RPV LA or to the oral 
control arm (CAB 30 mg + ABC/3TC).  Randomization will be stratified by HIV-1 RNA 
result before Week (-8) (<50 c/mL yes or no).  Randomization will be conducted via a 
central randomization procedure. The central randomization schedule, including 
stratification, will be generated using the GSK validated randomization software 
RANDALL. Study site personnel will be required to call the central randomization 
service for assignment of a unique identifier (designating the subject’s randomization 
code and treatment sequence assignment) for each subject participating in the study. A 
unique treatment number will be assigned for each subject participating in the study.
5.3.
Blinding
This study is not blinded.
5.4.
Product Accountability
In accordance with local regulatory requirements, the investigator, designated site staff, 
or head of the medical institution (where applicable) must document the amount of 
investigational product dispensed and/or administered to study subjects, the amount 
returned by study subjects, and the amount received from and returned to GSK, when 
applicable.  Product accountability records must be maintained throughout the course of 
the study.
5.5.
Treatment Compliance
Treatment compliance will be evaluated using pill counts of unused IP (CAB 30 mg and 
RPV 25 mg tablets). This assessment will be conducted each time the subject receives a 
 
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new (refill) supply of oral study medication.  Additionally, the date and time of each 
injection of CAB LA and RPV LA will be noted.  These data will be recorded in the 
subject’s eCRF.
Treatment compliance will not be assessed during the Long-Term Follow-Up Period.
Due to the long acting nature of the CAB and RPV, it will be imperative that the subject 
is compliant with dosing instructions.  Subject awareness and knowledge of these dosing 
instructions will be assessed by reviewing the answers to the HIVMQ as discussed in 
Section 6.14.  
Investigators must have plans in place for adherence counselling.  In addition, 
Investigators must have plans in place to perform visit reminders and to verify the 
subject’s contact information at each visit.
5.6.
Protocol Permitted Substitutions
Subjects who are HLA-B*5701 positive at the Screening visit are allowed to enter the 
study on an approved dual-NRTI backbone that does not contain ABC (e.g. TDF/FTC).  
This regimen may be supplied regionally by GSK or reimbursement will be provided.
Switch of background NRTI therapy to an alternative approved NRTI therapy for toxicity 
or tolerability management is allowed once during the study. Switches of a background 
NRTI for any other reason are not permitted in the study. The date of the decision to 
switch background NRTI for toxicity or tolerability management must be documented in 
the eCRF.
If a subject needs to change background NRTI therapy for toxicity management, an 
alternative FDC (e.g. TDF/FTC) should be considered first.  If this switch is not possible 
or appropriate, alternative approved dual NRTI therapy may be considered after 
consultation with the study medical monitor.  This regimen may be supplied regionally
by GSK or reimbursement will be provided.
Local prescribing information should be consulted for information regarding use of these 
medications.  
NOTE:  When applying the MSDF algorithm (also known as the Snapshot algorithm), 
subjects switching background NRTIs after Week 2 may be considered a non-responder, 
however, these subjects will be allowed to continue in the study.
5.6.1.
Oral Bridging
In exceptional circumstances, the medical monitor may authorize the use of oral CAB 
30 mg and/or RPV 25 mg as a short-term “bridging” strategy for subjects who have 
begun CAB LA + RPV LA.  This strategy would only be employed to address any 
potential gap in CAB LA + RPV LA dosing as a result of unexpected scheduling 
conflicts which would prevent planned dosing.  Should a subject need “oral bridging”, 
sites must contact the medical monitor for authorization and guidance for treatment 
 
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strategies prior to a missed CAB LA + CAB LA dose.  Should a subject not notify the 
site in advance, the medical monitor must be contacted for further treatment guidance.
5.7.
Interruption of Study Treatment and Visit/Dosing Windows
IP or background NRTI may be interrupted at the discretion of the Investigator in the 
event of an AE, according to the severity of the AE.
If one or more antiretroviral medications is held due to toxicity or adverse events, all 
antiretroviral medications must be held to reduce the risk of development of resistance 
taking into account both the length of the planned interruption and the pharmacokinetic 
half-life of each antiretroviral of the regimen, in a way to minimize the risk of 
development of resistance.
It is important to note that keeping to the subject’s visit schedule is a very important 
component to the study.  
Note: All decisions regarding dose interruption / resumption must be discussed with 
the medical monitor in advance.
5.7.1.
Oral Dosing Including Long Term Follow Up
Visits for subjects on the oral dosing arm are expected to occur as projected according to 
the Baseline visit.  There is a (+ or -) 3 day visit window, from the projected visit date.  
However, the number of tablets dispensed should be considered when scheduling the next 
visit.
Any interruption in therapy (scheduling conflicts, life circumstances, etc) during any oral 
dosing period that is greater than 7 consecutive days must be discussed with the medical 
monitor prior to resumption of therapy.  The medical monitor must be contacted upon site 
staff becoming aware of resumption in therapy, if therapy was resumed without prior 
approval.
Visits for subjects in Long Term Follow Up are expected to occur as projected according 
to the last injection.  There is a (+ or -) 3 day visit window, from the projected visit date.  
5.7.2.
IM Dosing
Subjects receiving CAB LA and/or RPV LA are anticipated to be at high risk for 
development of virologic resistance if ART is interrupted.  The time period during which 
subjects are at risk for development of virologic resistance may be determined by the 
period between when drug levels fall below therapeutic values and when they fall below 
levels which exert selective pressure on HIV.  This time period will vary by ART agent 
and is dependent upon effective concentration, inhibitory concentration and half-life. 
Plasma concentrations of both drugs may be measurable for approximately 52 weeks 
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IM dosing is expected to occur during the week in which the subject’s projected visit falls 
(as according to the Day 1 visit).  An additional (+ or -) 7 day window, from the projected 
visit date, is allowable for IM dosing but not preferred.  At one-week post dose visits 
(Week 1, Week 25, and Week 41), there is no defined visit window, rather visits should 
occur approximately 1 week from the last injection.

Dosing may occur without consultation from the medical monitor if performed 
within the (+ or -) 7 day window.  

Any request for the visit/dosing to occur outside of the allowed window must be 
discussed and agreed with the medical monitor prior to dosing.  In the event of a 
late dose, a revised dosing schedule for subsequent dosing may be required and 
will be communicated to the site staff at the time of approval for continued 
dosing.  Temporary switch to oral dosing of CAB 30 mg and/or RPV 25 mg may 
be an option based on individual subject circumstance as described in Section 
5.6.1.  

See the SPM for scheduling guidance and further information and examples.
Note: All decisions regarding dose interruption/ resumption must be discussed with 
the medical monitor in advance.
5.8.
Discontinuation of Study Treatment
Subjects unable to manage drug toxicity or tolerate investigational product must have IP 
discontinued.
5.8.1.
Discontinuation of ABC/3TC
In the event of a discontinuation of an ABC-containing product for any reason, re-
initiation of this drug should be undertaken with caution. Health care providers should 
obtain a complete history of the events surrounding the discontinuation of the ABC-
containing product. If there are symptoms consistent with a hypersensitivity reaction, 
ABC must not be reinitiated. If there is no evidence of a prior reaction, the subject may 
restart treatment with the ABC-containing product. The subject and health care provider 
must be aware of the possibility of a rapid-onset hypersensitivity reaction upon 
reinitiation of ABC, which may be life-threatening or fatal, and the subject must be able 
to, if necessary, receive prompt medical evaluation (see also Section 6.10.6.14).
5.8.2.
Discontinuation of CAB LA or RPV LA
Any subject receiving at least one dose of CAB LA and /or RPV LA who discontinue IP / 
Withdraw will initiate treatment with HAART enter the Long-Term Follow-Up Period 
for 52 weeks of follow up (see Section 5.8.2).
 
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5.9.
Concomitant Medications and Non-Drug Therapies
Concomitant medications (prescription and non-prescription) should be administered 
only as medically necessary during the study. Subjects must be advised to 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.
5.9.1.
Permitted Medications and Non-Drug Therapies
Chemoprophylaxis for HIV-associated conditions is encouraged, if appropriate, at the 
discretion of the subject and their physician. All concomitant medications, blood 
products, and vaccines taken during the study will be recorded in the eCRF with dates of 
administration.
Because non-HIV vaccines may cause a temporary increase in the level of plasma HIV-1 
RNA, it is recommended that a vaccine, if necessary, be given during or immediately 
after a scheduled visit after all laboratory tests have been drawn. This approach will 
minimize the risk of non-specific increases in the level of plasma HIV-1 RNA at the next 
scheduled assessment.
Other IM injectables (with exceptions below) are permitted but must be administered
away from the site of IP administration.
Oral administration only: Antacid products containing divalent cations (e.g., aluminium, 
calcium and magnesium) must be taken at least 2 hours before or at least 4 hours after 
CAB and RPV, and H2-antagonists must be taken at least 12 hours before or at least 4 
hours after taking CAB and RPV.
Concurrent administration of multivitamins is acceptable.
5.9.2.
Prohibited Medications and Non-Drug Therapies
HIV immunotherapeutic vaccines are not permitted at any time during the study. 
Other experimental agents, antiretroviral drugs not otherwise specified in the protocol, 
cytotoxic chemotherapy, or radiation therapy may not be administered (see Exclusion 
Criteria #24, Section 4.3). 
Systemically administered immunomodulators are prohibited.
Acetaminophen cannot be used in patients with acute viral hepatitis.
Chronic use of oral glucocortioids must be avoided; however, short treatment courses 
(e.g., 10 days or less) and topical, inhaled or intranasal use of glucocortioids will be 
allowed.
 
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Hepatitis C infection therapy is allowed during the study, but interferon-based HCV 
therapy is prohibited throughout the entire study.  Options for treatment of hepatitis C 
must be discussed with the Medical Monitor prior to initiation of therapy.
For information on concurrent therapies and interactions suspected to be relevant to other 
antiretroviral therapy in the regimen (e.g. Epzicom / Kivexa), please consult the local 
prescribing information.
5.9.2.1.
Concurrent with CAB and/or RPV
For subjects receiving either formulation of CAB and/or RPV, the following 
medications could significantly decrease the levels of CAB and/or RPV due to enzyme 
induction and therefore must not be administered concurrently: 

Carbamazepine

Oxcarbazepine

Phenobarbital 

Phenytoin

Rifabutin

Rifampicin / Rifampin

Rifapentine

St. John’s wort
5.9.2.2.
Concurrent with RPV
In addition, subjects must discontinue the following (or change to an allowable 
alternative) while receiving treatment with oral RPV:

proton pump inhibitors, such as esomeprazole, lansoprazole, omeprazole, 
pantoprazole, rabeprazole;

systemic dexamethasone (more than a single dose).
If the subject cannot discontinue use or change to an allowable alternative while 
receiving treatment with RPV, the subject should not be randomized into the study.
5.9.2.3.
Concurrent with either CAB LA or RPV LA
In addition, for subjects receiving CAB LA and RPV LA, use of anticoagulation agents 
greater than 14 days are prohibited and systemic anticoagulation on the day of an IM 
injection should be avoided where possible.
 
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5.10.
Treatment after the End of the Study
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the patient’s medical condition whether or not GSK is providing specific 
post study treatment.
All subjects who successfully complete the Maintenance Period will be considered for 
inclusion in the Extension Period (see Section 3.2.5).
5.10.1.
Long-Term Follow-Up Period
Any subject who receives at least a single dose of CAB LA and/or RPV LA and 
discontinues the CAB LA + RPV LA regimen will enter the Long-Term Follow-Up 
Period (see Section 3.2.6).  Since these subjects are anticipated to be at high risk for the 
development of virologic resistance if ART is interrupted, they must switch to an 
Investigator selected HAART regimen and remain on study for at least 52 weeks 
following their last dose of CAB LA and / or RPV LA. 
Investigators must discuss choice of HAART regimen and timing of initiation with 
the medical monitor before initiating.  Subjects will continue to be dosed according to 
the agreed regimen selection for 52 weeks.
GSK may supply HAART regionally or reimbursement will be provided
5.11.
Treatment of Study Treatment Overdose
For subjects receiving CAB, any tablet intake exceeding a total daily dose of 30 mg will 
be considered an overdose. For subjects receiving RPV, any dose exceeding a total daily 
dose of 25 mg will be considered an overdose. For subjects receiving Epzicom / Kivexa, 
any tablet intake exceeding the protocol defined daily number of tablets (one tablet daily) 
will be considered an overdose.  
For CAB LA and RPV LA, any single dose in excess of the studied doses will be 
considered an overdose.  
Should IM maladministration be suspected at any time (e.g. suspected under or overdose 
or inadvertent IV dosing), the investigator may consider requesting the subject stay onsite 
for up to 2 hours post dose for safety monitoring and notifying the medical monitor.  An 
ECG or any other supportive testing may be obtained at the discretion of the investigator.
Additionally, a PK sample may be drawn approximately 2 hours post dosing for future 
evaluation of CAB and RPV concentrations.
For the purposes of this study, an overdose is not an AE (refer to Section 6.10.4.1 ) unless 
it is accompanied by a clinical manifestation associated with the overdose. If the clinical 
manifestation presents with serious criteria, the event is a SAE (see Section 6.10.4.2).
If an overdose occurs and is associated with an adverse event requiring action, all study 
medications must be temporarily discontinued until the adverse event resolves. 
The Investigator should use clinical judgement in treating overdose, as GSK is unable to 
recommend specific treatment.
 
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6.
STUDY ASSESSMENTS AND PROCEDURES
6.1.
Time and Events Table – Induction Period
Procedures  for Induction
Screening 
Period a
Baseline / 
Week (-20) 
Week 
(-16) 
Week
(-12)
Week
(-8)
Week
(-4)
WD
Notes 
Written Informed Consent 
X
a.
Complete all Screening assessments within 28 days.  
Subjects may begin the Induction Period as soon as all 
Screening assessments are complete.  Subjects may 
be rescreened once and will be assigned a new 
subject number.
b.
Physical exams should be conducted as part of normal 
routine clinical care but data will not be collected in the 
eCRF. Medical assessments include any decisions the 
study staff must make for subject management and / 
or care. 
c.
Height collected at Baseline only.
d.
Measure vital signs after about 5 minutes of rest in a 
semi-supine position.
e.
Perform ECG at Baseline in triplicate prior to dosing; 
preferably 2 – 4 hours post dosing for all other visits.
f.
Collect full routine medical history plus (report at 
Baseline visit): HIV risk factors (may be collected at a 
later study visit), cardiovascular risk factors 
(assessments include smoking status and history, 
family history of cardiac events), recent [6 months] 
illicit drug use, intravenous drug use, gastrointestinal 
disease, metabolic, psychiatric, renal and neurologic 
disorders.
g.
Collect SAEs at Screen only if associated to study 
participation.
h.
Confirmation of eligibility to enter the Maintenance 
Period.  See Section 3.2.3.
Demography
X
Eligibility Verification
X
X
X h
Physical Exam b
X
Symptom Directed Physical Exam and 
Medical Assessment b
X
X
X
X
X
X smoking 
status also
Weight and Height c
X
X
Vital Signs (BP, HR) d
X
X
X
X
12-Lead ECG e
X
X pre-dose x3
X
X
Medical History f
X
Medication History / Prior ART History
X
CDC Classification
X
X
HIV Associated Conditions
X
X
X
X
X
AE and SAE Assessment, Con Meds
X g
X
X
X
X
X
X
 
 
 
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Procedures  for Induction
Screening 
Period a
Baseline / 
Week (-20) 
Week 
(-16) 
Week
(-12)
Week
(-8)
Week
(-4)
WD
Notes 
Columbia Suicide Severity Rating Scale 
(eC-SSRS) i
X
X
X
X
X
X
X
i.
Preferably completed at the beginning of the visit.
j.
Collect for women of childbearing potential only.  A 
negative urine pregnancy test is required prior to 
beginning the Induction Period. S=Serum/U=Urine
k.
Plasma for storage will be used: to determine 
genotypic eligibility at Screen, for possible future 
analyses, as back- up in case samples are lost or 
damaged in transit to the lab and for genotypic and 
phenotypic analyses in cases of virologic failure.
l.
Overnight fast is preferred; however, a minimum of a 6 
hour fast is acceptable.
m.
Collect pharmacogenetics (PGx) sample at Baseline.  
May be collected later during the study if necessary.
HIVTSQ(s) i
X
X
X
HIVMQ
X 
Clinical Chemistry 
and Hematology
X
X
X
X
X
X
X
Pregnancy Testing j
S
U
S
S
S
S
S
HIV-1 RNA and sample for storage k 
Xand genotype
X
X
X
X
X
X
CD4+ 
X
X
X
X
X
X
CD8+
X
X
Urinalysis 
X
X
X
Fasting Lab Assessments:  Glucose, 
Cholesterol (Total, HDL and LDL) and 
Triglycerides l
X
X
X
Hepatitis B (HBsAg) and Hepatitis C 
(anti-HCV Ab), HLA-B*5701
X
PT/PTT/INR
X
X
PGx m
X
 
 
 
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Procedures  for Induction
Screening 
Period a
Baseline / 
Week (-20) 
Week 
(-16) 
Week
(-12)
Week
(-8)
Week
(-4)
WD
Notes 
PK Sample 
(S)torage
S
n.
Instruct subjects to continue to take the Induction 
regimen (including RPV) through Day 1 of the 
Maintenance Period.  Subjects should be reminded to 
take the Day 1 dose in the clinic for PK sampling and 
return the PK diary.  The PK diary will be completed by 
all subjects in case they are randomized to continue on 
the CAB 30 mg + ABC/3TC arm.
o.
Remind subjects of the potential change in study 
treatment and visit frequency beginning at Day 1.
Study Treatment Dispensation 
X
X
X
X
X n
Add RPV 
Study Treatment Accountability
(pill counts)
X
X
X
X
X
PK Diary Dispensation
X n
Subject Visit Reminder Contact
X
X
X
X
X
X o
X
Subject Contact Detail Confirmation
X
X
X
X
X
X
Follow Up Visit:  Conduct approximately 4 weeks after the last dose of IP.  Required only if the subject has ongoing AEs or 
lab abnormalities at the last on-study visit.  This visit may be conducted by telephone.
 
 
 
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6.2.
Time and Events Table – Maintenance Period for IM Regimen (CAB LA+RPV LA Q8W)
Procedures
For Maintenance 
– Q8W  regimen
D1
W
1
W
4
W
8
W
12
W
16
W
20
W
24
W 
25
W
28
W
32
W
36
W
40
W 
41
W
44
W
48
W
52
W
56
W
60
W
64
W
68
W
72
W
76
W
80
W
84
W
88
W
92
W
96
WD
p
Verify Eligibility 
X
Randomization
X
Symptom Directed 
PE, ISR & Medical 
Assessment a
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 
and 
smoking 
status
Vital Signs
(BP, HR) b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight and BMI
X
X
X
X
X
ECG c
Xpre
X
X
X
X
Xc
Xc
X
X
X
X
HIV Associated 
Conditions, AE 
and SAE 
Assessment, Con  
Meds 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ISR Diary 
(D)aily/(E)pisodic)d
D
E
E
E
E
E
E
D
E
E
E
E
D
E
E
E
E
E
E
E
E
E
E
Exercise Habit 
Assessment e
X
X
X
eC-SSRS f
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HIVTSQ(s) g
Xpre
X
X
X
X
X
HIVTSQ(c) g
X
X
HIVMQ g
X
X
X
X
X g
 
 
 
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Procedures
For Maintenance 
– Q8W  regimen
D1
W
1
W
4
W
8
W
12
W
16
W
20
W
24
W 
25
W
28
W
32
W
36
W
40
W 
41
W
44
W
48
W
52
W
56
W
60
W
64
W
68
W
72
W
76
W
80
W
84
W
88
W
92
W
96
WD
p
Clinical Chemistry 
and Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test 
(U)rine/(S)erum h
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
S
HIV-1 RNA &
sample for 
storagei
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CD4+
X
X
X
X
X
X
X
X
X
X
X
CD8+
X
X
X
X
Urinalysis 
X
X
X
X
X
X
Fasting:  Glucose,  
Cholesterol (Total, 
HDL and LDL) 
and 
Triglycerides j
X
X
X
X
X
X
X
PT/PTT/INR
X
X
X
X
X
PK Sample 
(S)torage k
X k
X 
X
X
X
X
X
X
X 
X
Xk
X
X
X 
X
Xk
S
S
S
S
S
S
X
Study Treatment 
Administration m
X l
X
X
X
X
X
X
X
X
X
X
X
X
Xn
Visit Reminder 
Contact
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Subject Contact 
Confirmation
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
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D=Day     W=Week    Pre=Pre-dosing   PE = Physical Exam  BMI=Body Mass Index
Gray shading indicates telephone safety assessments that will include interviewing the 
subject for adverse events, concomitant medications, HIV associated conditions and any 
other issues including injection site reactions.
a)
Physical exams should be conducted as part of normal routine clinical care but data will not 
be collected in the eCRF. Medical assessments include any decisions the study staff must 
make for subject management and/or care of the subject.  See Section 6.10.1 for ISR 
assessment requirements.
b)
Measure vital signs after about 5 minutes of rest in a semi-supine position.
c)
12-Lead ECG – Conduct pre-dose at Day 1.  At all other visits, the ECG may be done at any 
time during the visit. At Week 32 and Week 48, a second ECG will be obtained 
approximately 2 hours after the last injection and just prior to the 2 hour post dose PK 
sampling.
d)
Subjects will complete a (D)aily diary of injection site reactions from Day 1 to Week 1, from 
Week 24 to Week 25 and again from Week 40 to Week 41.  At all other visits subjects will 
complete a diary only if the subject experiences a reaction ((E)pisodic).  Subjects will be 
dispensed a new diary at each visit. Diary data will be entered into the eCRF.
e)
Subject’s exercise habits will be assessed daily from Day 1 to Week 1, from Week 24 to 
Week 25 and again from Week 40 to Week 41.  Assessments will include type and duration 
of cardiovascular exercise and duration of any strength or other strenuous exercises. This 
information will be collected via the daily ISR diary and entered into the eCRF.
f)
Preferably completed at the beginning of the visit. 
g)
Conduct the HIVTSQ(s) at Day 1 pre-dosing; at all other visits conduct post-dosing.  
Conduct the HIVTSQ(c, WD) at WD ONLY if the subject WD between Week 8 and Week 32.  
Conduct the HIVMQ post injection.
h)
Women of childbearing potential only.  A (-) urine pregnancy test is required prior to any 
injection and as required by medical monitor after a treatment interruption. A positive urine 
test should be confirmed with a stat serum test.  If positive, subject will need to be WD.
i)
Plasma for storage samples collected for possible analyses, back-up in case samples are 
lost or damaged in transit to lab, for geno/pheno analyses and virologic failures.
j)
Fast overnight; however, a minimum of a 6 hour fast is acceptable.
k)
Take PK samples pre-dose except Weeks 1, 12, 20, 25, 28, 36, 41 and 44 which can be 
taken at any time during the visit.  Day 1 PK sample should be taken after review of PK 
diary and pre-dose of CAB 30 mg+ABC/3TC+RPV 25 mg.  A second Day 1, Week 32 
and Week 48 PK sample will be collected approximately 2 hours after the last injection.
l)
Subjects should take CAB 30 mg+ABC/3TC+RPV 25 mg on Day 1 in the clinic after PK 
sampling and injections should be administered within 2 hours of this where possible.  
m)
Subjects will take final dose of Induction regimen in the clinic at Day 1 and begin 
injections.   Day 1 injections are 2 x CAB LA 400 mg IM + 1 x RPV LA 900 mg IM.    
Week 4 injection is 1 x CAB LA 600 mg IM (no RPV LA).  At Week 8 and Q8W, 
injections are 1 x CAB LA 600 mg IM + 1 x RPV LA 900 mg IM.  If possible, injections 
should be spaced approximately 2 cm from one another and from the site of any 
previous injection and or any injection site reaction.  Bring RPV LA to approximately 
room temperature prior to injecting.  Time and location of injection (right or left) as well 
as needle length used will be collected in the eCRF.  IM dosing expected to occur 
during week subject’s projected visit falls (as according to the Day 1 visit).  An 
additional (+ or -) 7 day window, from date of projected visit, is allowable for IM 
dosing but not preferred.  All decisions regarding dose interruption/ resumption 
must be discussed with the Medical Monitor in advance.  
n)
Subjects will continue to receive their Maintenance Period dosing regimen in the 
Extension period (Q8W) at this visit.  
o)
Subjects who WD must enter Long-Term Follow Up (see Section 3.2.6) instead of 
completing the WD visit.  If they cannot enter Long-Term Follow-Up complete WD and 
Follow Up assessments.
p)
Follow Up Visit:  Conduct approximately 4 weeks after the last dose of IP.  Required for 
subjects not entering Long-Term Follow Up and only if the subject has ongoing AEs or 
lab abnormalities at the last on-study visit.  This visit may be conducted by phone.
 
 
 
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6.3.
Time and Events Table – Maintenance Period for IM Regimen (CAB LA+RPV LA Q4W)
Procedures
For Maintenance 
– Q4W  regimen
D1
W
1
W
4
W
8
W
12
W
16
W
20
W
24
W 
25
W
28
W
32
W
36
W
40
W 
41
W
44
W
48
W
52
W
56
W
60
W
64
W
68
W
72
W
76
W
80
W
84
W
88
W
92
W
96
WD
p
Verify Eligibility 
X
Randomization
X
Symptom 
Directed PE, ISR 
& Medical 
Assessment a
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 
and 
smokin
g status
Vital Signs
(BP, HR) b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight and BMI
X
X
X
X
X
ECG c
Xpre
X
X
X
X
Xc
Xc
X
X
X
X
HIV Associated 
Conditions, AE 
and SAE 
Assessment, Con  
Meds 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ISR Diary 
(D)aily/(E)pisodicd
D
E
E
E
E
E
E
D
E
E
E
E
D
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
Exercise Habit 
Assessment e
X
X
X
eC-SSRS f
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HIVTSQ(s) g
Xpre
X
X
X
X
X
HIVTSQ(c) g
X
X
HIVMQ g
X
X
X
X
X g
 
 
 
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Procedures
For Maintenance 
– Q4W  regimen
D1
W
1
W
4
W
8
W
12
W
16
W
20
W
24
W 
25
W
28
W
32
W
36
W
40
W 
41
W
44
W
48
W
52
W
56
W
60
W
64
W
68
W
72
W
76
W
80
W
84
W
88
W
92
W
96
WD
p
Clinical Chemistry 
and Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test 
(U)rine/(S)erum h
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
S
HIV-1 RNA &
sample for 
storagei
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CD4+
X
X
X
X
X
X
X
X
X
X
X
CD8+
X
X
X
X
Urinalysis 
X
X
X
X
X
X
Fasting:  Glucose,  
Cholesterol (Total, 
HDL and LDL) 
and 
Triglycerides j
X
X
X
X
X
X
X
PT/PTT/INR
X
X
X
X
X
PK Sample 
(S)torage k
X 
X 
X
X
X
X
X
X
X 
X
Xk
X
X
X 
X
Xk
S
S
S
S
S
S
X
Study Treatment 
Administration m
X l
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xn
Visit Reminder 
Contact
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xo
X
X
Subject Contact 
Confirmation
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
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D=Day     W=Week    Pre=Pre-dosing   PE = Physical Exam  BMI=Body Mass Index
a)
Physical exams should be conducted as part of normal routine clinical care but data will not 
be collected in the eCRF. Medical assessments include any decisions the study staff must 
make for subject management and/or care of the subject.  See Section 6.10.1 for ISR 
assessment requirements.
b)
Measure vital signs after about 5 minutes of rest in a semi-supine position.
c)
12-Lead ECG – Conduct pre-dose at Day 1.  At all other visits, the ECG may be done at any 
time during the visit. At Week 32 and Week 48, a second ECG will be obtained 
approximately 2 hours after the last injection and just prior to the 2 hour post dose PK 
sampling.
d)
Subjects will complete a (D)aily diary of injection site reactions from Day 1 to Week 1, from 
Week 24 to Week 25 and again from Week 40 to Week 41.  At all other visits subjects will 
complete a diary only if the subject experiences a reaction ((E)pisodic).  Subjects will be 
dispensed a new diary at each visit. Diary data will be entered into the eCRF.
e)
Subject’s exercise habits will be assessed daily from Day 1 to Week 1, from Week 24 to 
Week 25 and again from Week 40 to Week 41.  Assessments will include type and duration 
of cardiovascular exercise and duration of any strength or other strenuous exercises. This 
information will be collected via the daily ISR diary and entered into the eCRF.
f)
Preferably completed at the beginning of the visit. 
g)
Conduct the HIVTSQ(s) at Day 1 pre-dosing; at all other visits conduct post-dosing.  
Conduct the HIVTSQ(c, WD) at WD ONLY if the subject WD between Week 8 and Week 32.  
Conduct the HIVMQ post injection.
h)
Women of childbearing potential only.  A (-) urine pregnancy test is required prior to any 
injection and as required by medical monitor after a treatment interruption. A positive urine 
test should be confirmed with a stat serum test.  If positive, subject will need to be WD.
i)
Plasma for storage samples collected for possible analyses, back-up in case samples are 
lost or damaged in transit to lab, for geno/pheno analyses and virologic failures.
j)
Fast overnight; however, a minimum of a 6 hour fast is acceptable.
k)
Take PK samples pre-dose except Week 1, Week 25 and Week 41 which can be taken 
at any time during the visit.  Day 1 PK sample should be taken after review of PK diary 
and pre-dose of CAB 30 mg+ABC/3TC+RPV 25 mg.  A second Day 1, Week 32 and 
Week 48 PK sample will be collected approximately 2 hours after the last injection.
l)
Subjects should take CAB 30 mg+ABC/3TC+RPV 25 mg on Day 1 in the clinic after PK 
sampling and injections should be administered within 2 hours of this where possible.  
m)
Subjects will take final dose of Induction regimen in the clinic at Day 1 and begin 
injections.   Day 1 injections are 2 x CAB LA 400 mg IM + 1 x RPV LA 600 mg IM.  At 
Week 4 and Q4W, injections are 1 x CAB LA 400 mg IM + 1 x RPV LA 600 mg IM.  If 
possible, injections should be spaced approximately 2 cm from one another and from 
the site of any previous injection and or any injection site reaction.  Bring RPV LA to 
approximately room temperature prior to injecting.   Time and location of injection (right 
or left) as well as needle length used will be collected in the eCRF.  IM dosing is 
expected to occur during the week in which the subject’s projected visit falls (as 
according to the Day 1 visit).  An additional (+ or -) 7 day window, from date of 
projected visit, is allowable for IM dosing but not preferred.  All decisions 
regarding dose interruption/ resumption must be discussed with the medical 
monitor in advance. 
n)
Subjects will continue to receive their Maintenance Period dosing regimen in the 
Extension period (Q4W) at this visit.  
o)
Subjects who WD must enter Long-Term Follow Up (see Section 3.2.6) instead of 
completing the WD visit.  If they cannot enter Long-Term Follow-Up complete WD and 
Follow Up assessments.
p)
Follow Up Visit:  Conduct approximately 4 weeks after the last dose of IP.  Required for 
subjects not entering Long-Term Follow Up and only if the subject has ongoing AEs or 
lab abnormalities at the last on-study visit.  This visit may be conducted by phone.
 
 
 
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6.4.
Time and Events Table – Maintenance Period for Oral Regimen (CAB 30 mg+ABC/3TC)
Procedures For 
Maintenance –
ORAL regimen
D1
W
4
W
8
W
12
W
16
W
20
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
52
W
56
W
60
W
64
W
68
W
72
W
76
W
80
W
84
W
88
W
92
W
96
WD p
Verify Eligibility 
X
X k
Randomization
X
Symptom 
Directed PE & 
Medical 
Assessment a
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X and smoking 
status
Vital Signs
(BP, HR) b
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight and BMI c
X
X
X
X
X
ECG c
X
pre
X
X
X
X
X
X
X
X
X
HIV Associated 
Conditions, AE 
and SAE 
Assessment, Con  
Meds 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK Diary 
(D)ispensation 
and (R)eview d
R
D
R
D
R
D
eC-SSRS e
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
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Procedures For 
Maintenance –
ORAL regimen
D1
W
4
W
8
W
12
W
16
W
20
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
52
W
56
W
60
W
64
W
68
W
72
W
76
W
80
W
84
W
88
W
92
W
96
WD p
HIVTSQ(s) f
X
pre
X
X
X
X
X
HIVTSQ(c) f
X
X
HIVMQ f
X
X
X
X
X f
Clinical Chemistry 
and Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test 
(S)erum/(U)rine g
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
HIV-1 RNA &
sample for 
storage h
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X m
X
CD4+
X
X
X
X
X
X
X
X
X
X
X
CD8+
X
X
X
X
Urinalysis
X
X
X
X
X
X
Fasting:  Glucose, 
Insulin, 
Cholesterol 
(Total, HDL and 
LDL) and 
Triglycerides i
X
X
X
X
X
X
X
PT/PTT/INR
X
X
X
X
X
PK Sample j
X 
X
X
S
X
 
 
 
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Procedures For 
Maintenance –
ORAL regimen
D1
W
4
W
8
W
12
W
16
W
20
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
52
W
56
W
60
W
64
W
68
W
72
W
76
W
80
W
84
W
88
W
92
W
96
WD p
Study Treatment 
Dispensation and 
Accountability n
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X q
Study Treatment
Administration 
Visit Reminder 
Contact
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xo
Xl,o
X
Subject Contact 
Confirmation
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xl
X
D=Day     W=Week    Pre=Pre-dosing  PE = Physical Exam   BMI=Body Mass Index
Gray shading indicates telephone safety assessments that will include interviewing the subject for 
adverse events, concomitant medications, HIV associated conditions and any other issues 
including compliance. 
a.
Physical exams should be conducted as part of normal routine clinical care but data will not 
be collected in the eCRF. Medical assessments include any decisions the study staff must 
make for subject management and/or care of the subject.
b.
Measure vital signs after about 5 minutes of rest in a semi-supine position.
c.
12-Lead ECG – Conduct pre-dose at Day 1.  At all other visits, it is preferable to conduct 2 – 4 
hours after dosing.
d.
Review PK diary at the beginning of the visit to verify time of last dose.  PK samples must be 
collected within the window of 20-28 hours after the last dose taken.  Contact the study team 
for guidance in cases when subject’s last dose is not within window.  Visit may need to be 
rescheduled.
h.
Plasma for storage samples are collected for possible future analyses, as 
back- up in case of lost or damaged in transit to the lab and for geno/pheno 
analyses for virologic failures
i.
Fast overnight; however, a minimum of a 6 hour fast is acceptable.
j.
All PK samples should be taken pre-dose within 20-28 hours after the last 
dose of IP taken.  Subjects will take their dose of IP in the clinic at PK visits. 
S=Storage
k.
Assess subject’s willingness to continue on to the Extension Period.  If not 
continuing into the Extension Period, this is the subject’s last study visit.
l.
For subjects continuing into the Extension Period only.  
m.
The Week 96 HIV-1 RNA result (or single re-test prior to Week 100) must be 
<50 c/mL to be eligible to continue into the Extension Period.  See Section 
3.2.5.2.  Subjects ineligible for Extension will end their study participation at 
Week 96 (withdrawal visit needed).
 
 
 
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e.
Preferably completed at the beginning of the visit.  
f.
Conduct the HIVTSQ(s) at Day 1 prior to dosing and post dosing where possible at all other 
visits.  Conduct the HIVTSQ(c, WD) at WD ONLY if the subject WD between Week 8 and 
Week 32.  Conduct the HIVMQ preferably at the beginning of the visit, but may be completed 
at any time during the visit.
g.
Women of childbearing potential only. A (-) urine pregnancy test is required prior to any 
injection and as required by medical monitor after a treatment interruption. A positive urine 
test should be confirmed with a stat serum test.  If positive, subject will need to be WD.
n.
Subjects will discontinue RPV at Day 1 and begin taking 1 x CAB 30 mg + 1 
x ABC/3TC tablet once daily. At Week 96, while awaiting eligibility for 
Extension, subjects will continue their CAB 30 mg+ABC/3TC regimen.  
o.
Remind subjects of the change in study and assessments for eligibility into 
Extension.
p.
Follow Up Visit:  Conduct approximately 4 weeks after the last dose of IP.  
Required only if the subject has ongoing AEs or lab abnormalities at the last 
on-study visit.  This visit may be conducted by telephone.
q.
Assess Treatment Accountability only
 
 
 
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6.5.
Time and Events Table – Extension Period for IM Regimen (CAB LA + RPV LA-Q8W)
Procedures for 
Extension -
Q8W 
W 
100 
n
W 
101 n
W 
104 o
W 
112
W 
120
W 
121 
n
W 
128
W
136 
W 
144
W
152
W
160
W
168
W
176
W 
184
W 
192 a
W 
200 
a
WD 
l, m
Notes
Symptom 
Directed 
Physical Exam, 
ISR and 
Medical 
Assessment b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
See footnote “a” for continuation of visit 
schedule after Week 200.  Continue until 
either locally approved and commercially 
available, the subject no longer derives 
clinical benefit or meets a protocol-defined 
reason for discontinuation or until 
development is terminated.
a.
Continue this pattern for visits for the 
remainder of the study.  For example, Week 
208 will be conducted just like Week 192, 
Week 216 will be conducted just like Week 
200 and Week 224 will be conducted just 
like Week 192.
b.
Physical exams should be conducted as 
part of normal routine clinical care but data 
will not be collected in the eCRF. Medical 
assessments include any decisions the 
study staff must make for subject 
management.
c.
Measure vital signs after about 5 minutes of 
rest in a semi-supine position.
d.
Can be done at any time during the visit.
e.
A (-) urine pregnancy test is required prior 
to any injection and as required by medical 
monitor after a treatment interruption. A (+) 
urine test should be confirmed with a stat 
serum test.  If (+), subject will need to be 
WD.
f.
Plasma for storage samples are collected 
Vital Signs
(BP, HR) c
X
X
X
X
X
X
X
X
X
Weight & BMI
X
X 
X
X
X
X
X
X
X
HIV Associated 
Conditions, AE 
and SAE 
Assessments, 
Con Meds
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG d
X
X
X
X
X
X
X
X
X
Clinical 
Chemistry and 
Hematology
X
X
X
X
X n
X
X
X
X
X
X
X
Pregnancy 
Testing
(U)rine e
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
 
 
 
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Procedures for 
Extension -
Q8W 
W 
100 
n
W 
101 n
W 
104 o
W 
112
W 
120
W 
121 
n
W 
128
W
136 
W 
144
W
152
W
160
W
168
W
176
W 
184
W 
192 a
W 
200 
a
WD 
l, m
Notes
HIV-1 RNA and 
sample for 
storage f
X
X
X
X n
X
X
X
X
X
X
for possible future analyses, back-up in 
cases of loss/damage in transit and 
geno/pheno analyses for virologic failures.
g.
Fast overnight; however, a minimum of a 6 
hour fast is acceptable.
h.
Take PK samples pre-dose except Week 
101 and Week 121 which can be taken at 
any time during the visit.  A second Week
100 and 128 PK sample will be collected 
approximately 2 hours after the last 
injection.
i.
Subjects will complete a diary only if the 
subject experiences a reaction ((E)pisodic).  
Subjects will be dispensed a new diary at 
each visit. Diary data will be entered into the 
eCRF.
j.
Q8W Injections are 1 x CAB LA 600 mg 
IM + 1 x RPV LA 900 mg IM.  If possible, 
injections should be spaced approximately 
2 cm from one another and from the site of 
any previous injection and or any injection 
site reaction.  Bring RPV LA to 
approximately room temperature prior to 
injecting.   Time and location of injection 
(right or left) as well as needle length used 
will be collected in the eCRF.  IM dosing is 
expected to occur during the week in 
which the subject’s projected visit falls 
(as according to the Day 1 visit).  An 
additional (+ or -) 7 day window from 
date of projected visit is allowable for IM 
dosing but not preferred.  All decisions 
regarding dose interruption/ resumption 
CD4+
X
X
X
X n
X
X
X
X
X
X
Urinalysis
X
X
X
X n
X
X
X
X
X
X
Fasting 
Glucose, 
Cholesterol 
(Total, HDL 
and LDL) and 
Triglycerides g
X
X
X
X n
X
X
X
X
X
X
PT/PTT/INR
X
PK Diary 
(D)ispensation 
and (R)eview
R n
PK Sample 
(S)torage h
S
S
S
S
S n
S
S
S
S
S
S
X
ISR Diary 
Dispensation i
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E 
review
Study 
Treatment 
Administration j
X k
X k
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
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Procedures for 
Extension -
Q8W 
W 
100 
n
W 
101 n
W 
104 o
W 
112
W 
120
W 
121 
n
W 
128
W
136 
W 
144
W
152
W
160
W
168
W
176
W 
184
W 
192 a
W 
200 
a
WD 
l, m
Notes
must be discussed with the medical 
monitor in advance.
k.
At Week 100, oral Maintenance subjects 
eligible for extension dosing will take final 
dose of CAB 30 mg+ABC/3TC in the clinic 
within 2 hours of the optimized Q8W IM 
regimen.  See Section 5.1.6 for IM dosing 
administration as loading doses are 
required. (W100=1st loading dose; 
W104=2nd loading dose)
l.
Or Long-Term Follow Up
m.
Follow Up Visit - Conduct ~4 weeks after 
the last dose of IP if not entering Long-Term 
Follow Up and only if the subject has 
ongoing AEs or lab abnormalities at the last 
on-study visit.  May be conducted by 
telephone.
n.
Procedures and visits for subjects who 
switch from oral to the optimized Q8W IM 
dosing regimen.
o.
First Extension Period visit for subjects 
continuing Q8W dosing from the 
Maintenance Period.
Subject Visit 
Reminder 
Contact
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Subject 
Contact Detail 
Confirmation
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
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6.6.
Time and Events Table – Extension Period for IM Regimen (CAB LA + RPV LA - Q4W)
Procedures for 
Extension - Q4W 
W 
100 
W 
101 
m
W 
104 
W 
108
W 
112
W
116
W 
120
W 
121 
m
W
124
W 
128 
W 
132 
a
W 
136 
a
W 
140 
a
W 
144
a
WD 
k, l
Notes
Symptom Directed 
Physical Exam, ISR 
and Medical 
Assessment b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
See footnote “a” for continuation of visit schedule 
after Week 144.  Continue until either locally 
approved and commercially available, the subject 
no longer derives clinical benefit or meets a 
protocol-defined reason for discontinuation or until 
development is terminated. 
a.
Continue this pattern for visits for the remainder of 
the study.  For example, Week 148 will be 
conducted just like Week 132, Week 152 will be 
conducted just like Week 136, Week 156 will be 
conducted just like Week 140 and Week 160 will 
be conducted just like Week 144.
b.
Physical exams should be conducted as part of 
normal routine clinical care but data will not be 
collected in the eCRF. Medical assessments 
include any decisions the study staff must make for 
subject management.
c.
Measure vital signs after about 5 minutes of rest in 
a semi-supine position.
d.
Can be done at any time during the visit.
e.
A (-) urine pregnancy test is required prior to any 
injection and as required by medical monitor after 
a treatment interruption. A (+) urine test should be 
confirmed with a stat serum test.  If (+), subject will 
need to be WD.
f.
Plasma for storage samples are collected for 
possible future analyses, back-up in cases of 
loss/damage in transit and geno/pheno analyses 
Vital Signs (BP, HR) c
X
X m
X m
X
X
X
X
Weight & BMI
X
X
X
X
X
X
HIV Associated 
Conditions, AE and 
SAE Assessments, 
Con Meds
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG d
X
X m
X m
X
X
X
X
Clinical Chemistry and 
Hematology
X
X
X
X
X 
X m
X m
X
X m
X
X
X
Pregnancy Testing
(U)rine e
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
HIV-1 RNA and 
sample for storage f
X
X
X
X
X m
X m
X m
X
X
X
CD4+
X
X
X
X
X m
X m
X m
X
X
X
 
 
 
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Procedures for 
Extension - Q4W 
W 
100 
W 
101 
m
W 
104 
W 
108
W 
112
W
116
W 
120
W 
121 
m
W
124
W 
128 
W 
132 
a
W 
136 
a
W 
140 
a
W 
144
a
WD 
k, l
Notes
Urinalysis
X
X m
X m
X
X m
X m
X m
X
X
X
for virologic failures.
g.
Fast overnight; however, a minimum of a 6 hour 
fast is acceptable.
h.
Take PK samples pre-dose except Week 101 and 
Week 121 which can be taken at any time during 
the visit.  Week 100 PK sample should be taken 
after review of PK diary and pre-dose of CAB 
30 mg+ABC/3TC.  A second Week 100 and Week 
128 PK sample will be collected approximately 2 
hours after the last injection.
i.
Subjects will complete a diary only if the subject 
experiences a reaction ((E)pisodic).  Subjects will 
be dispensed a new diary at each visit. Diary data 
will be entered into the eCRF.
j.
Q4W Injections are 1 x CAB LA 400 mg IM + 1 x 
RPV LA 600 mg IM.  If possible, injections should 
be spaced approximately 2 cm from one another 
and from the site of any previous injection and or 
any injection site reaction.  Bring RPV LA to 
approximately room temperature prior to injecting.   
Time and location of injection (right or left) as well 
as needle length used will be collected in the 
eCRF.  IM dosing is expected to occur during 
the week in which the subject’s projected visit 
falls (as according to the Day 1 visit).  An 
additional
(+ or -) 7 day window from date of projected 
visit is allowable for IM dosing but not 
preferred.  All decisions regarding dose 
interruption/ resumption must be discussed 
with the medical monitor in advance.
k.
Or Long-Term Follow Up
l.
Follow Up Visit - Conduct ~4 weeks after the last 
Fasting Glucose, 
Cholesterol (Total, 
HDL and LDL) and 
Triglycerides g
X
X m
X m
X
X m
X m
X m
X
X
X
PT/PTT/INR
X
PK Diary 
(D)ispensation and 
(R)eview
R m
PK Sample 
(S)torage  h
S
S
S
S
S
S m
S m
S
S m
S
S
X
ISR Diary 
Dispensationi
E
E
E
E
E
E
E
E
E
E
E
E
E 
review
Study Treatment 
Administration j
X n
X
X
X
X
X
X
X
X
X
X
X
Subject Visit Reminder 
Contact
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Subject Contact Detail 
Confirmation
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
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Procedures for 
Extension - Q4W 
W 
100 
W 
101 
m
W 
104 
W 
108
W 
112
W
116
W 
120
W 
121 
m
W
124
W 
128 
W 
132 
a
W 
136 
a
W 
140 
a
W 
144
a
WD 
k, l
Notes
dose of IP if not entering Long-Term Follow Up 
and only if the subject has ongoing AEs or lab 
abnormalities at the last on-study visit.  May be 
conducted by telephone.
m.
Procedures and visits for subjects who switch from 
oral to the optimized Q4W IM dosing regimen.
n.
At Week 100, oral Maintenance subjects eligible 
for extension dosing will take final dose of CAB 
30 mg+ABC/3TC in the clinic within 2 hours of the 
optimized Q4W IM regimen.  See Section 5.1.6 for 
IM dosing administration as loading doses are 
required.
 
 
 
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6.7.
Time and Events Table – Long-Term Follow Up Period
Procedures for Long-Term Follow Up
Month 1 a
Month 3
Month 6
Month 9
Month 12
WD
Notes
HIV Associated Conditions, AE and SAE 
Assessments, Con Meds
X
X
X
X
X
X
Every effort should be made to enter subjects into the Long-Term 
Follow Up if they withdraw from or discontinue the study after 
receiving at least one dose of CAB LA and / or RPV LA.
a)
The start of the 52-week follow up period begins the day 
of the last CAB LA and/or RPV LA dose.
b)
Women of childbearing potential only.  S = Serum
c)
Fast overnight; however, a minimum of a 6 hour fast is 
acceptable.
d)
Women of childbearing potential should continue to 
receive counselling on the need to use adequate 
contraception for the entirety of the Long-Term Follow-Up 
Period. 
e)
Investigators must discuss choice of HAART 
regimen and timing of initiation with the medical 
monitor before initiating.  This regimen may be 
supplied regionally by GSK or reimbursement will be 
provided.
HIV-1 RNA
X
X
X
X
X
X
CD4+
X
X
X
X
X
X
Plasma for Storage
X
X
X
X
X
X
PK Sample for Storage
S
S
S
S
S
S
Clinical Chemistry and Hematology
X
X
X
X
X
X
Pregnancy Testing b
S
S
S
S
S
S
Urinalysis
X
X
X
Fasting:  Glucose, Cholesterol (Total, 
HDL and LDL) and Triglycerides c
X
X
PT/PTT/INR
X
X
Contraception Counselling d
X
X
X
X
X
X
HAART Dispensation e
X
X
X
X
X
X
 
 
 
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6.8.
Critical Screening and Baseline Assessments
Written informed consent must be obtained from each potentially eligible subject by 
study site personnel prior to the initiation of any Screening procedures as outlined in this 
protocol.  The consent form must have been approved by the Institutional Review 
Board/Institutional Ethics Committee (IRB/IEC).  After signing an informed consent, 
subjects will complete Screening assessments to determine subject eligibility.  Each 
subject being screened for study enrollment evaluation will be assigned a subject number.  
This number will be given sequentially in chronological order of subject presentation 
according to a numeric roster provided by GSK.
Subjects must be counseled on the practice of safer sexual practices including the use of 
effective barrier methods (e.g. male condom/spermicide) and the length of time in which 
they are required for participation in this study as part of the eligibility process.
6.8.1.
Screening
All clinical and laboratory assessments of eligibility must be performed and reviewed 
within 28 days of initiating the Screening process. All Screening results must be 
available prior to randomization. 
Eligibility criteria must be carefully assessed at the Screening visit and confirmed at the 
first Induction Period visit prior to enrollment. 
Subjects may enroll and begin the Induction Period as soon as all Screening assessments 
are complete and the results are available and documented.  
Each subject screened will be assigned a subject number. Subjects not meeting all 
inclusion and exclusion criteria at initial screen may be re-screened one time with a new 
subject number. Subjects who are enrolled into the trial and subsequently withdrawn 
from the study for any reason may not be rescreened.
At Screening, samples for HIV-1 genotypic and phenotypic resistance testing and plasma 
HIV-1 RNA measurement will be obtained.
Subjects infected with HBV will not be enrolled in the study.  Subjects with an 
anticipated need for HCV therapy during the study must not be enrolled into this study, as 
HCV therapy currently includes the prohibited medication interferon.  The length of this 
study should be considered when assessing the potential need for therapy.
Physical exams should be conducted as part of normal routine clinical care but will not be 
collected systematically in the eCRF.
The electronic Columbia Suicidality Severity Rating Scale (eC-SSRS) (see Section 
6.10.10) assessed at the Screening visit will assess the subject’s lifetime risk (any suicidal 
ideation, behavior, etc occurring over the subject’s lifetime).  A positive alert (indicating 
some risk) is not necessarily exclusionary, rather a means to assess overall risk.
 
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6.8.2.
Baseline
Subjects will have “Baseline” assessments completed at the beginning of the Induction 
Period.
Any changes to the eligibility parameters must be assessed and any results required must 
be available and reviewed prior to enrollment (e.g. urine pregnancy test for women of 
child bearing potential).
HIV-1 genotypic resistance testing and plasma HIV-1 RNA measurement results from 
Screening must be available prior to the Baseline visit.
In addition to a full routine medical history, more detailed information will be collected 
for some disease processes such as:

cardiovascular risk factors (assessments will include smoking status and history; 
family history of cardiac events; 

history of illicit drug use [e.g. cocaine, heroin, and methamphetamine use]);

intravenous drug use history;

gastrointestinal disease (e.g. GI bleeding, PUD, etc);

metabolic (e.g. Type I or II diabetes mellitus);

psychiatric (e.g. depression);

renal (e.g. nephrolithiasis, nephropathy, renal failure); and,

neurologic disorders.
6.9.
Efficacy
6.9.1.
Plasma HIV-1 RNA
Plasma for quantitative HIV-1 RNA will be collected according to the Time and Events 
schedule (Section 6).  Methods to be used may include but are not limited to the Abbott 
RealTime HIV-1 Assay lower limit of detection (LLOD) 40 c/mL. In some cases (e.g., 
where the HIV-1 RNA is below the lower limit of detection for a given assay) additional 
exploratory methods will be used to further characterize HIV-1 RNA levels.
6.9.2.
Lymphocyte Subsets, CD4+ and CD8+
Lymphocyte subsets will be collected for assessment by flow cytometry (total 
lymphocyte counts, percentage and absolute CD4+ and CD8+ lymphocyte counts, ratios) 
according to Time and Events schedule (Section 6) and Labroatory Assessments
(Section 6.10.2).
 
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6.9.3.
HIV Associated Conditions
HIV-associated conditions will be recorded as per Time and Events schedule (Section 6).  
HIV-associated conditions will be assessed according to the 1993 CDC Revised 
Classification System for HIV Infection in Adults (see Section 11.1).  Indicators of 
clinical disease progression are defined as:
CDC Category A at enrollment Category B event;
CDC Category A at enrollment Category C event;
CDC Category B at enrollment Category C event;
CDC Category C at enrollment New Category C Event;
CDC Category A, B or C at enrollment Death.
6.10.
Safety
6.10.1.
Clinical evaluations
The following clinical evaluations will be performed according to the Time and Events 
schedule (see Section 6):

Monitoring and recording of all AEs and SAEs. Additional information on the Time 
Period and Frequency of Detecting AEs and SAEs is provided in Section 6.10.12.

Physical exams should be conducted as part of normal routine clinical care but will 
not be collected systematically in the eCRF. Abnormalities noted during any exam 
must be recorded in the eCRF (e.g., in the current medical conditions or AE logs).

Height and weight will be measured and recorded.  Height collected on the first day 
of the Induction Period only.

Vital Signs will include systolic and diastolic blood pressure and heart rate collected 
after resting for about 5 minutes.

Past medical history, family history, social history, medication history.  Targeted 
history on cardiovascular risk (smoking history, family and personal history).

Exercise habits will be assessed for subjects on the CAB LA+RPV LA regimen.

HIV-associated conditions will be recorded.

Electrocardiogram: A 12-lead ECG will be performed in a semi-supine position. At 
the first day of the Induction Period, ECGs should be performed in triplicate prior to 
first dose.  An ECG machine that automatically calculates the heart rate and 
measures PR, QRS, QT, and QTc intervals is preferred, and these calculated 
numbers can be used for reporting purposes. Otherwise, an appropriately qualified 
ECG reader must interpret the results. The same interpreter should assess all ECGs 
for each subject. Regardless, each ECG should be reviewed by a qualified ECG 
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
Regular monitoring of hematology, blood chemistry, urinalysis and fasting glucose 
and lipids (parameters to be tested listed below).  

Pregnancy testing.  A negative urine pregnancy test is required prior to initiation of 
IP, any dose of CAB LA or RPV LA or as required by the medical monitor following 
a treatment interruption(s).

Evaluation and documentation of all concomitant medications and blood products. 

Injection Site Reactions (ISRs) will be assessed for the following clinically as well as 
patient-reported by utilizing a subject diary:

Daily from Day 1 – 7, from Week 24 – Week 25 and again daily from Week 40
to Week 41:  Pain, tenderness, pruritis, warmth, bruising, discoloration, 
infections, rash, erythema, swelling, induration, and nodules (granulomas or 
cysts).  

Episodic (as reported by subject) for the Maintenance and Extension Period for 
the above parameters

The investigator should utilize subject diary reports to assist with a clinical 
assessment (using Division of Acquired Immunodeficiency Syndrome [DAIDS] 
grading scale).  A clinical assessment should be performed both before and after 
an injection to identify resolving and new ISRs.  All injection site reactions are 
considered adverse events.  The clinical assessment and interpretation of any 
ISR, including those reported by the subject via diary, will be documented in the 
ISR AE eCRF.  Daily diary data, or subject assessment, will be documented 
verbatim in the diary eCRF.

Columbia Suicide Severity Rating Scale (eC-SSRS) will be assessed as per the Time 
and Events Schedule (see Section 6 and Section 6.10.10).
Any appropriately qualified site personnel (e.g., Investigator, sub-Investigator, or study 
coordinator/nurse) can perform assessments.
6.10.2.
Laboratory Assessments
All protocol required laboratory assessments, as defined in the Time and Events Schedule 
(see Section 6), must be performed by the central laboratory.  Laboratory assessments 
must be conducted in accordance with the Central Laboratory Manual and Protocol Time 
and Events Schedule.  Laboratory requisition forms must be completed and samples must 
be clearly labeled 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 central 
laboratory.  Reference ranges for all safety parameters will be provided to the site by the 
central laboratory.
Refer to the lab manual for appropriate processing and handling of samples to avoid 
duplicate and/or additional blood draws.
Labs will be automatically graded by the central lab according to the DAIDS toxicity 
scales (See Section 11.2 “Division of AIDS Table for Grading the Severity of Adult and
Pediatric Adverse Events”).
 
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For fasting laboratory assessments, an overnight fast is preferred; however, a minimum of 
a 6 hour fast is acceptable.
Following are the lab parameters to be assessed as per the Time and Events Schedule (see 
Section 6):
Hematology
Chemistry
Platelet Count 
Automated WBC 
Differential: 
BUN
Total CO2
Total bilirubina 
RBC Count 
Neutrophils 
Creatinineb
Lipase 
Albumin
WBC Count 
(absolute) 
Lymphocytes 
Glucosed
AST 
Creatine 
phosphokinase 
Hemoglobin 
Monocytes 
Sodium
ALT 
Total 
Cholesterold
Hematocrit 
Eosinophils 
Potassium 
Alkaline 
phosphatase 
HDL and LDL 
Cholesterold
MCV 
Basophils 
Chloride 
Triglyceridesd
Other Laboratory Assessments
Plasma HIV-1 
RNA and sample 
for storage
Hepatitis B 
(HBsAg) and 
Hepatitis C (anti-
HCV Ab)e at 
Screening only
Urine Pregnancy test 
for women of child 
bearing potential
Prothrombin Time 
(PT)/International Normalized 
Ratio (INR)/ Partial 
Thromboplastin Time (PTT)
CD4+ and CD8+ 
cell counts 
[CD4/CD8 ratio]c
HLA-B*5701 at 
Screening only
Urinalysis and urine 
microalbumin/creatinine 
ratio
Pharmacogentics Sample (PGx)
a)
Direct bilirubin will be reflexively performed for all total bilirubin values > 1.5X ULN.
b)
Creatinine clearance will be estimated by the central laboratory and assessed at Screening, Baseline, Week (-12), 
Week (-4), Day 1 and Weeks 4, 16, 32, 48 and 96.
c)
CD8+ cells will only be reported at Baseline, Week (-4), Day 1 and Weeks 32, 48 and 96.
d)
Fasting overnight preferred; 6 hour fast is acceptable.
e)
HCV RNA may be requested through the central lab within 2 weeks of a positive anti-HCV antibody test.
6.10.3.
Liver Chemistry Stopping and Follow up Criteria
6.10.3.1.
Liver Chemistry Stopping Criteria
Liver chemistry threshold stopping criteria have been designed to assure subject safety
and to evaluate liver event etiology during administration of IP and the follow-up period. 
IP will be stopped if any of the following liver chemistry criteria are met:

ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin, bilirubin 
fractionation required).
NOTE: serum bilirubin fractionation should be performed if testing is available. If testing 
is unavailable, record presence of detectable urinary bilirubin on dipstick, indicating 
direct bilirubin elevations and suggesting liver injury.  If testing is unavailable and a 
subject meets the criterion of total bilirubin 2xULN, then the event meets liver stopping 
criteria.
 
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
ALT 8xULN.

ALT ≥3xULN (if Baseline ALT is < ULN) with symptoms or worsening of 
acute hepatitis or hypersensitivity such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, or eosinophilia, OR;

ALT ≥3x Baseline ALT with symptoms or worsening of acute hepatitis or 
hypersensitivity such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, or eosinophilia;

ALT ≥5xULN and <8xULN that persists ≥2 weeks (with bilirubin <2 ULN & no 
signs or symptoms of acute hepatitis or hypersensitivity).

ALT ≥5xULN but <8xULN and cannot be monitored weekly for >2 weeks.
NOTE: if serum bilirubin fractionation is not immediately available, withdraw study drug 
for that subject if ALT 3xULN and bilirubin 2xULN. Serum bilirubin fractionation 
should be performed if testing is available. If testing is unavailable, sites should evaluate 
the presence of detectable urinary bilirubin on dipstick, which indicates direct 
bilirubin elevations and suggests liver injury.
6.10.3.2.
Liver Chemistry Stopping Criteria, Subject Management
Subjects who develop ALT ≥5xULN must be followed weekly until resolution or
stabilization (ALT <5xULN on 2 consecutive evaluations).
When any of the liver chemistry stopping critera is met, do the following:

Immediately hold IP.  

Report the event to the medical monitor within 24 hours of learning its 
occurrence (Section 6.10.12, Section 6.10.14).

Complete the liver event eCRF and SAE eCRF, where applicable, (see 
Section 6.10.12).

Complete the liver imaging and/or liver biopsy eCRFs if these tests are 
performed.

Perform liver event follow up assessments (described below), and monitor the 
subject until liver chemistries resolve, stabilize, or return to Baseline values as
described below.

Make every reasonable attempt to have subjects return to clinic within 24 hours 
for repeat liver chemistries, liver event follow up assessments (see below), and 
close monitoring.

A specialist or hepatology consultation is recommended.

Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline
phosphatase, bilirubin) resolve, stabilize or return to within Baseline values.
Make every attempt to carry out the liver event follow up assessments described below:
 
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
Viral hepatitis serology including:
o
Hepatitis A IgM antibody;
o
HBsAg and Hepatitis B Core Antibody (IgM);
o
Hepatitis C RNA;
o
Hepatitis E IgM antibody;

Cytomegalovirus IgM antibody;

Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);

Syphilis screening;

Drugs of abuse screen including alcohol;

Serum acetaminophen test (APAP adduct test). The site must contact GSK 
when this test is required. Please refer to the central laboratory manual.

Blood sample for pharmacokinetic (PK) analysis, obtained within 60 hours of 
last dose.  Record the date/time of the PK blood sample draw and the date/time 
of the last dose of investigational product prior to blood sample draw on the 
eCRF. 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 SPM.

Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH);

Fractionate bilirubin, if total bilirubin is greater than 1.5xULN;

Obtain complete blood count with differential to assess eosinophilia;

Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver 
kidney microsomal antibodies;

Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to
evaluate liver disease;

Record the appearance or worsening of clinical symptoms of hepatitis, or
hypersensitivity, fatigue, decreased appetite, nausea, vomiting, abdominal pain,
jaundice, fever, or rash as relevant on the AE report form;

Record use of concomitant medications, acetaminophen, herbal remedies, other 
over the counter medications, or putative hepatotoxins, on the concomitant 
medications report form. Record alcohol use on the liver event alcohol intake 
case report form.
6.10.3.3.
Liver Chemistry Stopping Criteria - Rechallenge
Subjects who meet liver toxicity stopping criteria should not be retreated with 
investigational product unless an exemption has been approved by the ViiV Safety and 
Labeling Committee (VSLC).  The guideline for Rechallenge/Restart approved by the 
 
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VSLC, which is maintained as a separate document (See Section 11.4, Appendix 4), must 
be followed.
Drug Restart/Rechallenge Following Liver Events that are Possibly Related to IP
Approval by the VSLC for drug restart or additional IM administration can be considered 
where:

The subject is receiving compelling benefit, benefit of drug restart exceeds risk, 
and no effective alternative therapy is available. Ethics Committee or 
Institutional Review Board approval of drug restart/rechallenge must be 
obtained, as required.

If the restart/rechallenge is approved by the VSLC in writing, the subject must 
be provided with a clear description of the possible benefits and risks of drug
administration, including the possibility of recurrent, more severe liver injury or
death.

The subject must also provide signed informed consent specifically for the IP
restart/rechallenge. Documentation of informed consent must be recorded in the
study chart.

Study drug must be administered at the dose specified by the VSLC.

Subjects approved by the VSLC for rechallenge of IP must return to the clinic
twice a week for liver chemistry tests for a minimum of one month and 
thereafter for as long as clinically indicated and then laboratory monitoring may 
resume as per protocol.
Drug Restart Following Transient Resolving Liver Events Not Related to IP
Approval by the VSLC for drug restart or additional IM administration can be considered 
where:

Liver chemistries have a clear underlying cause (e.g., biliary obstruction,
hypotension and liver chemistries have improved to normal or are within 
1.5 x baseline and ALT <3xULN). Ethics Committee or Institutional Review 
Board approval of drug restart/rechallenge must be obtained, as required.

If restart of drug or continuation of LA dosing is approved by the VSLC in 
writing, the subject must be provided with a clear description of the possible 
benefits and risks of drug administration, including the possibility of recurrent, 
more severe liver injury or death.

The subject must also provide signed informed consent specifically for the 
restart.  Documentation of informed consent must be recorded in the study chart.

Study drug must be administered at the dose specified by the VSLC.
Subjects approved by the VSLC for restarting or re-dosing IP must return to the clinic 
once a week for liver chemistry tests for a minimum of one month and thereafter for as 
long as clinically indicated and then laboratory monitoring may resume as per protocol. 
 
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If protocol defined stopping criteria for liver chemistry elevations are met, study drug 
must be stopped.
See Section 11.4, Appendix 4 for further details.
6.10.4.
Adverse Events
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.
6.10.4.1.
Definition of an AE
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.  For marketed medicinal products, this 
also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse.
Events meeting the definition of an AE include:

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.

All injection site reactions.
“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 fulfill the definition of an AE or 
SAE.  
Events that do not meet the definition of an AE include:

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)
 
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
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

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
6.10.4.2.
Definition of an SAE
A serious adverse event is any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:  The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:  In general, hospitalization signifies that the subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred, or was 
necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from Baseline is not considered an AE.
d.
Results in disability/incapacity, or
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.
e.
Is a congenital anomaly/birth defect
f.
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.
 
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g.
All events of possible drug-induced liver injury with hyperbilirubinaemia defined as 
ALT 3xULN and bilirubin 2xULN (>35% direct) (or ALT 3xULN and 
INR>1.5, if INR measured) termed ‘Hy’s Law’ events (INR measurement is not 
required and the threshold value stated will not apply to patients receiving 
anticoagulants).
NOTE: bilirubin fractionation is performed if testing is available. If testing is 
unavailable, record the presence of detectable urinary bilirubin on dipstick which 
may indicate direct bilirubin elevations and may suggest liver injury. If testing is 
unavailable and a subject meets the criterion of total bilirubin 2xULN, then the 
event is still reported as an SAE. If INR is obtained, include values on the SAE form. 
INR elevations >1.5 suggest severe liver injury.   
6.10.5.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs
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 are to be recorded as AEs or SAEs. 
However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the subject’s condition, are not to be reported as AEs or SAEs.
6.10.6.
Specific Toxicities / Adverse Event Management
Adverse events that occur during the trial should be evaluated by the Investigator and 
graded according to the Division of AIDS (DAIDS) toxicity scales (See Section 11.2
“Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events”). Additional information regarding detecting, documenting and reporting AEs 
and SAEs are available in Section 6.10.12, “Adverse Events”.
6.10.6.1.
Treatment Interruption Due to an Adverse Event
The AE profile for CAB in combination with ABC/3TC or in combination with RPV has 
not yet been fully defined.  IP or background NRTI may be interrupted at the discretion 
of the Investigator and according to the severity of the AE. If one or more antiretroviral 
medications is held due to toxicity or adverse events, all antiretroviral medications must 
be held to reduce the risk of development of resistance taking into account both the 
length of the planned interruption and the pharmacokinetic half-life of each antiretroviral 
of the regimen, in a way to minimize the risk of development of resistance.
No toxicity-related dose reductions of IP will be allowed. IP and background NRTIs 
should be restarted as soon as medically appropriate; in general, for oral dosing, this 
should be no longer than 14 days after discontinuation (unless Grade 3 or 4 toxicities 
persist). Decisions regarding sequential reintroduction of IP or temporary interruption of 
one or more but not all drugs within the ART regimen should be made with the 
 
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understanding that these changes may result in incomplete viral suppression and selection 
of resistant virus.  Any interruption in therapy during the Maintenance Period, oral 
dosing, of greater than 7 consecutive days must be discussed with and agreed by the 
medical monitor prior to resumption of therapy.  The medical monitor must be contacted 
upon becoming aware of resumption in therapy, if therapy was resumed without prior 
approval (Section 5.7).  IM dosing is expected to occur during the week in which the 
subject’s projected visit falls (as according to the Day 1 visit).  An additional (+ or -) 
7 day window, from the projected visit date, is allowable for IM dosing but not 
preferred.  Any interruption outside of this guidance MUST be discussed with the 
medical monitor prior to reinitiating IM IP (see Section 5.7.2).
Guidance is provided below on general subject management and IP interruptions based 
on the severity of the AE. Information regarding permitted substitutions of background 
therapy is provided in Section 5.6.  All changes in the IP or background NRTI regimen 
must be accurately recorded in the subject’s eCRF.
In the event of a discontinuation of an ABC-containing product for any reason, re-
initiation of this drug must be undertaken with caution. Health care providers should 
obtain a complete history of the events surrounding the discontinuation of the ABC-
containing product. If there are symptoms consistent with a hypersensitivity reaction, 
ABC should not be reinitiated. If there is no evidence of a prior reaction, the subject may 
restart treatment with the ABC-containing product. The subject and health care provider 
should be aware of the possibility of a rapid-onset hypersensitivity reaction upon 
reinitiation of ABC, which may be life-threatening, and the subject should be able to, if 
necessary, receive prompt medical evaluation (see also Section 6.10.6.14).
6.10.6.2.
Grade 1 or Grade 2 Toxicity/Adverse Event
Subjects who develop a Grade 1 or Grade 2 AE or toxicity may continue IP at the 
discretion of the Investigator. (NOTE: See Section 6.10.6 “Specific Toxicities/Adverse 
Event Management” for exceptions to this guideline).  Subjects who choose to withdraw 
from study due to a Grade 1 or 2 AE should have study withdrawal and follow-up 
evaluations completed.
Subjects who develop a Grade 1 or 2 AE or toxicity, which the Investigator considers 
related or possibly related the background NRTI medications, may be addressed by 
substitution with another approved NRTI combination one time during the study, as 
described in Section 5.6 “Protocol-Permitted Substitutions”.
6.10.6.3.
Grade 3 Toxicity/Adverse Event
Subjects who develop a Grade 3 AE or toxicity should be managed as follows:

If the Investigator has compelling evidence that the Grade 3 AE or toxicity has 
not been caused by IP, dosing may continue after discussion with GSK medical 
monitor.
 
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
Subjects who develop a Grade 3 AE or toxicity, which the Investigator considers 
related or possibly related to the IP, should have the IP withheld and be 
rechecked each week until the AE returns to Grade 2. Once the AE is Grade 2, 
IP may be re-started. 

Should the same Grade 3 AE recur within 28 days in the same subject, the IP 
should be permanently discontinued and the subject withdrawn from study. 

Subjects experiencing Grade 3 AEs requiring permanent discontinuation of IP 
should be followed weekly until resolution of the AE and encouraged to have 
withdrawal study evaluations completed. A follow-up visit should be performed 
4 weeks after the last dose of IP.  Any subject receiving at least one dose of 
CAB LA and /or RPV LA who discontinue IP / Withdraw will initiate treatment 
with HAART and enter the Long-Term Follow-Up Period for 52 weeks of 
follow up. 

Subjects who develop a Grade 3 AE or toxicity, which the Investigator considers 
related or possibly related to one of the background ART medications may be 
addressed by substitution of the medication for another approved compound in 
the same class (e.g., a switch of ABC/3TC FDC for TDF/FTC FDC) one time 
during the study, as indicated in Section 5.6 “Protocol-Permitted Substitutions.”  
Subjects should be rechecked each week until the AE returns to Grade 2.

Subjects with Grade 3 asymptomatic laboratory abnormalities should be 
investigated for all potential non-drug related causes, and, following discussion 
with GSK medical monitor, may continue if the Investigator has compelling 
evidence that the toxicity is not related to IP, with the exception of liver 
chemistry stopping criteria (See Section 6.10.3).  Isolated Grade 3 and Grade 4 
lipid abnormalities do not require withdrawal of IP.
6.10.6.4.
Grade 4 Toxicity/Adverse Event

Subjects who develop a Grade 4 AE or toxicity must have IP permanently 
discontinued.  However, if the Investigator has compelling evidence that the AE 
is not causally related to the IP, dosing may continue after discussion with and 
assent from GSK.  Subjects should be rechecked each week until the AE returns 
to Grade 2.

Grade 4 AEs that the Investigator considers related or possibly related to one of 
the background ART medications may be addressed by substitution of the 
medication for another approved compound in the same class (e.g., a switch of 
ABC/3TC FDC for TDF/FTC FDC) one time during the study, as indicated in 
Section 5.6 “Protocol-Permitted Substitutions”. Subjects should be rechecked 
each week until the AE returns to Grade 2.

Subjects experiencing Grade 4 AEs requiring permanent discontinuation of IP 
should be followed weekly until resolution of the AE and encouraged to 
complete the withdrawal and follow-up study evaluations as noted above.  Any 
subject receiving at least one dose of CAB LA and /or RPV LA who discontinue 
 
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IP / Withdraw will initiate treatment with HAART and enter the Long-Term 
Follow-Up Period for 52 weeks of follow up. 

Subjects with Grade 4 asymptomatic laboratory abnormalities should be 
investigated for all potential non-drug related causes, and, following discussion 
with GSK, may continue therapy if the Investigator has compelling evidence 
that the toxicity is not related to IP, with the exception of liver chemistry 
stopping criteria (See Section 6.10.3). A follow-up visit should be performed 4 
weeks after the last dose of study medication if AEs or laboratory abnormalities 
are ongoing.
6.10.6.5.
Diarrhea
Subjects with Grade 1 or 2 diarrhea may continue study treatment without interruption. 
Subjects with diarrhea of any toxicity grade may be treated symptomatically with anti-
motility agents; however, the recommended daily dose of the chosen anti-motility agent 
must not be exceeded. If symptoms persist or get worse on the recommended daily dose 
of the chosen anti-motility agent, then the anti-motility agent must be discontinued and 
consultation made with GSK.
For subjects with Grade 3 diarrhea that is unresponsive to the recommended dose of the 
anti-motility agents and for which an alternative etiology (e.g., infectious diarrhea) is not 
established, the treatment with the anti-motility agent and IP must be interrupted until 
resolution of diarrhea to Grade 2 or Baseline, after which IP and background ART may 
be resumed after discussion and agreement with GSK. If Grade 3 diarrhea recurs within 
28 days upon the resumption of IP, the IP should be permanently discontinued and the 
subject withdrawn from the study. Any subject receiving at least one dose of CAB LA 
and /or RPV LA who discontinue IP / Withdraw will initiate treatment with HAART and 
enter the Long-Term Follow-Up Period for 52 weeks of follow up.
If loperamide is used for treatment of diarrhea, local prescribing information should be 
followed with respect to dose and frequency of administration.  Loperamide dosing 
should not exceed local prescribing information.
6.10.6.6.
Hypertriglyceridemia/ Hypercholesterolemia
Samples for lipid measurements must be obtained in a fasted state according to the Time 
and Events table (Section 6). Subjects who experience asymptomatic triglyceride or 
cholesterol elevations may continue to receive IP. Clinical management of subjects with 
hypertriglyceridemia/hypercholesterolemia should not be based upon non-fasting 
samples (obtained in the fed state). A confirmatory fasting triglyceride and/or cholesterol 
level should be obtained prior to the institution of medical therapy for hyperlipidemia.  
Isolated Grade 3 and Grade 4 lipid abnormalities do not require withdrawal of IP.
Please see the Recommendations of the Adult AIDS Clinical Trial Group Cardiovascular 
Disease Focus Group [Dube, 2003] for full discussion of management of hyperlipidemia 
in the context of HIV therapy.
 
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6.10.6.7.
Creatine Phosphokinase (CPK) Elevation
A Grade 3 or higher elevation in CPK should result in a repeat assessment within 2-4 
weeks to ensure the result is transient or due to exercise and will not require a change in 
study treatment. A history regarding use of drugs known to cause increase of CPK (such 
as statins) physical activity or exercise preceding the CPK evaluation should be obtained. 
Grade 4 elevations in CPK should have a repeat assessment after the subject has 
abstained from exercise for >24 hours. For persistent Grade 4 CPK elevations that are 
considered possibly or probably related to the IP, IP should be discontinued and the 
subject withdrawn from the study. Any subject receiving at least one dose of CAB LA 
and /or RPV LA who discontinue IP / Withdraw will initiate treatment with HAART 
enter the Long-Term Follow-Up Period for 52 weeks of follow up.
6.10.6.8.
Lipase Elevations and Pancreatitis
Subjects with asymptomatic Grade 1 or 2 elevations in lipase may be followed closely for 
the development of symptoms.
Subjects with asymptomatic Grade ≥3 elevations in lipase that are considered possibly or 
probably related to IP should have IP interrupted until serum lipase returns to Grade 2.  
The lipase assay should be repeated within 2 weeks of any Grade ≥3 result. Subjects with 
persistence of Grade ≥3 lipase in the absence of other diagnoses or reoccurrence of lipase 
elevation (at Grade ≥2) following reintroduction of IP should permanently discontinue IP.
Subjects with a confirmed diagnosis of clinical pancreatitis that is considered possibly or 
probably related to IP should have IP held. After complete resolution of the episode, 
subjects may be re-challenged with IP after discussion with the medical monitor, only if 
the Investigator has compelling evidence that the event was not caused by IP. Upon re-
challenge, lipase determinations should be performed every 2 weeks for at least 6 weeks 
after re-initiation of treatment. With any elevation of lipase of Grade ≥2 or any 
recurrence of symptoms, the subject should discontinue IP and be withdrawn from study.
Any subject receiving at least one dose of CAB LA and /or RPV LA who discontinue IP / 
Withdraw will initiate treatment with HAART and enter the Long-Term Follow-Up 
Period for 52 weeks of follow up.
6.10.6.9.
Decline in Renal Function
The following criteria are defined based on Cockcroft-Gault estimates of GFR.  The 
Cockcroft-Gault criteria are based on recommendations for changes in dosing 
administration for both ABC/3TC FDC and TDF/FTC FDC.  Current local prescribing 
information should be consulted for additional details on dosing in renally impaired 
subjects.
 
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Subjects who experience progression to an estimated GFR (calculated by Cockcroft-
Gault equation) of <50 mL/min must return for a confirmatory assessment within 4 
weeks.  A urinalysis should also be done at this confirmatory visit. If an estimated GFR 
of <50 mL/min is confirmed, any subjects receiving TDF/FTC FDC must be switched to 
an alternative nucleoside combination at the discretion of the Investigator and medical 
monitor.  Subjects on ABC/3TC FDC may switch to the individual components dose 
adjusted for renal dysfunction according to approved prescribing information, or switch 
to alternative nucleosides at the discretion of the Investigator and GSK Medical Monitor.
Proximal Renal Tubule Dysfunction (PRTD) is defined as:

Confirmed rise in serum creatinine of ≥0.5 mg/dL from Baseline AND serum 
phosphate <2.0 mg/dL

Either of the above accompanied by any two of the following:

Glycosuria (≥250 mg/dL) in a non-diabetic

Low serum potassium (<3 mEq/L)

Low serum bicarbonate (<19 mEq/L)
Subjects meeting criteria for PRTD must return for a confirmatory assessment within 4 
weeks.  A urinalysis should be done at the time of the confirmatory assessment.  If PRTD 
is confirmed subjects receiving TDF/FTC FDC must be switched to an alternative 
nucleoside combination.  Subjects on ABC/3TC FDC may switch to the individual 
components dose adjusted for renal dysfunction according to approved prescribing 
information, or switch to alternative nucleosides at the discretion of the Investigator and 
GSK Medical Monitor.
6.10.6.10. Proteinuria
Subjects with an abnormal urine microalbumin/creatinine ratio (>0.3 mg/mg, >300 mg/g 
or >34 mg/mmol) that represents a change from Baseline and no associated increase in 
creatinine, should have a repeat spot urine microalbumin/creatinine ratio performed 
within 2 to 4 weeks. If confirmed, then consideration should be made for additional 
evaluation after consultation with the Study medical monitor. Additional evaluation may 
include a 24 hr urine protein and creatinine measurement and nephrology referral.
Subjects with an abnormal urine albumin/creatinine ratio (>0.3 mg/mg, 300 mg/g 
or>34 mg/mmol and representing a change from Baseline) and a serum creatinine 
increase >45 Mol/L (or 0.5 mg/dL) should have confirmation of both results within 2 
weeks.  If confirmed, the study Medical Monitor should be immediately contacted.  
Further management should be agreed between the investigator and medical monitor.
 
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6.10.6.11. QTc Prolongation
Subjects with an average QTc interval > 500 msec or a >60 msec increase from baseline,
from three or more tracings separated by at least 5 minutes should have IP discontinued. 
These criteria are based on an average QTc value of triplicate ECGs. If an ECG 
demonstrates a prolonged QT interval, obtain 2 more ECGs over a brief period (~5-10 
minutes) and use the averaged QTc values of the 3 ECGs to determine whether the 
subject should be discontinued from the study. If an alternative cause of the QT 
prolongation is determined (e.g., subject receiving drug known to cause prolonged QT or 
TdP), then IP may be restarted after consultation with and agreement by the Study 
medical monitor. 
6.10.6.12. Injection Site Reactions (ISRs)
Injection site reactions will be managed through investigator assessment and subject
diary collection throughout the study.  All Grade 3 or 4 ISRs must be discussed with the 
medical monitor to determine etiology and assess appropriate continued study 
participation.  
Digital photographs will be documented where possible on all subjects who have an 
injection site reaction that is either serious or Grade 2 or above that persist beyond 2 
weeks.  Dermatology will be consulted on all subjects who have an injection site reaction 
considered serious, Grade 3 or above, or if clinically significant and persistent beyond 
30 days and others if the Investigator or Medical Monitor feels it is medically necessary.
Details regarding photo collection and any other follow up will be given by the Medical 
Monitor at the time of assessment.
ISR discomfort can be managed symptomatically (e.g. cold/warm compress, 
acetaminophen, ibuprofen) if the reaction is interfering with the subject’s ability to 
perform activities of daily living.  The required intervention should be documented on the 
appropriate eCRF page.
6.10.6.13. Allergic Reaction
Subjects may continue IP for Grade 1 or 2 allergic reactions at the discretion of the 
Investigator. The subject should be advised to contact the Investigator immediately if 
there is any worsening of symptoms or if further systemic signs or symptoms develop. 
Antihistamines, topical corticosteroids, or antipruritic agents may be prescribed. 
Subjects with Grade ≥3 allergic reactions that are considered to be possibly or probably 
related to the IP should permanently discontinue the IP regimen and the subject should be 
withdrawn from the study. Subjects should be treated as clinically appropriate and 
followed until resolution of the AE.
 
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Any subject receiving at least one dose of CAB LA and /or RPV LA who discontinue IP / 
Withdraw will initiate treatment with HAART and enter the Long-Term Follow-Up 
Period for 52 weeks of follow up.
As EPZICOM is being used as background therapy, subjects should also be assessed for 
clinically suspected ABC hypersensitivity, as described below.
6.10.6.14. Abacavir Hypersensitivity Reaction (ABC HSR)
The most significant toxicity associated with ABC is the well-characterized drug-related 
hypersensitivity reaction (HSR). A detailed clinical description of this reaction (including 
the type and severity of events that can occur on re-challenge or reintroduction following 
ABC interruption for non-HSR reasons) and guidance regarding its management are 
included in the Local Country Prescribing Information for EPZICOM.  Investigators must 
familiarize themselves with this information on ABC HSR in the Local Country 
Prescribing Information for each of these products prior to initiating subjects on ABC 
therapy.
Studies have shown that carriage of the HLA-B*5701 allele is associated with a 
significantly increased risk of a HSR to ABC. In the prospective study CNA106030 
(PREDICT-1), the use of pre-therapy screening for the presence of HLA-B*5701 and 
subsequently avoiding ABC in HLA-B*5701 positive patients, significantly reduced the 
incidence of clinically suspected ABC HSR from 7.8% (66 of 847) to 3.4% (27 of 803) 
(p<0.0001). In clinical studies EPZ108859 (ARIES) and CNA109586 (ASSERT), 0.8% 
(4/515) and 3.1% (6/192) of subjects who were HLA-B*5701 negative and who received 
ABC developed a clinically suspected ABC HSR, respectively.
In any subject treated with ABC, the clinical diagnosis of suspected HSR (as 
detailed in the Local Country Prescribing Information) must remain the basis of 
clinical decision making. Regardless of HLA-B*5701 status, it is important to 
permanently discontinue ABC and not re-challenge with ABC (i.e., ZIAGEN, 
EPZICOM/KIVEXA or TRIZIVIR) if a HSR cannot be ruled out on clinical 
grounds, due to the potential for a severe or even fatal reaction.
6.10.6.14.1.
Essential Patient Information
With reference to Local Country Prescribing Information and the ‘Subject Information 
and Consent Form’, Investigators must ensure that subjects are fully informed regarding 
the following information on the hypersensitivity reaction prior to commencing ABC 
therapy:

Subjects must be made aware of the possibility of a hypersensitivity reaction to 
abacavir that may result in a life-threatening reaction or death and that the risk of a 
hypersensitivity reaction is increased in individuals who are HLA-B*5701 positive.

Subjects must also be informed that HLA-B*5701 negative individuals can also 
experience abacavir hypersensitivity reaction. Therefore, ANY subject who develops 
 
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signs or symptoms consistent with a possible hypersensitivity reaction to abacavir 
MUST CONTACT their doctor IMMEDIATELY.

Subjects who are hypersensitive to abacavir should be reminded that they must never 
take any abacavir containing medicinal products (e.g. ZIAGEN, EPZICOM, 
KIVEXA or TRIZIVIR) again, regardless of their HLA-B*5701 status.

In order to avoid restarting abacavir, subjects who have experienced a 
hypersensitivity reaction should be asked to return any remaining EPZICOM / 
KIVEXA tablets to the Investigator or site staff.

Subjects, who have stopped abacavir for any reason, and particularly due to possible 
adverse reactions or illness, must be advised to contact their doctor before restarting 
EPZICOM / KIVEXA as more severe symptoms may recur within hours and may 
include life-threatening hypotension and death.

Each subject should be reminded to read the Package Leaflet included in the 
EPZICOM / KIVEXA pack. They should be reminded of the importance of 
removing the Alert Card included in the pack, and keeping it with them at all times. 
6.10.6.14.2.
Reporting of Hypersensitivity Reactions
If a clinically suspected case of HSR to ABC meets one of the International Conference 
on Harmonization (ICH)-E2A, 1994 definitions of seriousness listed in Section 6.10.4.2
then, in addition to reporting the case as an SAE, the ABC HSR eCRF should also be 
completed within one week of the onset of the hypersensitivity reaction.  Clinically 
suspected cases of HSR to ABC that do not meet criteria as an SAE can be recorded as an 
AE.
6.10.6.15. Rash Without ABC HSR Symptoms
Including serious skin reactions such as Stevens-Johnson Syndrome, Toxic 
Epidermal Necrolysis, Erythema Multiforme or rash with significant liver 
dysfunction 
Subjects should be instructed to contact the Investigator as soon as possible if they 
develop a rash on study.
Subjects who develop rash of any grade should be evaluated for the possibility of an 
ABC HSR or a serious skin reaction such as Stevens - Johnson syndrome (SJS), Toxic 
Epidermal Necrolysis (TEN) or Erythema Multiforme. SJS, TEN and Erythema 
Multiforme have been reported very rarely in patients taking ABC-containing products.  
These patients generally do not have the cluster of additional symptoms (e.g., 
gastrointestinal and respiratory) that characterize the ABC HSR, but they do have 
features typical of these serious skin reactions.
If a serious skin reaction develops, ABC (and / or all other concurrent medication(s) 
suspected in the Investigators causality assessment) should be discontinued, and the 
 
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subject should not be re-challenged with any ABC-containing medicinal product (i.e., 
ZIAGEN, TRIZIVIR, EPZICOM or KIVEXA).
As many products other than abacavir also cause rash and/or serious skin reactions, all 
other medicinal products that the subject is receiving should also be reviewed and 
discontinued as appropriate.
The following guidance is provided for clinical management of subjects who experience 
rash alone in the absence of accompanying diagnosis of ABC HSR, systemic or allergic 
symptoms or signs of mucosal or target lesions.
Subjects with an isolated Grade 1 rash may continue IP and background ART at the 
Investigator’s discretion. 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 involvement develops.
Subjects may continue IP and background ART for an isolated Grade 2 rash. However, IP 
and background ART (and all other concurrent medication(s) suspected in the 
Investigators causality assessment) should be permanently discontinued for any Grade ≥2 
rash that is associated with an increase in ALT. The subject should be advised to contact 
the physician immediately if rash fails to resolve (after more than two weeks), if there is 
any worsening of the rash, if any systemic signs or allergic symptoms develop, or if 
mucosal involvement develops.
Subjects should permanently discontinue IP and background ART (and all other 
concurrent medication(s) suspected in the Investigators causality assessment) for an 
isolated Grade 3 or 4 rash, and the subject should be withdrawn from the study. Subjects 
should be treated as clinically appropriate and followed until resolution of the AE.  Any 
subject receiving at least one dose of CAB LA and /or RPV LA who discontinue IP / 
Withdraw will initiate treatment with HAART and enter the Long-Term Follow-Up 
Period for 52 weeks of follow up.
The rash and any associated symptoms should be reported as adverse events and 
appropriate toxicity ratings should be used to grade the events (see Section 11.2).
If the etiology of the rash can be definitely diagnosed as being unrelated to IP and due to 
a specific medical event or a concomitant non-study medication, routine management 
should be performed and documentation of the diagnosis provided.
Any rash that is possibly related to study drug, and is present between Week (-4) 
and Day 1, must be discussed with the Medical Monitor prior to initiation of CAB
LA or RPV LA.
6.10.6.16. Seizures
Seizures that occur on study should be managed according to the local guidelines on 
emergency seizure management which may include treatment with benzodiazepines, 
general supportive treatment, exclusion of metabolic and toxicological abnormalities 
using laboratory tests, and septic workup and excluding underlying structural 
abnormalities with neuroimaging.
 
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Where seizures occur, the Sponsor would like to better characterize these occurrences to 
enable systematic analyses.
Investigators are requested to document and report seizure or possible seizure events 
promptly (within 24 hours of learning of the event) to the Sponsor for evaluation and 
onward reporting.  Data should be documented on the appropriate eCRF page.
6.10.7.
Cardiovascular Events
Investigators will be required to fill out event specific data collection tools 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

Revascularisation
This information should be recorded in the specific cardiovascular eCRF within one week 
of when the AE/SAE(s) are first reported.
6.10.8.
Death Events
In addition, all deaths will require a specific death data collection tool to be completed.  
The death data collection tool includes questions regarding cardiovascular (including 
sudden cardiac death) and noncardiovascular death.
This information should be recorded in the specific death eCRF within one week of when 
the death is first reported.
6.10.9.
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 Section 11.1)
 
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
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 eCRF using the HIV Associated 
Conditions eCRF.  These DREs will be monitored by the medical monitor, IDMC, 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. or

Lymphomas and invasive cervical carcinomas are excluded from this exemption; 
they must be reported as SAEs even if they are considered to be HIV related
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 (i.e., expedited 
reporting, see Section 6.10.12) to GSK.
6.10.10.
Monitoring Suicidal Ideation and Behavior
Patients with HIV infection may occasionally present with symptoms of depression 
and/or suicidal ideation or behavior. Therefore, it is appropriate to monitor subjects 
prospectively for suicidal ideation and / or behavior before and during treatment. It is 
recommended that the Investigator consider mental health consultation or referral for 
subjects who experience signs of suicidal ideation or behavior.
Suicidal ideation or behavior will be monitored during this study using the electronic 
version of the Columbia Suicide-Severity Rating Scale (eC-SSRS). The behavioral 
suicidal events used in this scale are based on those used in the Columbia Suicide History 
Form [Oquendo, 2003]. Questions are asked on suicidal behavior, suicidal ideation and 
intensity of ideation. Screening visit questions will be in relation to lifetime experiences 
and current experiences (within the past 2 months) and all subsequent questioning in 
relation to the last assessment. The eC-SSRS is to be administered at the time-points 
specified in the Time and Events Table (see Section 6).
Additionally, the investigator will collect information using the Possible Suicidality-
Related AE (PSRAE) eCRF form in addition to the Adverse Event (Non-serious or 
Serious Adverse Events) eCRF form on any subject that experiences a possible 
 
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suicidality-related adverse event while participating in this study. This may include, but is 
not limited to, an event that involves suicidal ideation, a preparatory act toward imminent 
suicidal behavior, a suicide attempt, or a completed suicide.  The investigator will 
exercise his or her medical and scientific judgment in deciding whether an event is 
possibly suicide-related.  PSRAE forms should be completed and reported to GSK within 
one week of the investigator diagnosing a possible suicidality-related adverse event.
6.10.11.
Pregnancy
6.10.11.1. Pregnancy Testing
Women of childbearing potential must have a negative pregnancy test at Screening, the 
first Induction Period visit and prior to administration of each CAB LA and / or RPV LA 
injection.   Pregnancy testing will also be conducted as per the Time and Events Table 
(see Section 6) and at anytime during the trial when pregnancy is suspected. 
Additionally, the medical monitor may request that a pregnancy test be performed in the 
event of a treatment interruption greater than 7 days. 
6.10.11.2. Time Period for Collecting Pregnancy Information
Pregnancy information will be collected after the start of Induction until the last follow-
up assessment.  This includes the entirety of the Long-Term Follow-Up Period.
Female subjects that have received at least one dose of CAB LA or RPV LA and do not 
enter the Long-Term Follow-Up Period should use an acceptable method of 
contraception (see the SPM for a listing of examples of acceptable hormonal 
contraception) until at least 52 weeks after the last dose of study drug.  If a subject 
becomes pregnant within 52 weeks of the last dose of study drug the subject should 
notify the study site.  
6.10.11.3. Action to be Taken if Pregnancy Occurs
Any female who becomes pregnant (intrauterine) while participating in this study must be 
withdrawn from the study and must immediately discontinue IP.  Subjects who have 
received at least one dose of CAB LA and/or RPV LA should discontinue further dosing 
and continue oral HAART in the Long-Term Follow-Up Period (see Section 3.2.6), after 
discussion with the medical monitor.
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form.  To ensure subject safety, each pregnancy must be reported to GSK 
within 2 weeks of learning of its occurrence.  The pregnancy must be followed up to 
determine outcome (including premature termination) and status of mother and child.  
Pregnancy complications and elective terminations for medical reasons must be reported 
as an AE or SAE.  Spontaneous abortions must be reported as an SAE.
 
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Any SAE occurring in association with a pregnancy brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
possibly related to the study treatment, must be promptly reported to GSK.
GSK’s central safety department will also forward this information to the Antiretroviral 
Pregnancy Registry. The international registry is jointly sponsored by manufacturers or 
licensees of antiretroviral products. Additional information and a list of participating 
manufacturers/licensees are available from http://apregistry.com/index.htm.
6.10.12.
Time Period and Frequency of Detecting AEs and SAEs
The investigator or site staff is responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.
AEs will be collected from the start of study treatment and until the follow up contact.  
SAEs will be collected over the same time period as stated above for AEs. However, any 
SAEs assessed as related to study participation (e.g., study treatment, protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant 
medication, 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 reported to GSK within 24 
hours, as indicated in Section 6.10.13. 
6.10.13.
Method of Detecting AEs and SAEs
Care must 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?”
 
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6.10.14.
Prompt Reporting of Serious Adverse Events and Other Events 
to GSK
SAEs, pregnancies, and liver function abnormalities meeting pre-defined criteria will be 
reported promptly by the investigator to GSK as described in the following table once the 
investigator determines that the event meets the protocol definition for that event.
Initial Reports
Follow-up Information on a Previous 
Report
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
“SAE” data 
collection tool
24 hours
Updated “SAE” 
data collection tool
Cardiovascular (CV) 
or death event
Initial and 
follow up 
reports to be 
completed 
within one 
week of when 
the 
cardiovascular 
event or death 
is reported 
“CV events” 
and/or “death” 
data collection 
tool(s) if 
applicable
Initial and follow 
up reports to be 
completed within 
one week of when 
the cardiovascular 
event or death is 
reported
Updated “CV 
events” and/or 
“death” data 
collection tool(s) if 
applicable
PRSAE
1 week
PRSAE data 
collection tool
1 weeks
Updated PRSAE 
data collection tool
Suspected ABC 
HSR3
24 hours
ABC HSR eCRF
1 Week
Updated ABC HSR 
eCRF
Pregnancy
2 weeks
“Pregnancy 
Notification Form”
2 weeks
“Pregnancy Follow-
up Form”
Seizure or suspected 
seizure
24 hours
eCRF
24 hours
eCRF
Non-serious adverse 
events related to 
study treatment
5 calendar 
days
“Adverse 
Reaction” data 
collection tool
2 weeks
Updated “Adverse 
Reaction” data 
collection tool
Liver chemistry abnormalities see Section 6.10.31,2:
ALT≥3xULN plus 
Bilirubin≥2xULN 
(35% direct) 
24 hours 
SAE data 
collection tool 
Liver Event eCRF 
and liver imaging 
and/or biopsy 
eCRFs if 
applicable 
24 hours 
Updated SAE data 
collection tool 
Updated Liver 
Event eCRF 
ALT≥5xULN that 
persists ≥2 weeks 
24 hours 
Liver Event eCRF 
24 hours 
Updated Liver 
Event eCRF 
ALT ≥8xULN 
24 hours 
Liver Event eCRF 
24 hours 
Updated Liver 
Event eCRF 
 
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Initial Reports
Follow-up Information on a Previous 
Report
Type of Event
Time Frame
Documents
Time Frame
Documents
ALT ≥3xULN or ALT 
≥3 fold increase from 
Baseline value with 
appearance or 
worsening of 
symptoms of 
hepatitis or 
hypersensitivity
24 hours 
Liver Event eCRF 
24 hours 
Updated Liver 
Event eCRF 
1.
GSK must be contacted at onset of liver chemistry elevations to discuss subject safety.
2.
Liver Event Documents (i.e., “Liver Event eCRF” and “Liver Imaging eCRF” and/or “Liver Biopsy eCRF”, as 
applicable) should be completed as soon as possible.
3.
ABC HSR eCRF required only if event meets one of the ICH-E2A, 1994 definitions of seriousness (see 
Section 6.10.6.14.2).
The method of recording, evaluating and follow-up of AEs and SAEs plus procedures for 
completing and transmitting SAE reports to GSK are provided in the SPM.  Procedures 
for post-study AEs/SAEs are provided in the SPM.
6.10.14.1. Regulatory Reporting Requirements for SAEs
Prompt notification of SAEs by the investigator to GSK is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects 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.
6.11.
Pharmacokinetics
Plasma samples for determination of CAB and RPV concentration will be collected 
throughout the Maintenance Period and from Week 100 – Week 128 in the Extension 
Period of the study for subjects switching from oral Maintenance period regimen to the 
optimized IM dosing regimen of their choice.  Additional samples will be collected for 
storage during the Extension and Long-Term Follow Up Period.  Samples for 
determination of RPV will be protected from light until analyzed.
 
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6.11.1.
PK Sample Collection
Blood samples for evaluation of CAB (2 mL each) and RPV (2 mL each) plasma PK will 
be collected from all subjects randomized to receive CAB LA + RPV LA for 
determination of CAB and RPV concentrations as described in Table 4.  All PK samples 
will be collected prior to IM dosing and may be collected at anytime during visits that 
study treatment is not administered.  The exact date and time of the PK sample should be 
recorded in eCRF.
For subjects randomized to CAB 30 mg, pre-dose blood samples for evaluation of CAB
(2 mL each) and RPV (2 mL, Day 1 pre-dose only) will be collected as described in 
Table 4. These samples must be collected within the window of 20-28 hours after the last 
dose taken.  Subjects will be expected to complete a PK dosing diary card noting the date 
and time of the last three doses of IP prior to the scheduled clinic visits on Day 1, 
Weeks 32, 48 and 100.  The information from the diary card will be recorded in the 
eCRF.  Additionally, dosing information on the clinic day, including whether or not the 
dose was administered with food, if the subject vomited within 4 hours of dosing and the 
actual date and time of the PK samples, must be recorded on the eCRF.  Subjects will 
take their dose of oral IP in the clinic at PK visits.
 
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Table 4
CAB and RPV Plasma Pharmacokinetic Sample Schedule
Group
Analyte
Week
Sample Times Relative to Dose
IM
CAB
Day 1 (prior to LA and 
last oral Induction 
dose), Weeks: 1, 4, 8, 
12, 16, 20, 24, 25, 28,  
32, 36, 40, 41, 44 and
48
100* (prior to LA and 
last oral Maintenance 
dose), 104*, 108*, 112*, 
116*, 120*, 124* and 
128*
Pre-Dose (Q8W):  Day 1, Weeks 4, 8, 
16, 24, 32, 40, 48, 100*, 104*, 112*, 
120* and 128*
Pre-Dose (Q4W):  Day 1, Weeks 4, 8, 
12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 
100*, 104*, 108*, 112*, 116*, 120*, 
124* and 128*
2 Hours Post Dose:  Day 1, Weeks
32, 48, 100*a and 128*a
1 Week Post Dose: Week 1, Weeks
25, 41, 101*a and Week 121*a
4 Weeks Post Dose (Q8W):  Weeks 
12, 20, 28, 36 and 44
RPV
Day 1 (prior to LA and 
last oral Induction 
dose), Weeks: 1, 4, 8, 
12, 16, 20, 24, 25, 28, 
32, 36, 40, 41, 44 and
48
100* (prior to LA and 
last oral Maintenance 
dose), 104*, 108*, 112*, 
116*, 120*, 124* and 
128*
Pre-Dose (Q8W):  Day 1, Weeks 4, 8, 
16, 24, 32, 40, 48, 100*, 104*, 112*, 
120* and 128*
Pre-Dose (Q4W):  Day 1, Weeks 4, 8, 
12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 
100*, 104*, 108*, 112*, 116*, 120*, 
124* and 128*
2 Hours Post Dose:  Day 1, Weeks
32, 48, 100*a and 128*a
1 Week Post Dose:  Week 1, Weeks
25, 41, 101*a and Week 121*a
4 Weeks Post Dose (Q8W):  Weeks 
12, 20, 28, 36 and 44
Oral 
CAB
Day 1, Weeks: 32 and 
48
Pre-Dose:  Day 1, Weeks 32 and 48
RPV
Day 1
Pre-Dose:  Day 1
* Denotes PK sample times for subjects in the Extension Period.  Samples will be placed in storage.
a.
PK sample time for subjects switching from oral to an optimized IM dosing regimen only.
 
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Additional CAB and RPV PK samples for storage will be collected pre-dose at Weeks 
56, 64, 72, 80, 88 and 96 for subjects on CAB LA+RPV LA as per the Time and Events 
Table (see Section 6.2 and Section 6.3) and in the Extension Period (see Section 6.5 and 
Section 6.6).  Samples for storage will also be collected at Week 96 subjects on CAB 
30 mg+ABC/3TC, Weeks 100, 101, 104, 108, 112, 116, 120, 124 and 128 for subjects in 
the Extension Period, and at Months 1, 3, 6, 9 and 12 for subjects in the Long-Term 
Follow Up Period.  These samples may be analyzed in case of protocol-defined virologic 
failure or to investigate any PK related issues (such as missing dose, missing sample, 
suspected non-adherence etc.).
In addition, if a subject withdraws from the study a PK sample should be collected as 
early as practically possible (i.e. at withdrawal visit or on the day the withdrawal decision 
was made). 
Additional details concerning handling of PK samples, labeling and shipping directions 
will be supplied in the central laboratory manual.
6.11.2.
Rationale of PK Sampling Strategy
Given that PK data has been collected following oral administration of CAB and RPV 
(LAI116482), there will be no sampling during the Induction Period of the study.  Blood 
sampling for CAB and RPV concentrations will be performed during the Maintenance 
and Extension Periods of the study to evaluate PK in HIV infected subjects.  The 
proposed PK visits and sampling scheme at each visit presented in Table 4 is based on 
consideration of available PK data to support interim and final PK and 
PK/Pharmacodynamic (PD) analysis planned in this study.
6.11.3.
Bioanalysis of CAB and RPV
Plasma CAB analysis will be performed under the control of GSK PTSDMPK/ Scinovo.  
Concentrations of CAB will be determined in plasma samples using the currently 
approved bioanalytical methodology. Raw data will be archived at the bioanalytical site.
Once the plasma has been analyzed for CAB any remaining plasma may be analyzed for 
other compound-related metabolites and the results reported under a separate GSK PTS-
DMPK protocol.
Once the plasma has been analysed for RPV any remaining plasma may be used by the 
sponsor for further exploratory work on pharmacokinetics, metabolites, plasma protein 
binding, protein analysis, and biochemistry. No human DNA analysis will be performed.
Plasma CAB analysis will be performed under the control of Janssen R&D. 
Concentrations of CAB will be determined in plasma samples using the currently 
approved bioanalytical methodology. Raw data will be archived at the bioanalytical site.
 
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6.12.
Viral Genotyping and Phenotyping
Whole venous blood samples will be obtained from each subject to provide “plasma for 
storage samples” according to the Time and Events Schedule in Section 6 (for potential 
viral genotypic and phenotypic analyses). 
Details concerning the handling, labeling and shipping of these samples will be supplied 
separately.  Genotypic and phenotypic analyses may be carried out by Monogram 
Biosciences using, but not limited to, their Standard Phenosense and GenoSure testing 
methods for protease (PRO) and reverse transcriptase (RT), or with their GeneSeq 
Integrase and PhenoSense Integrase assays.
For Screening virologic evaluations, only viral genotype will be analyzed and this will be 
performed through the central laboratory.
6.12.1.
HIV-1 pol Viral Genotyping and Phenotyping
At screening, samples will be collected for HIV-1 RT and PRO genotype using a Quest 
Diagnostics genotype assay and results will be provided to the Investigator to assist in the 
determination of subject eligibility.
Subjects experiencing confirmed virologic failure will have plasma samples tested for 
HIV-1 PRO and RT genotype and phenotype and HIV-1 integrase genotype and 
phenotype from both Baseline samples and from samples collected at the time of 
suspected virologic failure; these results will be reported to the Investigator as soon as 
available to provide guidance for election of a switch regimen.
6.12.2.
HIV-1 Exploratory Analysis
Additional exploratory analyses for HIV-1 pol resistance may include viral genotyping 
and/or phenotyping on a representative subset of Baseline samples or virologic analysis 
on stored plasma samples from other time points. These analyses may also include but 
are not limited to additional viral genotyping and/or phenotyping, as well as other 
virologic evaluations such as linkage and minority species analyses, super low HIV-1 
RNA quantitation and measurement of viral replicative capacity.  HIV-1 integrase 
genotype and phenotype will also be determined on the last on-treatment isolates from all 
subjects who have HIV-1 RNA >200 c/mL regardless of confirmatory HIV-1 RNA.
6.13.
Pharmacogenetic Research
Information regarding pharmacogenetic (PGx) research is included in Section 11.3.  
The IEC/IRB and, where required, the applicable regulatory agency must approve the 
PGx assessments before these can be conducted at the site. The approval(s) must be in 
writing and will clearly specify approval of the PGx assessments (i.e., approval of 
Section 11.3).  In some cases, approval of the PGx assessments can occur after approval 
is obtained for the rest of the study. If so, then the written approval will clearly indicate 
approval of the PGx assessments is being deferred and the study, except for PGx 
 
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assessments, can be initiated. When PGx assessments will not be approved, then the 
approval for the rest of the study will clearly indicate this and therefore, PGx assessments 
will not be conducted.
6.14.
Health Outcomes
The HIV Treatment Satisfaction Questionnaire (HIVTSQ) [Woodcock, 2001 and 
Woodcock, 2006] was developed to evaluate treatments for HIV and patient satisfaction. 
The higher the score, the greater the improvement in treatment satisfaction as compared 
to the past few weeks. A smaller score represents a decline in treatment satisfaction 
compared to the past few weeks.  The HIVTSQ items are summed up to produce a 
treatment satisfaction score (0 to 60) and an individual satisfaction rating for each item 
(0 to 6) and two subscales: general satisfaction/clinical and lifestyle/ease subscales.
This study will be using the HIVTSQ(s) (status version) and the revised HIVTSQ(c) 
(change version). These measures will assess change in treatment satisfaction over time 
(in the same subjects) and compare current satisfaction with previous treatment 
satisfaction, from an earlier time point. 
The HIV Medication Questionnaire (HIVMQ) was developed to assess subject reported 
medication adherence.
The HIVTSQ(s) will be administered at the following time points: 

Induction: Week -(-16) and Week (-4) (pre-dose if possible) 

Maintenance:  pre-dose at Day 1, and post-dose (where possible in oral dosing 
arm) Week 8, Week 32, Week 48 and Week 96 

Withdrawal
The HIVTSQ(c) will be administered at the following time points:  

Maintenance:  Week 32
The HIVTSQ(c, WD) will be administered at the following time points:   

Withdrawal for subjects withdrawn between Week 8 and Week 32
HIVMQ will be administered at the following time points:

Induction: Week (-4)

Maintenance:  Week 8, Week 32, Week 48, Week 96 & Withdrawal
o
IM Regimen:  Complete post-injection
o
Oral Regimen:  Preferably completed at the beginning of the visit, but may 
be completed at any time during the visit.
 
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Qualitative interviews with 20-30 subjects may be conducted regarding the subject’s 
experience on the injection regimen. This would be conducted under a separate IRB/IEC 
approved consent. Participation in the interviews would be voluntary.
7.
DATA MANAGEMENT
For this study, subject data will be entered into GSK defined electronic case report forms 
(eCRFs), 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.  eCRFs (including queries and audit trails) will be retained by GSK, and 
copies will be sent to the investigator to maintain as the investigator copy.  In all cases, 
subject initials will not be collected or transmitted to GSK according to GSK policy.
8.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
8.1.
Hypotheses
The study is designed to evaluate the efficacy and safety of CAB LA 400 mg IM plus 
RPV LA 600 mg IM every 4 weeks and CAB LA 600 mg IM plus RPV LA 900 mg IM 
every 8 weeks, relative to CAB 30 mg once daily plus ABC/3TC once daily, through 
Week 32 of the Maintenance Period.
To claim positive outcome, the following hypotheses will be tested:
H0: Response rate for CAB LA plus RPV LA two-drug regimen CAB plus 
ABC/3TC -10%
H1: Response rate for CAB LA plus RPV LA two-drug regimen > CAB plus 
ABC/3TC -10%
8.2.
Study Design Considerations
8.2.1.
Sample Size Assumptions
IM treatment relative to Oral treatment
The sample size of 45 subjects in the oral treatment arm and 90 subjects each in the IM
treatment arms were chosen to ensure a high probability that a long-acting two drug 
treatment with truly poor response relative to CAB 30 mg once daily plus ABC/3TC once 
daily will not be studied further, while allowing for formal considerations of other factors 
should efficacy be similar between the treatment arms.  It is assumed that 85% subjects 
enrolled will be suppressed at Week (-16), approximately 265 subjects will be enrolled in 
order to have 225 subjects randomized at Day 1.
 
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The study is designed to test the comparability of CAB LA plus RPV LA two-drug 
regimen to CAB 30 mg once daily plus ABC/3TC. The primary comparison of interest 
will be performed using a Bayesian probability model. If the posterior probability that the 
difference is greater than -10% is large (i.e., 90%), then sufficient statistical evidence 
has been provided for the positive outcome. A response rate of 82% in the CAB LA plus 
RPV LA two-drug regimen (compared with an CAB 30 mg plus ABC/3TC response rate 
of 92%) would result in a rejection of the null hypothesis with a probability of 
approximately 0.064 (type I error). The given sample size is unlikely to select a random 
sample that would falsely conclude that CAB LA plus RPV LA two-drug regimen is 
comparable with CAB 30 mg plus ABC/3TC if the response rates are truly 82% versus 
92%, respectively. If the CAB LA plus RPV LA two-drug regimen yields a response rate 
of greater than 92%, then there is a high probability of rejecting the null hypothesis and 
correctly concluding that CAB LA plus RPV LA two-drug regimen is at least as good as 
CAB 30 mg plus ABC/3TC.
Historical response rates of dolutegravir, an integrase compound similar to CAB, were 
used as reference for the oral control arm.  Response rates for dolutegravir plus 
ABC/3TC ranged from 92% to 94% at Week 60 in studies SPRING-1, SPRING-2 and 
SINGLE among subjects who were suppressed (HIV-1 viral load <50 c/mL) at Week 24. 
The probability of a positive outcome assuming the true response rate for CAB LA plus 
RPV LA two-drug regimen is presented in Table 5.
Table 5
Probability of Positive Outcome Assuming True Response Rates of 
CAB LA plus RPV LA
True Response Rate for CAB LA 
plus RPV LA two-drug regimen 
(Q4W or Q8W)
80%
82%a
86%
90%
92%
94%
96%
Probability of Positive 
Outcomeb
2.8%
6.4%
26%
63%
82%
95%
99%
a.
Type I error is <10%.
b.
It is assumed that the response rate for CAB 30 mg plus ABC/3TC is 92%.
Incorporation of prior beliefs and information about population parameters is a required 
part of any Bayesian probability model. The assumptions made will help provide a more 
reliable estimate when the prior beliefs are combined with the observed data than the data 
alone as long as the beliefs are reasonable. Therefore, the trial will utilize a Beta (23, 2) 
distribution with the mean response rate being 92%, with 97.5th percentile of 99% and 
2.5th percentile of 78%.
Furthermore, a non- informative prior belief is assumed for the response rate for CAB LA 
plus RPV LA two-drug regimen. Therefore, the trial will conservatively utilize a Beta (1, 
1) distribution. These priors are displayed in Figure 15.
 
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Figure 15
Plot of Prior Distribution for Response Rate for CAB LA plus RPV LA 
two-drug regimen and CAB 30 mg plus ABC/3TC
The posterior probability limit is used as a measure of evidence in support of a 
hypothesis. Selection of the critical value to base a decision of comparability can be 
made so that the type I error rate is controlled and the desired power profile is attained.
The total number of responders in each treatment arm (experimental and active control) is 
modelled as independent binomially distributed random variables. Conjugate beta priors 
are selected to reflect the beliefs about the response rates previously described.
8.2.2.
Sample Size Sensitivity
Long Acting IM treatment relative to Oral treatment
The operating characteristic (power) curve is used to evaluate any decision criteria 
(Bayesian and non-Bayesian alike). The operating characteristic curve for the proposed 
sample sizes for each treatment arm and prior information is shown in Figure 16.
 
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Figure 16
Operating Characteristic Curve of Probability of Positive Outcome of 
CAB LA plus RPV LA two-drug regimen and CAB 30 mg plus 
ABC/3TC
8.2.3.
Sample Size Re-estimation
No sample size re-estimation is planned for this study.
8.3.
Data Analysis Considerations
8.3.1.
Analysis Populations
The following populations will be assessed:
8.3.1.1.
Intent-to-Treat Exposed Population (ITT-E)
The ITT-E population consists of all enrolled subjects who receive at least one dose of IP. 
Subjects will be analyzed according to their randomized treatment regardless of what 
treatment was actually received. Those that are not randomized will be summarized 
together under a ‘Not Randomized’ category. The ITT-E population will be the 
secondary population for some efficacy analyses.  
 
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8.3.1.2.
Intent-to-Treat Maintenance Exposed Population (ITT-ME)
The ITT-ME population consists of all randomized subjects who receive at least one dose 
of IP during the Maintenance Period of the study.  Subjects will be analyzed according to 
the randomized treatment regardless of what treatment was actually received. Unless 
stated otherwise, the ITT-ME population will be the primary population for efficacy 
analyses.
8.3.1.3.
Per Protocol Maintenance Exposed Population (PP-ME)
This population will consist of subjects in the ITT-ME population with the exception of 
major protocol violators (these will be defined in the RAP of this study).  The PP-ME
population will be a secondary population for efficacy purposes. 
8.3.1.4.
PK Population
The PK Population will include all subjects who receive CAB and /or RPV and undergo 
PK sampling during the study, and provide evaluable CAB and /or RPV plasma 
concentration data. Subjects in this population will be included in the PK analysis. 
8.3.1.5.
Safety Population
The Safety Population consists of all enrolled subjects who were exposed to 
investigational products with the exception of any subjects with documented evidence of 
not having consumed any amount of investigational product.  Subjects will be analyzed 
according to the actual treatments received.  Subjects will not be excluded from this 
population as a result of changes to the background regimen.  The safety population will 
be the primary population for safety analyses.  All safety analyses will be produced using 
the safety population.
Analysis populations for genotypic and phenotypic analyses will be described in the 
RAP.
8.3.1.6.
Extension Switch Population
The Extension Switch population will include all subjects randomized to the oral 30 mg + 
ABC/3TC arm who switch to and receive at least one dose of the optimized IM dosing 
regimen of their choice (either Q8W or Q4W) in the Extension Period.
The Extension Switch population will be used to evaluate safety and efficacy of the 
optimized IM dosing regimens during the Extension Period.
8.3.2.
Analysis Data Sets
The primary efficacy analysis data set will be based on the ITT-ME population described 
in Section 8.3.1.1. The efficacy dataset will include missing, switch, or discontinuation 
equals failure (MSDF) (also referred to as Snapshot), and the observed case (OC) 
endpoints for the proportion of subjects with plasma HIV-1 RNA less than the pre-
 
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defined threshold (e.g., <200 c/mL and <50 c/mL). The MSDF endpoint will be 
considered the primary analysis approach and will be determined based on the current 
Food and Drug Administration (FDA) definition of the Snapshot algorithm. Full details 
on this algorithm will be contained in the RAP.  The OC endpoint will not impute for any 
missing assessments. Details of the endpoint derivations will be described in the RAP for 
this study.
8.3.3.
Treatment Comparisons
8.3.3.1.
Primary Comparisons of Interest
The primary efficacy analysis will be performed at Week 32 based on the proportion of 
subjects in the ITT-ME population with plasma HIV-1 RNA <50 c/mL using MSDF 
algorithm. The primary comparison of interest will be the response rate of each IM 
dosing arm to the oral control arm performed using a Bayesian probability model.  The 
probability of (Response rate for IM arm > Response rate for Oral arm -10%) will be 
calculated.
8.3.3.2.
Other Comparisons of Interest
The probability of Q8W comparable to Q4W will be provided using the Bayesian 
probability model.
Measures of safety and tolerability will be assessed as detailed in the RAP.
8.3.4.
Planned Analysis
The ITT-ME population will be primary efficacy population and the safety population 
will be the primary safety population for all analyses.  All available data will be included 
in all interim analyses, including data beyond the designated time point except for the 
Day 1 analysis, if preformed, will only include data from the Induction Period.  
At the first interim analysis the IDMC will evaluate the efficacy, safety and tolerability of 
CAB to determine if the CAB regimen is suboptimal such that it should be discontinued 
before all subjects transition into the Maintenance Period of the study.  Full details of the 
analyses, estimated timing and the decision criteria that will be used to determine 
regimen performance will be pre-specified in the IDMC Charter.
This interim analysis schedule does not require an adjustment for multiplicity since there 
is no possibility of a false positive finding at any of the interim analyses conducted before 
Week 32, and since the Week 48 and 96 analyses will be used to further characterise the 
long-term safety and efficacy profile of CAB.  As no hypothesis is being tested for 
rejection during the constant monitoring of virologic response, no adjustment for 
multiplicity will be performed.
 
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8.3.4.1.
IDMC Interim Analyses
The purpose of these analyses is for the IDMC to evaluate the efficacy, safety and 
tolerability of CAB at early time points in the study and to monitor the occurrence of 
protocol defined virologic failure in subjects switching from oral CAB 30 mg +ABC/3TC 
to an optimized IM dosing regimens during the Extension Period.  
The IDMC intends to review at least one analysis before all eligible subjects have 
transitioned from the Induction Period to the Maintenance Period, or as soon as 
reasonably possible after subjects begin to enter the Maintenance Period.  Full details of 
the analyses, estimated timing and the decision criteria that will be used to determine 
regimen performance will be pre-specified in the IDMC Charter, with IDMC agreement.
All of the IDMC reviews will be produced by a Statistics and Data Analysis Centre 
(SDAC).  
8.3.4.2.
Futility Interim Monitoring
Continuous monitoring of the number of protocol defined virologic failures during the 
Maintenance Period and a futility interim analysis when 50% subjects have completed 
Week 24 is planned.
Continuous monitoring of the number of protocol defined virologic failures for subjects 
switching from oral CAB 30 mg + ABC/3TC to the optimized IM dosing regimen of their 
choice (Q8W or Q4W) will also be monitored during the Extension Period.
Continuous Monitoring
Plasma HIV-1 RNA data will be monitored closely as subjects enter the Maintenance 
Period in order to prevent subjects from continuing on a regimen if existing data indicates 
that they are at unacceptable risk of inadequate maintenance of virologic suppression. 
The number of protocol defined virologic failures during the Maintenance Period will be 
monitored in all subjects that have at least 4 weeks of either of the Maintenance Period 
IM dosing regimens (Week 4). If the number of failures meets or exceeds the thresholds 
specified in the table below (Table 6), this will be considered strong evidence of an 
inadequate response and will trigger a comprehensive IDMC data review and possible 
discontinuation of that treatment arm.  If an inadequate response is seen in any arm and it 
is determined by IDMC that that arm should be discontinued, then subjects on that 
treatment arm can be switched to the remaining IM arm.
Table 6
Number of protocol-defined virologic failures on Maintenance Period 
that constitute strong evidence of inadequate virologic response
Number of subjects that had at least 
four weeks of maintenance dose on IM
Number of protocol-defined virologic 
failures after maintenance dose on IM
3-21
>=3
22-32
>=4
33-43
>=5
44-54
>=6
 
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Number of subjects that had at least 
four weeks of maintenance dose on IM
Number of protocol-defined virologic 
failures after maintenance dose on IM
55-65
>=7
66-75
>=8
76-86
>=9
87-97
>=10
98-100
>=11
The thresholds described in this table are derived on the basis of the ratio of the 
likelihoods for the null hypothesis (H0) that there is a subgroup of subjects with 
inadequate maintenance of virologic suppression and the alternative hypothesis (H1) that 
the only failures in the study are due to poor compliance. For this analysis, H0 translates 
to a protocol defined virologic failure rate of 20% or higher (as defined in Section 4.6) 
and H1 translates to an expected 3% rate of protocol defined virologic failures.  For the 
first IDMC review, if the true rate of virologic failure is 20% as specified in H0, the 
probability to detect the inadequate virologic suppression is greater than 70%.  If the true 
rate of virologic failure is 3%, the probability that the number of virologic failures 
observed will exceed the threshold is less than<1%. Further details on this method are 
contained in the IDMC charter. Each threshold represents strong evidence in favour of H0
over H1 [Royall, 1997].
The scenarios described above are not exhaustive – it is possible that the overall failure 
rate does not meet the threshold but that a subgroup of subjects (e.g. with a given 
combination of mutations or fold resistance to CAB above an as yet unknown threshold) 
are consistently failing. GSK will monitor virologic response by Baseline genotype and 
may halt one or more treatment arms if at any time subjects are deemed to be at an 
unacceptable risk of an inadequate response on the basis of such monitoring, although the 
high number of possible genotypic subgroups precludes pre-specification of precise 
thresholds for such action.
The number of protocol defined virologic failures will also be monitored in subjects 
switching from oral CAB 30 mg + ABC/3TC to the optimized IM dosing regimen of their 
choice (Q8W or Q4W) during the Extension Period.  For subjects that have at least 4 
weeks of treatment with an optimized IM dosing regimen, if the number of protocol 
defined virologic failures meets or exceeds the thresholds specified in the table below 
(Table 7) prior to all subjects completing Week 160, this will be considered strong 
evidence of an inadequate response and will trigger a comprehensive IDMC data review.  
If an inadequate response is seen in any arm and it is determined by IDMC that that arm 
should be discontinued, then subjects on that treatment arm can be switched to the 
remaining IM dosing regimens.
 
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Table 7
Number of protocol-defined virologic failures for each Extension 
Period optimized IM dosing regimen that constitutes strong 
evidence of inadequate virologic response – Subjects switching 
from Maintenance oral CAB + ABC/3TC only 
Number of subjects with at least four 
weeks of IM dosing
Number of protocol-defined virologic 
failures needed to trigger IDMC review 
3-21
>=3
22-32
>=4
33-43
>=5
44-54
>=6
Futility Analysis after 50% of subjects complete Week 24
An interim analysis for the purpose of review by the IDMC will be performed after 
approximately 50% of subjects complete Week 24.  A futility rule based on Bayesian
posterior probability approach will be applied to assess the probability that the IM
treatment arm demonstrates comparability with the oral control arm given the partial data
set. Posterior probabilities of success (Prob (pIM > poral - 0.1 | data)) are provided in 
Table 8 for a subset of possible outcomes that could occur at the interim. Those outcomes 
associated with a posterior probability of success <40% may trigger a comprehensive 
IDMC data review and possible discontinuation of that treatment arm, although all data 
will be taken into consideration for making this decision.
Table 8
Posterior Probability of Successa at the Interim Analysis Under 
Various Scenarios
# Successes in IM arm (out of 45)
# 
Successes 
in Oral 
arm (out 
of 23)
35
(78%)
36
(80%)
37
(82%)
38
(84%)
39
(87%)
40
(89%)
41
(91%)
42
(93%)
18(78%)
0.564
0.678
0.753
0.850
0.913
0.955
0.979
0.993
19(83%)
0.454
0.558
0.679
0.782
0.859
0.931
0.966
0.986
20(87%)
0.346
0.465
0.574
0.694
0.805
0.890
0.942
0.974
21(91%)
0.244
0.348
0.455
0.584
0.706
0.829
0.907
0.961
22(96%)
0.146
0.231
0.335
0.461
0.604
0.736
0.845
0.926
23(100%)
0.081
0.135
0.218
0.324
0.473
0.612
0.755
0.874
a.
Posterior probability of success is defined as (prob(pIM > poral - 0.1 | data)) with informative prior Beta (23,2) for oral 
arm and non-informative prior Beta (1,1) for IM arm.
b.
Highlighted cells represent outcomes with posterior probability <0.4 that may trigger a comprehensive IDMC data 
review.
The proposed futility analysis has 91% chance to stop the study at the interim analysis if 
the true response rates are 92% and 72% for the oral arm and IM arm, respectively.  The 
power to stop the study is 46% if the true response rates are 92% and 82% for the oral 
arm and IM arm, respectively. The chance of stopping the study by error is 2% if the true 
response rates are 92% for both the oral arm and IM arm.
 
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8.3.4.3.
Day 1 Interim Analysis
A Day 1 interim analysis may be conducted to support regulatory submissions and/or 
scientific conference presentations once the last randomized subject has completed the 
Day 1 study visit and the database has been cleaned and released for analysis. The results 
of this analysis will be used to evaluate efficacy, safety and tolerability of CAB 30 mg 
once daily plus ABC/3TC once daily in the Induction Period.  Only data from the 
Induction Period would be summarized in this analysis.
8.3.4.4.
Week 32 Primary Analysis
The Week 32 primary analysis will be conducted once the last randomized subject has 
completed the Week 32 study visit and the database has been cleaned and released for 
analysis.  The results of this analysis will be used to characterize safety, tolerability and 
durability of antiviral response of both IM dosing regimens of CAB LA + RPV LA and 
to select a regimen for further development should both IM dosing regimens be 
comparable to the oral control arm.
8.3.4.5.
Week 48 Analysis
The Week 48 analysis will be conducted once the last randomized subject has completed 
the Week 48 study visit and the database has been cleaned and released for analysis.  The 
results of this analysis will be used to characterize the safety, tolerability and durability of 
antiviral response of both IM dosing regimens of CAB LA + CAB LA and to confirm the 
selected regimen for further development should both IM dosing regimens be comparable 
to the oral control arm.
8.3.4.6.
Week 96 Analysis
The Week 96 analysis will be conducted once the last randomized subject has completed 
the Week 96 study visit and the database has been cleaned and released for analysis.  The 
results of this analysis will be used to fully characterise the long term safety and efficacy 
profile of both IM dosing regimens of CAB LA and RPV LA.
8.3.4.7.
Week 128 Extension Switch Analysis
The Week 128 analysis will be conducted once the last randomized subject has 
completed the Week 128 study visit and the database has been cleaned and released for 
analysis.  The results of this analysis will be used to characterize the efficacy, tolerability, 
and safety of optimized IM dosing regimens for subjects switching from the oral regimen 
therapy at the end of the Maintenace Period.
8.3.4.8.
Week 160 Analysis
The Week 160 analysis will be conducted once the last randomized subject has 
completed the Week 160 study visit and the database has been cleaned and released for 
analysis.  The results of this analysis will be used to characterize the following: (a) the 
long-term safety and efficacy profile of both IM dosing regimens for subjects who 
 
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continued randomized IM dosing in the Extension Period and (b) the safety, tolerability 
and durability of antiviral response of the optimized IM dosing regimens for subjects 
switching from the oral regimen therapy at the end of the Maintenace Period.
Follow-up analyses after the Week 160 analysis may be conducted to more fully 
characterize the long-term safety and efficacy profile of CAB LA + RPV LA dosing 
regimens.
8.3.5.
Key Elements of Analysis Plan
8.3.5.1.
Efficacy Analyses
All efficacy analyses, except as stated otherwise, will be based on the ITT-ME 
population.
The primary efficacy analysis will be based on the MSDF approach mentioned in 
Section 8.3.2. For the MSDF analysis, any switches in background ART after HIV-1 
RNA has been collected may be considered as failures even if the switch was done to 
manage intolerance issues. Plasma HIV-1 RNA will be log10-transformed prior to 
statistical analyses. Data will be allocated to visit windows using actual visit dates rather 
than nominal visit numbers. Data collected from extra visits within a window will be 
included in the derivation of the time to protocol defined virologic failure, but summary 
tables using OC datasets will only use the data captured closest to the target visit date. 
Detailed explanations of the derivation of visit windows will be included in the RAP.
Any deviations from the planned analyses described in this protocol or the RAP will be 
detailed in the clinical study report (CSR).
For the analysis of CAB LA+RPV LA arms (IM arms) response rate relative to CAB 
30 mg + ABC/3TC (oral arm), let:
XLA = number of responder in IM arm, and 
Xoral = number of responder in oral arm
The binomial distribution is the assumed likelihood of the response data, as follows:
XLA ~ Binomial (90, pIM)  
Xoral ~ Binomial (45, poral)  
Since the true response rate is unknown, prior distributions are placed on these 
parameters of interest to reflect current beliefs and balanced with acceptable decision 
criteria performance. Conjugate beta densities are assumed. The information pertaining 
to the oral arm response rate is well understood and the prior that was chosen reflects the 
belief that the response rate is between 78% and 99% with 95% certainty. There is very 
few information about the response rate for IM arm, therefore, a non-informative prior 
assumed. 
PLA ~ Beta (1, 1)
 
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Poral ~ Beta (23, 2)
The posterior probability that the response rate for IM arm demonstrates the 
comparability of oral arm is as follows: 
p1 = P (PIM > poral - 0.1 | data)
A posterior probability of at least 90% (i.e., p1 >0.90) corresponds to “substantial 
evidence of positive outcome” and is chosen as the weight of evidence threshold. 
Sensitivity analyses may be performed to assess the impact of the choice of informative 
prior for oral arm response rate though the analysis described above will remain primary 
for indication of efficacy decision-making purposes. As an alternative to the informative 
prior, a Beta (1, 1) prior distribution for oral arm may be considered. Full details of the 
planned Bayesian analyses will be provided in the RAP.
The proportion of subjects with plasma HIV-1 RNA <50 c/mL as determined by the 
MSDF algorithm will be provided by treatment group over the entire time on study by 
visit for the ITT-ME population and the ITT-E population. 
In addition, an OC analysis may be performed for supportive purposes.
For the probability of comparability between two IM arms, a non-informative prior of 
Beta (1, 1) will be used for both IM treatment arms.
8.3.5.2.
Safety Analyses
The study is designed to characterize a regimen for further evaluation on the basis of 
tolerability and virologic efficacy in conjunction with immunological response, safety 
and pharmacokinetic measures. Measures of safety and tolerability will be used to assess 
the regimen as detailed in the RAP of the study.
Exposure to study medication, measured by the number of weeks on study drug, will be 
summarized by treatment arm. The proportion of subjects reporting adverse events (AEs) 
will be tabulated for each treatment arm. The following summaries of AEs will be 
provided:
Incidence and severity of All AEs including injection site reactions;
Incidence and severity of treatment related AEs;
Incidence and severity of AEs leading to withdrawal from study;
Incidence of serious AEs (SAEs).
Laboratory data, vital signs and ECG data (absolute values and change from Baseline) 
will be summarized by visit and treatment group. In addition, the number and percentage 
of subjects with laboratory values of clinical concern will be summarized by treatment 
group. The proportion of subjects experiencing changes from Baseline in their National 
 
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Cholesterol Education Program (NCEP) and DAIDS lipid categories will be summarized 
by treatment arm.
Framingham Risk assessment will be calculated as detailed in the RAP and will be 
summarized by treatment arm.
8.3.5.3.
Treatment Compliance
The overall proportion of IP study medication taken relative to the planned amount will 
be estimated via pill counts and scheduled injections and summarized by treatment arm 
for each IP.
8.3.5.4.
Health Outcomes Analyses
Data from the eC-SSRS, HIVTSQ(s), HIVTSQ(c), and HIVMQ will be summarised by 
visit.  Total satisfaction scores and lifestyle/ease sub-scores will be summarised at each 
time point by treatment group using the mean, SD, median, min and max.
In an effort to reduce ‘potentially avoidable’ study discontinuations (for example, lost to 
follow up, subject withdrawal, non-compliance, protocol violation) and to improve data 
quality, patient characteristics will be studied to focus retention efforts on subgroups of 
subjects more likely to withdraw prematurely from the study.
Further details of the analyses to be performed will be specified in the reporting and 
analysis plan (RAP).
8.3.5.5.
Pharmacokinetic Analyses
The GSK Division of Clinical Pharmacology Modelling and Simulation (CPMS) will be 
responsible for the PK analysis of CAB. The Divisions of Clinical Pharmacology and 
Model-Based Drug Development at Janssen Research and Development will be 
responsible for conduct or oversight of the PK analysis for RPV.
PK analysis of the plasma CAB and RPV concentration-time data will be conducted 
using non-compartmental methods with WinNonlin (Version 5.2 or higher).  Actual 
sampling and dosing times as recorded in the eCRF will be used for analysis.  Predose 
concentration (C0) for CAB and RPV will be estimated.
Plasma CAB and RPV concentration data will be listed and summarized by week, day, 
and planned sampling time in both tabular and graphical forms. Plasma CAB and RPV
PK parameters will be listed and summarized by CAB or RPV treatment.  
Details of the PK analyses in the PK Population for CAB will be provided in the RAP.
Population PK Analysis:
A population-based PK model may be constructed based on the CAB and/or RPV PK 
data and individual Bayesian PK parameter estimates may be obtained, if the quality of 
the data permits.  Data from the study could be merged with some previous data to help 
 
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the model building process.  The effect of age, body size (weight, height, body surface 
area, and body mass index), gender, ethnic origin, HIV status, and concurrent 
medications (such as oral and injectable contraceptives) on CAB and/or RPV PK may be 
explored. Population PK analyses will be done under separate Population-PK Reporting 
and Analysis Plans.
8.3.5.6.
Pharmacokinetic/Pharmacodynamic Analyses
Relationships between various plasma CAB and / or RPV PK parameters and 
pharmacodynamic measures (e.g., HIV-1 RNA, or safety measures) may be explored 
using simple correlation analyses or population-based PK/PD approach.  Additional 
factors that may be considered include age, weight, BMI, gender, race, Baseline HIV-1 
RNA, HIV risk factors, CDC classification, and CD4+ cell count.  Details of the PK/PD 
analyses plans for CAB and / or RPV will be provided in separate RAPs.
8.3.5.7.
Viral Genotyping/Phenotyping Analyses
The incidence of treatment emergent genotypic and phenotypic resistance to NRTIs and 
INIs will be summarized by treatment arm. Details of the analyses to be performed will 
be specified in the reporting and analysis plan (RAP).
8.3.5.8.
Pharmacogenetic Analyses
See Section 11.3 for details about the Pharmacogenetics Analysis Plan.
9.
STUDY CONDUCT CONSIDERATIONS
9.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of subjects begins.
9.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a study 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.
The study will be conducted in accordance with ICH GCP, all applicable subject privacy 
requirements, and the ethical principles that are outlined in the Declaration of Helsinki 
2008, including, but not limited to:
 
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Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
favourable opinion/approval of study protocol and any subsequent amendments.
Subject informed consent.
Investigator reporting requirements.
GSK will provide full details of the above procedures, either verbally, in writing, or 
both.
Written informed consent must be obtained from each subject prior to participation in the 
study.
In approving the clinical protocol the IEC/IRB and, where required, the applicable 
regulatory agency are also approving the optional assessments e.g., PGx assessments 
described in Section 11.3, unless otherwise indicated.  Where permitted by regulatory 
authorities, approval of the optional assessments can occur after approval is obtained for 
the rest of the study.  If so, then the written approval will clearly indicate approval of the 
optional assessments is being deferred and the study, except for the optional assessments, 
can be initiated.  When the optional assessments are not approved, then the approval for 
the rest of the study will clearly indicate this and therefore, the optional assessments will 
not be conducted.
9.3.
Quality Control (Study Monitoring)
In accordance with applicable regulations, 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 include 
identification, agreement and documentation of data items for which the eCRF will serve 
as the source document.
GSK will monitor the study to ensure that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents.
9.4.
Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance assessment and/or audit of the site records, and the regulatory 
agencies may conduct a regulatory inspection at any time during or after completion of 
the study. In the event of an assessment, audit or inspection, the investigator (and 
institution) must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to 
 
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all relevant documents and to allocate their time and the time of their staff to discuss the 
conduct of the study, any findings/relevant issues and to implement any corrective and/or 
preventative actions to address any findings/issues identified.
9.5.
Study and Site Closure
The study is considered complete once all subjects have transitioned to commercially 
available IP, transitioned to another study for access to IP, withdrawn or completed the 
study per Section 3.2.
Upon completion or termination of the study, the GSK monitor will conduct site closure 
activities with the investigator or site staff (as appropriate), in accordance with applicable 
regulations, GCP, and GSK Standard Operating Procedures.
GSK reserves the right to temporarily suspend or terminate the study at any time for 
reasons including (but not limited to) safety issues, ethical issues, or severe non-
compliance.  If GSK determines that such action is required, GSK will discuss the 
reasons for taking such action with the investigator or head of the medical institution 
(where applicable).  When feasible, GSK will provide advance notice to the investigator 
or head of the medical institution of the impending action.
If a study is suspended or terminated for safety reasons, GSK will promptly inform all 
investigators, heads of the medical institutions (where applicable), and/or institutions 
conducting the study.  GSK will also promptly inform the relevant regulatory authorities 
of the suspension/termination along with the reasons for such action.  Where required by 
applicable regulations, the investigator or head of the medical institution must inform the 
IRB/IEC promptly and provide the reason(s) for the suspension/termination.
9.6.
Records Retention
Following closure of the study, the investigator or 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 easily accessible 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 the 
records may be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution must 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.  In addition, they must meet accessibility and retrieval standards, 
including regeneration of a hard copy, if required.  The investigator must also ensure that 
an acceptable back-up of the reproductions exists and that there is an acceptable quality 
control procedure in place for creating the reproductions.
GSK will inform the investigator of the time period for retaining the site records in order 
to comply with all applicable regulatory requirements.  The minimum retention time will 
 
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meet the strictest standard applicable to a particular site, as dictated by local 
laws/regulations, GSK standard operating procedures, and/or institutional requirements.
The investigator must notify GSK of any changes in the archival arrangements, including, 
but not limited to archival of records at an off-site facility or transfer of ownership of the 
records in the event that the investigator is no longer associated with the site.
9.7.
Provision of Study Results to Investigators, Posting of 
Information on Publicly 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 results summary will be posted to the Clinical Study Register no later than eight 
months after the final primary completion date, the date that the final subject was 
examined or received an intervention for the purposes of final collection of data for the 
primary outcome.  In addition, a manuscript will be submitted to a peer reviewed journal 
for publication no later than 18 months after the last subject’s last visit (LSLV).  When 
manuscript publication in a peer reviewed journal is not feasible, a statement will be 
added to the register to explain the reason for not publishing.
9.8.
Independent Data Monitoring Committee (IDMC)
An IDMC will be utilised in this study to ensure external objective medical and/or 
statistical review of safety and/or efficacy issues in order to protect the ethical and safety 
interests of subjects and to protect the scientific validity of the study.  The schedule of 
any planned interim analysis and the analysis plan for IDMC review is described in the 
charter, which is available upon request.
 
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9:320-333
 
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11.
APPENDICES
11.1.
Appendix 1: CDC Classification System for HIV-1 Infections 
(1993)
Clinical Categories
The clinical categories of HIV infection are defined as follows:
Category A
Category A consists of one or more of the conditions listed below in an adolescent or 
adult (>13 years) with documented HIV infection.  Conditions listed in Categories B and 
C must not have occurred.

Asymptomatic HIV infection

Persistent generalized lymphadenopathy

Acute (primary) HIV infection with accompanying illness or history of acute 
HIV infection
Category B (Symptomatic non-AIDS conditions)
Category B consists of symptomatic conditions in an HIV-infected adolescent or adult 
that are not included among conditions listed in clinical Category C and that meet at least 
one of the following criteria:  a) the conditions are attributed to HIV infection or are 
indicative of a defect in cell-mediated immunity; or b) the conditions are considered by 
physicians to have a clinical course or to require management that is complicated by HIV 
infection.  
Examples of conditions in clinical Category B include, but are not limited to:

Bacillary angiomatosis

Candidiasis, oropharyngeal (thrush)

Candidiasis, vulvovaginal; persistent, frequent, or poorly responsive to therapy

Cervical dysplasia (moderate or severe)/cervical carcinoma in situ

Constitutional symptoms, such as fever (38.5C) or diarrhea lasting >1 month

Hairy leukoplakia, oral

Herpes zoster (shingles), involving at least two distinct episodes or more than 
one dermatome

Idiopathic thrombocytopenic purpura

Listeriosis

Pelvic inflammatory disease, particularly if complicated by tubo-ovarian abscess
 
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
Peripheral neuropathy
For classification purposes, Category B conditions take precedence over those in 
Category A.  For example, someone previously treated for oral or persistent vaginal 
candidiasis (and who has not developed a Category C disease) but who is now 
asymptomatic should be classified in clinical Category B.
Category C (AIDS indicator conditions as defined by diagnostic or presumptive 
measures).
Category C includes the clinical conditions listed in the AIDS surveillance case 
definition.  For classification purposes, once a Category C condition has occurred, the 
person will remain in Category C.
Conditions in Category C include:

Candidiasis of bronchi, trachea, or lungs

Candidiasis, esophageal

Cervical cancer, invasive

Coccidioidomycosis, disseminated or extrapulmonary

Cryptococcosis, extrapulmonary

Cryptosporidiosis, chronic intestinal (>1 month’s duration)

Cytomegalovirus disease (other than liver, spleen, or nodes)

Cytomegalovirus retinitis (with loss of vision)

Encephalopathy, HIV-related

Herpes simplex:  chronic ulcer(s) (>1 month’s duration);or bronchitis, 
pneumonitis, or esophagitis

Histoplasmosis, disseminated or extrapulmonary

Isosporiasis, chronic intestinal (>1 month’s duration)

Kaposi’s sarcoma

Lymphoma, Burkitt’s (or equivalent term)

Lymphoma, immunoblastic (or equivalent term)

Lymphoma, primary, of brain

Mycobacterium avium complex or M. kansasii, disseminated or extrapulmonary

Mycobacterium tuberculosis, any site (pulmonary or extrapulmonary)

Mycobacterium, other species or unidentified species, disseminated or 
extrapulmonary

Pneumocystis carinii pneumonia

Pneumonia, recurrent
 
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
Progressive multifocal leukoencephalopathy

Salmonella septicemia, recurrent

Toxoplasmosis of brain

Wasting syndrome due to HIV

Non-CDC, HIV-associated conditions.
 
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11.2.
Appendix 2: Division of AIDS Table for Grading the Severity 
of Adult and Pediatric Adverse Events
VERSION 1.0, DECEMBER 2004; CLARIFICATION AUGUST 2009
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events (“DAIDS AE Grading Table”) is a descriptive terminology which can be utilized 
for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE 
term.
 
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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
ESTIMATING SEVERITY GRADE1
Clinical adverse event NOT 
identified elsewhere in this DAIDS 
AE grading table
Symptoms causing no or minimal 
interference with usual social & 
functional activities3, 4
Symptoms causing greater than 
minimal interference with usual 
social & functional activities3, 4
Symptoms causing inability to 
perform usual social & functional 
activities3, 4
Symptoms causing inability to perform 
basic self-care functions1, 2 OR Medical 
or operative intervention indicated to 
prevent permanent impairment, 
persistent disability, or death
SYSTEMIC
Acute systemic allergic reaction
Localized urticaria (wheals) with 
no medical intervention indicated
Localized urticaria with medical 
intervention indicated OR Mild 
angioedema with no medical 
intervention indicated
Generalized urticaria OR 
Angioedema with medical 
intervention indicated OR 
Symptomatic 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
Fatigue
Malaise
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 fatigue/malaise 
symptoms
causing inability to perform basic self-
care functions
Fever (nonaxillary)
37.7 – 38.6C
38.7 – 39.3C
39.4 – 40.5C
> 40.5C
Pain (indicate body site)
DO NOT use for pain due to 
injection (See Injection Site 
Reactions: Injection site pain)
See also Headache, Arthralgia,
and Myalgia
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 (other than emergency 
room visit) indicated
Unintentional weight loss
NA
5 – 9% loss in body weight from 
baseline
10 – 19% loss in body weight from 
baseline
20% loss in body weight from 
baseline OR Aggressive intervention 
indicated [e.g., tube feeding or total 
parenteral nutrition (TPN)]
 
 
 
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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
INFECTION
Infection (any other than HIV 
infection)
Localized, no systemic 
antimicrobial treatment indicated 
AND Symptoms causing no or 
minimal interference with usual 
social & functional activities
Systemic antimicrobial treatment 
indicated OR Symptoms causing 
greater than minimal interference 
with usual social & functional 
activities
Systemic antimicrobial treatment 
indicated AND Symptoms causing 
inability to perform usual social & 
functional activities OR Operative 
intervention (other than simple 
incision and drainage) indicated
Life-threatening consequences (e.g., 
septic shock)
INJECTION SITE REACTIONS
Injection site pain (pain without 
touching)
Or
Tenderness (pain when area is 
touched)
Pain/tenderness causing no or 
minimal limitation of use of limb
Pain/tenderness limiting use of limb 
OR Pain/tenderness causing 
greater than minimal interference 
with usual social & functional 
activities
Pain/tenderness causing inability to 
perform usual social & functional 
activities
Pain/tenderness causing inability to 
perform basic self-care function OR 
Hospitalization (other than emergency 
room visit) indicated for management 
of pain/tenderness
Injection site reaction (localized)
Adult > 15 years
Erythema OR Induration of 5x5 cm 
– 9x9 cm (or 25 cm2 – 81cm2)
Erythema OR Induration OR
Edema > 9 cm any diameter (or > 
81 cm2)
Ulceration OR Secondary infection 
OR Phlebitis OR Sterile abscess OR 
Drainage
Necrosis (involving dermis and deeper
tissue)
Pediatric 15 Years
Erythema OR Induration OR 
Edema present but 2.5 cm 
diameter
Erythema OR Induration OR 
Edema > 2.5 cm diameter but < 
50% surface area of the extremity 
segment (e.g., upper arm/thigh)
Erythema OR Induration OR Edema 
involving 50% surface area of the 
extremity segment (e.g., upper 
arm/thigh) OR Ulceration OR 
Secondary infection OR Phlebitis OR 
Sterile abscess OR Drainage
Necrosis (involving dermis and deeper 
tissue)
Pruritis associated with injection
See also Skin: Pruritis (itching - no 
skin lesions)
Itching localized to injection site 
AND Relieved spontaneously or 
with < 48 hours treatment
Itching beyond the injection site but 
not generalized OR Itching 
localized to injection site requiring 
48 hours treatment
Generalized itching causing inability 
to perform usual social & functional 
activities
NA
 
 
 
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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
SKIN – DERMATOLOGICAL
Alopecia
Thinning detectable by study 
participant (or by caregiver for 
young children and disabled 
adults)
Thinning or patchy hair loss 
detectable by health care provider
Complete hair loss
NA
Cutaneous reaction – rash
Localized macular rash
Diffuse macular, maculopapular, or 
morbilliform rash OR Target lesions
Diffuse macular, maculopapular, or 
morbilliform rash with vesicles or 
limited number of bullae OR 
Superficial ulcerations of mucous 
membrane limited to one site
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)
Hyperpigmentation
Slight or localized
Marked or generalized
NA
NA
Hypopigmentation
Slight or localized
Marked or generalized
NA
NA
Pruritis (itching – no skin lesions)
(See also Injection Site Reactions: 
Pruritis associated with injection)
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
CARDIOVASCULAR
Cardiac arrhythmia (general)
(By ECG or physical exam)
Asymptomatic AND No 
intervention indicated
Asymptomatic AND Non-urgent 
medical intervention indicated
Symptomatic, non-life-threatening 
AND Non-urgent medical intervention 
indicated
Life-threatening arrhythmia OR Urgent 
intervention indicated
Cardiac-ischemia/infarction
NA
NA
Symptomatic ischemia (stable 
angina) OR Testing consistent with 
ischemia
Unstable angina OR Acute myocardial 
infarction
Hemorrhage (significant acute 
blood loss)
NA
Symptomatic AND No transfusion 
indicated
Symptomatic AND Transfusion of 2 
units packed RBCs (for children 10 
cc/kg) indicated
Life-threatening hypotension OR 
Transfusion of > 2 units packed RBCs 
(for children >10 cc/kg) indicated
Hypertension
Adult > 17 years
(with repeat testing at same 
visit)
140 – 159 mmHg systolic
OR
90 – 99 mmHg diastolic
160 – 179 mmHg systolic
OR
100 – 109 mmHg diastolic
180 mmHg systolic
OR
110 mmHg diastolic
Life-threatening consequences (e.g., 
malignant hypertension) OR 
Hospitalization indicated (other than 
emergency room visit)
 
 
 
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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
Pediatric 17 Years
(with repeat testing at same 
visit)
NA
91st – 94th percentile adjusted for 
age, height, and gender (systolic 
and/or diastolic)
95th percentile adjusted for age, 
height, and gender (systolic and/or 
diastolic)
Life-threatening consequences (e.g., 
malignant hypertension) OR 
Hospitalization indicated (other than 
emergency room visit)
Hypotension
NA
Symptomatic, corrected with oral 
fluid replacement
Symptomatic, IV fluids indicated
Shock requiring use of vasopressors or 
mechanical assistance to maintain 
blood pressure
Pericardial effusion
Asymptomatic, small effusion 
requiring no intervention
Asymptomatic, moderate or larger 
effusion requiring no intervention
Effusion with non-life threatening 
physiologic consequences OR 
Effusion with non-urgent intervention 
indicated
Life-threatening consequences (e.g., 
tamponade) OR Urgent intervention 
indicated
Prolonged PR interval
Adult > 16 years
PR interval
0.21 – 0.25 sec
PR interval
> 0.25 sec
Type II 2nd degree AV block OR 
Ventricular pause > 3.0 sec
Complete AV block
Pediatric 16 Years
1st degree AV block (PR > normal 
for age and rate)
Type I 2nd degree AV block
Type II 2nd degree AV block
Complete AV block
Prolonged QTc
Adult > 16 years
Asymptomatic, QTc interval 
0.45-0.47 sec OR Increase interval 
<0.03 sec above baseline
Asymptomatic, QTc interval 
0.48-0.49 sec OR Increase in 
interval 0.03 – 0.05 sec above 
baseline
Asymptomatic, QTc interval 0.50 
sec OR Increase in interval 0.06 
sec above baseline
Life-threatening consequences, e.g., 
Torsade de pointes or other associated 
serious ventricular dysrhythmia
Pediatric 16 years
Asymptomatic, QTc interval 
0.450–0.464 sec
Asymptomatic, QTc interval 
0.465-0.479 sec
Asymptomatic, QTc
interval 0.480 sec
Life-threatening consequences, e.g., 
Torsade de pointes or other associated 
serious ventricular dysrhythmia
Thrombosis/embolism
NA
Deep vein thrombosis AND No 
intervention indicated (e.g., 
anticoagulation, lysis filter, invasive 
procedure)
Deep vein thrombosis AND 
Intervention indicated (e.g., 
anticoagulation, lysis filter, invasive 
procedure)
Embolic event (e.g., pulmonary 
embolism, life-threatening thrombus)
Vasovagal episode (associated 
with a procedure of any kind)
Present without loss of 
consciousness
Present with transient loss of 
consciousness
NA
NA
Ventricular dysfunction 
(congestive heart failure)
NA
Asymptomatic diagnostic finding 
AND intervention indicated
New onset with symptoms OR 
Worsening symptomatic congestive 
heart failure
Life-threatening congestive heart 
failure
 
 
 
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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
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 or   total parenteral 
nutrition (TPN)]
Comment: Please note that, while the grading scale provided for Unintentional Weight Loss may be used as a guideline when grading anorexia, this is not a requirement and should 
not be used as a substitute for clinical judgment.
Ascites
Asymptomatic
Symptomatic AND Intervention 
indicated (e.g., diuretics or 
therapeutic paracentesis)
Symptomatic despite intervention
Life-threatening consequences
Cholecystitis
NA
Symptomatic AND Medical 
intervention indicated
Radiologic, endoscopic, or operative 
intervention indicated
Life-threatening consequences (e.g., 
sepsis or 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
Adult and
Pediatric 1 year
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 – 6 
stools over baseline per 24-hour 
period
Bloody diarrhea OR Increase of 7 
stools per 24-hour period OR IV fluid 
replacement indicated
Life-threatening consequences (e.g., 
hypotensive shock)
Pediatric < 1 year
Liquid stools (more unformed than 
usual) but usual number of stools
Liquid stools with increased number 
of stools OR Mild dehydration
Liquid stools with moderate 
dehydration
Liquid stools resulting in severe 
dehydration with aggressive 
rehydration indicated OR Hypotensive 
shock
Dysphagia-
Odynophagia
Symptomatic but able to eat usual 
diet
Symptoms causing altered dietary 
intake without medical intervention 
indicated
Symptoms causing severely altered 
dietary intake with medical 
intervention indicated
Life-threatening reduction in oral intake
 
 
 
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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
Mucositis/stomatitis (clinical 
exam)
Indicate site (e.g., larynx, oral)
See Genitourinary for 
Vulvovaginitis 
See also Dysphagia-Odynophagia 
and Proctitis
Erythema of the mucosa
Patchy pseudomembranes or 
ulcerations
Confluent pseudomembranes or 
ulcerations OR Mucosal bleeding 
with minor trauma
Tissue necrosis OR Diffuse 
spontaneous mucosal bleeding OR 
Life-threatening consequences (e.g., 
aspiration, choking)
Nausea
Transient (< 24 hours) or 
intermittent nausea with no or 
minimal interference with oral 
intake
Persistent nausea resulting in 
decreased oral intake for 24 – 48 
hours
Persistent nausea resulting in 
minimal oral intake for > 48 hours OR 
Aggressive rehydration indicated 
(e.g., IV fluids)
Life-threatening consequences (e.g., 
hypotensive shock)
Pancreatitis
NA
Symptomatic AND Hospitalization 
not indicated (other than 
emergency room visit)
Symptomatic AND Hospitalization 
indicated (other than emergency 
room visit)
Life-threatening consequences (e.g., 
circulatory failure, hemorrhage, sepsis)
Proctitis (functional-symptomatic)
Also see Mucositis/stomatitis for 
clinical exam
Rectal discomfort AND 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)
Vomiting
Transient or intermittent vomiting 
with no or minimal interference 
with oral intake
Frequent episodes of vomiting 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)
 
 
 
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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
NEUROLOGIC
Alteration in personality-behavior 
or in mood (e.g., agitation, 
anxiety, depression, mania, 
psychosis)
Alteration causing no or minimal 
interference with usual social & 
functional activities
Alteration causing greater than 
minimal interference with usual 
social & functional activities
Alteration causing inability to perform 
usual social & functional activities
Behavior potentially harmful to self or 
others (e.g., suicidal and homicidal 
ideation or attempt, acute psychosis) 
OR Causing inability to perform basic 
self-care functions
Altered Mental Status
For Dementia, see Cognitive and 
behavioral/attentional disturbance 
(including dementia and attention 
deficit disorder)
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
Asymptomatic ataxia detectable on 
exam OR Minimal ataxia causing 
no or minimal interference with 
usual  social & functional activities
Symptomatic ataxia causing greater 
than minimal interference with usual 
social & functional activities
Symptomatic ataxia causing inability 
to perform usual social & functional 
activities
Disabling ataxia causing inability to 
perform basic self-care functions
Cognitive and 
behavioral/attentional disturbance 
(including dementia and attention 
deficit disorder)
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
CNS ischemia (acute)
NA
NA
Transient ischemic attack
Cerebral vascular accident (CVA, 
stroke) with neurological deficit
Developmental delay
– Pediatric 16 Years
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 (other than 
emergency room visit) OR Headache 
with significant impairment of alertness 
or other neurologic function
 
 
 
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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
Insomnia
NA
Difficulty sleeping causing greater 
than minimal interference with usual 
social & functional activities
Difficulty sleeping causing inability to 
perform usual social & functional 
activities
Disabling insomnia causing inability to 
perform basic self-care functions
Neuromuscular weakness 
(including myopathy & 
neuropathy)
Asymptomatic with decreased 
strength on exam OR Minimal 
muscle weakness causing no or 
minimal interference with usual 
social & functional activities
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 (including 
paresthesia and painful 
neuropathy)
Asymptomatic with sensory 
alteration on exam or minimal 
paresthesia causing no or minimal 
interference with usual social & 
functional activities
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
Seizure: (new onset)
– Adult 18 years
See also Seizure: (known pre-
existing seizure disorder)
NA
1 seizure
2 – 4 seizures
Seizures of any kind which are 
prolonged, repetitive (e.g., status 
epilepticus), or difficult to control (e.g., 
refractory epilepsy)
Seizure: (known pre-existing 
seizure disorder)
– Adult 18 years
For worsening of existing epilepsy 
the grades should be based on an 
increase from previous level of 
control to any of these levels.
NA
Increased frequency of pre-existing 
seizures (non-repetitive) without 
change in seizure character OR 
Infrequent break-through seizures 
while on stable medication in a 
previously controlled seizure 
disorder
Change in seizure character from 
baseline either in duration or quality 
(e.g., severity or focality)
Seizures of any kind which are 
prolonged, repetitive (e.g., status 
epilepticus), or difficult to control (e.g., 
refractory epilepsy)
Seizure
– Pediatric < 18 years
Seizure, generalized onset with or 
without secondary generalization, 
lasting < 5 minutes with < 24 hours 
post ictal state
Seizure, generalized onset with or 
without secondary generalization, 
lasting 5 – 20 minutes with <24 
hours post ictal state
Seizure, generalized onset with or 
without secondary generalization, 
lasting >20 minutes
Seizure, generalized onset with or 
without Secondary generalization, 
requiring intubation and sedation
Syncope (not associated with a 
procedure)
NA
Present
NA
NA
 
 
 
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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
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
RESPIRATORY
Bronchospasm (acute)
FEV1 or peak flow reduced to 
70-80%
FEV1 or peak flow 50–69%
FEV1 or peak flow 25–49%
Cyanosis OR FEV1 or peak flow < 
25% OR Intubation
Dyspnea or respiratory distress
Adult 14 years
Dyspnea on exertion with no or 
minimal interference with usual 
social & functional activities
Dyspnea on exertion causing 
greater than minimal interference 
with usual social & functional 
activities
Dyspnea at rest causing inability to 
perform usual social & functional 
activities
Respiratory failure with ventilatory 
support Indicated
Pediatric < 14 years
Wheezing OR minimal increase in 
respiratory rate for age
Nasal flaring OR Intercostal
retractions OR Pulse oximetry 90 –
95%
Dyspnea at rest causing inability to 
perform usual social & functional 
activities OR Pulse oximetry < 90%
Respiratory failure with ventilatory 
support indicated
MUSCULOSKELETAL
Arthralgia
See also Arthritis
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
See also Arthralgia
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
Bone Mineral Loss
Adult 21 years
BMD t-score -2.5 to -1.0
BMD t-score < -2.5
Pathological fracture (including loss 
of vertebral height)
Pathologic fracture causing life-
threatening Consequences
Pediatric < 21 years
BMD z-score -2.5 to -1.0
BMD z-score < -2.5
Pathological fracture (including loss 
of vertebral height)
Pathologic fracture causing life-
threatening Consequences
Myalgia (non-injection site)
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
Asymptomatic with radiographic 
findings AND No operative 
intervention indicated
Symptomatic bone pain with 
radiographic findings OR Operative 
intervention indicated
Disabling bone pain with radiographic 
findings causing inability to perform 
basic self-care functions
 
 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
GENITOURINARY
Cervicitis (symptoms)
(For use in studies evaluating 
topical study agents)
For other cervicitis see Infection: 
Infection (any other than HIV 
infection)
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
Cervicitis (clinical exam)
(For use in studies evaluating 
topical study agents)
For other cervicitis see Infection: 
Infection (any other than HIV 
infection)
Minimal cervical abnormalities on 
examination (erythema,
Mucopurulent discharge, or 
friability) OR Epithelial disruption < 
25% of total surface
Moderate cervical abnormalities on 
examination (erythema, 
mucopurulent discharge, or 
friability) OR Epithelial disruption of 
25 – 49% total surface
Severe cervical abnormalities on 
examination (erythema, 
mucopurulent discharge, or friability) 
OR Epithelial disruption 50 – 75% 
total surface
Epithelial disruption > 75% total 
surface
Inter-menstrual bleeding (IMB)
Spotting observed by participant 
OR Minimal blood observed during 
clinical or colposcopic examination
Inter-menstrual bleeding not greater 
in duration or amount than usual 
menstrual cycle
Inter-menstrual bleeding greater in 
duration or amount than usual 
menstrual cycle
Hemorrhage with life-threatening 
hypotension OR Operative intervention 
indicated
Urinary tract obstruction (e.g., 
stone)
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
Vulvovaginitis (symptoms)
(Use in studies evaluating topical 
study agents) 
For other vulvovaginitis see 
Infection: Infection (any other than 
HIV infection)
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
 
 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
Vulvovaginitis (clinical exam)
(Use in studies evaluating topical 
study agents)
For other vulvovaginitis see 
Infection: Infection (any other than 
HIV infection)
Minimal vaginal abnormalities on 
examination OR Epithelial 
disruption <25% of total surface
Moderate vaginal abnormalities on
examination OR Epithelial 
disruption of 25 - 49% total surface
Severe vaginal abnormalities on 
examination OR Epithelial disruption 
50 - 75% total surface
Vaginal perforation OR Epithelial 
disruption > 75% total surface
OCULAR/VISUAL
Uveitis
Asymptomatic but detectable on 
exam
Symptomatic anterior uveitis OR 
Medical intervention indicated
Posterior or pan-uveitis OR Operative 
intervention indicated
Disabling visual loss in affected eye(s)
Visual changes (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)
ENDOCRINE/METABOLIC
Abnormal fat accumulation (e.g., 
back of neck, breasts, abdomen)
Detectable by study participant (or 
by caregiver for young children 
and disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious changes on 
casual visual inspection
NA
Diabetes mellitus
NA
New onset without need to initiate 
medication OR Modification of 
current medications to regain 
glucose control
New onset with initiation of 
medication indicated OR Diabetes 
uncontrolled despite treatment 
modification
Life-threatening consequences (e.g., 
ketoacidosis, hyperosmolar non-ketotic 
coma)
Gynecomastia
Detectable by study participant or 
caregiver (for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious on casual 
visual inspection
NA
Hyperthyroidism
Asymptomatic
Symptomatic 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)
 
 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
Hypothyroidism
Asymptomatic
Symptomatic 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)
Lipoatrophy (e.g., fat loss from the 
face, extremities, buttocks)
Detectable by study participant (or 
by caregiver for young children 
and disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious on casual 
visual inspection
NA
1.
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
2.
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally appropriate eating implement).
3.
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc.
4.
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play activities, learning tasks, etc.).
 
 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
LABORATORY
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
HEMATOLOGY
Standard International Units are listed in italics
Absolute CD4+ count
– Adult and Pediatric
> 13 years
(HIV NEGATIVE ONLY)
300 – 400/mm3
300 – 400/µL
200 – 299/mm3
200 – 299/µL
100 – 199/mm3
100 – 199/µL
< 100/mm3
< 100/µL
Absolute lymphocyte
count
– Adult and Pediatric
> 13 years
(HIV NEGATIVE ONLY)
600 – 650/mm3
0.600 x 109 –
0.650 x 109/L
500 – 599/mm3
0.500 x 109 –
0.599 x 109/L
350 – 499/mm3
0.350 x 109 –
0.499 x 109/L
< 350/mm3
< 0.350 x 109/L
Comment:  Values in children 13 years are not given for the two parameters above because the absolute counts are variable.
Absolute neutrophil count (ANC)
Adult and Pediatric,
> 7 days
1,000 – 1,300/mm3
1.000 x 109 –
1.300 x 109/L
750 – 999/mm3
0.750 x 109 –
0.999 x 109/L
500 – 749/mm3
0.500 x 109 –
0.749 x 109/L
< 500/mm3
< 0.500 x 109/L
Infant*†, 2 – 7 days
1,250 – 1,500/mm3
1.250 x 109 –
1.500 x 109/L
1,000 – 1,249/mm3
1.000 x 109 –
1.249 x 109/L
750 – 999/mm3
0.750 x 109 –
0.999 x 109/L
< 750/mm3
< 0.750 x 109/L
Infant*†, 1 day
4,000 – 5,000/mm3
4.000 x 109 –
5.000 x 109/L
3,000 – 3,999/mm3
3.000 x 109 –
3.999 x109/L
1,500 – 2,999/mm3
1.500 x 109 –
2.999 x 109/L
< 1,500/mm3
< 1.500 x 109/L
Fibrinogen, decreased
100 – 200 mg/dL
1.00 – 2.00 g/L
OR
0.75 – 0.99 x LLN
75 – 99 mg/dL
0.75 – 0.99 g/L
OR
0.50 – 0.74 x LLN
50 – 74 mg/dL
0.50 – 0.74 g/L
OR
0.25 – 0.49 x LLN
< 50 mg/dL
< 0.50 g/L
OR
< 0.25 x LLN
OR
Associated with gross bleeding
 
 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
Hemoglobin (Hgb)
Adult and Pediatric
57 days
(HIV POSITIVE ONLY)
8.5 – 10.0 g/dL
5.24 – 6.23 mmol/L
7.5 – 8.4 g/dL
4.62 – 5.23 mmol/L
6.50 – 7.4 g/dL
4.03 – 4.61 mmol/L
< 6.5 g/dL
< 4.03 mmol/L
Adult and Pediatric
57 days
(HIV NEGATIVE ONLY)
10.0 – 10.9 g/dL
6.18 – 6.79 mmol/L
OR
Any decrease
2.5 – 3.4 g/dL
1.58 – 2.13 mmol/L
9.0 – 9.9 g/dL
5.55 – 6.17 mmol/L
OR
Any decrease
3.5 – 4.4 g/dL
2.14 – 2.78 mmol/L
7.0 – 8.9 g/dL
4.34 – 5.54 mmol/L
OR
Any decrease
4.5 g/dL
2.79 mmol/L
< 7.0 g/dL
< 4.34 mmol/L
Infant*†, 36 – 56 days
(HIV POSITIVE OR 
NEGATIVE)
8.5 – 9.4 g/dL
5.24 – 5.86 mmol/L
7.0 – 8.4 g/dL
4.31 – 5.23 mmol/L
6.0 – 6.9 g/dL
3.72 – 4.30 mmol/L
< 6.00 g/dL
< 3.72 mmol/L
Infant*†, 22 – 35 days
(HIV POSITIVE OR 
NEGATIVE)
9.5 – 10.5 g/dL
5.87 – 6.54 mmol/L
8.0 – 9.4 g/dL
4.93 – 5.86 mmol/L
7.0 – 7.9 g/dL
4.34 – 4.92 mmol/L
< 7.00 g/dL
< 4.34 mmol/L
Infant*†, 21 days
(HIV POSITIVE OR 
NEGATIVE)
12.0 – 13.0 g/dL
7.42 – 8.09 mmol/L
10.0 – 11.9 g/dL
6.18 – 7.41 mmol/L
9.0 – 9.9 g/dL
5.59 – 6.17 mmol/L
< 9.0 g/dL
< 5.59 mmol/L
International Normalized
Ratio of prothrombin time
(INR)
1.1 – 1.5 x ULN
1.6 – 2.0 x ULN
2.1 – 3.0 x ULN
> 3.0 x ULN
Methemoglobin
5.0 – 10.0%
10.1 – 15.0%
15.1 – 20.0%
> 20.0%
Prothrombin Time (PT)
1.1 – 1.25 x ULN
1.26 – 1.50 x ULN
1.51 – 3.00 x ULN
> 3.00 x ULN
Partial Thromboplastin
Time (PTT)
1.1 – 1.66 x ULN
1.67 – 2.33 x ULN
2.34 – 3.00 x ULN
> 3.00 x ULN
Platelets, decreased
100,000 –
124,999/mm3
100.000 x 109 –
124.999 x 109/L
50,000 –
99,999/mm3
50.000 x 109 –
99.999 x 109/L
25,000 –
49,999/mm3
25.000 x 109 –
49.999 x 109/L
< 25,000/mm3
< 25.000 x 109/L
WBC, decreased
2,000 – 2,500/mm3
2.000 x 109 –
2.500 x 109/L
1,500 – 1,999/mm3
1.500 x 109 –
1.999 x 109/L
1,000 – 1,499/mm3
1.000 x 109 –
1.499 x 109/L
< 1,000/mm3
< 1.000 x 109/L
 
 
 
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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
CHEMISTRIES
Standard International Units are listed in italics
Acidosis
NA
pH < normal, but 7.3
pH < 7.3 without life-threatening 
consequences
pH < 7.3 with life-threatening 
consequences
Albumin, serum, low
3.0 g/dL – < LLN
30 g/L – < LLN
2.0 – 2.9 g/dL
20 – 29 g/L
< 2.0 g/dL
< 20 g/L
NA
Alkaline Phosphatase
1.25 – 2.5 x ULN†
2.6 – 5.0 x ULN†
5.1 – 10.0 x ULN†
> 10.0 x ULN†
Alkalosis
NA
pH > normal, but 7.5
pH > 7.5 without life-threatening 
consequences
pH > 7.5 with life-threatening 
consequences
ALT (SGPT)
1.25 – 2.5 x ULN
2.6 – 5.0 x ULN
5.1 – 10.0 x ULN
> 10.0 x ULN
AST (SGOT)
1.25 – 2.5 x ULN
2.6 – 5.0 x ULN
5.1 – 10.0 x ULN
> 10.0 x ULN
Bicarbonate, serum, low
16.0 mEq/L – < LLN
16.0 mmol/L – < LLN
11.0 – 15.9 mEq/L
11.0 – 15.9 mmol/L
8.0 – 10.9 mEq/L
8.0 – 10.9 mmol/L
< 8.0 mEq/L
< 8.0 mmol/L
Bilirubin (Total)
Adult and Pediatric >14 
days
1.1 – 1.5 x ULN
1.6 – 2.5 x ULN
2.6 – 5.0 x ULN
> 5.0 x ULN
Infant*†, 14 days (non-
hemolytic)
NA
20.0 – 25.0 mg/dL
342 – 428 µmol/L
25.1 – 30.0 mg/dL
429 – 513 µmol/L
> 30.0 mg/dL
> 513.0 µmol/L
Infant*†, 14 days
(hemolytic)
NA
NA
20.0 – 25.0 mg/dL
342 – 428 µmol/L
> 25.0 mg/dL
> 428 µmol/L
Calcium, serum, high (corrected for albumin)
Adult and Pediatric 7 
days
10.6 – 11.5 mg/dL
2.65 – 2.88 mmol/L
11.6 – 12.5 mg/dL
2.89 – 3.13 mmol/L
12.6 – 13.5 mg/dL
3.14 – 3.38 mmol/L
> 13.5 mg/dL
> 3.38 mmol/L
Infant*†, < 7 days
11.5 – 12.4 mg/dL
2.88 – 3.10 mmol/L
12.5 – 12.9 mg/dL
3.11 – 3.23 mmol/L
13.0 – 13.5 mg/dL
3.245 – 3.38 mmol/L
> 13.5 mg/dL
> 3.38 mmol/L
Calcium, serum, low 
Adult and Pediatric 7 
days
7.8 – 8.4 mg/dL
1.95 – 2.10 mmol/L
7.0 – 7.7 mg/dL
1.75 – 1.94 mmol/L
6.1 – 6.9 mg/dL
1.53 – 1.74 mmol/L
< 6.1 mg/dL
< 1.53 mmol/L
Infant*†, < 7 days
6.5 – 7.5 mg/dL
1.63 – 1.88 mmol/L
6.0 – 6.4 mg/dL
1.50 – 1.62 mmol/L
5.50 – 5.90 mg/dL
1.38 – 1.51 mmol/L
< 5.50 mg/dL
< 1.38 mmol/L
Cardiac troponin I (cTnI)
NA
NA
NA
Levels consistent with myocardial 
infarction or unstable angina as defined 
by the manufacturer
 
 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
Cardiac troponin T (cTnT)
NA
NA
NA
0.20 ng/mL
OR
Levels consistent with myocardial 
infarction or unstable angina as defined 
by the manufacturer
Cholesterol (fasting)
Adult 18 years
200 – 239 mg/dL
5.18 – 6.19 mmol/L
240 – 300 mg/dL
6.20 – 7.77 mmol/L
> 300 mg/dL
> 7.77 mmol/L
NA
Pediatric < 18 years
170 – 199 mg/dL
4.40 – 5.15 mmol/L
200 – 300 mg/dL
5.16 – 7.77 mmol/L
> 300 mg/dL
> 7.77 mmol/L
NA
Creatine Kinase
3.0 – 5.9 x ULN†
6.0 – 9.9 x ULN†
10.0 – 19.9 x ULN†
20.0 x ULN†
Creatinine
1.1 – 1.3 x ULN†
1.4 – 1.8 x ULN†
1.9 – 3.4 x ULN†
3.5 x ULN†
Glucose, serum, high
Nonfasting
116 – 160 mg/dL
6.44 – 8.88 mmol/L
161 – 250 mg/dL
8.89 – 13.88 mmol/L
251 – 500 mg/dL
13.89 – 27.75 mmol/L
> 500 mg/dL
> 27.75 mmol/L
Fasting
110 – 125 mg/dL
6.11 – 6.94 mmol/L
126 – 250 mg/dL
6.95 – 13.88 mmol/L
251 – 500 mg/dL
13.89 – 27.75 mmol/L
> 500 mg/dL
> 27.75 mmol/L
Glucose, serum, low
Adult and Pediatric 1 
month
55 – 64 mg/dL
3.05 – 3.55 mmol/L
40 – 54 mg/dL
2.22 – 3.06 mmol/L
30 – 39 mg/dL
1.67 – 2.23 mmol/L
< 30 mg/dL
< 1.67 mmol/L
Infant*†, < 1 month
50 – 54 mg/dL
2.78 – 3.00 mmol/L
40 – 49 mg/dL
2.22 – 2.77 mmol/L
30 – 39 mg/dL
1.67 – 2.21 mmol/L
< 30 mg/dL
< 1.67 mmol/L
Lactate
ULN - < 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
LDL cholesterol (fasting)
Adult 18 years
130 – 159 mg/dL
3.37 – 4.12 mmol/L
160 – 190 mg/dL
4.13 – 4.90 mmol/L
190 mg/dL
4.91 mmol/L
NA
Pediatric > 2 - < 18 years
110 – 129 mg/dL
2.85 – 3.34 mmol/L
130 – 189 mg/dL
3.35 – 4.90 mmol/L
190 mg/dL
4.91 mmol/L
NA
Lipase
1.1 – 1.5 x ULN
1.6 – 3.0 x ULN
3.1 – 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
Magnesium, serum, low
1.2 – 1.4 mEq/L
0.60 – 0.70 mmol/L
0.9 – 1.1 mEq/L
0.45 – 0.59 mmol/L
0.6 – 0.8 mEq/L
0.30 – 0.44 mmol/L
< 0.60 mEq/L
< 0.30 mmol/L
Pancreatic amylase
1.1 – 1.5 x ULN
1.6 – 2.0 x ULN
2.1 – 5.0 x ULN
> 5.0 x ULN
Phosphate, serum, low
Adult and Pediatric > 14 
years
2.5 mg/dL – < LLN
0.81 mmol/L – < LLN
2.0 – 2.4 mg/dL
0.65 – 0.80 mmol/L
1.0 – 1.9 mg/dL
0.32 – 0.64 mmol/L
< 1.00 mg/dL
< 0.32 mmol/L
Pediatric 1 year – 14 years
3.0 – 3.5 mg/dL
0.97 – 1.13 mmol/L
2.5 – 2.9 mg/dL
0.81 – 0.96 mmol/L
1.5 – 2.4 mg/dL
0.48 – 0.80 mmol/L
< 1.50 mg/dL
< 0.48 mmol/L
Pediatric < 1 year
3.5 – 4.5 mg/dL
1.13 – 1.45 mmol/L
2.5 – 3.4 mg/dL
0.81 – 1.12 mmol/L
1.5 – 2.4 mg/dL
0.48 – 0.80 mmol/L
< 1.50 mg/dL
< 0.48 mmol/L
Potassium, serum, high
5.6 – 6.0 mEq/L
5.6 – 6.0 mmol/L
6.1 – 6.5 mEq/L
6.1 – 6.5 mmol/L
6.6 – 7.0 mEq/L
6.6 – 7.0 mmol/L
> 7.0 mEq/L
> 7.0 mmol/L
Potassium, serum, low
3.0 – 3.4 mEq/L
3.0 – 3.4 mmol/L
2.5 – 2.9 mEq/L
2.5 – 2.9 mmol/L
2.0 – 2.4 mEq/L
2.0 – 2.4 mmol/L
< 2.0 mEq/L
< 2.0 mmol/L
Sodium, serum, high
146 – 150 mEq/L
146 – 150 mmol/L
151 – 154 mEq/L
151 – 154 mmol/L
155 – 159 mEq/L
155 – 159 mmol/L
160 mEq/L
160 mmol/L
Sodium, serum, low
130 – 135 mEq/L
130 – 135 mmol/L
125 – 129 mEq/L
125 – 129 mmol/L
121 – 124 mEq/L
121 – 124 mmol/L
120 mEq/L
120 mmol/L
Triglycerides (fasting)
NA
500 – 750 mg/dL
5.65 – 8.48 mmol/L
751 – 1,200 mg/dL
8.49 – 13.56 mmol/L
> 1,200 mg/dL
> 13.56 mmol/L
Uric acid
7.5 – 10.0 mg/dL
0.45 – 0.59 mmol/L
10.1 – 12.0 mg/dL
0.60 – 0.71 mmol/L
12.1 – 15.0 mg/dL
0.72 – 0.89 mmol/L
> 15.0 mg/dL
> 0.89 mmol/L
URINALYSIS
Standard International Units are listed in italics
Hematuria (microscopic)
6 – 10 RBC/HPF
> 10 RBC/HPF
Gross, with or without clots OR with 
RBC casts
Transfusion indicated
Proteinuria, random
Collection
1 +
2 – 3 +
4 +
NA
 
 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
Proteinuria, 24 hour collection
Adult and Pediatric  10 
years
200 – 999 mg/24 h
0.200 – 0.999 g/d
1,000 – 1,999 mg/24 h
1.000 – 1.999 g/d
2,000 – 3,500 mg/24 h
2.000 – 3.500 g/d
> 3,500 mg/24 h
> 3.500 g/d
Pediatric > 3 mo -< 10 
years
201 – 499 mg/m2/24 h
0.201 – 0.499 g/d
500 – 799 mg/m2/24 h
0.500 – 0.799 g/d
800 – 1,000 mg/m2/24 h
0.800 – 1.000 g/d
> 1,000 mg/ m2/24 h
> 1.000 g/d
Values are for term infants.  Preterm infants should be assessed using local normal ranges.
† Use age and sex appropriate values (e.g., bilirubin).
 
 
 
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11.3.
Appendix 3: Pharmacogenetic Research
Pharmacogenetics – Background
Pharmacogenetics (PGx) is the study of variability in drug response due to hereditary 
factors in populations.  There is increasing evidence that an individual's genetic 
background (i.e., genotype) may impact the pharmacokinetics (absorption, distribution, 
metabolism, elimination), pharmacodynamics (relationship between concentrations and 
pharmacologic effects or the time course of pharmacologic effects) and/or clinical 
outcome (in terms of efficacy and/or safety and tolerability).  Some reported examples of 
PGx associations with safety/adverse events include:
Drug
Disease
Gene Variant
Outcome
Abacavir
HIV 
[Hetherington, 
2002; 
Mallal, 2002; 
Mallal, 2008]
HLA-B* 57:01 
(Human 
Leukocyte 
Antigen B)
Carriage of the HLA-B*57:01 variant has been 
shown to increase a patient's risk for 
experiencing hypersensitivity to abacavir.  
Prospective HLA-B*57:01 screening and 
exclusion of HLA-B*57:01 positive patients 
from abacavir treatment significantly 
decreased the incidence of abacavir 
hypersensitivity.  Treatment guidelines and 
abacavir product labeling in the United States 
and Europe now recommend (US) or require 
(EU) prospective HLA-B*57:01 screening prior 
to initiation of abacavir to reduce the incidence 
of abacavir hypersensitivity.  HLA-B*57:01
screening should supplement but must never 
replace clinical risk management strategies for 
abacavir hypersensitivity.
Carbamaze
pine
Seizure, Bipolar 
disorders & 
Analgesia 
[Chung, 2010; 
Ferrell, 2008]
HLA-B*15:02
Independent studies indicated that patients of 
East Asian ancestry who carry HLA-B*15:02
are at higher risk of Stevens-Johnson 
Syndrome and toxic epidermal necrolysis.  
Regulators, including the US FDA and the 
Taiwanese TFDA, have updated the 
carbamazepine drug label to indicate that 
patients with ancestry in genetically at risk 
populations should be screened for the 
presence of HLA-B*15:02 prior to initiating 
treatment with carbamazepine.
 
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Drug
Disease
Gene Variant
Outcome
Irinotecan
Cancer 
[Innocenti, 2004; 
Liu, 2008; 
Schulz, 2009]
UGT1A1*28
Variations in the UGT1A1 gene can influence 
a patient’s ability to break down irinotecan, 
which can lead to increased blood levels of the 
drug and a higher risk of side effects. A dose 
of irinotecan that is safe for one patient with a 
particular UGT1A1 gene variation might be too 
high for another patient without this variation, 
raising the risk of certain side-effects that 
include neutropenia following initiation of 
Irinotecan treatment.  The irinotecan drug 
label indicates that individuals who have two 
copies of the UGT1A1*28 variant are at 
increased risk of neutropenia.  A genetic blood 
test is available that can detect variations in 
the gene.    
A key component to successful PGx research is the collection of samples during the 
conduct of clinical studies.
Collection of whole blood samples, even when no a priori hypothesis has been identified, 
may enable PGx analysis to be conducted if at any time it appears that there is a potential 
unexpected or unexplained variation in response to GSK1265744.
Pharmacogenetic Research Objectives
The objective of the PGx research (if there is a potential unexpected or unexplained 
variation) is to investigate a relationship between genetic factors and response to 
GSK1265744.  If at any time it appears there is potential variability in response in this 
clinical study or in a series of clinical studies with GSK1265744 the following objectives 
may be investigated – the relationship between genetic variants and study treatment with 
respect to:

Pharmacokinetics and/or pharmacodynamics of study treatment

Safety and/or tolerability 

Efficacy
Study Population
Any subject who is enrolled in the clinical study, can participate in PGx research.  Any 
subject who has received an allogeneic bone marrow transplant must be excluded from 
the PGx research.
Subject participation in the PGx research is voluntary and refusal to participate will not 
indicate withdrawal from the clinical study or result in any penalty or loss of benefits to 
which the subject would otherwise be entitled.
 
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Study Assessments and Procedures
Blood samples can be taken for Deoxyribonucleic acid (DNA) extraction and used in 
PGx assessments.
If taking blood samples: in addition to any blood samples taken for the clinical study, a 
whole blood sample (~6ml) will be collected for the PGx research using a tube containing 
EDTA.  It is recommended that the blood sample be taken at the first opportunity after a 
subject has been randomised and provided informed consent for PGx research, but may 
be taken at any time while the subject is participating in the clinical study.

The PGx sample is labelled (or “coded”) with a study specific number that can be 
traced or linked back to the subject by the investigator or site staff.  Coded samples 
do not carry personal identifiers (such as name or social security number).  The 
blood sample is taken on a single occasion unless a duplicate sample is required due 
to inability to utilise the original sample.  
The DNA extracted from the blood sample may be subjected to sample quality control 
analysis.  This analysis will involve the genotyping of several genetic markers to confirm 
the integrity of individual samples.  If inconsistencies are noted in the analysis, then those 
samples may be destroyed.
The need to conduct PGx analysis may be identified after a study (or a set of studies) of 
GSK1265744 has been completed and the clinical study data reviewed.  In some cases, 
the samples may not be studied. e.g., no questions are raised about how people respond to 
GSK1265744.
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 use samples collected from the study for 
the purpose stated in this protocol and in the informed consent form.  
Subjects can request their sample to be destroyed at any time.
Subject Withdrawal from Study
If a subject who has consented to participate in PGx 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 PGx sample, if already collected:

Continue to participate in the PGx research with the PGx sample retained for 
analysis 

Withdraw from the PGx research and destroy the PGx sample 
If a subject withdraws consent for PGx 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. The investigator should forward the Pharmacogenetic Sample 
 
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Destruction Request Form to GSK as directed on the form. This can be done at any time 
when a subject wishes to withdraw from the PGx research or have their sample destroyed 
whether during the study or during the retention period following close of the main study.
Screen and Baseline Failures
If a blood sample for PGx research has been collected and it is determined that the 
subject does not meet the entry criteria for participation in the clinical study, then the 
investigator should instruct the participant that their PGx sample will be destroyed. No 
forms are required to complete this process as it will be completed as part of the consent 
and sample reconciliation process.  In this instance a sample destruction form will not be 
available to include in the site files.
Pharmacogenetics Analyses
1.
Specific genes may be studied that encode the drug targets, or drug mechanism of 
action pathways, drug metabolizing enzymes, drug transporters or which may 
underpin adverse events, disease risk or drug response. These candidate genes may 
include a common set of ADME (Absorption, Distribution, Metabolism and 
Excretion) genes that are studied to determine the relationship between gene variants 
or treatment response and/or tolerance. 
In addition, continuing research may identify other enzymes, transporters, proteins or 
receptors that may be involved in response to GSK1265744.  The genes that may code for 
these proteins may also be studied.
2.
Genome-wide scans involving a large number of polymorphic markers (e.g., single 
nucleotide polymorphisms) at defined locations in the genome, often correlated with 
a candidate gene, may be studied to determine the relationship between genetic 
variants and treatment response or tolerance. This approach is often employed when 
a definitive candidate gene(s) does not exist and/or the potential genetic effects are 
not well understood. 
If applicable and PGx research is conducted, appropriate statistical analysis methods will 
be used to evaluate pharmacogenetic data in the context of the other clinical data. Results 
of PGx investigations will be reported either as part of the main clinical study report or as 
a separate report. Endpoints of interest from all comparisons will be descriptively and/or 
graphically summarised as appropriate to the data.  A detailed description of the analysis 
to be performed will be documented in the study reporting and analysis plan (RAP) or in 
a separate pharmacogenetics RAP, as appropriate.  
Informed Consent
Subjects who do not wish to participate in the PGx research may still participate in the 
clinical study.  PGx informed consent must be obtained prior to any blood being taken for 
PGx research.
 
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Provision of Study Results and Confidentiality of Subject’s PGx Data
GSK may summarise the PGx research results in the clinical study report, or separately, 
or may publish the results in scientific journals. 
GSK does not inform the investigator, subject, or anyone else (e.g., family members, 
study investigators, primary care physicians, 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 PGx studies is generally preliminary in nature, and therefore the 
significance and scientific validity of the results are undetermined.
References
Chung WH, Hung SL, Chen YT. Genetic predisposition of life-threatening antiepileptic-
induced skin reactions.  Expert Opin. Drug Saf. 2010; 9: 15-21.
Ferrell PB, McLeod HL.  Carbamazepine, HLA-B*1502 and risk of Stevens-Johnson 
syndrome and toxic epidermal necrolysis: US FDA recommendations.  
Pharmacogenomics. 2008; 9: 1543-1546.
Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, Lai E, 
Davies K, Handley A, Dow DJ, Fling ME, Stocum M, Bowman C, Thurmond LM, Roses 
AD. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. 
Lancet. 2002; 359:1121-1122.
Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, Karrison T, Janisch 
L, Ramirez J, Rudin CM, Vokes EE, Ratain MJ.  Genetic variants in the UDP-
glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J 
Clin Oncol 2004; 22: 1382-1388.
Liu CY, Chen PM, Chiou TJ, Liu JH, Lin JK, Lin TC, Chen WS, Jiang JK, Wang HS, 
Wang WS.  UGT1A1*28 polymorphism predicts irinotecan-induced severe toxicities 
without affecting treatment outcome and survival in patients with metastatic colorectal 
carcinoma.  Cancer. 2008; 112: 1932-1940.
Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte 
C, Maxwell D, James I.  Association between presence of HLA-B*5701, HLA-DR7, and 
HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir.  
Lancet. 2002; 359:727-732.
Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomazic J, Jägel-Guedes E, 
Rugina S, Kozyrev O, Cid JF, Hay P, Nolan D, Hughes S, Hughes A, Ryan S, Fitch N, 
Thorborn D, Benbow A; PREDICT-1 Study Team.  HLA-B*5701 screening for 
hypersensitivity to abacavir. N Engl J Med. 2008; 358; 568-579
Schulz C, Heinemann V, Schalhorn A, Moosmann N, Zwingers T, Boeck S, Giessen C, 
Stemmler HJ. UGT1A1 gene polymorphism: Impact on toxicity and efficacy of 
irinotecan-based regimens in metastatic colorectal cancer.  World J. Gastroenterol. 2009; 
15: 5058-5066.
 
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11.4.
Appendix 4: Liver Safety Drug Restart or Rechallenge 
Guidelines
VSLC GUIDELINES FOR DRUG RESTART OR RECHALLENGE AFTER STOP
FOR LIVER CRITERIA
1. Drug rechallenge may be considered for a subject exhibiting compelling benefit 
for a critical medicine following drug-induced liver injury, if favorable benefit: 
risk and no alternative medicine available (Table 9, Figure 17)
2. In Phase III, drug restart may be considered for liver events with a clear 
underlying cause (e.g. biliary, pancreatic events, hypotension, acute viral 
hepatitis), if not associated with drug-induced liver injury, alcoholic hepatitis or 
hypersensitivity, and drug not associated with HLA marker of liver injury, when 
liver chemistries improve to within 1.5xbaseline and ALT<3xULN) (Table 10,
Figure 18).
Background: Following drug-induced liver injury, drug rechallenge is associated with 
a 13% mortality across all drugs in prospective studies.  Clinical outcomes vary by 
drug, with nearly 50% fatality with halothane re-administered in one month of initial 
injury [Andrade, 2009].  However, some drugs seldom result in recurrent liver injury or 
fatality.
Risk factors for a fatal drug rechallenge outcome include:

hypersensitivity with initial liver injury (e.g. fever, rash, eosinophilia) [Andrade
2009]

jaundice or bilirubin2xULN with initial liver injury 

prior serious adverse event or fatality has earlier been observed with drug 
rechallenge [Papay, 2009; Hunt, 2010]

evidence of drug-related preclinical liability (e.g. reactive metabolites; 
mitochondrial impairment) [Hunt, 2010] 
 
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VSLC Decision Process for Drug Rechallenge Approval or 
Disapproval (See Figure 17)

Principal Investigator (PI) requests consideration of drug rechallenge for a 
subject receiving compelling benefit from a critical or life-saving drug, who 
exhibits liver chemistry elevation meeting subject stopping criteria, with no 
alternative treatment

By definition treatment naïve subjects will only be considered for rechallenge if 
they were infected with a multi-resistant virus.

Medical Monitor and Global Clinical Safety and Pharmacovigilance (GCSP) 
Physician to review the subject’s rechallenge risk factors (consultation with the 
Hepatotoxicity Panel is available) and complete checklist (Table 9).

The Medical Monitor and GCSP Physician are accountable to review and agree 
on:
–
compelling benefit of the investigational product (IP) for this subject and no 
alternative therapy 
–
must present source data defining the patient’s current resistance profile with 
documented evidence of extensive drug resistance and previous drug history 
–
Relative benefit-risk of drug rechallenge, with consideration of the following 
high risk factors:
Initial liver injury event included: fever, rash, eosinophilia, or 
bilirubin2xULN (or direct bilirubin >35% of total, if available)
subject currently exhibits severe liver injury defined by: ALT 3xULN, 
bilirubin 2xULN (direct bilirubin >35% of total, if available), or INR1.5
SAE or fatality has earlier been observed with IP rechallenge
IP associated with known preclinical hepatic liability/ injury

Relevant physicians must review and agree on request for drug rechallenge:  

Safety Team Leader, VP, or Senior Safety Physician (GSK)

Medicines Development Leader and Project Physician Leader (GSK)

Request is taken to full VSLC for final decision 
 
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Figure 17
VSLC process for drug rechallenge approval or disapproval
The local operating company (LOC) ViiV medical director (and GSK where applicable)
should be informed that study drug rechallenge is under consideration and of the final 
decision, whether or not to proceed.
Table 9
Checklist for drug rechallenge for critical medicine (Following drug-
induced liver injury, drug rechallenge is associated with 13% 
mortality across all drugs in prospective studies)
Yes
No
Compelling benefit of the investigational product (IP) for this subject and no 
alternative therapy.  Provide brief explanation:
Relative benefit-risk favorable for drug rechallenge, after considering the 
following high risk factors:

Initial liver injury event included: 
o
fever, rash, eosinophilia, or hypersensitivity
o
or bilirubin2xULN (direct bilirubin >35% of total)
o
Subject currently exhibits ALT 3xULN, bilirubin 2xULN (direct 
bilirubin >35% of total, if available), or INR1.5
o
SAE or fatality has earlier been observed with IP rechallenge
If yes, please provide brief explanation:
o
IP associated with known preclinical hepatic liability/ injury
o
Source data defining the patients current resistance profile
o
Previous drug history
 
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Drug Restart
Phase II “drug restart” can be approved by the VSLC for transient, defined non-drug-
induced liver injury if no evidence of:
•
immunoallergic injury /HLA association with injury
•
DILI
•
alcoholic hepatitis
Study drug held while labs and evaluation is completed to assess diagnosis.
VSLC Decision Process for Drug Restart Approval or Disapproval 
(Figure 18): 

PI requests consideration of drug re-initiation for a subject stable or improving 
on IP, who exhibits liver chemistry elevation meeting subject stopping criteria, 
which is transient, non-drug-related, and liver chemistries improve to within 
1.5x baseline and ALT< 3xULN. 

GSK Medical Monitor and Clinical Safety Physician to review the subject’s
diagnosis, restart risk factors and complete checklist (Table 10).
–
must present source data defining the patient’s current resistance profile with 
documented evidence of extensive drug resistance and previous drug history.

The LOC ViiV medical director (and GSK where applicable) should be 
informed that study drug restart is under consideration and of the final decision, 
whether or not to proceed.
Table 10
Checklist for Phase II drug restart after well-explained liver injury 
(e.g. biliary, pancreatic, hypotensive events, congestive heart 
failure, acute viral hepatitis), improving to liver chemistry 5x 
baseline & ALT<3xULN
Yes
No
Is subject stable or improving on the investigational product (IP)?
Do not restart if the following risk factors at initial liver injury:

fever, rash, eosinophilia, or hypersensitivity 

drug-induced liver injury 

alcoholic hepatitis (AST>ALT, typically <10xULN)

IP has an HLA genetic marker associated with liver injury (e.g. lapatinib, 
abacavir, amoxicillin/clavulanate)
Source data defining the patients current resistance profile
Previous drug history
 
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
Relevant physicians must review and agree on request for drug restart:  

Safety Team Leader, VP, or Senior Safety Physician

Medicines Development Leader and Project Physician Leader (GSK).

Hepatotoxicity Panel consultation is available.

Justification for drug restart outlining the benefit and risk for this subject must 
be recorded by GCSP Physician and sent to the VSLC Secretary.

VSLC must approve drug re-initiation and dosing regimen
Figure 18
VSLC process for drug restart approval or disapproval
1. Andrade, 2009; 2. Papay, 2009; 3. Hunt, 2010
 
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Medical monitor, GCSP Physician and PI actions for Restart or 
Rechallenge following VSLC decision
Medical Monitor and Global Clinical Safety and Pharmacovigilance (GCSP)
Physician Actions

Medical Monitor must notify PI of VSLC’s rechallenge (or restart) decision and 
recommended dosing regimen in writing and Medical Monitor must record note 
in study files.

The Safety Review Team must record rechallenge (or restart) outcomes and the 
GCSP Physician must send these to the VSLC

All severe reactions (rechallenge associated with bilirubin>2xULN or jaundice, 
or INR1.5), SAEs or fatalities with drug rechallenge (or restart) must be 
immediately reported to Line Management, VSLC Chair, VP Global Medical 
Strategy (ViiV) and EU Qualified Person for Pharmacovigilance. 
Principal Investigator Actions:

The PI must obtain IRB/EC approval of drug rechallenge or restart, as required. 

If drug re-initiation VSLC-approved, the patient must provide informed consent 
with a clear description of possible benefits and risks of drug administration 
including recurrent, more severe liver injury or possible death.
–
Targeted drug rechallenge or drug restart consent form must be used.

The patient’s informed consent must be recorded in the study chart, and the drug 
administered at agreed dose, as communicated by Medical Monitor.

Liver chemistries must be followed twice weekly for ‘rechallenge’ cases and 
once weekly for ‘restart’ cases for one month or for as long as clinically 
indicated following drug re-initiation.  If subject exhibits protocol-defined liver 
chemistry elevations, IP should be discontinued as protocol specified.
VSLC and the IRB/EC must be informed of the patient’s outcome following drug 
rechallenge or restart.
Rechallenge/restart safety outcomes:

0 = no liver chemistry elevation

1 = recurrent liver chemistry elevation not meeting subject stopping criteria

2 = recurrent liver chemistry elevation meeting subject stopping criteria

3 = serious adverse event

4 = fatality
 
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REFERENCES:
Andrade RJ, Robles M, Lucena MI.  Rechallenge in drug-induced liver injury: the 
attractive hazard.  Expert Opin Drug Saf. 2009;8:709-714.
Hunt, CM.  Mitochondrial and immunoallergic injury increase risk of positive drug 
rechallenge after drug-induced liver injury: A systematic review.  Hepatol. 2010;52:2216-
2222.
Papay JI, Clines D, Rafi R, Yuen N, Britt SD, Walsh JS, Hunt CM.  Drug-induced liver 
injury following positive drug rechallenge.  Regul Tox Pharm. 2009;54:84-90.
 
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11.5.
Appendix 5: Country Specific Requirements
No country-specific requirements exist. 
 
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11.6.
Appendix 6: Changes to the Protocol
Amendment 1
Amendment 1 was finalized 28 October 2013 and applied to all countries, however, was 
never implemented due to a design change requiring a second amendment.  
Amendment 1 was prepared to address the following changes:  universal changes to 
naming conventions for the long acting formulation of GSK1265744, simplifying the 
protocol summary to allow better understanding of the protocol, clarifying the study 
schematic to increase understanding, clarification the purpose of and analyses to be 
performed by the IDMC to reflect current plans, clarification of the intent of the Day 1 
analysis as a possible analysis if needed, clarification to study treatments including the 
addition of the ingredients of the long acting formulations of both study treatments, 
clarification of health outcomes objectives, timings and questionnaires, adding the 
assessment of exercises habits and intravenous drug use, removing some assessments to 
simplify study visits, updates and simplification to the time and events tables and 
additional miscellaneous clarifications.
General
Universal changes were made to the naming convention of the injectable formulation of 
GSK1265744.  This was changed from GSK744 LAP to GSK744 LA and is further 
identified as the long acting injectable formulation.  In addition, throughout the 
document, the term parenteral was removed therefore any abbreviations of  long acting 
parenteral “LAP” were revised to long acting “LA”.  Reference to a “parenteral” regimen 
was revised to an “IM” regimen. 
Any reference to “control regimen” or “control arm” was revised to “oral regimen” or 
“oral arm”.  Any reference to a “monthly” regimen was revised to an “every 4 weeks” 
regimen.
The “chronology” on the first page of the Amendment clarifies the rationale for multiple 
“Document Generator Numbers” or DNG numbers.  For example, this is Amendment 1, 
but the DNG number assigned to the final version of Amendment 1 is 2013N168152_03.
Abbreviations
Addition of several abbreviations:  
HIVTSQc
HIV Treatment Satisfaction Questionnaire change version
HIVTSQs
HIV Treatment Satisfaction Questionnaire status version
HIVMQ
HIV medication questionnaire
LA
Long acting
Trademarks
Added “Truvada” as a Trademark not owned by ViiV Healthcare.
 
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Protocol Summary
This section was revised to include only key pieces of the protocol to allow the reader to 
better understand the protocol at a glance.  Removed background, study rationale and 
secondary study objectives and added notable eligibility criteria, key study assessments, 
permitted study treatment substitutions and the definition of virologic failure.
References to Investigator’s Brochures
Throughout the document, any reference to the Investigator’s Brochure for either 
GSK1265744 or TMC278 were updated to the newest version dates 2013 and 2012 
respectively.
Study Rationale, Induction Period, 4th sentence, Section 1.8
Revised to (changes struck through and underlined):
Virologic suppression in the LAI116482 study was rapid, with 837% of GSK744 30 mg
treated subjects achieving an HIV-1 RNA <50 c/mL by Week 8 suggesting that the 
majority of subjects in the 200056 study will be virologically suppressed for at least 8 
weeks on the 16 week induction arm and for at least 16 weeks on the 24 week induction 
arm, prior to randomization into the Maintenance Period.
Study Rationale, Maintenance Period, 1st sentence, Section 1.8 - clarification
Revised to (changes struck through and underlined):
Subjects must achieve an undetectable HIV-1 RNA (<50 c/mL) at Week (-4) in order to 
be eligible to enter the Maintenance Period. Subjects with an undetectable HIV-1 RNA 
(50 c/mL) at the Week (-4) visit are eligible to enter the Maintenance Period.
Study Rationale, Extension Period, 2nd and last sentence, Section 1.8 - clarification
Revised to (changes struck through and underlined):
These subjects will also have their regimen modified at Week 96 by adding RPV 25 mg 
orally once daily for 14 days2 weeks.  
These switch subjects must achievewith an undetectable HIV-1 RNA (<50 c/mL) at the
Week 96 visit will in order to be eligible to enter the Extension Period. 
Dose Rationale, 3rd paragraph and last paragraph, Section 1.9.1 - clarification
The 3rd paragraph was bulleted for better readability.
Revised to (changes struck through and underlined):
 
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The preferred maximum IM injection volume of 2 mL using a 200 mg/mL GSK744 LA 
nanosuspension formulation would limits the maximum a single injection to 400 mg IM.
Study Objectives, Section 2 - addition
Revised to (changes struck through and underlined):
To evaluate the change in treatment satisfaction 
for subjects in the long-acting and oral regimens 
through Week 96 of the Maintenance Period.
To evaluate the treatment satisfaction for 
subjects on the long-acting injectable regimen 
with those on the oral regimen through Week 96 
of the Maintenance Period.
Change from Baseline in treatment satisfaction 
for the LAP and oral regimens at Maintenance 
Weeks 24, 48 and 96.
Summarize treatment satisfaction using the HIV 
Treatment Satisfaction Questionnaire Status 
(HIVTSQ(s)) over time. 
To evaluate the change in treatment satisfaction 
for subjects in both the long-acting injectable 
and oral regimens through Week 24 of the 
Maintenance Period.
Measure change in treatment satisfaction using 
the HIV Treatment Satisfaction Questionnaire 
Change (HIVTSQ(c)) over time.
To evaluate medication adherence over time.
Summarize subject reported medication 
adherence using the HIV Medication 
Questionnaire (HIVMQ) over time.
 
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Study Schematic, Section 3.1 - clarification
Revised from
Oral Induction Period
•HIV-1 
infected
ART-naïve 
•CD4 ≥200 
cells/mm3
•HIV-1 RNA
•≥1000 c/mL
Oral Control
(n ≈ 25)
LAP Regimen
(n ≈ 50)
Oral Control
(n ≈ 25)
LAP Regimen
(n ≈ 50)
Randomization
2:1
2
1
2
1
Randomization
1:1
GSK744 30 mg + ABC/3TC
(n ≈ 90)
GSK744 30 mg + ABC/3TC
(n ≈ 90)
Add 
RPV 25 mg 
Once Daily
Week -24
Week -20
Week -16
Week -12
Week -8
Week -4
Day 1
1
1
Add 
RPV 25 mg 
Once Daily
Extension Period
Maintenance Period
GSK744  LAP 400 mg IM
+ 
TMC278  LA 600 mg IM
Every 4 Weeks†
Oral GSK744 30 mg + ABC/3TC
(n ≈ 50)
Maintenance LAP Doses Every 4 Weeks
† Subjects who withdraw 
from LAP will be followed on 
study via Long Term Follow 
Up Period with ~quarterly 
visits for 52 weeks
Oral RPV 25 mg Once 
Daily for 2 weeks; then 
GSK744 LAP 800 mg IM
LD + TMC278 LA 600 mg 
IM † then
GSK744 LAP 400 mg IM + 
TMC278 LA 600 mg IM
Every 4 Weeks† 
GSK744 LAP 800 mg (2 x 400 mg) IM Loading Dose (LD)  + 
TMC 278 LA 600 mg IM on Day 1 then
GSK744 LAP 400 mg IM + TMC278 LA 600 mg IM every 4 Weeks†
(N ≈ 100)
Continued 
From  
Induction 
Period
Schema
Last Induction Regimen Dose 
on Day 1 in Clinic
 
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To
Induction Period
•HIV-1 
infected
ART-naïve 
•CD4 ≥200 
cells/mm3
•HIV-1 RNA
•≥1000 c/mL
Continue Oral 
Regimen
Begin IM 
Regimen
Continue Oral 
Regimen
Begin IM 
Regimen
Randomization
2:1
2
1
2
1
Randomization
1:1
GSK744 30 mg + ABC/3TC 
Orally Once Daily
(n ≈ 90)
GSK744 30 mg + ABC/3TC 
Orally Once Daily
(n ≈ 90)
Add 
RPV 25 mg 
Orally Once 
Daily
Week -24
Week -20
Week -16
Week -12
Week -8
Week -4
Day 1
1
1
Add 
RPV 25 mg 
Orally Once 
Daily
Extension Period
Maintenance Period
GSK744  LA 400 mg IM
+ 
TMC278  LA 600 mg IM
Every 4 Weeks†
GSK744 30 mg + ABC/3TC  Orally Once Daily
IM Doses Every 4 Weeks
† Subjects who withdraw 
after receiving any IM dose 
will be followed on study via 
Long-Term Follow Up Period 
with ~quarterly visits for 52 
weeks
GSK744 LA 800 mg IM
Loading Dose + TMC278 
LA 600 mg IM †
then 
GSK744 LA 400 mg IM + 
TMC278 LA 600 mg IM
Every 4 Weeks† 
GSK744 LA 800 mg IM Loading Dose  + 
TMC 278 LA 600 mg IM on Day 1 
then
GSK744 LA 400 mg IM + TMC278 LA 600 mg IM every 4 Weeks†
Continued 
From  
Induction 
Period
Schema
Last Induction Regimen Dose 
on Day 1 in Clinic
IM 
regimen
Oral 
regimen
Add 
RPV 25 
mg 
Orally 
Once 
Daily for 
2wks
 
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Induction Period, 2nd paragraph, Section 3.2.2 - clarification
Revised to (changes struck through and underlined):
Subjects first day on study treatment will be either Weeks (-24) or Weeks (-16) 
depending on the outcome of randomization.  Further weeks of treatment throughout the 
Induction Period will be counted up to Day 01 (Day 1 initiates the Maintenance Period).
Eligibility for Maintenance, 1st paragraph, Section 3.2.3 - clarification
Revised to (changes struck through and underlined):
Subjects must achieve with an undetectable HIV-1 RNA (<50 c/mL) at the Week (-4) 
visit in order to be are eligible to enter the Maintenance Period. A single repeat to 
determine eligibility may be allowed ONLY after consultation with the medical monitor.  
Subjects with HIV-1 RNA 400 c/mL at Week (-4) are not eligible to enter the 
Maintenance Period and will not be allowed a repeat to determine eligibility.
Maintenance Period, 2nd paragraph and last sentence, Section 3.2.4 - clarification
Revised to (changes struck through and underlined):
On the first day of the Maintenance Period (Day 1), subjects will receive their last dose of 
GSK744ABC/3TCRPV Induction Period regimen in the clinic and initiate either IM 
injections or be dispensed the oral regimen depending on the outcome of randomization 
arm.  Add-on RPV treatment will be discontinued for all subjects after the first day of 
MaintenanceDay 1.  
See the Time and Events Schedule Section 6.3 and Section 6.4 for more information.
Extension Period, 4th paragraph, last sentence, Section 3.2.5.2 - clarification
Revised to (changes struck through and underlined):
If eligible, subjects will be taking GSK744 + ABC/3TC + RPV for the next 2 weeksfrom 
Week 98 to Week 100 of the Extension Period.  
Independent Data Monitoring Committee, Section 3.2.8 – IDMC specifics will now 
be in the IDMC charter
Revised to (changes struck through and underlined):
An Independent Data Monitoring Committee (IDMC) will evaluate the efficacy, 
tolerability, and safety of GSK1265744 and TMC278 before all eligible subjects have 
transitioned from the Induction Period to the Maintenance Period.  This IDMC review 
may be conducted after approximately 45 subjects have reached Week 8 of the 
Maintenance Period, depending on IDMC agreement.  The intent of this analysis is to 
identify any early safety or tolerability signals from the long acting regimen. Full details 
 
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of the analyses, estimated timing and the decision criteria that will be used to determine 
regimen performance will be pre-specified in the IDMC Charter. An Independent Data 
Monitoring Committee (IDMC) will evaluate the efficacy, tolerability, and safety of 
GSK744 and TMC278 after 45 subjects reach Week 8 of the Maintenance Period.  The 
intent of this analysis is to identify any early safety or tolerability signals from the long-
acting regimen. At the time of this analysis, it is expected that subjects will have 
exposure to GSK744 LAP and TMC278 LA of up to approximately 3 months in the 
subset of subjects in the 16 week Induction Period, and a shorter exposure in those who 
are in the 24 week Induction Period.
Primary Analysis, 1st paragraph, last sentence, Section 3.2.9 – Revised planned 
analyses and allowed for additional analyses as needed.
Revised to (changes struck through and underlined):
Additional analyses will be conducted at Day 1, Week 24, Week 48 and Week 96.  
Planned analyses will be conducted at Week 48 and Week 96. Additional analyses, for 
example at Day 1, may be conducted to support internal decision making, scientific 
presentations or regulatory document preparation, as needed.
Number of Subjects, Section 4.1 – not needed
Removed the following sentences:
Approximately 150 subjects are planned to enter the Maintenance Period.  The 
anticipated overall study withdrawal rate is approximately 30%.  
Inclusion Criteria and Additional Eligibility Criteria, Section 4.2 and Section 4.4 –
removed dates to allow for various updates that may occur over the life of the 
study
Removed reference to dated product labels and Investigator’s Brochures.
Exclusion Criteria, criteria #22, Section 4.3 - clarification
Revised to (changes struck through and underlined):
Subjects who are HLA-B*5701 positive and unable to use an alternative NRTI backbone 
(subjects who are HLA-B*5701 positive may be enrolled if they use an alternative NRTI 
backbone that does not contain abacavir.
 
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Withdrawal Criteria, Section 4.5 – allow for additional data collection
Added:
All subjects who discontinue prematurely from the study, irrespective of arm, will be 
asked for additional information to establish the reason for withdrawal.
And

Subjects who cannot or do not wish to continue on to the Long-Term Follow Up 
Period (see Section 3.2.6).
TMC278 Tablet, Section 5.1.2 - clarification
Revised to (changes struck through and underlined):
RPV [Edurant Product Information, 2012) is provided by Janssen Research & 
Development, a division of Janssen Pharmaceuticals as 25 mg tablets that are off-white, 
round, biconvex, film-coated and debossed on one side with “TMC” and the other side 
with “25”. RPV is manufactured by Janssen -Cilag S.p.A, Latina, Italy. RPV will be 
provided as globally commercialmarketed product, including US and the European 
Union, and overlabeled, packaged in bottles of 30 tablets.  RPV tablets are to be stored at 
25°C and protected from light.
GSK1265744 Injectable Suspension, Section 5.1.4 – additional information
Revised to (changes struck through and underlined):
GSK744 LA is manufactured by GlaxoSmithKline and is a sterile white to slightly 
colored suspension containing 200 mg/mL of GSK744 as free acid for administration by 
intramuscular (IM) injection.  The product is packaged in a 3 mL USP Type I glass vial 
with a 13 mm gray stopper and aluminium seal. Each vial is for single use containing a 
nominal fill of 1.5 mL or 2.0 mL, and does not require dilution prior to administration.  
GSK744 LA injectable suspension is to be stored at up to 30°C, do not freeze.
GSK744 LA is composed of GSK1265744 free acid, polysorbate 20, polyethylene glycol 
3350, mannitol, and water for injection.
TMC278 Injectable Suspension, Section 5.1.5 – additional information
Revised to (changes struck through and underlined):
TMC278 LA, also named JNJ-16150108-AAA 300 mg/mL Extended Release Suspension 
for Injection (G001), is provided by Janssen Research & Development, a division of 
Janssen Pharmaceuticals as a sterile white suspension containing 300 mg/mL of TMC278 
as free base for administration by intramuscular (IM) injection.  The product is packaged 
in a 2 mL USP Type I glass vial with a 13 mm grey stopper and aluminium seal. Each 
vial is for single use containing a nominal fill of 2.0 mL, and does not require dilution 
 
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prior to administration but requires refrigeration.  TMC278 LA injectable suspension is to 
be stored 2-8°C, do not freeze, protected from light and kept in the outer package.
TMC278 LA is composed of TMC278 free base, poloxamer 338, sodium dihydrogen 
phosphate monohydrate, citric acid monohydrate, glucose monohydrate, sodium 
hydroxide, water for injection.
Dosage and Administration, Induction Period, Section 5.1.6 - clarification
Clarified to require only RPV to be taken with a meal.
Dosing Considerations for GSK744 LA + TMC278 LA, Section 5.1.7 – additional 
information
Added:
If possible, injections should be spaced approximately 2 cm from one another and from 
the site of any previous injection and or any injection site reaction.
Treatment Compliance, Section 5.5 – allow for additional data collection
Added:
Subject awareness and knowledge of these dosing instructions will be assessed by 
reviewing the answers to the HIVMQ as discussed in Section 6.13.  
Prohibited Medications and Non-Drug Therapies, 4th sentence, Section 5.9.2 -
clarification
Revised to (changes struck through and underlined):
Acetaminophen is cannot be used in patients with acute viral hepatitis.
Time and Events Schedule, Section 6 – clarification, simplification, additional 
information
In general, the following changes were made:

Specified in top left of each table which period the table applies to (i.e. 
Procedures for 24 Week Induction)

Added that rescreened subjects would be assigned a new subject number

Changed “Medical” exam to “Physical” exam

Added timings for ECG completion

Changed requirement for vital signs to be assessed after 5 minutes of rest to 
“about” 5 minutes of rest
 
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
Clarified “Health Outcomes Questionnaire” to actual questionnaires being 
completed:  HIVSTQs, HIVSTQc, HIVMQ.  Included timings of completion.

Removed some unnecessary assessments:  some fasting labs, some ECGs, some 
chemistry and hematology assessments

Added Follow Up visit to all

Split the Maintenance Time and Events (T&E) table in to 2 tables:  1 for the IM 
regimen (GSK744 LA+TMC278 LA) and 1 for the oral regimen 
(GSK744+ABC/3TC)

Added the following to both the Maintenance and Extension T&E:
Dosing is expected to occur within 21-35 days from the previous dose while keeping to 
the subjects visit schedule projected from Day 1 of the Maintenance Period.  All 
decisions regarding dose interruption/ resumption must be discussed with the 
medical monitor in advance.

Moved Week 98 to the Maintenance T&E, oral regimen

Simplified telephone visits for subjects on the oral regimen

Clarified the Extension T&E to be more clear and readable

Changed pregnancy testing in Long-Term Follow Up to be serum instead of 
urine
Baseline Assessments, Medical History, Section 6.7.2 – allow for additional data 
collection
Changed “recent” illicit drug use to “history” of illicit drug use.
Added: 
intravenous drug use history
Safety Assessments, Clinical Evaluations, Section 6.9.1 – allow for additional data 
collection
Added:
Exercise habits will be assessed for subjects on the GSK744 LATMC278 LA regimen.
 
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Laboratory Assessments, Section 6.9.2 – not collected
Removed:
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in patient management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the subject’s CRF. 
Health Outcomes, Section 6.13 – clarification, additional information
Revised to (changes struck through and underlined):
Health outcomes assessments will be conducted in all countries where translations of the 
instruments are available.  Assessments are recommended to be administered at the 
beginning of the visit.
The HIV Treatment Satisfaction Questionnaire (HIVTSQ) Woodcock [Woodcock, 2001 
and Woodcock, 2006] was developed to evaluate treatments for HIV and patient 
satisfaction. The higher the score, the greater the improvement in treatment satisfaction as 
compared to the past few weeks. A smaller score represents a decline in treatment 
satisfaction compared to the past few weeks.  The HIVTSQ items are summed up to 
produce a treatment satisfaction score (0 to 60) and an individual satisfaction rating for 
each item (0 to 6) and two subscales: general satisfaction/clinical and lifestyle/ease 
subscales.
This study will be using the HIVTSQ(s) (status version) and the revised HIVTSQ(c) 
(change version). Thishese measures is specifically designed towill assess change in 
treatment satisfaction over time (in the same subjects) and compare current satisfaction 
with previous satisfactiontreatment satisfaction, from an earlier time point. 
The HIV Medication Questionnaire (HIVMQ) was developed to assess subject reported 
medication adherence.
The HIVTSQ items are summed up to produce a treatment satisfaction score (0 to 60) 
and an individual satisfaction rating for each item (0 to 6) and two subscales: general 
satisfaction/clinical and lifestyle/ease subscales. These scores will be summarized and 
compared between the treatment groups in an exploratory analysis at Week (-12), Week 
(-4), Day 1, Week 24, Week 48, and Week 96, or withdrawal by treatment group.
In addition, subject tolerability data will be collected at Week (-12), Week (-4), Day 1, 
Week 24, Week 48, and Week 96.  Details of the data collection methods will be detailed 
in the SPM.
Moreover, data will be collected evaluating subject adherence to study treatment at Week 
(-12), Week (-4), Day 1, Week 24, Week 48 and Week 96. Details of the data collection 
methods will be detailed in the SPM.
The HIVTSQ(s) will be administered at the following time points: 
 
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
Induction: Week -20 in the 24 Week Induction Period and Week -12 in the 16 
Week Induction Period and Week (-4) (pre-dose) in both Induction Periods

Maintenance:  pre-dose at Day 1 and post-dose at Week 4, Week 8, Week 24, 
Week 48, Week 96 & Withdrawal
The HIVTSQ(c) will be administered at the following time points:  

Maintenance:  Week 24 and at Withdrawal for subjects withdrawn between Week 
4 and Week 24
HIVMQ will be administered at the following time points:

Induction: Week (-4)

Maintenance:  Week 8, Week 24, Week 48, Week 96 & Withdrawal
o
IM Regimen:  Complete post-injection
o
Oral Regimen:  Preferably completed at the beginning of the visit, but may 
be completed at any time during the visit
Qualitative interviews with 20-30 subjects may be conducted regarding the subject’s 
experience on the injection regimen. This would be conducted under a separate IRB/IEC 
approved consent. Participation in the interviews would be voluntary.
Interim and Final Analysis, Section 8.3.4 – allow for IDMC details to be listed in the 
charter instead of the protocol and clarification
Revised to (changes struck through and underlined):
The ITT-E population will be primary efficacy population and the safety population will 
be the primary safety population for all analyses.  All available data will be included in 
all interim analyses, including data beyond the designated time point except for the Day 1 
analysis, if preformed, will only include data from the Induction Period.  
At the first interim analysis the IDMC will evaluate the efficacy, safety and tolerability of 
GSK744 to determine if the GSK744 regimen is suboptimal such that it should be 
discontinued before all subjects transition into the Maintenance Period of the study.  Full 
details of the analyses, estimated timing and the decision criteria that will be used to 
determine regimen performance will be pre-specified in the IDMC Charter.
This interim analysis schedule does not require an adjustment for multiplicity since there 
is no possibility of a false positive finding at any of the interim analyses conducted before 
Week 24, and since the Week 48 and 96 analyses will be used to further characterise the 
long-term safety and efficacy profile of GSK744.  As no hypothesis is being tested for 
rejection during the constant monitoring of virologic response, no adjustment for 
multiplicity will be performed.
 
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At the first interim analysis the IDMC will evaluate the efficacy, safety and tolerability of 
GSK744 to determine if the GSK744 regimen or the shorter length of induction is 
suboptimal and should be discontinued before all subjects transition into the Maintenance 
Period of the study.  This analysis will be performed after 45 subjects reach Week 8 of 
the Maintenance Period and will include all data available at that time.  Full details of the 
analyses that will be preformed and the criteria that will be used to determine if an 
induction length should be discontinued will be pre-specified in the IDMC Charter.
This interim analysis schedule does not require an adjustment for multiplicity since there 
is no possibility of a false positive at any of the interim analyses conducted before Week 
24, and since the Week 96 analysis will just be used to fully characterise the long-term 
safety and efficacy profile of GSK744.  As no hypothesis is being tested for rejection 
during the constant monitoring of virologic response, no adjustment for multiplicity will 
be performed.
Futility Interim Monitoring, 3rd and 4th sentence, Section 8.3.4.1 - clarification
Revised to (changes struck through and underlined):
If the number of failures meets or exceeds the thresholds specified in the table below 
(Table 6), this will be considered strong evidence of an inadequate response and will 
trigger a comprehensive IDMC data review and possible discontinuation of that treatment 
arm.  If an inadequate response is seen in the shorter induction length arm and it is 
determined that that arm should be discontinued, then subjects on that treatment arm still 
in the Induction Period canwill be switched to the longer induction length.
IDMC Interim Analysis, Section 8.3.4.2 – allow for IDMC details to be listed in the 
IDMC charter instead of the protocol, clarification
Revised to (changes struck through and underlined):
The purpose of these analyses is for the Independent Data Monitoring Committee to 
evaluate the efficacy, safety and tolerability of GSK744 at early time points in the study.  
The IDMC will review at least one analysis, an analysis of all data available at the time 
45 subjects reach Week 8 of the Maintenance Period. This analysis will be used to 
remove any sub optimal induction length from the study before all subjects transition into 
the Maintenance Period.  As subjects enter the Maintenance Period of the study the 
protocol defined virologic failure rate will be continually monitored. If the number of 
failures meets or exceeds the thresholds specified in Table 4, this will be considered 
strong evidence of an inadequate response and will trigger a comprehensive data review 
by the IDMC should this occur prior to all subjects completing Week 24.  The IDMC 
charter will contain detailed safety summaries and efficacy analyses that will be provided
The purpose of these analyses is for the Independent Data Monitoring Committee 
(IDMC) to evaluate the efficacy, safety and tolerability of GSK744 at early time points in 
the study.  The IDMC will review at least one analysis before all eligible subjects have 
transitioned from the Induction Period to the Maintenance Period.  Full details of the 
 
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analyses, estimated timing and the decision criteria that will be used to determine 
regimen performance will be pre-specified in the IDMC Charter, with IDMC agreement.  
As subjects enter the Maintenance Period of the study, the protocol defined virologic 
failure rate will be continually monitored. If the number of failures meets or exceeds the 
pre-specified thresholds specified in the IDMC Charter, this will be considered strong 
evidence of an inadequate response and will trigger a comprehensive data review by the 
IDMC.  The IDMC charter will contain details of this continual monitoring of the 
protocol defined virologic failure rates, the specifics around what will trigger a data 
review, and the safety summaries and efficacy analyses that will be provided should a 
data review be required.
Day 1 Interim Analysis, Section 8.3.4.3 - clarification
Revised to (changes struck through and underlined):
A Day 1 interim analysis may be conducted to support regulatory submissions and/or 
scientific conference presentations once the last randomized subject has completed the 
Day 1 study visit and the database has been cleaned and released for analysis. The results 
of this analysis will be used to evaluate efficacy, safety and tolerability of GSK744 30 mg 
once daily plus ABC/3TC once daily in the Induction Period.  Only data from the 
Induction Period would be summarized in this analysis.  The Day 1 interim analysis will 
be conducted once the last randomized subject has completed the Day 1 study visit and 
the database has been cleaned and released for analysis. The results of this analysis will 
be used to evaluate efficacy, safety and tolerability of GSK744 30 mg once daily plus 
ABC/3TC once daily in the Induction Period.
Health Outcomes, Section 8.3.5.4 - clarification
Revised to (changes struck through and underlined):
Data from the eC-SSRS, HIVTSQ(s), HIVTSQ(c), and HIVMQ will be summarised by 
visit.  Total satisfaction scores and lifestyle/ease sub-scores will be summarised at each 
time point by treatment group using the mean, SD, median, min and max.
Data from the C-SSRS will be summarised by visit.
In an effort to reduce ‘potentially avoidable’ study discontinuations (for example, lost to 
follow up, subject withdrawal, non-compliance, protocol violation) and to improve data 
quality, patient characteristics will be studied to focus retention efforts on subgroups of 
subjects more likely to withdraw prematurely from the study.
Each HIVTSQ item is scored 0-6 where a higher score indicates greater satisfaction with 
treatment. The HIVTSQ items are summed up to produce a treatment satisfaction total 
score (0 to 60) and a lifestyle/ease sub-score (0 to 30). 
The number and proportion of subjects with each response (0-6) to each of the 10 items 
in the HIVTSQ will be summarised at Week (-12), Week (-4), Day 1, Week 24, Week 48 
and Week 96 by treatment group. Total satisfaction scores and lifestyle/ease sub-scores 
 
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will be summarised at Week (-12), Week (-4), Day 1, Week 24, Week 48 and Week 96
by treatment group using the mean, SD, median, min and max.
 
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Amendment 2
Amendment 2 applies to all countries.  
Amendment 2 was prepared to introduce a major a design change.  The Induction Period 
was consolidated into a single 20 Week arm.  An additional IM dosing arm was added:  
GSK744 LA 600 mg IM + TMC278 LA 900 mg IM every 8 weeks (Q8W).  As such, 
much of the protocol was amended to consolidate the Induction Period and to add a 3rd
dosing arm.  
Major changes include complete replacement of the protocol summary, the dose rationale 
was revised to support the Q8W IM dosing regimen, objectives and endpoints were 
updated including changing the primary endpoint from Week 24 to Week 32, updated the 
dosing and administration to reflect requirements for the Q8W arm, the study design and 
schematic updated, increased sample size to 265 subjects, all Time and Event Tables 
were replaced, PK sampling strategy and data analysis and statistical considerations 
updated.
Additionally, the liver stopping criteria and subsequent IP restarting / rechallenge 
information was revised and added, respectively.
Finally, the requirement to have hepatic impairment measured by Child-Pugh 
assessments was removed.  Hepatic impairment will be assessed by multiple other means 
(labs and physical assessments).
General
Clarifications of naming conventions of GSK1265744 and TMC278 (both formulations) 
were made throughout to document to be in line with the defined terms in Section 1.2.  In 
addition, the Induction Period was revised throughout the document to be 20 weeks 
instead of 24 and 16 Weeks.  The dosing regimen was modified to reflect two IM dosing 
regimens are being evaluated [every 4 weeks (Q4W) and every 8 weeks (Q8W)] and one 
oral dosing is being evaluated (oral).  This change was made throughout the document.
Week 48 data from LAI116482 was added.
Updates to the Sponsor contact information.
Various clarifications throughout.
 
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Abbreviations
Addition of several abbreviations:  
BMI
Body Mass Index
eC-SSRS
Electronic Columbia Suicidality Severity Rating Scale
PDVF
Protocol Defined Virologic Failure
PopPK
Population Pharmacokinetics
Q4W
Every 4 Weeks
Q8W
Every 8 Weeks
SVF
Suspected Virologic Failure
VSLC
ViiV Safety and Labeling Committee
Protocol Summary
This section was completely replaced to reflect the new design.  Most sections were 
revised with the exception of key study assessments, permitted study treatment 
substitutions and the definition of virologic failure.
References to Investigator’s Brochures and Product Information
Throughout the document, any reference to the Investigator’s Brochure or product 
information for TMC278 was updated to the newest version dates 2013 and June 2013 
(Edurant) respectively.
Section 1.4 GSK1265744 – Long Acting Injectable (GSK744 LA)
Original text:
A long acting (LA) injectable formulation of GSK1265744 (GSK744 LA) is also in 
development and has been dosed in over 98 HIV-1 uninfected subjects at doses between 
100-800 mg with an adverse event (AE) profile similar to oral dosing of GSK744.  The 
LA injectable formulation has been dosed intramuscularly (IM) and subcutaneously (SC), 
and has been generally well-tolerated.  Painless nodules were more common following 
SC injections than IM injections.  Intramuscular injection site reactions have been 
predominantly mild or Grade 1 (85%), self-limited, and have not led to study 
discontinuation in any subject to date. No treatment emergent serious AEs have been 
reported.  [Preliminary data from ongoing study LAI115428 GlaxoSmithKline Document 
Number 2011N112455_03 and GlaxoSmithKline Document Number RM2010/00170/04: 
LAI114433]. 
All of the above characteristics make GSK744 an attractive compound for continued HIV 
drug development.
Revised text:
GSK744 LA, a long acting injectable formulation of GSK1265744, has been dosed in 
136 healthy subjects.  Subjects have received single or repeat doses of GSK744 LA at 
doses between 100 to 800 mg, either intramuscularly (IM) or subcutaneously (SC) and 
 
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either alone or in combination with TMC 278 LA(completed study LAI114433 [single 
dose LA, n=58], ongoing study LAI115428 [repeat dose LA, n=40], and ongoing study 
LAI116815 [single dose LA, n=38]). The adverse event (AE) profile has been similar 
tothose of GSK744 (oral).  To date, no studies in HIV-1 infected subjects have been 
conducted with GSK744 LA.  
GSK744 LA (has been generally well-tolerated as either an IM or SC dose.    
Intramuscular injection site reactions (ISRs) have been predominantly mild or Grade 1 
(85%), self-limited, and have not led to study discontinuation in any subject to date. 
Erythema, nodules, induration, and warmth at the injection site were most commonly
reported in healthy subjects. Painless nodules were more common following SC 
injections than IM injections.  No treatment emergent serious AEs have been reported.  
[Preliminary data from ongoing study LAI115428 GlaxoSmithKline Document Number 
2011N112455_03 and GlaxoSmithKline Document Number RM2010/00170/04: 
LAI114433]. 
All of the above characteristics make GSK1265744 an attractive compound for continued 
HIV drug development.
Section 1.5 TMC278 - Oral (RPV)
Revised to (changes struck through and underlined).
RPV, the oral formulation of TMC278 (rilpivirine, RPVEdurant), is a diarylpyrimidine 
derivative, isand a potent non-nucleoside reverse transcriptase inhibitor (NNRTI) with in 
vitro activity against wild type HIV-1 and select NNRTI-resistant mutants.  RPV, and is 
currently approved as a 25 mg oral tablet formulation in for use in antiretroviral (ARV) 
treatment-naïve patients in the multiple countries such as the US, EU and Canada for use 
in antiretroviral (ARV) treatment-naïve patients and other countries as per the approved 
label in each country / region. 
Section 1.6 TMC278 – Long Acting Injectable (TMC278 LA)
Revised to (changes struck through and underlined).
Rilpivirine TMC278 can is also be formulated as a long acting injectable (TMC278 LA) 
with PK that could supports IM dosing every 4 or 8 or more weeks. 
And
In C158 (N=2019) , TMC278 LA injectable suspension in the current formulation after 
single IM injection of 300 mg or of 600 mg, or after multiple dosing regimens of 3 
successive IM doses was generally safe and well tolerated.  
Added:
In LAI115428, TMC278 LA was administered as successive monthly IM injections as 
1200/900 mg or 1200/600 mg along with GSK744 LA.  As noted in Section 1.4, the 
injections were generally well tolerated, no subject discontinued due to an ISR, and no 
 
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treatment emergent serious AEs have been reported.  [Preliminary data from ongoing 
study LAI115428 GlaxoSmithKline Document Number 2011N112455_03].
Section 1.7 - Study LAI116482
Original text:
LAI116482 is an ongoing Phase IIb dose-ranging study (GSK744 10 mg, 30 mg, 60 mg) 
evaluating the utility of a two-drug, two-class combination (GSK744 + RPV) when both 
are given as a once daily oral regimen following induction of virologic suppression using 
GSK744 plus 2 investigator selected NRTIs.  To date, the study has enrolled 244 
subjects, 181 of whom received one of three oral dose regimens of GSK744 (10 mg, 30 
mg or 60 mg) plus 2 NRTIs. A Week 24 planned interim analysis is complete and 
demonstrated similar antiviral activity across the three dosing arms of GSK744 in 
combination with 2 NRTIs, which compared favourably to the control regimen of EFV 
600 mg once daily plus 2 NRTIs.  Rates of protocol defined virologic failure through 
Week 24 were low across all study arms (one subject receiving each dose of GSK744 and 
three subjects receiving EFV) without emergence of new genotypic or phenotypic 
resistance in any of these subjects. 
Sixty-one percent of subjects were treated with investigator selected Truvada 
(tenofovir/emtricitibine, TDF/FTC) and 39% of the subjects were treated with 
EPZICOM/KIVEXA (abacavir/lamivudine, ABC/3TC) at randomization.  Similar 
virologic response rates (HIV-1 RNA < 50c/mL) through 24 weeks were seen in subjects 
taking GSK744 + ABC/3TC (87%) and in subjects taking GSK744 + TDF/FTC (87%). 
The most common treatment-emergent AEs reported for subjects on one of the GSK744 
doses, were nausea, headache, and diarrhea.  One subject receiving GSK744 60 mg had a 
Grade 3 headache.  All other AEs were Grade 1 or 2 with the majority of them being
Grade 1.  Four subjects on GSK744 verses eight on EFV withdrew due to an AE, one 
receiving 30 mg (panic attack) and three receiving 60 mg (hepatitis, blood lactate 
dehydrogenase increased, and musculoskeletal pain).  The majority of GSK744 related 
AEs were Grade 1 and few of those AEs led to withdrawal through Week 24 (n=4 (2%)).  
There have been no drug related SAEs to date.  
Two of the subjects that withdrew due to AE met liver stopping criteria with an 
ALT>10x ULN at approximately Week 4 and Week 8 after initiating study drug.  Both 
had pre-existing steatohepatitis and were dosed with GSK744 60 mg + ABC/3TC.  Both 
subjects remained asymptomatic, had normal serum bilirubin levels and had resolution of 
the ALT values after drug discontinuation.  These 2 subjects were the only Grade 3-4 
ALT abnormalities to date.  Overall, the rates of any graded ALT or AST abnormality 
were similar between GSK744 and EFV dosed subjects through Week 24: ALT:  15% 
and 19% respectively; AST:  18% and 15% respectively. 
Based upon the results through Week 24 of the LAI116482 study, and in accordance with 
the pre-specified dose selection criteria, a 30 mg oral dose of GSK744 has been selected 
to be used in combination with ABC/3TC for induction of virologic suppression in study 
200056.
 
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These data from LAI116482 support the conduct of study 200056 by demonstrating the 
antiviral activity of oral GSK744 when used as part of a HAART regimen.  Additionally, 
it is anticipated that LAI116482 will provide proof of principle for GSK744 LA + 
TMC278 LA as a maintenance regimen, through a demonstration of oral efficacy of 
GSK744 + RPV as maintenance therapy.  
All subjects in the ongoing LAI116482 study have entered into the Maintenance Phase.  
Eligible subjects enter Maintenance at Week 24 where they begin the GSK744 + RPV 
regimen.  All subjects will have completed 24 weeks of the maintenance regimen at the 
time 200056 begins, permitting a robust evaluation of the virologic efficacy of the oral 
two drug regimen of GSK744 and RPV, prior to the conduct of the current study.  These 
data will be made available to Investigators.
Revised text:
LAI116482 is an ongoing Phase IIb dose-ranging study (GSK744 10 mg, 30 mg, 60 mg) 
evaluating the utility of a two-drug, two-class combination (GSK744 + RPV) when both 
are given as a once daily oral regimen following induction of virologic suppression using 
GSK744 plus 2 investigator selected NRTIs. Eligible subjects enter Maintenance at 
Week 24 where they began the GSK744 + RPV regimen.  
To date, the study has enrolled 244 subjects, 181 of whom received one of three oral dose 
regimens of GSK744 (10 mg, 30 mg or 60 mg) plus 2 NRTIs. A planned Week 48 (24 
weeks on Induction and 24 weeks on two-drug Maintenance) analysis is complete and 
demonstrated similar antiviral activity across the three dosing arms of GSK744 in 
combination with RPV, which compared favorably to the control regimen of EFV 600 
mg once daily plus 2 NRTIs.  
Rates of protocol defined virologic failure (PDVF) through Week 48 were low across all 
study arms. Three subjects receiving GSK744 (one at each dose) and three subjects 
receiving EFV were characterized as PDVFs during Induction.  During Maintenance, two 
subjects receiving GSK744 (10 mg and 30 mg) and one subject receiving EFV were 
characterized as PDVF.   
During Maintenance, treatment emergent INI (Q148R) and NNRTI (E138Q) resistance
mutations were identified in one of the subjects on GSK744 (10 mg).   The subject 
experienced suspected virologic failure (SVF) at Week 48, which was subsequently 
confirmed.  There was no change in RPV susceptibility, and a 3.08 fold change in 
susceptibility to GSK744.  The subject reported starting an extreme low calorie diet prior 
to SVF.  Week 26 and Week 36 RPV pre-dose concentrations for the subject were lower 
than concentrations seen in the Phase III RPV studies.  The subject also had lower 
GSK744 predose concentrations in Maintenance compared to Induction.  Week 48 PK for 
this subject is pending.  By Week 16 or at time of IP discontinuation if before Week 16, 
63% of subjects were treated with Truvada (tenofovir/emtricitibine, TDF/FTC) as their 
background dual NRTI and 37% of the subjects were treated with EPZICOM/KIVEXA 
(abacavir/lamivudine, ABC/3TC).  Similar virologic response rates (HIV-1 RNA < 
50 c/mL) through 24 weeks were seen in subjects taking GSK744 + ABC/3TC (87%) and 
in subjects taking GSK744 + TDF/FTC (86%). Rates continued to be similar through 
 
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Week 48, 79% for subjects taking GSK744 + ABC/3TC and 84% in subjects taking 
GSK744 + TDF/FTC.
The most common treatment-emergent AEs reported for subjects on any of the GSK744 
doses, were nausea, headache, and diarrhea.  One subject receiving GSK744 60 mg and 
one subject receiving GSK744 30mg had a Grade 3 headache.  The Grade 3 headache for 
the GSK744 60mg subject occurred very early, study day 3, while the Grade 3 headache 
for the GSK744 30mg subject occurred on study day 343.  All other AEs were Grade 1 or 
2 with the majority of them being Grade 1.  Six subjects on GSK744 verses eight on EFV 
withdrew due to an AE, one receiving 10mg (ECG abnormal and palpitations), one 
receiving 30 mg (panic attack) and four receiving 60 mg (hepatitis, transaminases 
increased, anxiety disorder and musculoskeletal pain).  The majority of GSK744 related 
AEs were Grade 1 and few of those AEs led to withdrawal through Week 48 (n=4 (2%)).  
There have been no GSK744 drug related SAEs to date.  
Two of the subjects that withdrew due to AE met liver stopping criteria with an 
ALT>10x ULN at approximately Week 4 and Week 8 after initiating study drug.  Both 
had pre-existing steatohepatitis and were dosed with GSK744 60 mg + ABC/3TC.  Both 
subjects remained asymptomatic, had normal serum bilirubin levels and had resolution of 
the ALT values after drug discontinuation.  These 2 subjects were the only Grade 3-4 
ALT abnormalities to date.  Overall, the rates of any graded ALT or AST abnormality 
were similar between GSK744 and EFV dosed subjects through Week 48: ALT:  17% 
and 21% respectively; AST:  20% and 18% respectively.
These data from LAI116482 support the conduct of study 200056 by demonstrating the 
antiviral activity of GSK744 when used initially as part of a HAART regimen to induce 
virologic suppression.  In addition, this data confirmed antiviral activity of GSK744 + 
RPV as a two-drug oral Maintenance regimen and provides proof of principle for 
GSK744 LA + TMC278 LA as a maintenance regimen.  
Based upon the results through Week 48 of the LAI116482 study, and in accordance with 
the pre-specified dose selection criteria at Week 24, a 30 mg oral dose of GSK744 has 
been selected to be used in combination with ABC/3TC for induction of virologic 
suppression in study 200056.
All ongoing subjects in the LAI116482 study have entered into Maintenance where they 
have completed 24 weeks or more of the two-drug Maintenance regimen.  All subjects 
will have completed 48 weeks of the Maintenance regimen at the time study 200056 
begins dosing any IM regimen, permitting a robust evaluation of the virologic efficacy of 
the oral two drug regimen of GSK744 and RPV, prior to initiating the long acting 
injectable regimen.  These data will be made available to Investigators.
Section 1.8 – Study Rationale
Revised to (changes struck through and underlined).
The overall objective of this study is to select an intramuscular dosing regimen of 
GSK744 LA plus TMC278 LA based on a comparison of the Week 32 antiviral activity, 
 
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tolerability, and safety of two IM dosing regimens, relative to GSK744 30 mg plus 
ABC/3TC orally once daily The overall objective of this study is to evaluate the efficacy, 
tolerability, and safety of GSK744 LA plus TMC278 LA when both are administered as 
once-monthly IM injections, following once daily GSK744 + ABC/3TC FDC, in HIV-1 
infected antiretroviral-naïve subjects.  
Induction Period
The objective of the Induction Period is to induce virologic suppression prior to the 
initiation of the GSK744 LA + TMC278 LA regimen.  In addition, the Induction Period 
will evaluate the safety, tolerability and efficacy of GSK744 in combination with 
ABC/3TC in HIV-1-infected, ART-naive adults. The Induction Period consists of an 
evaluation of GSK744 30 mg once daily plus ABC/3TC through 2016 weeks or 24 
weeks.  The varied length of induction, 16 weeks or 24 weeks, will help establish whether 
the length of time a subject remains virologically suppressed (HIV-1 RNA <50 c/mL) 
prior to initiating GSK744 LA + TMC278 LA treatment, impacts virologic response 
during the Maintenance Period.  Virologic suppression in the LAI116482 study was 
rapid, with 83% of GSK744 30 mg treated subjects achieving an HIV-1 RNA <50 c/mL 
by Week 8 suggesting that the majority of subjects in the 200056 study will be 
virologically suppressed for at least 128 weeks on the 16 week induction arm and for at 
least 16 weeks on the 24 week induction arm, prior to randomization into the 
Maintenance Period.  A review of the virology data from LAI116482 suggests that few 
subjects required greater than 16 weeks of therapy to achieve virologic suppression 
(HIV-1 RNA <50 c/mL), including subjects who entered the study with HIV-1 
RNA >100,000 c/mL.  
Subjects will be randomized at study entry to either the 16 or 24 week Induction Period 
and a difference in virologic response rates, between the two arms, is not anticipated. 
Initial randomization will be stratified by screening HIV-1 RNA (<100,000 or 
≥100,000 c/mL). 
Unless subjects meet a study withdrawal criterion, their regimen will be modified during 
Induction at Week (-4) by adding on RPV 25 mg orally once daily.  RPV is being added 
to the ART regimen for all subjects at Week (-4) to establish safety and tolerability of 
RPV in individual subjects prior to initiating treatment with GSK744 LA + TMC278 LA 
during the Maintenance Period.  Subjects who do not or cannot tolerate GSK744 or RPV 
during this period should not enter the Maintenance Period. At the majority of time 
points, the incidence of (treatment related) AEs in the Phase III RPV studies were 
comparable between the RPV and control group and highest during the first 4 weeks of 
treatment.  Median time to onset of first rash events was 10.5 days.  No grade 4 rash 
events were reported.  In addition, this RPV add on will serve as a pharmacokinetic lead 
in, achieving steady state levels of RPV, prior to the administration of TMC278 LA 
[Rashbaum, 2011a and Rashbaum, 2011b].
Maintenance Period
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Subjects with an undetectable HIV-1 RNA (<50 c/mL) at the Week (-4) visit are eligible 
to enter the Maintenance Period. 
The objective of the Maintenance Period of this study is to assess the ability of a long-
acting two-drug ART regimen, consisting of intramuscularly injected GSK744 LA 
400 mg (following a loading dose of 800 mg) plus TMC278 LA 600 mg every 4 weeks, 
to maintain virologic suppression for 96 weeks with the primary endpoint at Maintenance 
Period Week 24.  Subjects eligible to enter the Maintenance Period will enter a second 
randomization at Day 1 onto either the IM regimen or will remain on GSK744 (30 mg) + 
ABC/3TC (oral regimen).  All subjects will discontinue the Induction regimen (including 
the add-on of RPV) after a final dose in the clinic on Day 1.  Data from the Maintenance 
Period will be used to evaluate the ability of this long-acting two-drug ART regimen to 
maintain virologic suppression through Week 96 of the Maintenance Period.  The second 
randomization period will serve to ensure an equal comparison between the two-drug 
long acting regimen and the oral comparator, through Week 24, Week 48 and Week 96 in 
virologically suppressed subjects.  This well-characterized study population will permit a 
thorough evaluation of the ability of an investigational two-drug, long-acting injectable 
combination to maintain virologic suppression.  While both drugs, GSK744 LA and TMC 
278 LA, have been studied with both SC and IM administration, the IM administration is 
being progressed into study 200056 to best accommodate the required injection volumes 
of both drugs and the better tolerability of TMC278 LA IM, relative to SC.  
The selection of GSK744 30 mg + ABC/3TC as an oral comparator regimen in this study, 
will allow for a direct comparison of subjects who either i) continue their existing 
regimen or ii) simplify their regimen to a once monthly long-acting regimen.  The chosen 
comparator will also allow for a direct comparison of oral daily pill taking vs. every 4 
week IM administration, as it relates to efficacy, tolerability, safety, and acceptability.  
Normalizing the comparator populations through a second randomization at Day 1, will 
also serve to strengthen this comparison.
Long-term maintenance of HIV virologic suppression will be assessed.  
Revised text:
All subjects with an undetectable HIV-1 RNA (<50 c/mL) at the Week (-4) visit are 
eligible to enter the Maintenance Period. 
The objective of the Maintenance Period of this study is to assess the ability of a two-
drug regimen of GSK744 LA and TMC278 LA to maintain virologic suppression for 96 
weeks with the primary endpoint occurring after 32 weeks.  Two injectable IM dosing 
regimens (Q8W and Q4W) and one oral control dosing regimen will be evaluated.  
Subjects eligible to enter the Maintenance Period will be randomized 2:2:1 at Day 1 to 
one of the dosing regimens described below:

GSK744 LA 600 mg + TMC278 LA 900 mg IM every 8 Weeks (Q8W)
o
+ Loading Dose of GSK744 800 mg at Day 1
 
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o
+ Loading Dose of GSK744 600 mg at Week 4

GSK744 LA 400 mg + TMC278 LA 600 mg IM every 4 Weeks (Q4W)
o
+ Loading Dose of GSK744 800 mg at Day 1

GSK744 30 mg + ABC/3TC once daily
Randomization will be stratified by HIV-1 RNA <50 c/mL before Week (-8) (yes or no).
All subjects on either IM regimen will discontinue the Induction regimen (including the 
add-on of RPV) after a final dose in the clinic on Day 1.  Subjects on the oral regimen 
will discontinue the add-on of RPV after a final dose in the clinic on Day 1.  
While both drugs, GSK744 LA and TMC 278 LA, have been studied with both SC and 
IM administration, the IM administration is being progressed into study 200056 to best 
accommodate the required injection volumes of both drugs and to ensure good 
tolerability.  
The selection of GSK744 30 mg + ABC/3TC as an oral comparator regimen in this study, 
will allow for a direct comparison of subjects who either i) continue their existing 
regimen or ii) simplify their regimen to one of the IM regimens.  The chosen comparator 
will also allow for a direct comparison of oral daily pill taking vs. Q4W and Q8W IM 
administration, as it relates to efficacy, tolerability, safety, and acceptability.  
Normalizing the comparator populations byrandomizing only suppressed subjects at Day 
1, will also serve to strengthen this comparison.
Long-term maintenance of HIV virologic suppression will be assessed.  
Extension Period
Original text:
The Extension Period of this study will allow for a collection of longer term efficacy and 
safety and tolerability data from subjects receiving GSK744 LA and TMC278 LA.
Unless subjects meet a study withdrawal criterion, subjects on the oral regimen may elect 
to continue on the Extension Period via switching to the GSK744 LA + TMC278 LA 
regimen.  These subjects will also have their regimen modified at Week 96 by adding 
RPV 25 mg orally once daily for 2 weeks.  This short RPV add on will allow eligible 
subjects to achieve steady state levels of RPV, prior to the administration of the GSK744 
LA + TMC278 LA regimen.  These switch subjects with an undetectable HIV-1 RNA 
(<50 c/mL) at the Week 96 visit will be eligible to enter the Extension Period.
Revised text:
The Extension Period of this study will allow for a collection of longer term efficacy and 
safety and tolerability data from subjects receiving GSK744 LA and TMC278 LA.  Only 
 
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one IM dosing regimen, either Q4W or Q8W, will be taken into the Extension Period of 
the study [based on criteria described in the Reporting and Analysis Plan (RAP)].
Unless subjects meet a study withdrawal criterion, subjects on the oral regimen may elect 
to continue on the Extension Period by switching to the selected GSK744 LA + TMC278 
LA dosing regimen.  If eligible, their regimen will be modified prior to entering 
Extension by adding RPV 25 mg orally once daily for 2 weeks.  This short RPV add on 
will allow eligible subjects to achieve steady state levels of RPV, prior to the 
administration of the GSK744 LA + TMC278 LA.  
Long-Term Follow-Up Period
Original text:
Subjects who have received at least one dose of GSK744 LA and/or TMC278 LA are 
anticipated to be at high risk for development of virologic resistance if ART is 
interrupted. The time period during which subjects may be at greatest risk for developing 
virologic resistance may be the period between when drug levels fall below therapeutic 
exposures and when they fall below levels which exert selective pressure on HIV. This 
time period will vary by ART agent and may be dependent upon effective concentration, 
inhibitory concentration and half-life.  After a single 800 mg dose of GSK744 LA, 
concentrations may be measurable for up to 52 weeks and after a single 600 mg dose of 
TMC278 LA, concentrations may be measurable for up to 24 weeks.
Therefore, any subject who receives at least a single dose of GSK744 LA and/or 
TMC278 LA and who discontinue the GSK744 LA + TMC278 LA regimen for any 
reason must remain on suppressive HAART for at least 52 weeks after the last dose of 
GSK744 LA and/or TMC278 LA in order to prevent selective pressure on HIV and the 
potential for selection of resistant mutants.  In this study, this will be accomplished by a 
Long-Term Follow-Up Period.
Revised text:
Subjects who have received at least one dose of GSK744 LA and/or TMC278 LA are 
anticipated to be at high risk for development of virologic resistance if ART is 
interrupted. The time period during which subjects may be at greatest risk for developing 
virologic resistance may be the period between when drug levels fall below therapeutic 
exposures and when they fall below levels which exert selective pressure on HIV. This 
time period will vary by ART agent and may be dependent upon effective concentration, 
inhibitory concentration and half-life.   Plasma concentrations of both drugs may be 
measurable for approximately 52 weeks following IM injections.
 
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Section 1.9 – Dose Rationale
Original text:
GSK1265744 – Oral and Long Acting Injectable
The oral dosing period intended for induction of virologic suppression will also serve as a 
lead-in period required to confirm tolerability in each subject prior to initiating the 
prolonged exposure following GSK744 LA injection, which has been observed to be up 
to 52 weeks following a single injection in some subjects [GlaxoSmithKline Document 
Number RM2010/00170/04: LAI114433].  GSK744 10 mg, 30 mg and 60 mg once daily 
in combination with 2 NRTIs achieved undetectable HIV RNA at Week 24 in 85 to 88% 
of HIV infected subjects [GlaxoSmithKline Document Number 2012N134026_02:  
LAI116482].  Plasma exposures following these oral doses are shown in Table 1.  Given 
the equivalent efficacy across all doses at Week 24 and the more frequent ALT elevations 
observed following 60 mg once daily, GSK744 30 mg once daily is the clinical dose that 
has been selected for the Induction Period.
During the IM dosing period intended to maintain virologic suppression, GSK744 LA 
800 mg IM (split into two 2 mL, 400 mg IM injections) will be administered as a loading 
dose on the same day as the final oral dose to maintain GSK744 plasma concentrations 
above the protein adjusted 90% inhibitory concentration (PA-IC90) while prolonged 
absorption from the depot site begins.  GSK744 LA 400 mg IM every 4 weeks starting 28 
days following the loading dose was selected to approximate the plasma GSK744 
concentrations of the selected oral dose of 30 mg once-daily at steady state.  Following an 
800 mg IM loading dose and three subsequent 400 mg IM maintenance doses 
administered every 4 weeks in healthy subjects (LAI115428), the geometric mean 
GSK744 Cτ was 3.2 μg/mL, 19-fold above the PA-IC90, whereas oral 30 mg once daily 
(LAI116482) achieved a geometric mean plasma C0 of 4.2μg/mL,~25-fold above the PA-
IC90.  Geometric mean plasma area under the curve (AUC) (0-τ) following the fourth 
monthly dose (third monthly 400 mg IM dose) in healthy subjects was 2362μg∙h/mL 
(LAI115428), below the AUC (0-∞) of 2652μg∙h/mL observed in healthy subjects 
receiving a single dose of 400 mg IM in another study (LAI114433), suggesting that 
accumulation may be ongoing and steady state concentrations may be higher than 
observed after four monthly doses.  
Plasma exposures after administration of GSK744 LA IM every 4 weeks:

are expected to be similar those observed in healthy subjects (geometric mean 
maximum plasma drug concentration [Cmax] 4.37 μg/mL and AUC(0-τ) 
2652μg∙h/mL (LAI115428), 

are not expected to exceed those following oral 30 mg once daily (geometric 
mean Cmax, steady state (ss) 4.20 μg/mL and 28*AUC (0-τ), ss 3752μg∙h/mL) 
studied in LAI116482,  

are expected to remain well-below exposures observed in the 60 mg level 
(geometric mean Cmax, ss 13.1 g/mL and 28*AUC, (0-τ) ss 6384 μg∙h/mL) in 
LAI116482 (See Table 1).
 
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Despite a geometric mean Clower than 30 mg orally once daily, Cvalues observed 
following 800 mg/400 mg IM in healthy subjects were ~2.4-fold higher than following 
10 mg orally once daily in HIV infected subjects, which was equally efficacious to 30 mg 
orally once daily at 24 Weeks.  Mean observed GSK744 concentration-time profile 
following GSK744 LA administration in healthy subjects with superposition of steady-
state oral dosing is compared to simulated 10 mg and 30 mg orally every day regimens 
based on LAI116482 data in Figure 1. 
The preferred IM injection volume of 2 mL using a 200 mg/mL GSK744 LA 
nanosuspension formulation would limit a single injection to 400 mg IM. As dose 
splitting increases the number of injections, possibly reducing patient tolerability, single 
injection maintenance doses are preferred.  In addition, a maximum SC injection volume 
of 1mL using the 200 mg/mL nanosuspension would require a 4-injection loading dose 
and 2-injection maintenance doses, limiting the acceptability of delivery by the SC route 
of administration.
Table 1
Summary of GSK1265744 PK Parameters following oral 
administration in HIV infected subjects and GSK744 LA 
administration in healthy subjects
Route
Study
Population
GSK1265744 Regimen
GSK1265744 PK Parameter
C  or C0
(g/mL)1
Cmax
(g/mL)2
AUC(0-)
(gh/mL)3
IQ
(C0:IC90 
ratio)4
Oral
LAI116482
HIV
10 mg orally every day
1.35
[45%]
2.77
[33%]
45.7
[32%]
8.13
30 mg orally every day
4.20
[40%]
7.49
[28%]
134
[32%]
25.3
60 mg orally every day
7.93
[39%]
13.1
[44%]
228
[57%]
47.8
IM
LAI115428 
HVs
800 mg IM Loading Dose/ 
400 mg IM q4wk x3
3.22
[28%]
4.37
[33%]
2362
[27%]
19.4
Data presented as Geometric mean [CVb%], HV = Healthy Volunteers
1.
C0:  n= 57 (10 mg orally), 53 (30 mg orally), 55 (60 mg orally), 9 (800 mg/400 mg IM), 
2.
Cmax:  n= 14 (10 mg orally), 12 (30 mg orally), 11 (60 mg orally), 9 (800 mg/400 mg IM)
3.
AUC(0-):  n= 14 (10 mg orally), 12 (30 mg orally), 11 (60 mg orally), 9 (800 mg/400 mg IM)
4.
PA-IC90 determined in vitro 0.166g/mL.
 
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Figure 1
Mean (SD) GSK1265744 Concentration-Time Profiles following 800 
mg/400 mg IM LA Administration and with Superposition of Final 30 
mg oral Steady State Dose at Day 0 compared to simulated 30 mg 
and 10 mg orally once daily
TMC278 – Oral and Long Acting Injectable
All subjects will receive 4 weeks of RPV 25 mg daily, from Week (-4) through Day 1 to 
confirm tolerability in each subject prior to IM dosing with TMC278 LA.  RPV will thus 
be co-administered with the GSK744 + ABC/3TC regimen. Data from study LAI116182 
[GlaxoSmithKline Document Number 2012N134026_02:  LAI116482] have 
demonstrated that there is no clinically relevant drug-drug interaction following repeat 
oral administration of GSK744 with RPV. With this RPV add-on, subjects will also have 
steady-state RPV plasma concentrations prior to starting TMC278 LA dosing.
During the Maintenance Period, subjects will receive IM injections of TMC278 LA 
600 mg every 4 weeks. The selection of the TMC278 LA dosing regimen is based on 
achieving RPV plasma concentrations comparable to those observed with RPV 25 mg 
every day in HIV-infected patients. 
Figure 2 shows the model predicted RPV plasma concentrations with this TMC278 LA 
dosing regimen. The graph shows the mean profile (red curve) with the 90% prediction 
interval (shaded area). The curve shows a full PK profile for the first 2 injections and for 
the 11th injection, while for the injections in between only the trough plasma 
concentration (Ctrough) is shown. Figure 2 also indicates the mean PK parameters for 
RPV 25 mg every day in HIV-infected patients (Phase III): Ctrough of 80 ng/mL, and 
 
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Cavg (i.e., average RPV plasma concentration within a 24 hour dosing interval) of 
100 ng/mL.
For the simulations, a pharmacokinetic model was used based on all available data from 
studies with the current TMC278 LA formulation (TMC278-C158, SSAT040, 
LAI115428) and the population PK model of RPV. With this model, the TMC278 LA 
dosing regimen (i.e., 4 weeks RPV 25 mg every day followed by IM injections every 
4 weeks of TMC278 LA 600 mg) was simulated for 100 subjects. For each of these 
individuals, the median Ct between day 168 (i.e. after injection 5) and day 336 (i.e., after 
injection 11) was determined, and from these median values, the mean across subjects 
was calculated [GlaxoSmithKline Document Number 2011N112455_03: LAI115428].
As such, the mean steady-state Ctrough with this TMC278 LA dosing regimen is 
predicted to be around 95 ng/mL. This is above the mean RPV Ctrough (80 ng/mL) and 
close to the mean Cavg (100 ng/mL) for RPV 25 mg every day. Furthermore, as shown in 
Figure 2, the mean RPV plasma concentrations are already above the mean Ctrough for 
RPV as of the 1st injection with TMC278 LA 600 mg.
 
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Figure 2
Predicted Mean (90% prediction interval) RPV Plasma 
Concentration-Time Profile for IM injections every 4 weeks of 
TMC278 LA 600 mg (immediately following 4 weeks RPV 25 mg 
every day)
(green dotted line represents mean Ctrough for RPV 25 mg every 
day; blue dotted line represents mean Cavg for RPV 25 mg every 
day)
Revised text:
GSK744 
GSK744 10 mg, 30 mg and 60 mg oral once daily achieved similar efficacy at Week 24 
of Induction when coadministered with 2 NRTIs and at Week 48 of Maintenance (24 
weeks on Maintenance) when coadministered with RPV 25 mg once daily (Table 1).  
Rates of virologic suppression through Week 48 (Maintenance) on the two drug regimen 
remained similar to that attained through Week 24 (Induction) on three drug ART.  
The oral dosing period intended for induction of virologic suppression also serves as a 
lead-in period required to confirm tolerability in each subject prior to initiating the 
prolonged exposure following GSK744 LA injection, which has been observed to be up 
to 52 weeks following a single injection in some subjects GlaxoSmithKline Document 
Number RM2010/00170/04: LAI114433].  Although all doses provided similar induction 
 
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and maintenance of viral suppression, GSK744 30 mg once daily was selected as the oral 
dose to be used in combination with ABC/3TC for induction of virologic suppression in 
this study.  GSK744 30mg achieves higher plasma exposures than the 10mg oral dose, 
providing higher toxicity coverage prior to initiating IM dosing.  
Based upon the results through Week 48 of the LAI116482 study, and in accordance with 
the pre-specified dose selection criteria at Week 24, a 30 mg oral dose of GSK744 has 
been selected to be used in combination with ABC/3TC for induction of virologic 
suppression in this study.
GSK744 LA
GSK744 10 mg, 30 mg and 60 mg orally once daily achieved similar efficacy at Week 24 
of Induction when coadministered with 2 NRTIs and at Week 48 of Maintenance (24 
weeks on Maintenance) when coadministered with RPV 25 mg once daily (Table 1).  
Rates of virologic suppression through Week 48 (Maintenance) on the two drug regimen 
remained similar to that attained through Week 24 (Induction) on three drug ART.  The 
similar efficacy in all three treatment arms in LAI116482 suggests that maintaining target 
Cfollowing IM administration of GSK744 LA with TMC278 LA at approximately the 
level of the 10 mg oral dose (geometric mean 1.35 g/mL, 8.1-fold above PA-IC90) 
should also maintain suppression of HIV infection.  Once safety and tolerability are 
confirmed with oral dosing, maintaining target Cfollowing IM administration of 
GSK744 LA with TMC278 LA at approximately the level of the 10 mg oral dose 
(geometric mean 1.35 g/mL, 8.1-fold above PA-IC90) should be sufficient to maintain 
suppression of HIV infection.  Maintaining a target at approximately the level of the 30 
mg oral dose is not needed in Maintenance, as viral suppression and short-term 
tolerability have been established during Induction.  
Using population pharmacokinetic (PK) modelling and simulations, GSK1265744 C
values for several IM dosing regimens were calculated and two regimens were selected 
based upon:

ability to reach target concentration early in treatment,

ability to maintain mean Cabove that obtained with oral GSK744 10 mg once 
daily during treatment (GSK744 trough concentrations 1.35 g/mL), and

minimizing the total number of injections per visit.
 
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Table 1
Proportion of Subjects with Plasma HIV-1 RNA <50 c/mL at Key Visits 
- Snapshot (MSDF) Analysis (ITT-E Population)
Visit
GSK744
10 mg
N=60
n (%)
GSK744
30 mg
N=60
n (%)
GSK744
60 mg
N=61
n (%)
GSK744 
Subtotal
N=181
n (%)
EFV 
600 mg
N=62
n (%)
Week 16 – Induction
54 (90)
50 (83)
53 (87)
157 (87)
46 (74)
Week 24 – Induction
52 (87)
51 (85)
53 (87)
156 (86)
46 (74)
Week 48 - Maintenance
48 (80)
48 (80)
53 (87)
149 (82)
44 (71)
GSK744 LA Q8W
Subjects randomized to GSK744 LA Q8W will receive a GSK744 800 mg IM Loading 
Dose on Day 1 (within 2 hours of final oral dosing), a 600 mg IM Second Loading Dose 
at Week 4, and 600 mg IM Q8W starting at Week 8. 
The first 800 mg IM loading dose and second 600 mg IM loading dose were selected so 
that 80% of subjects will be above 1.35 g/mL throughout treatment.  Mean (90% CI) 
simulated GSK744 Cvalues versus time across doses for GSK744 LA Q8W are 
presented graphically in Figure 1.  
Figure 1
Simulated Mean (90% CI) GSK744 Trough Concentrations versus 
Time for GSK744 LA Q8W
 
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At Week 56 (approximately one year of dosing), GSK744 LA Q8W is predicted to 
achieve GSK744 trough concentrations 1.35 g/mL (target) in 84% of subjects.  
Although the lower bound of the 90% CI falls below 1.35 g/mL, Cfor all subjects 
remains above 4PA-IC90 (0.166 g/mL).  At Week 56, geometric mean GSK744 Cfor 
GSK744 LA Q8W is predicted to be 2.02 g/mL, 1.5-fold above target and 12.2-fold 
above PA-IC90 (Table 2).  
A one week delay in dosing at steady state the Q8W regimen is predicted to result in a 
geometric mean Cthat is 9% lower than for dosing that is administered on schedule 
while remaining above the 1.35 g/mL target associated with the 10mg oral dose.  
GSK744 LA Q4W
Subjects randomized to the Q4W dosing arm will first receive GSK744 800 mg IM as a 
loading dose on Day 1 (within 2 hours of final oral dosing) and then, starting at Week 4, 
will receive GSK744 400 mg IM Q4W. 
The 800 mg loading dose was selected so that 80% of subjects will be above 
1.35 µg/mL throughout treatment, including the end of the first dosing interval.  Mean 
(90% CI) simulated GSK744 Cvalues versus time across Q4W doses for GSK744 LA 
are presented graphically in Figure 2.
Figure 2
Simulated Mean (90% CI) GSK744 Trough Concentrations versus 
Time for GSK744 LA Q4W
 
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At Week 56 (approximately one year of dosing), GSK744 LA Q4W is predicted to 
achieve GSK744 trough concentrations 1.35 g/mL (target) in 99.6% of subjects.  
Geometric mean GSK744 Cfor GSK744 LA Q4W at Week 56 is predicted to be 
3.35 g/mL, 2.5-fold above target, 20.2-fold above the PA-IC90 (0.166 g/mL), and 
similar to the observed mean Cafter 16 weeks of this regimen in healthy subjects (Table 
2).
A one week delay in dosing at steady state for the Q4W regimen is predicted to result in a 
geometric mean Cthat is 8% lower than for dosing that is administered on schedule 
while remaining above the 1.35g/mL target associated with the 10 mg oral dose.
Table 2
Summary of GSK744 PK Parameters following oral administration in 
HIV infected subjects, GSK744 LA administration in healthy subjects, 
and following Simulations
Route
Study
Population
GSK1265744 Regimen
GSK1265744 PK Parameter
C  or C0
(g/mL)a
Cmax
(g/mL)b
AUC(0-)
(gh/mL)c
IQ
(C0:IC90
ratio)d
Oral
LAI116482
HIV
10 mg orally every day
1.35
[45%]
2.77
[33%]
45.7
[32%]
8.13
30 mg orally every day
4.20
[40%]
7.49
[28%]
134
[32%]
25.3
60 mg orally every day
7.93
[39%]
13.1
[44%]
195
[48%]
47.8
IM
LAI115428 
HVs
800 mg IM LD
400 mg IM Q4W x3
3.22
[28%]
4.37
[33%]
2362
[27%]
19.4
IM 
PopPK 
simulation
HIV
LA Regimen #1 (200056):
800mg IM LD
400mg IM Q4W from W4
3.35
[35%]
ND
ND
20.2
IM
PopPK 
simulation
HIV
LA Regimen #2 (200056):
800mg IM LD 1
600mg IM LD 2 (Week 4)
600mg IM Q8W from W8
2.02
[52%]
ND
ND
12.2
Data presented as Geometric mean [CVb%], HIV = HIV infected subjects, HV = Healthy Volunteers, ND=Not 
determined, LD = Loading Dose
a.
C0: n=57 (10 mg orally), 53 (30 mg orally), 55 (60 mg orally), 9 (800 mg/400 mg IM), 
b.
Cmax:  n=14 (10 mg orally), 12 (30 mg orally), 11 (60 mg orally), 9 (800 mg/400 mg IM)
c.
AUC(0-):  n=14 (10 mg orally), 12 (30 mg orally), 11 (60 mg orally), 9 (800 mg/400 mg IM)
d.
PA-IC90 determined in vitro 0.166 g/mL.
RPV
All subjects will receive 4 weeks of RPV 25 mg once daily, co-administered with 
GSK744+ABC/3TC, from Week (-4) through Day 1 to confirm tolerability in each 
subject prior to possible IM dosing with TMC278 LA.  Subjects switching from the oral 
regimen to the IM regimen in the Extension Period will receive 2 weeks of RPV 25 mg 
 
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once daily, from Week 102 through Week 104.  Data from study LAI116182 
[GlaxoSmithKline Document Number 2012N134026_02:  LAI116482] have 
demonstrated that there is no clinically relevant drug-drug interaction following repeat 
oral administration of GSK744 with RPV.  With this oral RPV add-on, subjects will also 
have steady-state RPV plasma concentrations prior to starting TMC278 LA dosing.
TMC278 LA
During the Maintenance Period, subjects will receive either IM injections of TMC278 LA 
600 mg every 4 weeks (Q4W) or TMC278 LA 900 mg every 8 weeks (Q8W).  The 
selection of the TMC278 LA dosing regimens is based on achieving RPV plasma 
concentrations in the range of those observed with oral RPV 25 mg once daily in HIV-
infected patients (mean (SD) Ctrough of 80 (36) ng/mL in pooled Phase III studies (RPV + 
2 NRTIs); and 77 (34) ng/mL in the Maintenance Phase of LAI116482 (RPV + 
GSK744), as well as constructing a regimen that is most practical for patients, i.e. by 
reducing the number of dosing/clinic visits while maintaining an acceptable injection 
volume.
Figure 3 and Figure 4 show the model-predicted RPV plasma concentrations over a 
dosing interval at steady-state with the respective Q4W and Q8W TMC278 LA dosing 
regimens.  The graphs show the mean profile (red curve) with the 90% prediction interval 
(shaded area).  Also indicated are the mean Ctrough for oral RPV 25 mg once daily in HIV-
infected patients (Phase III, 80 ng/mL) and the protein-binding adjusted IC90 for RPV 
(12 ng/mL), as well as a scatter of the individual Ctrough values (plotted both at the 
beginning and at the end of the TMC278 LA dosing interval) in HIV-infected patients 
(Phase III).
For the simulations, a pharmacokinetic model was used based on all available data from 
studies with the current TMC278 LA formulation (TMC278-C158, SSAT040, 
LAI115428) and the population PK model of RPV. With this model, the TMC278 LA 
dosing regimen (i.e., 4 weeks RPV 25 mg every day followed by IM injections every 
4 weeks of TMC278 LA 600 mg) was simulated for 100 subjects. For each of these 
individuals, the median Ct between day 168 (i.e. after injection 5) and day 336 (i.e., after 
injection 11) was determined, and from these median values, the mean across subjects 
was calculated [GlaxoSmithKline Document Number 2011N112455_03: LAI115428].
 
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Figure 3
Model-Predicted Mean (90% prediction interval) TMC278 Plasma 
Concentration-Time Profile at steady-state after Q4W IM injections of 
TMC278 LA 600 mg (immediately following 4 weeks oral RPV 25 mg 
once daily)
Red line represents the predicted mean steady state Ctrough concentration.
Blue dotted line represents mean Ctrough for oral RPV 25 mg once daily ; 
Green dotted line represents protein-binding adjusted IC90 for RPV; 
Black open circles represent individual Ctrough values with oral RPV 25 mg once daily 
Figure 4
Model-Predicted Mean (90% prediction interval) TMC278 Plasma 
Concentration-Time Profile at steady-state after Q8W IM injections of 
TMC278 LA 900 mg (immediately following 4 weeks oral RPV 25 mg 
once daily)
Red line represents the predicted mean steady state Ctrough concentration.
Blue dotted line represents mean Ctrough for oral RPV 25 mg once daily; 
Green dotted line represents protein-binding adjusted IC90 for RPV; 
Black open circles represent individual Ctrough values with oral RPV 25 mg once daily
 
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TMC278 LA Q8W
For the Q8W TMC278 LA dosing regimen, the mean steady-state Ctrough is predicted to 
be around 65 ng/mL, as of the 1st injection. Though this is below the mean RPV Ctrough
with oral RPV 25 mg once daily, the range of model-predicted Ctrough is similar to the 
range of Ctrough with oral RPV 25 mg once daily in the RPV Phase III studies (Figure 4) 
and in LAI116482 (Maintenance). The RPV plasma concentrations are also higher during 
the larger part of the TMC278 LA dosing interval. Furthermore, all patients are 
virologically suppressed before switching to the TMC278 LA regimen. In LAI116482, 
there were 59/160 HIV-infected patients with a RPV Ctrough (based on population PK 
modeling) below 65 ng/mL These 59 patients all maintained virologic suppression.
TMC278 LA Q4W
As such, the mean steady-state Ctrough with theQ4W TMC278 LA dosing regimen is 
predicted to be around 115 ng/mL. This is above the mean RPV Ctrough (80 ng/mL) and 
the mean Cavg (100 ng/mL) for RPV 25 mg once daily (Phase III). Furthermore, the 
mean RPV plasma concentrations are already above the mean Ctrough for RPV as of the 1st
injection with TMC278 LA 600 mg.
Section 1.10.1.3 TMC278 Benefit Risk
Revised to (changes struck through and underlined).
Rash
Some observations of grade 1 and 2 rashes rash with RPV have been reported in clinical 
studies executed to date (the majority are Grade 1 or 2).
Section 1.10.1.6 Efficacy Risk
Original text:
This study employs an induction / maintenance approach to the treatment of HIV-1 
infection.  Following virologic suppression, subjects will be transitioned off of a 3 drug 
ART regimen to a 2 drug ART regimen.  Although both GSK744 and TMC278 have 
demonstrated antiviral activity in large clinical studies and the two drug combination is 
currently being evaluated in study 200056, the risk of virologic failure is unknown.  Viral 
loads will be closely monitored throughout the study.
Doses of the GSK744 LA and TMC278 LA have been selected to achieve exposures 
similar to the oral formulations.  Pharmacokinetics will be closely monitored throughout 
the study.
Revised text:
 
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This study employs an induction / maintenance approach to the treatment of HIV-1 
infection.  Following virologic suppression, subjects will be transitioned off of a 3 drug 
ART regimen to a 2 drug ART regimen.  Although both GSK744 and TMC278 have 
demonstrated antiviral activity in large clinical studies and the two drug combination has 
demonstrated antiviral activity in study LAI116482, the risk of virologic failure in study 
200056 is unknown.  Viral loads will be closely monitored throughout the study.
Doses of the GSK744 LA and TMC278 LA have been selected to achieve exposures that 
are expected to maintain virologic efficacy on the basis of available data with the oral 
formulations.  Neither GSK744 LA or TMC278 LA, at any dose, has been used in HIV-1 
infected subjects.  Plasma samples will be collected throughout the Maintenance Period 
for determination of GSK744 and TMC278 concentration and possible pharmacokinetic 
correlation with virologic response. 
Section 1.10.2 Benefit Assessment
Revised to (changes struck through and underlined).
Efficacy of the two-drug regimen, as oral agents, will behas been demonstrated through 
Week 48 of the ongoing LAI116482 study prior to the initiation of this study.
Section 2 - Objectives and Endpoints
Original text:
Objective
Endpoint
Primary
To evaluate the efficacy, tolerability, and safety 
of a regimen of GSK744 LA 400 mg IM plus 
TMC278 LA 600 mg IM every 4 weeks, relative 
to GSK744 30 mg plus ABC/3TC orally once 
daily, through Week 24 of the Maintenance 
Period.
The proportion of subjects with HIV-1 RNA 
<50 c/mL at Maintenance Week 24 based on 
intent to treat-exposed (ITT-E) population using 
the Missing, Switch, or Discontinuation = Failure 
(MSDF) algorithm.
Incidence and severity of AEs and laboratory 
abnormalities over time.
Secondary
To evaluate the antiviral activity, tolerability, and 
safety of GSK744 30 mg plus ABC/3TC orally 
once daily through the Induction and 
Maintenance Periods.
Proportion of subjects with plasma HIV-1 RNA 
<200 c/mL and <50 c/mL over time.
Absolute values and change from Baseline in 
plasma HIV-1 RNA.
Absolute values and changes from Baseline in 
CD4+ cell counts.
 
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Objective
Endpoint
Incidence of disease progression (HIV-
associated conditions, acquired 
immunodeficiency syndrome [AIDS] and death).
Incidence and severity of AEs and laboratory 
abnormalities over time.
Absolute values and changes in laboratory 
parameters over time.
To evaluate the impact of the duration of 
virologic suppression with GSK744 30 mg plus 
ABC/3TC orally once daily during the 16 and 24 
week Induction Period, on the ability of a 
regimen of GSK744 LA 400 mg IM plus 
TMC278 LA 600 mg IM every 4 weeks to 
maintain virologic suppression through Week 96 
of the Maintenance Period. 
Proportion of subjects with plasma HIV-1 RNA 
<200 c/mL and <50 c/mL over time.
Absolute values and change from Baseline in 
plasma HIV-1 RNA.
Absolute values and changes from Baseline in 
CD4+ cell counts.
Incidence of disease progression (HIV-
associated conditions, acquired 
immunodeficiency syndrome [AIDS] and death).
To evaluate the efficacy, tolerability, and safety 
of a regimen of GSK744 LA 400 mg IM plus 
TMC278 LA 600 mg IM every 4 weeks, relative 
to GSK744 30 mg plus ABC/3TC orally once 
daily, through Week 96 of the Maintenance 
Period.
Proportion of subjects with plasma HIV-1 RNA 
<200 c/mL and <50 c/mL over time.
Absolute values and change from Baseline in 
plasma HIV-1 RNA.
Absolute values and changes from Baseline in 
CD4+ cell counts.
Incidence of disease progression (HIV-
associated conditions, acquired 
immunodeficiency syndrome [AIDS] and death.
Incidence and severity of AEs and laboratory 
abnormalities over time.
Absolute values and changes in laboratory 
parameters over time.
To evaluate achievement of steady state for 
GSK744 LA and TMC278 LA regimens.
Determination of achievement of steady state 
following GSK744 LA and TMC278 LA 
administration.
To characterize the PK profile (Ctrough) of 
Plasma GSK744 and rilpivirine trough 
 
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Objective
Endpoint
GSK1265744 and rilpivirine and to explore 
exposure-response relationships (e.g., the 
relationship between GSK744 and TMC278 
plasma exposure and virologic response or 
occurrence of adverse events [AEs] through 
Week 48 of the Maintenance Period.
concentrations over time during the 
Maintenance Period.
To assess the development of viral resistance in 
subjects experiencing protocol defined virologic 
failure.
Incidence of treatment emergent genotypic and 
phenotypic resistance to GSK744, TMC278, 
and other on-study ART.
To explore the effect of various demographic 
Baseline characteristics and adherence on 
virologic response of GSK744 and TMC278 
over time.
Proportion of subjects with plasma HIV-1 RNA 
<50 c/mL over time.
To evaluate the treatment satisfaction for 
subjects on the long-acting injectable regimen 
with those on the oral regimen through Week 96 
of the Maintenance Period.
Summarize treatment satisfaction using the HIV 
Treatment Satisfaction Questionnaire Status 
(HIVTSQ(s)) over time. 
To evaluate the change in treatment satisfaction 
for subjects in both the long-acting injectable 
and oral regimens through Week 24 of the 
Maintenance Period.
Measure change in treatment satisfaction using 
the HIV Treatment Satisfaction Questionnaire 
Change (HIVTSQ(c)) over time.
To evaluate medication adherence over time.
Summarize subject reported medication 
adherence using the HIV Medication 
Questionnaire (HIVMQ) over time.
Revised text:
Objective
Endpoint
Primary
To select an intramuscular dosing regimen of 
GSK744 LA plus TMC278 LA based on a 
comparison of the Week 32 antiviral activity, 
tolerability, and safety of two IM dosing 
regimens, relative to GSK744 30 mg plus 
ABC/3TC orally once daily.
The proportion of subjects with HIV-1 RNA 
<50 c/mL at Maintenance Week 32 based on 
intent to treat-maintenance exposed (ITT-ME) 
population using the Missing, Switch, or 
Discontinuation = Failure (MSDF) algorithm.
Proportion of subjects with protocol defined 
virologic failures over time
 
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Objective
Endpoint
Incidence and severity of AEs and laboratory 
abnormalities over time.
Secondary
To evaluate the antiviral activity, tolerability, and 
safety of GSK744 30 mg plus ABC/3TC orally 
once daily through the Induction and 
Maintenance Periods.
Proportion of subjects with plasma HIV-1 RNA 
<200 c/mL and <50 c/mL over time.
Absolute values and change from Baseline in 
plasma HIV-1 RNA.
Absolute values and changes from Baseline in 
CD4+ cell counts.
Incidence of disease progression (HIV-
associated conditions, acquired 
immunodeficiency syndrome [AIDS] and death).
Incidence and severity of AEs and laboratory 
abnormalities over time.
Absolute values and changes in laboratory 
parameters over time.
To evaluate the efficacy, tolerability, and safety 
of GSK744 LA 400 mg IM plus TMC278 LA 600 
mg IM every 4 weeks and GSK744 LA 600 mg 
IM plus TMC278 LA 900 mg every 8 weeks, 
relative to GSK744 30 mg plus ABC/3TC orally 
once daily, through Week 96 of the 
Maintenance Period.
Proportion of subjects with plasma HIV-1 RNA 
<200 c/mL and <50 c/mL over time.
Proportion of subjects with protocol defined 
virologic failures over time
Absolute values and change from Baseline in
plasma HIV-1 RNA.
Absolute values and changes from Baseline in 
CD4+ cell counts.
Incidence of disease progression (HIV-
associated conditions, acquired 
immunodeficiency syndrome [AIDS] and death.
Incidence and severity of AEs and laboratory 
abnormalities over time.
Absolute values and changes in laboratory 
parameters over time.
To characterize GSK744 LA and TMC278 LA 
Plasma PK parameters for GSK744 LA and 
 
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Objective
Endpoint
PK and to explore PK-PD relationships.  
TMC278 LA (Ctrough and concentrations post 
dose [~Cmax]) during the Maintenance Period.  
Plasma GSK744 and RPV trough 
concentrations will be used to determine when
steady state is achieved for each GSK744 LA 
and TMC278 LA regimen.
Relationship between plasma PK parameters 
and plasma HIV-1 RNA, CD4+ cell counts 
and/or occurrence of adverse events [AEs] 
through Week 48 of the Maintenance Period will 
be explored.
To assess the development of viral resistance in 
subjects experiencing protocol defined virologic 
failure.
Incidence of treatment emergent genotypic and 
phenotypic resistance to GSK1265744, 
TMC278, and other on-study ART.
To explore the effect of various demographic 
Baseline characteristics and adherence on 
virologic response of GSK1265744 and 
TMC278 over time.
Proportion of subjects with plasma HIV-1 RNA 
<50 c/mL over time.
To evaluate the treatment satisfaction for 
subjects on the long-acting injectable regimens
with those on the oral regimen through Week 96 
of the Maintenance Period.
Summarize treatment satisfaction using the HIV 
Treatment Satisfaction Questionnaire Status 
(HIVTSQ(s)) over time. 
To evaluate the change in treatment satisfaction 
for subjects in both the long-acting injectable 
and oral regimens through Week 32 of the 
Maintenance Period.
Measure change in treatment satisfaction using 
the HIV Treatment Satisfaction Questionnaire 
Change (HIVTSQ(c)) over time.
To evaluate medication adherence over time.
Summarize subject reported medication 
adherence using the HIV Medication 
Questionnaire (HIVMQ) over time.
 
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Section 3.1 - Study Design Schematic
Original text:
Induction Period
Induction Period
•HIV-1 
infected
ART-naïve 
•CD4 ≥200 
cells/mm3
•HIV-1 RNA
•≥1000 c/mL
Continue Oral 
Regimen
Begin IM 
Regimen
Continue Oral 
Regimen
Begin IM 
Regimen
Randomization
2:1
2
1
2
1
Randomization
1:1
GSK744 30 mg + ABC/3TC 
Orally Once Daily
(n ≈ 90)
GSK744 30 mg + ABC/3TC 
Orally Once Daily
(n ≈ 90)
Add 
RPV 25 mg 
Orally Once 
Daily
Week -24
Week -20
Week -16
Week -12
Week -8
Week -4
Day 1
1
1
Add 
RPV 25 mg 
Orally Once 
Daily
Maintenance and Extension Period
Extension Period
Maintenance Period
GSK744  LA 400 mg IM
+ 
TMC278  LA 600 mg IM
Every 4 Weeks†
GSK744 30 mg + ABC/3TC  Orally Once Daily
IM Doses Every 4 Weeks
† Subjects who withdraw 
after receiving any IM dose 
will be followed on study via 
Long-Term Follow Up Period 
with ~quarterly visits for 52 
weeks
GSK744 LA 800 mg IM
Loading Dose + TMC278 
LA 600 mg IM †
then 
GSK744 LA 400 mg IM + 
TMC278 LA 600 mg IM
Every 4 Weeks† 
GSK744 LA 800 mg IM Loading Dose  + 
TMC 278 LA 600 mg IM on Day 1 
then
GSK744 LA 400 mg IM + TMC278 LA 600 mg IM every 4 Weeks†
Continued 
From  
Induction 
Period
Schema
Last Induction Regimen Dose 
on Day 1 in Clinic
IM 
regimen
Oral 
regimen
Add 
RPV 25 
mg 
Orally 
Once 
Daily for 
2wks
 
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Revised text:
Induction Period
Maintenance and Extension Period
 
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Section 3.2 - Study Design
Revised to (changes struck through and underlined).
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct. 
Study 200056 is a Phase IIb, randomized, multicentre, parallel group, open-label, three-
part study to be conducted in approximately 180 HIV-1 infected ART-naive adults.  The 
study will enroll approximately 265 subjects in order to randomize approximately 225 
subjects at Day 1.
This study will consist of a Screening Period, Induction Period, Maintenance Period, 
Extension Period and a Long-term Follow-up Period (withdrawn subjects only). 
A subject is considered to have completed the study if they complete the Induction and 
Maintenance Period through Week 96.
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM).  The SPM will provide 
the site personnel with administrative and detailed technical information that does not 
impact subject safety.
 
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Section 3.2.2 - Induction Period
Original text:
Following the Screening Period, eligible subjects will be randomized 1:1 to either 16 or 
24 weeks of induction of virologic suppression utilizing an oral regimen of GSK744 
30 mg once daily plus ABC/3TC 600/300 mg once daily.  Randomization will be 
stratified by screening HIV-1 RNA (<100,000 c/mL or 100,000 c/mL).  
Subjects first day on study treatment will be either Weeks (-24) or Weeks (-16) 
depending on the outcome of randomization.  Further weeks of treatment throughout the 
Induction Period will be counted up to Day 1 (Day 1 initiates the Maintenance Period).
Example:  First day on study Week (-16)
Next visit Week (-12)
Next visit Week (-8), etc
Subjects will initiate treatment on their first day on study and will be seen every 4 weeks 
for study treatment dispensing and safety and efficacy assessments (see Time and Events 
Section 6.1 or Section 6.2).
Revised text:
Following the Screening Period, eligible subjects will be enrolled into the study and 
begin a 20 week Induction Period utilizing an oral regimen of GSK744 30 mg once daily 
plus ABC/3TC 600/300 mg once daily.  
Week -20 is considered the Baseline visit and is the first day on study treatment.  Further 
weeks of treatment throughout the Induction Period will be counted up to Day 1 (Day 1 
initiates the Maintenance Period).
Example:  First day on study Week (-20)
Next visit Week (-16)
Next visit Week (-12), etc
Subjects will initiate treatment at Baseline (Week -20) and will be seen every 4 weeks for 
study treatment dispensing and safety and efficacy assessments (see Time and Events 
Section 6.1).  
Section 3.2.3 - Eligibility for the Maintenance Period
Revised to (changes struck through and underlined).
All subjects with an undetectable HIV-1 RNA (<50 c/mL) at the Week (-4) visit are 
eligible to enter the Maintenance Period. 
And:
 
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The medical monitor may advise the site to withdraw a subject from the study prior to 
Week (-4) to avoid initiating RPV in a subject who is unlikely to be eligible for the 
Maintenance Period.
In addition to the viral load criteria above, if in the opinion of the Investigator, a subject 
experiences a significant safety event while taking either GSK744 or RPV, Maintenance 
eligibility will be determined ONLY in consultation with the medical monitor.  Any rash 
that is possibly related to study drug, and is present between Week (-4) and Day 1, 
must be discussed with the Medical Monitor prior to initiation of GSK744 LA or 
TMC278 LA  (See Section 6.10.6.15).
Subjects ineligible for the Maintenance Period will be withdrawn.  
And:
Sites may be reimbursed for up to a one month supply of antiretroviral medication to 
facilitate transition to non-study ART for subjects that do not qualify for the Maintenance 
Period due to incomplete virologic suppression.
Section 3.2.4 - Maintenance Period
Original text:
At Day 1, the Maintenance Period begins.  Eligible subjects will be randomized a second 
time 2:1 to receive either an IM regimen of GSK744 LA 400 mg + TMC278 LA 600 mg  
every 4 weeks or to continue on the oral Induction Period regimen of GSK744 30 mg + 
ABC/3TC for 96 weeks.  This second randomization will be stratified by subjects’ 
previous randomized length of induction and by their screening HIV-1 RNA (<100,000 
c/mL or 100,000 c/mL).
On the first day of the Maintenance Period (Day 1), subjects will receive their last dose of 
GSK744+ABC/3TC+RPV in the clinic and initiate either IM injections or be dispensed 
the oral regimen depending on the randomization arm.  Add-on RPV treatment will be 
discontinued for all subjects after Day 1.  
Those subjects randomized to begin treatment with GSK744 LA + TMC278 LA will first 
receive a loading dose of GSK744 LA 800 mg (delivered as two 400 mg IM injections) 
as well as TMC278 LA 600 mg IM.  Thereafter, subjects will receive GSK744 LA 400 
mg IM + TMC278 LA 600 mg IM every 4 weeks for 96 weeks.
Those subjects randomized to continue treatment with GSK744 + ABC/3TC will be 
dispensed this regimen as per the Time and Events Schedule Section 6.2.
All subjects are then seen approximately every 4 weeks for dosing / dispensing and 
safety, efficacy and PK assessments for 24 weeks.  
Thereafter, subjects on the GSK744 LA + TMC278 LA arm will continue to be seen 
every 4 weeks for dosing, safety, efficacy and PK assessments through Week 96.  
Subjects on the GSK744+ABC/3TC arm will be seen in the clinic at Weeks 32, 40, 48, 
 
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60, 72, 84 and 96 for dosing, safety, efficacy and / or PK assessments.  These subjects 
will also be assessed for safety via phone interview at Weeks 28, 36, 44, 52, 56, 64, 68, 
76, 80, 88 and 92.  
See the Time and Events Schedule Section 6.2 and Section 6.3 for more information.
Revised text:
At Day 1, the Maintenance Period begins.  Eligible subjects will be randomized 2:2:1 to 
receive an IM regimen of GSK744 LA 400 mg + TMC278 LA 600 mg every 4 weeks for 
96 weeks, an IM regimen of GSK744 LA 600 mg + TMC278 LA 900 mg every 8 weeks 
for 96 weeks, or to continue on the oral Induction Period regimen of GSK744 30 mg + 
ABC/3TC once daily for 96 weeks (or 104 weeks if continuing on to the Extension 
Period).  Subject randomization will be stratified by subjects’ HIV-1 RNA prior to Week 
(-8) (<50 c/mL, yes or no).
On the first day of the Maintenance Period (Day 1), subjects will receive their last dose of
the Induction regimen (GSK744+ABC/3TC+RPV) in the clinic and initiate either IM 
injections or be dispensed the oral regimen depending on the randomization arm.  Add-on 
RPV treatment will be discontinued for all subjects after Day 1.  
Dosing for each arm is as follows (all injections are single injections unless otherwise 
noted):

IM injections every 8 weeks (Q8W)
o
Day 1 only – GSK744 LA 800 mg (loading dose delivered as two 400 mg 
IM injections) + TMC278 LA 900 mg IM
o
Week 4 only - GSK744 LA 600 mg IM (second loading dose, no 
TMC278)
o
Week 8 - GSK744 LA 600 mg IM + TMC278 LA 900 mg IM every 8 
weeks for 96 weeks

IM injections every 4 weeks (Q4W)
o
Day 1 only - GSK744 LA 800 mg (loading dose delivered as two 400 mg 
IM injections) + TMC278 LA 600 mg IM
o
Week 4 - GSK744 LA 400 mg IM + TMC278 LA 600 mg IM every 4 
weeks for 96 weeks

Oral Control Arm
o
GSK744 30 mg + ABC/3TC once daily for 96 weeks (or 104 weeks if 
continuing on to the Extension Period)
 
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It is important to note that keeping to the subject’s visit schedule is a very important 
component to the study.  IM dosing is expected to occur during the week in which 
the subject’s projected visit falls (as according to the Day 1 visit).  A (+ or -) 7 day 
window is allowable for IM dosing but not preferred.  Oral dosing is expected to 
occur during the week in which the subject’s projected visit falls (as according to the 
Baseline visit).  
All subjects are seen approximately every 4 weeks for safety, efficacy and PK 
assessments through Week 32.  After Week 32, subjects will continue to be seen as per 
the Time and Events Schedule (see Section 6) for dosing, safety, efficacy and PK 
assessments through Week 96 (or Week 104 for the oral arm if subject is continuing on to 
the Extension Period).  
Some visits that are not aligned with dosing will be conducted by telephone interview.  
This allows for safety assessments to be conducted at all visits, but limits clinic visits for 
non-dosing visits.  Telephone safety assessments will include interviewing the subject for 
adverse events, concomitant medications, HIV associated conditions and any other issues 
including injection site reactions or oral compliance issues.  Telephone visits will be 
clearly noted in the Time and Events Schedule.  
See the Time and Events Schedule Section 6.2 and Section 6.3 for more information.  See 
Section 3.2.5.2 for additional information regarding special requirements from Week 96 
to Week 104 for subjects on the oral arm entering the Extension Period
If one of the IM dosing regimens (Q4W or Q8W) is discontinued as a result of an IDMC 
review or any subsequent analysis, those subjects who have not met any clinical 
management criteria for discontinuation and who were randomized to the discontinued 
dosing regimen may be given the option to discontinue permanently from the study or to 
continue on the remaining IM dosing regimen at the next scheduled visit. 
Section 3.2.5 - Extension Period
Original text:
Entering From the GSK744 LA + TMC278 LA Arm
All subjects who successfully complete 96 weeks of GSK744 LA + TMC278 LA 
treatment in the Maintenance Period will continue to have access to both GSK744 LA 
400 mg IM and TMC278 LA 600 mg IM every 4 weeks via the Extension Period until it 
is either locally approved and commercially available, the subject no longer derives 
clinical benefit, the subject meets a protocol-defined reason for discontinuation or until 
development of either GSK744 LA or TMC278 LA is terminated.  At Week 96, these 
subjects will continue to receive GSK744 LA 400 mg IM and TMC278 LA 600 mg IM 
every 4 weeks for the remainder of study participation.  Safety and efficacy assessments 
will be conducted every 4 weeks until Week 112.  These assessments will then be 
quarterly for the remainder of the study (dosing and AE assessments remain every 4 
weeks).  See the Time and Events Schedule Section 6.5 for more information.
 
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Entering From the GSK744 + ABC/3TC Arm
All subjects who successfully complete 96 weeks of GSK744 + ABC/3TC treatment in 
the Maintenance Period will have the option to either continue study participation by 
switching to GSK744 LA + TMC278 LA in the Extension Period, or to discontinue from 
the study. 
Subjects not choosing to switch to the long acting regimen will complete their study 
participation.
Subjects who choose to continue on to the Extension Period will need to be assessed for 
eligibility to begin the GSK744 LA + TMC278 LA regimen.  Subjects must have an 
undetectable HIV-1 RNA (<50 c/mL) at the Week 96 visit in order to be eligible to enter 
the Extension Period.  Subjects with an HIV-1 RNA 50 c/mL may be allowed to enter 
the Extension Period at the discretion of the medical monitor or may be withdrawn.
Subjects eligible to enter the Extension Period will add a short course (2 weeks) of RPV 
25 mg orally once daily to their GSK744 + ABC/3TC regimen at Week 98 before 
initiating dosing with the long acting regimen at Week 100.  This allows these subjects to 
achieve steady state of RPV prior to beginning the long acting regimen.  Therefore, for 
the first 2 weeks of the Extension Period, subjects will remain on their oral Maintenance 
Period regimen until eligibility is confirmed.  If eligible, subjects will be taking GSK744 
+ ABC/3TC + RPV from Week 98 to Week 100 of the Extension Period.  
At Week 100, subjects will receive their last dose of GSK744 + ABC/3TC + RPV in the 
clinic and will receive a loading dose of GSK744 LA 800 mg (delivered as two 400 mg 
IM injections) as well as TMC278 LA 600 mg IM.  At Week 104, subjects will receive 
GSK744 LA 400 mg IM + TMC278 LA 600 mg IM every 4 weeks until it is either 
locally approved and commercially available, the subject no longer derives clinical 
benefit, the subject meets a protocol-defined reason for discontinuation or until 
development of either GSK744 LA or TMC278 LA is terminated. Safety and efficacy 
assessments will be conducted every 4 weeks until Week 112.  These assessments will 
then be quarterly for the remainder of the study (dosing and AE assessments remain 
every 4 weeks).  See the Time and Events Schedule Section 6.3 and Section 6.5 for more 
information.
Revised text:
A single IM dosing regimen will be selected as according to the RAP to be evaluated in 
the Extension period.
Entering From the GSK744 LA + TMC278 LA Arm
All subjects who successfully complete 96 weeks of GSK744 LA + TMC278 LA 
treatment in the Maintenance Period will continue to have access to both GSK744 LA
and TMC278 LA in the Extension Period until study treatment is eitherlocally approved 
and commercially available, the subject no longer derives clinical benefit, the subject 
meets a protocol-defined reason for discontinuation or until development of either 
GSK744 LA or TMC278 LA is terminated.  
 
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Subjects will be switched to the selected dose at Week 96 and will continue to receive the 
selected IM dosing regimen for the remainder of study participation.  Safety and efficacy 
assessments will be conducted every 16 weeks after the initial switch.  Dosing visits will 
occur according to the selected dosing regimen.  See the Time and Events Schedule 
Section 6.5 and Section 6.6 for more information.
Entering From the GSK744 + ABC/3TC Arm
All subjects who successfully complete 96 weeks of GSK744 + ABC/3TC treatment in 
the Maintenance Period will have the option to either continue study participation by 
switching to GSK744 LA + TMC278 LA in the Extension Period, or to complete their 
study participation at Week 96 (no withdraw visit needed).
Subjects who choose to continue on to the Extension Period will need to be assessed for 
eligibility to begin the selected GSK744 LA + TMC278 LA regimen.  Subjects will 
continue on their Maintenance regimen (GSK744 + ABC/3TC) while eligibility is being 
confirmed.  The Week 100 HIV-1 RNA result will be used to determine eligibility and 
subjects will have a visit at approximately (depending on availability of results) Week 
102 to assess eligibility.  All subjects with an undetectable HIV-1 RNA (<50 c/mL) result 
from the Week 100 visit are eligible to enter the Extension Period.   Note: Subjects with 
an HIV-1 RNA 50 c/mL result from the Week 100 visit may be allowed to enter the 
Extension Period only at the discretion of the medical monitor or withdrawn.
Subjects eligible to enter the Extension Period will add a short course (2 weeks) of RPV 
25 mg orally once daily to their GSK744 + ABC/3TC regimen at Week 102 before 
initiating dosing with the long acting regimen at Week 104.  This allows subjects to 
achieve steady state of RPV prior to beginning the long acting regimen.    
At Week 104, subjects will receive their last dose of GSK744 + ABC/3TC + RPV in the 
clinic and will begin IM dosing with the selected the IM regimen.  These subjects will 
receive loading doses as per the requirement of the selected regimen (see Section 5.1.6 
for dosing regimens).
Subjects will continue study treatment until GSK744 LA and TMC278 LA are either 
locally approved and commercially available, the subject no longer derives clinical 
benefit, the subject meets a protocol-defined reason for discontinuation or until 
development of either GSK744 LA or TMC278 LA is terminated. Safety and efficacy 
assessments will be conducted every 16 weeks after the initial switch .    Dosing will 
occur according to the selected regimen. See the Time and Events Schedule Section 6.5
and Section 6.6 for more information.
Subjects not eligible to enter the Extension Period will end their study participation 
(Week 102 will be the last study visit, no withdraw visit needed).  Sites may be 
reimbursed for up to a one month supply of antiretroviral medication to facilitate 
transition to non-study ART for subjects that do not qualify for the Extension Period.
Section 3.2.8 - Independent Data Monitoring Committee
Revised to (changes struck through and underlined).
 
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In addition, futility guidance (e.g., a Bayesian posterior probability approach when 50% 
of subjects have completed Week 24 of the Maintenance Period) is included to monitor 
the performance of all treatment arms in order to prevent subjects from continuing on a 
dosing regimen if existing data indicates that subjects are at unacceptable risk of 
inadequate maintenance of virologic suppression. Full details of the analyses, estimated 
timing and the decision criteria that will be used to determine regimen performance will 
be pre-specified in the IDMC Charter.If one of the IM dosing regimens (Q4W or Q8W) is 
discontinued as a result of an IDMC review or any subsequent analysis, those subjects 
who have not met any clinical management criteria for discontinuation and who were 
randomized to the discontinued dosing regimen may be given the option to discontinue 
permanently from the study or to continue on the remaining IM dosing regimen at the 
next scheduled visit. 
As subjects enter the Maintenance Period of the study, if the number of failures meets or 
exceeds the pre-specified thresholds specified in the IDMC Charter, this will be 
considered strong evidence of an inadequate response and will trigger a comprehensive 
data review by the IDMC.  The IDMC charter will contain details of this continual 
monitoring of the protocol defined virologic failure rates, the specifics around what will 
trigger a data review, and the safety summaries and efficacy analyses that will be 
provided should a data review be required.
Full details of the analyses, estimated timing and the decision criteria that will be used to 
determine regimen performance will be pre-specified in the IDMC Charter.
Section 3.2.9 - Primary Analysis
Revised to (changes struck through and underlined).
The primary analysis will be conducted when all subjects have completed their 
Maintenance Period Week 3224 visit. This analysis will characterize the safety, 
tolerability and durability of antiviral response combining data from both the Induction 
Period and the Maintenance Period. Planned analyses will also be conducted at Week 48 
and Week 96. Follow-up analyses of data collected after subjects have entered into the 
Extension Period may be conducted to more fully characterize the long-term safety and 
efficacy profile of GSK1265744 and TMC278. Additional analyses, for example at Day 
1, may be conducted to support internal decision making, scientific presentations or 
regulatory document preparation, as needed. 
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM).  The SPM will provide 
the site personnel with administrative and detailed technical information that does not 
impact subject safety.
Section 3.3 – Discussion of Design
Original text:
 
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Study 200056 is a Phase IIb assessment of a regimen consisting of the long-acting 
injectable forms of GSK744 and TMC278 to maintain virologic suppression in 
previously untreated HIV-infected subjects without evidence of transmitted resistance
who achieve virologic suppression on GSK744 plus ABC/3TC.  The ongoing study 
LAI116482 provides support for this unique approach of a two-class, two-drug regimen. 
Results from planned analyses of LAI116482 support the choice of 30 mg GSK744 for 
use in the Induction Period of this study.  Exposure and efficacy data from LAI116482 as 
well as exposure data from the repeat dose studies with GSK744 LA and TMC278 LA 
defined the target doses and exposures for GSK744 LA and TMC278 LA during the 
Maintenance Period.  Systemic exposure of TMC278 obtained with TMC278 LA is 
aimed to be comparable to that obtained with RPV, for which the antiviral activity and 
safety has been well established through Phase III studies.  
Long acting GSK744 has been investigated in approximately 134 healthy subjects to date 
as both SC and IM injections. Long-acting TMC278 has been investigated in 
approximately 159 healthy subjects to date as both SC and IM injections. This study will 
be the first evaluation of GSK744 LA or TMC278 LA in HIV-infected subjects.  The 
results to date support GSK744 LA and TMC278 LA for continued clinical development.  
Injection site reactions (ISR) of both agents have been generally mild, self-limited, and 
well-tolerated in single and multiple dose studies.  
The early results of LAI116482 support the use of oral GSK744 plus NRTIs as a 
reference regimen to the investigational two-drug long-acting regimen. At Week 24, the 
response rates (HIV-1 RNA <50 c/mL; ITT, MSDF) for the three doses of GSK744 in the 
LAI116482 study were 88%, 85% and 87% for the 10 mg, 30 mg, and 60 mg arms, 
respectively.  These rates compare favourably to the control regimen of EFV plus NRTIs 
in this study where 74% of subjects achieved HIV-1 RNA <50 c/mL at Week 24. The 
response rates seen at Week 24 are also consistent with a similarly sized study of 
dolutegravir vs. EFV (ING112276), where each was administered to ART-naive subjects 
in combination with NRTIs.  In the study ING112276, the Week 24 response rates (HIV-
1 RNA <50 c/mL) for dolutegravir and efavirenz were 94% and 82%, respectively 
[GlaxoSmithKline Document Number 2011N117114_01].
The background NRTIs (ABC/3TC) are accepted agents for initiation of antiretroviral 
therapy in treatment guidelines [EACS, 2012; DHHS, 2013] and as such are considered 
appropriate for this trial.  RPV is approved as Edurant for use in combination ART at an 
oral dose of 25 mg, once daily with a meal in treatment naive patients [Edurant Product 
Information, 2012].
This trial is designed to allow for both an evaluation of the antiviral efficacy of two 
discrete induction periods of GSK744 in combination with a background of NRTIs as 
well as the evaluation of a long-acting two-drug regimen for the maintenance of 
previously achieved virologic suppression for 96 weeks while using control regimen of 
oral GSK744 plus NRTIs.  The primary endpoint, proportion of subjects with plasma 
HIV-1 RNA < 50 c/mL at Week 24, is a well established surrogate endpoint for 
prognosis of HIV-1 infection and disease progression [CDER, 2002]. The Week 48 time 
point will permit an evaluation of the ability of this investigational two-drug long-acting 
combination to maintain virologic suppression. Longer term durability of virologic 
 
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suppression of this long-acting two-drug regimen will also be evaluated through a formal 
Week 96 analysis.
Revised text:
Long acting GSK744 has been investigated in 136 healthy subjects to date as both SC 
and IM injections. This study will be the first evaluation of GSK744 LA or TMC278 LA 
in HIV-infected subjects.  The results to date support GSK744 LA and TMC278 LA for 
continued clinical development.  Injection site reactions (ISR) of both agents have been 
generally mild, self-limited, and well-tolerated in single and multiple dose studies.  
The results of LAI116482 support the use of oral GSK744 plus NRTIs as a reference 
regimen to the investigational two-drug long-acting regimen. At the primary endpoint of 
Week 48, the response rates (HIV-1 RNA <50 c/mL; ITT, MSDF, Table 1) for the three 
doses of GSK744 in the LAI116482 study were 80%, 80% and 87% for the 10 mg, 30 
mg, and 60 mg arms, respectively.  These rates compare favorably to the control regimen 
of EFV plus NRTIs in this study where 71% of subjects achieved HIV-1 RNA <50 c/mL 
at Week 48. 
These data indicate continued viral suppression after 24 weeks of the two drug GSK744 
and RPV regimen.
The ITT-Maintenance Exposed (ITT-ME) Population consists of all randomized subjects 
who received at least one dose of investigational product during the Maintenance Phase 
of the study.  Of the subjects who entered the Maintenance Phase of the study, the 
majority remained suppressed through Week 48 (24 weeks of two drug therapy) (Table 
3).
Table 3
Proportion of Subjects with Plasma HIV-1 RNA <50 c/mL at Key Visits 
- Snapshot (MSDF) Analysis (ITT-ME Population)
Visit
GSK744
10 mg
N=52
n (%)
GSK744
30 mg
N=53
n (%)
GSK744
60 mg
N=55
n (%)
GSK744 
Subtotal
N=160
n (%)
EFV 
600 mg
N=47
n (%)
Week 16 - Induction
50 (96)
49 (92)
52 (95)
151 (94)
43 (91)
Week 24 - Induction
50 (96)
50 (94)
53 (96)
153 (96)
45 (96)
Week 48 - Maintenance
48 (92)
48 (91)
53 (96)
149 (93)
44 (94)
The background NRTIs (ABC/3TC) are accepted agents for initiation of antiretroviral 
therapy in treatment guidelines [EACS, 2012; DHHS, 2013] and as such are considered 
appropriate for this trial.  RPV is approved as Edurant for use in combination ART at an 
oral dose of 25 mg, once daily with a meal in treatment naive patients [Edurant Product 
Information, 2013].
This trial is designed to evaluate two distinct periods.  First, to evaluate the ability of 
GSK744 + background NRTIs to induce virologic suppression during the Induction 
Period.  Second, during the Maintenance Period, two different dosing strategies of a long-
acting, two-drug, two-class regimen will be evaluated on their ability to maintain 
 
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virologic efficacy for 96 weeks compared to a control regimen of oral GSK744 + 
ABC/3TC.  
The primary endpoint, proportion of subjects with plasma HIV-1 RNA < 50 c/mL, is a 
well established surrogate endpoint for prognosis of HIV-1 infection and disease 
progression [CDER, 2002]. The primary endpoint for this study is proportion of subjects 
with plasma HIV-1 RNA < 50 c/mL at Week 32 and will be used to select an IM dosing 
regimen (Q8W or Q4W).  Week 32 has been selected to allow a comparable evaluation 
among the dosing regimens.  Q8W begins dosing at Week 8, following a loading dose at 
Day 1 and Week 4.  Therefore choosing Week 32 as an endpoint allows for a 24 week 
evaluation of the Q8W arm at steady state.  
The Week 48 analysis will permit an evaluation of the ability of the investigational two-
drug long-acting combinations to maintain virologic suppression over time, and will 
serve as the dose confirmation of the dosing regimen selected at Week 32. Longer term 
durability of virologic suppression for these long-acting two-drug regimens will also be 
evaluated through a formal Week 96 analysis.
Section 4.1 - Number of Subjects
Original text:
Sufficient subjects will be screened (approximately 260) in order to ensure that a total of 
approximately 180 subjects will be randomized at the beginning of the Induction Period, 
(approximately 90 to each treatment arm).  
Revised text:
Sufficient subjects will be screened (approximately 350) in order to ensure that a total of 
approximately 265 subjects areenrolled at the beginning of the Induction Period and to 
ensure approximately 225 subjects are randomized into the Maintenance Period.  
Section 4.2 – Inclusion Criteria
Revised to (changes struck through and underlined).
Criteria 2b.
2. A female subject is eligible to enter and participate in the study if she:
b. is of child-bearing potential with a negative pregnancy test at both Screening and 
first day of the Induction Period [either Week (-16) or Week (-24)] and agrees to use 
one of the following methods of contraception to avoid pregnancy 2 weeks prior to 
administration of IP, throughout the study, and for at least 2 weeks after 
discontinuation of all oral study medications and for at least 52 weeks after 
discontinuation of GSK744 LA and TMC278 LA
 
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Section 4.3 – Exclusion Criteria
Revised to (changes struck through and underlined).
Subjects with known moderate to severe hepatic impairment. Subjects with known 
hepatic impairment must be assessed using the Child-Pugh classification and must be 
excluded if found to be Class B or C classification [Pugh, 1973].
Added:
Notwithstanding these minimum inclusion and exclusion criteria, investigators must also 
follow country specific guidelines where they exist when making decisions about 
subjects who are eligible for study participation.
Section 4.5 - Withdrawal Criteria
Revised to (changes underlined).
Added:
Subjects permanently discontinuing study treatments prior to Week 96 are considered to 
be withdrawn from the study treatments and also from the study. Similarly, subjects
permanently discontinuing participation from the Extension and Long-Term Follow-Up 
Period prior to commercially available drug supply are considered to be withdrawn from 
the study treatments and also from the study.
And:
Subjects must be withdrawn from the study for any of the following reasons:

Subjects who do not wish to continue on the remaining dosing regimen if one 
dosing regimen is discontinued further to an IDMC decision (see Section 3.2.8).

Liver toxicity where Stopping Criteria as described in Section 6.10.3 are met 
and no compelling alternative cause is identified.

Renal toxicity as specified in Section 6.10.6.9 and Section 6.10.6.10 is met and 
no compelling alternate cause is identified. 
Section 5.1.1 - GSK1265744 – Tablet (GSK744)
Revised to (changes underlined).
GSK744 is manufactured by GlaxoSmithKline and is formulated as white to almost white 
oval shaped film coated 30 mg tablets for oral administration, packaged in high density 
polyethylene (HDPE) bottles with desiccant and child-resistant closure that include an 
induction seal.
 
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Section 5.1.4 - GSK1265744 – Injectable Suspension (GSK744 LA)
Revised to (changes struck through and underlined).
GSK744 LA is manufactured by GlaxoSmithKline and is a sterile white to slightly 
colored suspension containing 200 mg/mL of GSK744 as free acid for administration by 
intramuscular (IM) injection.  The product is packaged in a 3 mL USP Type I glass vial 
with a 13 mm gray stopper and aluminium seal. Each vial is for single use containing a 
nominal withdrawable fill volume of 1.5 mL or 2.0 mL, and does not require dilution 
prior to administration.  GSK744 LA injectable suspension is to be stored at up to 30°C, 
do not freeze.
Section 5.1.6 - Dosage and Administration
Original text:
Following is a table of dosing and administration for all treatment arms:
Background NRTI combination and 
Investigational Product
Dose and Dose Interval
Induction Period – RPV to be taken with a meal
16 week Induction Arm
ABC/3TC
1 X 600 mg / 300 mg tablet once daily from 
Week (-16) through Day 1 of Maintenance (Day 1 taken in 
clinic)
GSK744
1 X 30 mg tablet once daily from Week (-16) through Day 
1 of Maintenance (Day 1 taken in clinic)
RPV
1 X 25 mg tablet once daily from Week (-4) through Day 1 
of Maintenance (Day 1 taken in clinic)
24 week Induction Arm
ABC/3TC 
1 X 600 mg / 300 mg tablet once daily from 
Week (-24) through Day 1 of Maintenance (Day 1 taken in 
clinic)
GSK744
1 X 30 mg tablet once daily from Week (-24) through Day 
1 of Maintenance (Day 1 taken in clinic)
RPV
1 X 25 mg tablet once daily from Week (-4) through Day 1 
of Maintenance (Day 1 taken in clinic)
Maintenance Period – no food requirements
GSK744 LA + TMC278 LA Dosing Arm
GSK744 LA
2 X 2 mL Injections (4 mL [800 mg] total) intramuscularly 
(IM) as loading dose (Day 1 only) followed by 1 X 2 mL 
injection (400 mg) IM every 4 weeks for 96 weeks
TMC278 LA
1 X 2 mL Injection (600 mg) intramuscularly every 4 
weeks for 96 weeks
Oral Control Arm
ABC/3TC 
1 X 600 mg / 300 mg tablet once daily for 96 weeks
GSK744
1 X 30 mg tablet once daily for 96 weeks
Extension Period
GSK744 LA + TMC278 LA Dosing Arm – no food requirements
GSK744 LA
1 X 2 mL injection (400 mg) IM every 4 weeks*
 
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Background NRTI combination and 
Investigational Product
Dose and Dose Interval
TMC278 LA
1 X 2 mL Injection (600 mg) IM every 4 weeks*
following Oral Control Arm – RPV to be taken with a meal
RPV
1 X 25 mg tablet once daily from Week 98 through Week 
100 
GSK744 LA
2 X 2 mL Injection (4 mL [800 mg] total) as loading dose 
(Week 100 only) followed by 1 X 2mL injection (400 mg) 
IM every 4 weeks*
TMC278 LA
1 X 2 mL injection (600 mg) IM every 4 weeks (starting at 
Week 100)*
*until it is either locally approved and commercially available, the subject no longer derives clinical benefit, 
the subject meets a protocol-defined reason for discontinuation or until development of GSK744 or 
TMC278 is terminated
Revised text:
Following is a table of dosing and administration for all treatment arms:
Induction Period (Week -20 through Day 1)
Week -20 to Week (-4)
(2 tablets once daily)
Take 1 X ABC 600 mg / 3TC 300 mg tablet once daily 
Take 1 X GSK744 30 mg tablet once daily
Week (-4) to Day 1
(3 tablets once daily)
Take 1 X ABC 600 mg / 3TC 300 mg tablet once daily 
Take 1 X GSK744 30 mg tablet once daily
Take 1 X RPV 25 mg tablet once daily

Take with a meal

Take Day 1 doses in the clinic
Maintenance Period (Day 1 to Week 96*)
GSK744 LA 600 mg + TMC278 LA 900 mg IM every 8 Weeks (Q8W)
Day 1 – loading dose
(3 injections once)
Receive last dose of Induction regimen
Receive GSK744 LA 800 mg given as 2 X 2 mL IM injections 
Receive TMC278 LA 900 mg given as 1 X 3 mL IM injection 
Week 4 – 2nd loading dose
(1 injection once)
Receive GSK744 LA 600 mg given as 1 X 3 mL IM injections 
(No TMC278 LA)
 
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Week 8 to Week 88
(2 injections every 8 weeks)
Receive GSK744 LA 600 mg given as 1 X 3 mL IM injection 
Receive TMC278 LA 900 mg given as 1 X 3 mL IM injection
GSK744 LA 400 mg + TMC278 LA 600 mg IM every 4 Weeks (Q4W)
Day 1 – loading dose
(3 injections once)
Receive last dose of Induction regimen
Receive GSK744 LA 800 mg given as 2 X 2 mL IM injections 
Receive TMC278 LA 600 mg given as 1 X 2 mL IM injection 
Week 4 to Week 92
(2 injections every 4 weeks)
Receive GSK744 LA 400 mg given as 1 X 2 mL IM injection
Receive TMC278 LA 600 mg given as 1 X 2 mL IM injection
GSK744 30 mg + ABC/3TC once daily
Day 1
Receive last dose of Induction regimen
Day 2 to Week 96
(2 tablets once daily)
Take 1 X ABC 600 mg / 3TC 300 mg tablet once daily 
Take 1 X GSK744 30 mg tablet once daily
If continuing to Extension Period:
Week 96 to Week 102
(2 tablets once daily)
Take 1 X ABC 600 mg / 3TC 300 mg tablet once daily 
Take 1 X GSK744 30 mg tablet once daily
If eligible to enter Extension Period:
Week 102 to Week 104
(3 tablets once daily)
Take 1 X ABC 600 mg / 3TC 300 mg tablet once daily 
Take 1 X GSK744 30 mg tablet once daily
Take 1 X RPV 25 mg tablet once daily

Take with a meal
Extension Period (Week 96 plus+) 
If GSK744 LA 600 mg + TMC278 LA 900 mg IM every 8 Weeks is selected:
Week 96 plus+
(2 injections every 8 weeks)
Receive GSK744 LA 600 mg given as 1 X 3 mL IM injection 
Receive TMC278 LA 900 mg given as 1 X 3 mL IM injection
 
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If switching from Oral Arm:
Week 104 – loading dose
(3 injections once)
Receive last dose of Maintenance regimen
Receive GSK744 LA 800 mg given as 2 X 2 mL IM injections 
Receive TMC278 LA 900 mg given as 1 X 3 mL IM injection
Week 108 – 2nd loading dose
(1 injection once)
Receive GSK744 LA 600 mg given as 1 X 3 mL IM injections 
(No TMC278 LA)
Week 112 plus+
(2 injections every 8 weeks)
Receive GSK744 LA 600 mg given as 1 X 3 mL IM injection 
Receive TMC278 LA 900 mg given as 1 X 3 mL IM injection
If GSK744 LA 400 mg + TMC278 LA 600 mg IM every 4 Weeks is selected:
Week 96 plus+
(2 injections every 4 weeks)
Receive GSK744 LA 400 mg given as 1 X 2 mL IM injection 
Receive TMC278 LA 600 mg given as 1 X 2 mL IM injection
If switching from Oral Arm:
Week 104 – loading dose
(3 injections once)
Receive last dose of Maintenance regimen
Receive GSK744 LA 800 mg given as 2 X 2 mL IM injections 
Receive TMC278 LA 600 mg given as 1 X 2 mL IM injection 
Week 108 plus+
(2 injections every 4 weeks)
Receive GSK744 LA 400 mg given as 1 X 2 mL IM injection 
Receive TMC278 LA 600 mg given as 1 X 2 mL IM injection
* Or through Week 104 if eligible to enter the Extension Period.
+ until locally approved and commercially available, the subject no longer derives clinical benefit, the subject meets a 
protocol-defined reason for discontinuation or until development of GSK744 or TMC278 is terminated
Section 5.1.7 - Dosing Considerations for GSK744 LA + TMC278 LA
Revised to (changes struck through and underlined).
IM injections should be administered at a 90 degree angle into the gluteus medius muscle 
using a 1.5” 25 gauge needle for GSK744 LA and a 1.5” 21 gauge needle for TMC278 
LA in most subjects.  The needle should be long enough to reach the muscle mass and 
prevent study drug from seeping into subcutaneous tissue, but not so long as to involve 
underlying nerves, blood vessels, or bone. Longer needle lengths will be required for 
subjects with higher body mass indexes (BMIs, example > 30), to ensure that injections 
are administered intramuscularly as opposed to subcutaneously.  BMI and needle length 
used will be collected in the eCRF.
 
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On Day 1, subject should be dosed with the IM regimen within 2 hours of taking the last 
Induction regimen dose where possible. The same should apply to subjects switching 
from the oral regimen to an IM regimen at Week 104.
Should the subject have intolerance to the single 3 mL injection, the injection may be 
administered as 2 separate 1.5 mL injections with the assent of the medical monitor.  If 
the injection is split, this will be noted in the eCRF and the intolerance captured as an 
AE.
Detailed Additional dosing instructions and considerations can be found in the SPM.
Section 5.2 – Treatment Assignment
Original text:
There are 2 randomizations in the study; both will be stratified by screening HIV-1 RNA 
(<100,000 or 100,000 c/mL).  At the first randomization, study eligible subjects will be 
randomized to their length of induction treatment (either 16 or 24 weeks) at a1:1 ratio.  
Following completion of their Induction Period, subjects eligible to enter the 
Maintenance Period will be randomized again to either the GSK744 LA + TMC278 LA 
arm or the oral control arm (GSK744 + ABC/3TC) at a ratio of 2:1.  This second 
randomization will be stratified by subjects’ previous randomized length of induction and 
by their screening HIV-1 RNA.
Revised text:
Following completion of the Induction Period, subjects eligible to enter the Maintenance 
Period will be randomized 2:2:1 to Q8W or Q4W of GSK744 LA + TMC278 LA or to 
the oral control arm (GSK744 + ABC/3TC).  Randomization will be stratified by HIV-1 
RNA result before Week (-8) (<50 c/mL yes or no).
Section 5.7 - Interruption of Study Treatment and Visit/Dosing Windows
Revised to (changes struck through and underlined).
It is important to note that keeping to the subject’s visit schedule is a very important 
component to the study.  
Note: All decisions regarding dose interruption / resumption must be discussed with 
the medical monitor in advance.
Should study treatment be interrupted, the following guidance must be used:
GSK744 and/or RPV Containing ArmsOral Dosing
Oral dosing is expected to occur during the week in which the subject’s projected 
visit falls (as according to the Baseline visit).  
And:
 
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GSK744 LA and / or TMC278 LA Containing ArmsIM Dosing
Plasma concentrations of both drugs may be measurable for approximately 52 weeks 
following IM injections.
IM dosing is expected to occur during the week in which the subject’s projected visit 
falls (as according to the Day 1 visit).  An additional (+ or -) 7 day window is 
allowable for IM dosing but not preferred.  
After a single 800 mg dose of GSK744 LA, concentrations may be measurable for up to 
52 weeks and after a single 600 mg dose of TMC278 LA, concentrations may be 
measurable for up to 24 weeks.
Dosing frequency during the Maintenance and Extension Periods is scheduled to occur 
approximately every 4 weeks (28 days).  Dose timing with GSK744 LA + TMC278 LA 
is critical to assure therapeutic drug levels are maintained and therefore the following 
guidance is provided regarding allowable windows around dosing:

Dosing is expected to occur within 21-35 days from the previous dose while 
simultaneously keeping to the subjects original visit schedule projected from 
Day 1 of the Maintenance Period (or Week 100 of the Extension Period for oral 
control arm switch subjects).  

Over time, the subject who comes in late in the visit window should return for 
the next injection on the early side of the window to get back on track with the 
original projected visit schedule.  

Dosing may occur without consultation from the medical monitor if performed 
within the this dosing 7 day window.  

Any request for the visit/dosing to occur outside of the allowed window either 
≥36 days or ≤20 days from the previous dose must be discussed and agreed with 
the medical monitor prior to dosing.  In the event of a late dose, a revised dosing 
schedule for subsequent dosing may be required and will be communicated to 
the site staff at the time of approval for continued dosing.  Temporary switch to 
oral dosing of GSK744 and/or RPV may be an option based on individual 
subject circumstance as described in Section 5.6.1.  

See the SPM for scheduling guidance and further information and examples.
 
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Section 6 – Time and Events tables
Original text:
Time and Events Table – 24 Week Induction Period
Procedures  for the 24 Week Induction
Screening 
Period a
Baseline / 
Week (-
24) 
Wee
k 
(-20) 
Wee
k
(-16)
Wee
k
(-12)
Wee
k
(-8)
Wee
k
(-4)
WD p
Notes 
Written Informed Consent 
X
a.
Complete all Screening assessments within 28 days.  
Subjects may be randomized and begin the 
Induction Period as soon as all Screening 
assessments are complete.  Subjects may be 
rescreened once and will be assigned a new subject 
number.
b.
Physical exams should be conducted as part of 
normal routine clinical care but data will not be 
collected in the eCRF. Medical assessments include 
any decisions the study staff must make for subject 
management and / or care.
c.
Measure height at Screening Period only.  Measure 
weight at Screening Period and WD only.
d.
Measure vital signs after about 5 minutes of rest in a 
semi-supine position.
e.
Perform ECG at Baseline in triplicate prior to dosing; 
preferably 2 – 4 hours post dosing for all other visits.
f.
Collect full routine medical history plus; 
cardiovascular risk factors (assessments include 
smoking status and history, family history of cardiac 
events, recent [6 months] illicit drug use), 
gastrointestinal disease, metabolic, psychiatric, renal 
and neurologic disorders.
Demography
X
Eligibility Verification
X
X
X n
Randomization
X
Physical Exam b
X
Symptom Directed Physical Exam and 
Medical Assessment b
X
X
X
X
X
X
X and 
smoking 
status
Vital Signs (BP, HR), Weight, Height c, d
X
X
X
X
12-Lead ECG e
X pre-dose
X
X
X
Medical History and CDC Classification f
X
Medication History / Prior ART History
X
 
 
 
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Procedures  for the 24 Week Induction
Screening 
Period a
Baseline / 
Week (-
24) 
Wee
k 
(-20) 
Wee
k
(-16)
Wee
k
(-12)
Wee
k
(-8)
Wee
k
(-4)
WD p
Notes 
HIV Associated Conditions , AE and 
SAE Assessment, Concomitant Meds 
X g
X
X
X
X
X
X
X
g.
Collect SAEs at Screen only if associated to study 
participation.
h.
Preferably completed at the beginning of the visit.
i.
Collect for women of childbearing potential only.  A 
negative urine pregnancy test is required prior to 
beginning the Induction Period. S=Serum/U=Urine
j.
Plasma for storage will be used: to determine 
genotypic eligibility at Screen, for possible future 
analyses, as back- up in case samples are lost or 
damaged in transit to the lab and for genotypic and 
phenotypic analyses in cases of virologic failure.
k.
Overnight fast is preferred; however, a minimum of a 
6 hour fast is acceptable.
l.
Collect PGx sample at Baseline.  May be collected 
later during the study if necessary.
m.
Instruct subjects to continue to take the Induction 
regimen (including RPV) through Day 1 of the 
Maintenance Period.  Subjects should be reminded 
to take the Day 1 dose in the clinic and return the PK 
diary.  The PK diary will be completed for all subjects 
in case they are randomized to continue on the 
GSK744 + ABC/3TC arm.
n.
Confirmation of eligibility to enter the Maintenance 
Period.  See Section 3.2.3.
o.
Remind subjects of the potential change in study 
Columbia Suicide Severity Rating Scale 
(eC-SSRS) h
X
X
X
X
X
X
X
X
HIVTSQ(s) h
X
X
X
HIVMQ
X 
Chemistry and Hematology
X
X
X
X
X
X
X
X
Pregnancy Testingi
S
U
S
S
S
S
S
S
HIV-1 RNA and sample for storage j 
X
X
X
X
X
X
X
X
CD4+ and CD8+
X
X
X
X
X
X
Urinalysis and urine 
microalbumin/creatinine ratio
X
X
X
Fasting Lab Assessments:  Glucose, 
Cholesterol (Total, HDL and LDL) and 
Triglycerides k
X
X
X
Hepatitis B (HBsAg) and Hepatitis C 
(anti-HCV Ab), HLA-B*5701
X
PT/PTT/INR
X
X
 
 
 
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Procedures  for the 24 Week Induction
Screening 
Period a
Baseline / 
Week (-
24) 
Wee
k 
(-20) 
Wee
k
(-16)
Wee
k
(-12)
Wee
k
(-8)
Wee
k
(-4)
WD p
Notes 
PGx l
X
treatment and visit frequency which begins at 
Day 1.
p.
Follow Up Visit:  Conduct approximately 4 weeks 
after the last dose of IP.  Required only if the subject 
has ongoing AEs or lab abnormalities at the last on-
study visit.  This visit may be conducted by 
telephone.
PK Sample for Storage
X
Study Treatment Dispensation 
X
X
X
X
X
X Add 
RPV m
Study Treatment Accountability
(pill counts)
X
X
X
X
X
X
RPV  and PK Diary Dispensation m
X
Subject Visit Reminder Contact
X
X
X
X
X
X
X o
X
Subject Contact Detail Confirmation
X
X
X
X
X
X
X
 
 
 
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Time and Events Table – 16 Week Induction Period
Procedures for the 16 Week Induction Period
Screenin
g Period a
Baseline / 
Week (-16) 
Wee
k (-
12) 
Week 
(-8)
Week 
(-4)
WD p
Notes 
Written Informed Consent 
X
q.
Complete all Screening assessments within 28 days.  
Subjects may be randomized and begin the Induction 
Period as soon as all Screening assessments are 
complete.  Subjects may be rescreened once and will 
be assigned a new subject number.
r.
Physical exams should be conducted as part of 
normal routine clinical care but data will not be 
collected in the eCRF. Medical assessments include 
any decisions the study staff must make for subject 
management and / or care.  
s.
Measure height at Screening Period only.  Measure 
weight at Screening Period and WD only.
t.
Measure vital signs after about 5 minutes of rest in a 
semi-supine position.
u.
Perform ECG at Baseline in triplicate prior to dosing; 
preferably 2 – 4 hours post dosing for all other visits.
v.
Collect full routine medical history plus; 
cardiovascular risk factors (assessments include 
smoking status and history, family history of cardiac 
events, recent [6 months] illicit drug use), 
gastrointestinal disease, metabolic, psychiatric, renal 
and neurologic disorders.
w.
Collect SAEs at Screen only if associated to study 
participation.
x.
Preferably completed at the beginning of the visit.
Demography
X
Eligibility Verification
X
X
X n
Randomization
X
Physical Exam b
X
Symptom Directed Physical Exam and Medical 
Assessment b
X
X
X
X
X and 
smoking 
status
Vital Signs (BP, HR), Weight, Height c, d
X
X
X
X
12-Lead ECG e
X pre-dose
X
X
X
Medical History and CDC HIV-1 Classification f
X
Medication History including Prior ART History
X
HIV Associated Conditions , AE and SAE 
Assessment, Concomitant Meds 
X g
X
X
X
X
X
Columbia Suicide Severity Rating Scale (eC-
SSRS) h
X
X
X
X
X
X
HIVTSQ(s) h
X
X
X
 
 
 
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Procedures for the 16 Week Induction Period
Screenin
g Period a
Baseline / 
Week (-16) 
Wee
k (-
12) 
Week 
(-8)
Week 
(-4)
WD p
Notes 
HIVMQ
X
y.
Collect for women of childbearing potential only.  A 
negative urine pregnancy test is required prior to 
beginning the Induction Period. S=Serum/U=Urine
z.
Plasma for storage will be used: to determine 
genotypic eligibility at Screen, for possible future 
analyses, as back- up in case samples are lost or 
damaged in transit to the lab and for genotypic and 
phenotypic analyses in cases of virologic failure.
aa. Overnight fast is preferred; however, a minimum of a 
6 hour fast is acceptable.
bb. Collect PGx sample at Baseline.  May be collected 
later during the study if necessary.
cc. Instruct subjects to continue to take the Induction 
regimen (including RPV) through Day 1 of the 
Maintenance Period.  Subjects should be reminded to 
take the Day 1 dose in the clinic and return the PK 
diary.  The PK diary will be completed for all subjects 
in case they are randomized to the oral regimen arm.
dd. Confirmation of eligibility to enter the Maintenance 
Period.  See Section 3.2.3.
ee. Remind subjects of the potential change in study 
treatment and visit frequency which begins at Day 1.
ff.
Follow Up Visit:  Conduct approximately 4 weeks 
after the last dose of IP.  Required only if the subject 
has ongoing AEs or lab abnormalities at the last on-
study visit. This visit may be conducted by telephone.
Chemistry and Hematology
X
X
X
X
X
X
Pregnancy Testing i
S
U
S
S
S
S
HIV-1 RNA and sample for storage j 
X
X
X
X
X
X
CD4+ and CD8+
X
X
X
X
X
Urinalysis and urine microalbumin / creatinine ratio
X
X
X
Fasting Lab Assessments:  Glucose, Cholesterol 
(Total, HDL and LDL) and Triglycerides k
X
X
X
Hep B (HBsAg), Hep C (anti-HCV Ab), HLA-
B*5701
X
PT/PTT/INR
X
X
PGx l
X
PK Sample for Storage
X
Study Treatment Dispensation 
X
X
X
X Add RPV m
Study Treatment Accountability (pill counts)
X
X
X
X
RPV  and PK Diary Dispensation m
X
Subject Visit Reminder Contact
X
X
X
X
X o
X
 
 
 
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Procedures for the 16 Week Induction Period
Screenin
g Period a
Baseline / 
Week (-16) 
Wee
k (-
12) 
Week 
(-8)
Week 
(-4)
WD p
Notes 
Subject Contact Detail Confirmation
X
X
X
X
X
Time and Events Table – Maintenance Period for IM Regimen (GSK744 LA+TMC278 LA)
Procedures
For Maintenance 
– IM regimen
D1
W
1
W
4
W
8
W
12
W
16
W
20
W
24
W
28
W
29
W
32
W
36
W
40
W
44
W
48
W
52
W
56
W
60
W
64
W
68
W
72
W
76
W
80
W
84
W
88
W
92
W
96
WD 
m,n
Verify Eligibility 
X
Randomization
X
Symptom 
Directed PE, ISR 
& Medical 
Assessment a
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 
and 
smoking 
status
Vital Signs
(BP, HR) b
X
X
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
ECG c
Xpre
X
X
X
X
X
X
X
X
X
X
X
HIV Associated 
Conditions, AE 
and SAE 
Assessment, Con  
Meds 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ISR Diary 
D
E
E
E
E
E
E
E
D
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
 
 
 
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Procedures
For Maintenance 
– IM regimen
D1
W
1
W
4
W
8
W
12
W
16
W
20
W
24
W
28
W
29
W
32
W
36
W
40
W
44
W
48
W
52
W
56
W
60
W
64
W
68
W
72
W
76
W
80
W
84
W
88
W
92
W
96
WD 
m,n
Dispensation and 
Review d
Exercise Habit 
Assessment e
X
X
eC-SSRS f
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HIVTSQ(s) g
Xpre
X
X
X
X
X
X
HIVTSQ(c) g
X
X
HIVMQ g
X
X
X
X
X g
Chemistry and 
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy 
Testing h
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
S
HIV-1 RNA &
sample for 
storage i
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CD4+/ CD8+
X
X
X
X
X
X
X
X
X
X
X
Urinalysis and 
urine 
microalbumin/
creatinine ratio
X
X
X
X
X
X
 
 
 
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Procedures
For Maintenance 
– IM regimen
D1
W
1
W
4
W
8
W
12
W
16
W
20
W
24
W
28
W
29
W
32
W
36
W
40
W
44
W
48
W
52
W
56
W
60
W
64
W
68
W
72
W
76
W
80
W
84
W
88
W
92
W
96
WD 
m,n
Fasting:  Glucose, 
Cholesterol (Total, 
HDL and LDL) 
and 
Triglycerides j
X
X
X
X
X
X
X
 
 
 
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Procedures
For Maintenance 
– IM regimen
D1
W
1
W
4
W
8
W
12
W
16
W
20
W
24
W
28
W
29
W
32
W
36
W
40
W
44
W
48
W
52
W
56
W
60
W
64
W
68
W
72
W
76
W
80
W
84
W
88
W
92
W
96
WD 
m,n
Procedures
For Maintenance 
– IM regimen
D1
W
1
W
4
W
8
W
12
W
16
W
20
W
24
W
28
W
29
W
32
W
36
W
40
W
44
W
48
W
52
W
56
W
60
W
64
W
68
W
72
W
76
W
80
W
84
W
88
W
92
W
96
WD 
m,n
PT/PTT/INR
X
X
X
X
X
PK Sample k
X 
X 
X
X
X
X
X
X
X
X 
X
X
X
X
X
S
S
S
S
S
S
S
S
S
S
S
S
S
Study Treatment 
Administration o
X l
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Visit Reminder 
Contact
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Subject Contact 
Confirmation
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
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D=Day     W=Week    Pre=Pre-dosing   PE = Physical Exam
a)
Physical exams should be conducted as part of normal routine clinical care but data 
will not be collected in the eCRF. Medical assessments include any decisions the 
study staff must make for subject management and/or care of the subject.
b)
Measure vital signs after about 5 minutes of rest in a semi-supine position.
c)
12-Lead ECG – Conduct pre-dose at Day 1.  At all other visits, the ECG may be 
done at any time during the visit.
d)
D = Daily  E = Episodic.  Subjects will complete a daily diary of injection site 
reactions from Day 1 to Week 1 and again from Week 28 to Week 29 (daily).  At all 
other visits subjects will complete a diary only if the subject experiences a reaction 
(episodic).  Subjects will be dispensed a new diary at each visit.  
e)
Subject’s exercise habits will be assessed daily between Day 1 and Week 1 and 
again between Week 28 and Week 29.  Assessments will include type and duration 
of cardiovascular exercise and duration of any strength or other strenuous
exercises. This information will be collected via the daily ISR diary.
f)
Preferably completed at the beginning of the visit. 
g)
Conduct the HIVTSQ(s) at Day 1 pre- dosing; at all other visits conduct post-
dosing.  Conduct the HIVTSQ(c) at WD ONLY if the subject WD between Week 4 
and Week 24.  Conduct the HIVMQ post injection.
h)
Women of childbearing potential only.  A (-) urine pregnancy test is required prior to 
any injection and prior to reinitiating injections after > 7 days of treatment 
interruption. A positive urine test should be confirmed with a stat serum test.  If 
positive, subject will need to be WD.  U=Urine  S=Serum
i)
Plasma for storage samples collected for possible analyses, back-up in case 
samples are lost or damaged in transit to lab, for geno/pheno analyses and 
virologic failures.
j)
Fast overnight; however, a minimum of a 6 hour fast is acceptable.
k)
Take PK samples pre-dose except Week 1 and Week 29 which can be taken at 
any time during the visit.  Day 1 PK sample should be taken after review of PK 
diary and pre-dose of GSK744+ABC/3TC+RPV and another sample taken 2 
hours after the last injection.  S=Sample for storage
l)
Subjects should take GSK744+ABC/3TC+RPV on Day 1 in the clinic prior to PK 
sampling.  Day 1 injections will include 2 x GSK744 LA 400 mg + 1 x TMC278 LA 
600 mg IM.  Thereafter injections are 1 x GSK744 LA 400 mg + 1 TMC278 LA 
600 mg IM.  
m)
Subjects who WD must enter Long-Term Follow Up (see Section 3.2.6) instead 
of completing the WD visit.  If they cannot enter Long-Term Follow-Up complete
WD assessments.
n)
Follow Up Visit:  Conduct approximately 4 weeks after the last dose of IP.  
Required only if the subject has ongoing AEs or lab abnormalities at the last on-
study visit.  This visit may be conducted by telephone.
o)
If possible, injections should be spaced approximately 2 cm from one another 
and from the site of any previous injection and or any injection site reaction.  
Bring TMC278 LA to approximately room temperature prior to injecting; note time 
and location of injection (right or left) in eCRF.  Dosing is expected to occur 
within 21-35 days from the previous dose while keeping to the subjects visit 
schedule projected from Day 1 of the Maintenance Period.  All decisions 
regarding dose interruption/ resumption must be discussed with the 
medical monitor in advance.
 
 
 
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Time and Events Table – Maintenance Period for Oral Regimen (GSK744+ABC/3TC)
Procedures
For 
Maintenance -
oral regimen 
D1
W
4
W
8
W
12
W
16
W
20
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
52
W
56
W
60
W
64
W
68
W
72
W
76
W
80
W
84
W
88
W
92
W
96
W
98 n
WD o
Verify Eligibility
X
X j
X k
X k
Randomization
X
Symptom 
Directed PE and 
Medical 
Assessment a
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X and 
smoking 
status
Vital Signs
(BP, HR) b
X
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
ECG c
Xpre
X
X
X
X
X
X
X
X
X
X
HIV Associated 
Conditions, AE 
and SAE 
Assessment, 
Concomitant 
Meds 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 
PK Diary d
D/R
D/R
D/R
R
R
eC-SSRS e
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
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Procedures
For 
Maintenance -
oral regimen 
D1
W
4
W
8
W
12
W
16
W
20
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
52
W
56
W
60
W
64
W
68
W
72
W
76
W
80
W
84
W
88
W
92
W
96
W
98 n
WD o
HIVTSQ(s) e
Xpre
X
X
X
X
X
X
HIVTSQ(c) e
X
X e
HIVMQ e
X
X
X
X
X
Chemistry and 
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy 
Testing f
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
HIV-1 RNA &
sample for 
storage g
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CD4+/ CD8+
X
X
X
X
X
X
X
X
X
X
X
Urinalysis and 
urine
microalbumin/
creatinine ratio
X
X
X
X
X
X
Fasting:  
Glucose, 
Cholesterol 
(Total, HDL and 
LDL) and 
Triglycerides h
X
X
X
X
X
X
X
PT/PTT/INR
X
X
X
X
X
PK Sample i
X
X
X
X
X
Study 
Treatment 
Dispensation & 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 
Add
RPV, 
 
 
 
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Procedures
For 
Maintenance -
oral regimen 
D1
W
4
W
8
W
12
W
16
W
20
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
52
W
56
W
60
W
64
W
68
W
72
W
76
W
80
W
84
W
88
W
92
W
96
W
98 n
WD o
Accountability 
l
Subject Visit 
Reminder 
Contact
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X m
X
Subject Contact 
Detail 
Confirmation
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Grey shading indicates visits may be conducted via telephone.  The purpose of these 
visits will be to assess the subject for any AEs, changes to Con Meds, changes to their 
overall health and any other medical concerns. 
D=Day     W=Week    Pre=Pre-dosing  PE = Physical Exam
a.
Physical exams should be conducted as part of normal routine clinical care but data 
will not be collected in the eCRF. Medical assessments include any decisions the 
study staff must make for subject management and/or care of the subject.
b.
.Measure vital signs after about 5 minutes of rest in a semi-supine position.
c.
12-Lead ECG – Conduct pre-dose at Day 1.  At all other visits, it is preferable to 
conduct 2 – 4 hours after dosing.
d.
D=Dispense   R=Review
e.
Preferably completed at the beginning of the visit.  Conduct the HIVTSQ(s) at Day 1 
prior to dosing.  Conduct the HIVTSQ(c) at WD ONLY if the subject WD between 
Week 4 and Week 24.
f.
Women of childbearing potential only.  S=Serum
g.
Plasma for storage samples are collected for possible future analyses, as back- up 
in case of lost or damaged in transit to the lab and for geno/pheno analyses for 
virologic failures
h.
Plasma for storage samples are collected for possible future analyses, as back-
up in case of lost or damaged in transit to the lab and for geno/pheno analyses 
for virologic failures
i.
Fast overnight; however, a minimum of a 6 hour fast is acceptable.
j.
All PK samples should be taken pre-dose within 20-28 hours after the last dose 
of IP taken.  Subjects will take their dose of IP in the clinic at PK visits.
k.
Assess subject willingness to continue on to the Extension Period.
l.
The results from the Week 96 HIV-1 RNA sample must be <50 c/mL and 
results available at the time of the Week 98 visit.  See Section 3.2.5.2.
m.
For subjects eligible to enter the Extension Period Add RPV to current 
treatment regimen.  Subjects will take their Maintenance treatment 
regimen+RPV until Week 100.
n.
Remind subjects of the change in study treatment and visit frequency which 
begins at Week 100.
o.
Only for those subjects electing to transition to GSK744 LA+TMC278 LA.
p.
Follow Up Visit:  Conduct approximately 4 weeks after the last dose of IP.  
Required only if the subject has ongoing AEs or lab abnormalities at the last 
on-study visit.  This visit may be conducted by telephone
 
 
 
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Time and Events Table – Extension Period
Procedures for 
Extension
W 
100
W 
104
W 
108
W 
112
W
116
W 
120
W
124
W
128
W
132
W
136
W 
140 a
W 
144 a
W 
148 a
Continue until either locally approved and commercially available, the subject no longer derives clinical 
benefit or meets a protocol-defined reason for discontinuation or until development is terminated.
WD k,l
Notes
See footnote “a” for continuation of 
visit schedule after Week 148.
Symptom Directed 
Physical Exam, ISR 
and Medical 
Assessment b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
a.
Continue this pattern for visits for the 
remainder of the study.  For example, 
Week 152 will be conducted just like 
Week 140.  Week 156 will be 
conducted just like Week 144 and 
Week 160 will be conducted just like 
Week 148.
b.
Physical exams should be conducted 
as part of normal routine clinical care 
but data will not be collected in the 
eCRF. Medical assessments include 
any decisions the study staff must 
make for subject management.
c.
Measure vital signs after about 5 
minutes of rest in a semi-supine 
position.
d.
Can be done at any time during the 
visit.
e.
Preferably completed at the 
beginning of the visit.
f.
Women of childbearing potential must 
have a (-) urine pregnancy test prior 
to any injection and prior to 
reinitiating injections after > 7 days of 
treatment interruption. U=Urine
g.
Plasma for storage samples are 
collected for possible future analyses, 
as back-up in case of lost damaged in 
Vital Signs (BP, HR) c
X
X
X
X
X
X
Weight
X
X
X
X
X
X
HIV Associated 
Conditions, AE and 
SAE Assessments, 
Con Meds
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG d
X
X
X
X
X
Columbia Suicide 
Severity Rating Scale 
(eC-SSRS) e
X
X
X
X
X
X
X
X
Chemistry and 
Hematology
X
X
X
X
X
X
X
X
Pregnancy Testing f
U
U
U
U
U
U
U
U
U
U
U
U
U
U
HIV-1 RNA and 
sample for storage g
X
X
X
X
X
X
X
X
 
 
 
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Procedures for 
Extension
W 
100
W 
104
W 
108
W 
112
W
116
W 
120
W
124
W
128
W
132
W
136
W 
140 a
W 
144 a
W 
148 a
Continue 
until either 
WD k,l
Notes
See footnote “a” for continuation of 
visit schedule after Week 148.
CD4+
X
X
X
X
X
X
transit to the lab and for geno/pheno 
analyses for virologic failures.
h.
Fast overnight; minimum of a 6 hour 
fast is acceptable.
i.
Dispense at each visit.  E = Episodic
j.
If possible, injections should be 
spaced approximately 2 cm from one 
another and from the site of any 
previous injection and or any injection 
site reaction.  Bring TMC278 LA to 
approximately room temperature prior 
to injecting; note time and location of 
injection (right or left) in eCRF.  
Dosing is expected to occur within 
21-35 days from the previous dose 
while keeping to the subjects visit 
schedule projected from Day 1 of the 
Maintenance Period.  All decisions 
regarding dose interruption/ 
resumption must be discussed 
with the medical monitor in 
advance.
k.
Or  Long-Term Follow Up
l.
Follow Up Visit: ~4 weeks after the 
last dose of IP only if subject has 
ongoing AEs/lab abnormalities at the 
last visit.
Urinalysis and urine 
microalbumin/
creatinine ratio
X
X
X
X
X
Continue until either locally approved and commercially available, the 
subject no longer derives clinical benefit or meets a protocol-defined reason 
X
Fasting:  Glucose, 
Cholesterol (Total, 
HDL and LDL) and 
Triglycerides h
X
X
X
X
X
X
PT/PTT/INR
X
ISR Diary 
Dispensation 
and Review i
E
E
E
E
E
E
E
E
E
E
E
E
E
E 
review
Study Treatment 
Administration j
X 
X
X
X
X
X
X
X
X
X
X
X
X
Subject Visit 
Reminder Contact
X
X
X
X
X
X
X
X
X
X
X
X
X
Subject Contact Detail 
Confirmation
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
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Time and Events Table – Long-Term Follow Up Period
Procedures for Long-Term Follow Up
Month 1 a
Month 
3
Month 
6
Month 
9
Month 12
WD
Notes
HIV Associated Conditions, AE and 
SAE Assessments, Con Meds
X
X
X
X
X
X
Every effort should be made to enter subjects into the Long-
Term Follow Up if they withdraw from or discontinue the study 
after receiving at least one dose of GSK744 LA and / or 
TMC278 LA.
a)
The start of the 52-week follow up period begins the 
day of the last GSK744 LA and/or TMC278 LA dose.
b)
Women of childbearing potential only.  S = Serum
c)
Fast overnight; however, a minimum of a 6 hour fast 
is acceptable.
d)
Women of childbearing potential should continue to 
receive counselling on the need to use adequate 
contraception for the entirety of the Long-Term 
Follow-Up Period. 
e)
Investigators must discuss choice of HAART 
regimen and timing of initiation with the medical 
monitor before initiating.  This regimen is not 
provided by the study but the Sponsor will 
reimburse sites for cost.
HIV-1 RNA
X
X
X
X
X
X
CD4+
X
X
X
X
X
X
Plasma for Storage
X
X
X
X
X
X
Chemistry and Hematology
X
X
X
X
X
X
Pregnancy Testing b
S
S
S
S
S
S
Urinalysis and urine microalbumin/
creatinine ratio
X
X
X
Fasting:  Glucose, Cholesterol (Total, 
HDL and LDL) and Triglycerides c
X
X
PT/PTT/INR
X
X
Contraception Counselling d
X
X
X
X
X
X
HAART Dispensation e
X
X
X
X
X
X
 
 
 
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Revised text:
Time and Events Table – Induction Period
Procedures  for Induction
Screening 
Period a
Baseline / 
Week (-
20) 
Week 
(-16) 
Week
(-12)
Week
(-8)
Week
(-4)
WD
Notes 
Written Informed Consent 
X
a.
Complete all Screening assessments within 28
days.  Subjects may be randomized and begin the 
Induction Period as soon as all Screening 
assessments are complete.  Subjects may be 
rescreened once and will be assigned a new 
subject number.
b.
Physical exams should be conducted as part of 
normal routine clinical care but data will not be 
collected in the eCRF. Medical assessments 
include any decisions the study staff must make 
for subject management and / or care. 
c.
Height collected at Baseline only.
d.
Measure vital signs after about 5 minutes of rest 
in a semi-supine position.
e.
Perform ECG at Baseline in triplicate prior to 
dosing; preferably 2 – 4 hours post dosing for all 
other visits.
f.
Collect full routine medical history plus; 
cardiovascular risk factors (assessments include 
smoking status and history, family history of 
cardiac events), recent [6 months] illicit drug 
use, intravenous drug use, gastrointestinal 
disease, metabolic, psychiatric, renal and 
neurologic disorders.
g.
Collect SAEs at Screen only if associated to study 
participation.
Demography
X
Eligibility Verification
X
X
X h
Physical Exam b
X
Symptom Directed Physical Exam and 
Medical Assessment b
X
X
X
X
X
X and 
smoking 
status
Weight and Height c
X
X
Vital Signs (BP, HR) d
X
X
X
X
12-Lead ECG e
X
X pre-dose x3
X
X
Medical History f
X
Medication History / Prior ART History
X
CDC Classification
X
X
HIV Associated Conditions
X
X
X
X
X
 
 
 
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Procedures  for Induction
Screening 
Period a
Baseline / 
Week (-
20) 
Week 
(-16) 
Week
(-12)
Week
(-8)
Week
(-4)
WD
Notes 
AE and SAE Assessment, Con Meds
X g
X
X
X
X
X
X
h.
Confirmation of eligibility to enter the Maintenance 
Period.  See Section 3.2.3.
i.
Preferably completed at the beginning of the visit.
j.
Collect for women of childbearing potential only.  
A negative urine pregnancy test is required prior 
to beginning the Induction Period. 
S=Serum/U=Urine
k.
Plasma for storage will be used: to determine 
genotypic eligibility at Screen, for possible future 
analyses, as back- up in case samples are lost or 
damaged in transit to the lab and for genotypic 
and phenotypic analyses in cases of virologic 
failure.
l.
Overnight fast is preferred; however, a minimum 
of a 6 hour fast is acceptable.
m.
Collect PGx sample at Baseline.  May be 
collected later during the study if necessary.
Columbia Suicide Severity Rating Scale 
(eC-SSRS) i
X
X
X
X
X
X
X
HIVTSQ(s) i
X
X
X
HIVMQ
X 
Clinical Chemistry 
and Hematology
X
X
X
X
X
X
X
Pregnancy Testing j
S
U
S
S
S
S
S
HIV-1 RNA and sample for storage k 
X
X
X
X
X
X
X
CD4+ and CD8+
X
X
X
X
X
X
Urinalysis 
X
X
X
Fasting Lab Assessments:  Glucose, 
Cholesterol (Total, HDL and LDL) and 
Triglycerides l
X
X
X
Hepatitis B (HBsAg) and Hepatitis C 
(anti-HCV Ab), HLA-B*5701
X
PT/PTT/INR
X
X
PGx m
X
 
 
 
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Procedures  for Induction
Screening 
Period a
Baseline / 
Week (-
20) 
Week 
(-16) 
Week
(-12)
Week
(-8)
Week
(-4)
WD
Notes 
PK Sample 
(S)torage
S
n.
Instruct subjects to continue to take the Induction 
regimen (including RPV) through Day 1 of the 
Maintenance Period.  Subjects should be 
reminded to take the Day 1 dose in the clinic for 
PK sampling and return the PK diary.  The PK 
diary will be completed by all subjects in case 
they are randomized to continue on the GSK744 + 
ABC/3TC arm.
o.
Remind subjects of the potential change in study 
treatment and visit frequency beginning at Day 1.
Study Treatment Dispensation 
X
X
X
X
X n
Add RPV 
Study Treatment Accountability
(pill counts)
X
X
X
X
X
PK Diary Dispensation
X n
Subject Visit Reminder Contact
X
X
X
X
X
X o
X
Subject Contact Detail Confirmation
X
X
X
X
X
X
Follow Up Visit:  Conduct approximately 4 weeks after the last dose of IP.  Required only if the subject has ongoing 
AEs or lab abnormalities at the last on-study visit.  This visit may be conducted by telephone.
 
 
 
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Time and Events Table – Maintenance Period for IM Regimen (GSK744 LA+TMC278 LA Q8W)
Procedures
For Maintenance –
Q8W  regimen
D1
W
1
W
4
W
8
W
12
W
16
W
20
W
24
W 
25
W
28
W
32
W
36
W
40
W 
41
W
44
W
48
W
52
W
56
W
60
W
64
W
68
W
72
W
76
W
80
W
84
W
88
W
92
W
96
WD
p, q
Verify Eligibility 
X
Randomization
X
Symptom Directed 
PE, ISR & Medical 
Assessment a
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 
and 
smoking 
status
Vital Signs
(BP, HR) b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight and BMI
X
X
X
X
X
ECG c
Xpre
X
X
X
X
X
X
X
X
X
X
HIV Associated 
Conditions, AE and 
SAE Assessment, 
Con  Meds 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ISR Diary 
(D)aily/(E)pisodic) d
D
E
E
E
E
E
E
D
E
E
E
E
D
E
E
E
E
E
E
E
E
E
E
Exercise Habit 
Assessment e
X
X
X
eC-SSRS f
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
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Procedures
For Maintenance –
Q8W  regimen
D1
W
1
W
4
W
8
W
12
W
16
W
20
W
24
W 
25
W
28
W
32
W
36
W
40
W 
41
W
44
W
48
W
52
W
56
W
60
W
64
W
68
W
72
W
76
W
80
W
84
W
88
W
92
W
96
WD
p, q
HIVTSQ(s) g
Xpre
X
X
X
X
X
HIVTSQ(c) g
X
X
HIVMQ g
X
X
X
X
X g
Clinical Chemistry 
and Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test 
(U)rine/(S)erum h
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
S
HIV-1 RNA &
sample for storagei
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CD4+/ CD8+
X
X
X
X
X
X
X
X
X
X
X
Urinalysis 
X
X
X
X
X
X
Fasting:  Glucose,  
Cholesterol (Total, 
HDL and LDL) and 
Triglycerides j
X
X
X
X
X
X
X
PT/PTT/INR
X
X
X
X
X
PK Sample 
(S)torage k
X 
X 
X
X
X
X
X
X
X 
X
X
X
X
X 
X
X
S
S
S
S
S
S
S
Study Treatment 
Administration m
X l
X
X
X
X
X
X
X
X
X
X
X
X
Xn
 
 
 
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Procedures
For Maintenance –
Q8W  regimen
D1
W
1
W
4
W
8
W
12
W
16
W
20
W
24
W 
25
W
28
W
32
W
36
W
40
W 
41
W
44
W
48
W
52
W
56
W
60
W
64
W
68
W
72
W
76
W
80
W
84
W
88
W
92
W
96
WD
p, q
Visit Reminder 
Contact
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xo
X
X
Subject Contact 
Confirmation
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
D=Day     W=Week    Pre=Pre-dosing   PE = Physical Exam  BMI=Body Mass Index
Gray shading indicates telephone safety assessments that will include interviewing the 
subject for adverse events, concomitant medications, HIV associated conditions and any 
other issues including injection site reactions.
a)
Physical exams should be conducted as part of normal routine clinical care but data will not 
be collected in the eCRF. Medical assessments include any decisions the study staff must 
make for subject management and/or care of the subject.  See Section 6.10.1 for ISR 
assessment requirements.
b)
Measure vital signs after about 5 minutes of rest in a semi-supine position.
c)
12-Lead ECG – Conduct pre-dose at Day 1.  At all other visits, the ECG may be done at any 
time during the visit.
d)
Subjects will complete a (D)aily diary of injection site reactions from Day 1 to Week 1, from 
Week 24 to Week 25 and again from Week 40 to Week 41.  At all other visits subjects will 
complete a diary only if the subject experiences a reaction ((E)pisodic).  Subjects will be 
dispensed a new diary at each visit. Diary data will be entered into the eCRF.
e)
Subject’s exercise habits will be assessed daily from Day 1 to Week 1, from Week 24 to 
Week 25 and again from Week 40 to Week 41.  Assessments will include type and duration 
of cardiovascular exercise and duration of any strength or other strenuous exercises. This 
information will be collected via the daily ISR diary and entered into the eCRF.
f)
Preferably completed at the beginning of the visit. 
g)
Conduct the HIVTSQ(s) at Day 1 pre-dosing; at all other visits conduct post-dosing.  
Conduct the HIVTSQ(c, WD) at WD ONLY if the subject WD between Week 8 and Week 32.  
Conduct the HIVMQ post injection.
h)
Women of childbearing potential only.  A (-) urine pregnancy test is required prior to any 
injection and as required by medical monitor after a treatment interruption. A positive urine 
test should be confirmed with a stat serum test.  If positive, subject will need to be WD.
i)
Plasma for storage samples collected for possible analyses, back-up in case samples are 
lost or damaged in transit to lab, for geno/pheno analyses and virologic failures.
j)
Fast overnight; however, a minimum of a 6 hour fast is acceptable.
k)
Take PK samples pre-dose except Weeks 1, 12, 20, 25, 28, 36, 41 and 44 which can 
be taken at any time during the visit.  Day 1 PK sample should be taken after review of 
PK diary and pre-dose of GSK744+ABC/3TC+RPV.  A second Day 1 PK sample will 
be collected 2 hours after the last injection.
l)
Subjects should take GSK744+ABC/3TC+RPV on Day 1 in the clinic prior to PK 
sampling and injections should be administered within 2 hours of this where possible.  
m)
Subjects will take final dose of Induction regimen in the clinic at Day 1 and begin 
injections.   Day 1 injections are 2 x GSK744 LA 400 mg IM + 1 x TMC278 LA 900 mg 
IM.    Week 4 injection is 1 x GSK744 LA 600 mg IM (no TMC278 LA).  At Week 8 and 
Q8W, injections are 1 x GSK744 LA 600 mg IM + 1 x TMC278 LA 900 mg IM.  If 
possible, injections should be spaced approximately 2 cm from one another and from 
the site of any previous injection and or any injection site reaction.  Bring TMC278 LA 
to approximately room temperature prior to injecting.  Time and location of injection 
(right or left) as well as needle length used will be collected in the eCRF.  IM dosing is 
expected to occur during the week in which the subject’s projected visit falls (as 
according to the Day 1 visit).  An additional (+ or -) 7 day window is allowable for 
IM dosing but not preferred.  All decisions regarding dose interruption/ 
resumption must be discussed with the medical monitor in advance.  
n)
Subjects will receive the selected Extension dosing regimen (either Q8W or Q4W) at 
this visit.  If switching to Q4W, injections are 1 x GSK744 LA 400 mg IM + 1 x TMC278 
LA 600 mg IM.  Subjects may immediately begin the new regimen at Week 96.
o)
Remind subjects of the potential change in study treatment and visit frequency 
beginning at Week 96.
p)
Subjects who WD must enter Long-Term Follow Up (see Section 3.2.6) instead of 
completing the WD visit.  If they cannot enter Long-Term Follow-Up complete WD and 
Follow Up assessments.
q)
Follow Up Visit:  Conduct approximately 4 weeks after the last dose of IP.  Required 
for subjects not entering Long-Term Follow Up and only if the subject has ongoing AEs 
or lab abnormalities at the last on-study visit.  This visit may be conducted by phone.
 
 
 
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Time and Events Table – Maintenance Period for IM Regimen (GSK744 LA+TMC278 LA Q4W)
Procedures
For Maintenance –
Q4W  regimen
D1
W
1
W
4
W
8
W
12
W
16
W
20
W
24
W 
25
W
28
W
32
W
36
W
40
W 
41
W
44
W
48
W
52
W
56
W
60
W
64
W
68
W
72
W
76
W
80
W
84
W
88
W
92
W
96
WD
p, q
Verify Eligibility 
X
Randomization
X
Symptom Directed 
PE, ISR & Medical 
Assessment a
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 
and 
smoking 
status
Vital Signs
(BP, HR) b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight and BMI
X
X
X
X
X
ECG c
Xpre
X
X
X
X
X
X
X
X
X
X
HIV Associated 
Conditions, AE and 
SAE Assessment, 
Con  Meds 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ISR Diary 
(D)aily/(E)pisodic) d
D
E
E
E
E
E
E
D
E
E
E
E
D
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
Exercise Habit 
Assessment e
X
X
X
eC-SSRS f
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
2018N380094_00

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Procedures
For Maintenance –
Q4W  regimen
D1
W
1
W
4
W
8
W
12
W
16
W
20
W
24
W 
25
W
28
W
32
W
36
W
40
W 
41
W
44
W
48
W
52
W
56
W
60
W
64
W
68
W
72
W
76
W
80
W
84
W
88
W
92
W
96
WD
p, q
HIVTSQ(s) g
Xpre
X
X
X
X
X
HIVTSQ(c) g
X
X
HIVMQ g
X
X
X
X
X g
Clinical Chemistry 
and Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test 
(U)rine/(S)erum h
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
S
HIV-1 RNA &
sample for storagei
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CD4+/ CD8+
X
X
X
X
X
X
X
X
X
X
X
Urinalysis 
X
X
X
X
X
X
Fasting:  Glucose,  
Cholesterol (Total, 
HDL and LDL) and 
Triglycerides j
X
X
X
X
X
X
X
PT/PTT/INR
X
X
X
X
X
PK Sample 
(S)torage k
X 
X 
X
X
X
X
X
X
X
X
X
X
X
X 
X
X
S
S
S
S
S
S
S
Study Treatment 
Administration m
X l
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xn
 
 
 
2018N380094_00

2013N168152_09
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200056
290
Procedures
For Maintenance –
Q4W  regimen
D1
W
1
W
4
W
8
W
12
W
16
W
20
W
24
W 
25
W
28
W
32
W
36
W
40
W 
41
W
44
W
48
W
52
W
56
W
60
W
64
W
68
W
72
W
76
W
80
W
84
W
88
W
92
W
96
WD
p, q
Visit Reminder 
Contact
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xo
X
X
Subject Contact 
Confirmation
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
D=Day     W=Week    Pre=Pre-dosing   PE = Physical Exam  BMI=Body Mass Index
a)
Physical exams should be conducted as part of normal routine clinical care but data will not 
be collected in the eCRF. Medical assessments include any decisions the study staff must 
make for subject management and/or care of the subject.  See Section 6.10.1 for ISR 
assessment requirements.
b)
Measure vital signs after about 5 minutes of rest in a semi-supine position.
c)
12-Lead ECG – Conduct pre-dose at Day 1.  At all other visits, the ECG may be done at any 
time during the visit.
d)
Subjects will complete a (D)aily diary of injection site reactions from Day 1 to Week 1, from 
Week 24 to Week 25 and again from Week 40 to Week 41.  At all other visits subjects will 
complete a diary only if the subject experiences a reaction ((E)pisodic).  Subjects will be 
dispensed a new diary at each visit. Diary data will be entered into the eCRF.
e)
Subject’s exercise habits will be assessed daily from Day 1 to Week 1, from Week 24 to 
Week 25 and again from Week 40 to Week 41.  Assessments will include type and duration 
of cardiovascular exercise and duration of any strength or other strenuous exercises. This 
information will be collected via the daily ISR diary and entered into the eCRF.
f)
Preferably completed at the beginning of the visit. 
g)
Conduct the HIVTSQ(s) at Day 1 pre-dosing; at all other visits conduct post-dosing.  
Conduct the HIVTSQ(c, WD) at WD ONLY if the subject WD between Week 8 and Week 32.  
Conduct the HIVMQ post injection.
h)
Women of childbearing potential only.  A (-) urine pregnancy test is required prior to any 
injection and as required by medical monitor after a treatment interruption. A positive urine 
test should be confirmed with a stat serum test. If positive, subject will need to be WD.
i)
Plasma for storage samples collected for possible analyses, back-up in case samples are 
lost or damaged in transit to lab, for geno/pheno analyses and virologic failures.
j)
Fast overnight; however, a minimum of a 6 hour fast is acceptable.
k)
Take PK samples pre-dose except Week 1, Week 25 and Week 41 which can be 
taken at any time during the visit.  Day 1 PK sample should be taken after review of PK 
diary and pre-dose of GSK744+ABC/3TC+RPV.  A second Day 1 PK sample will be 
collected 2 hours after the last injection.
l)
Subjects should take GSK744+ABC/3TC+RPV on Day 1 in the clinic prior to PK 
sampling and injections should be administered within 2 hours of this where possible.  
m)
Subjects will take final dose of Induction regimen in the clinic at Day 1 and begin 
injections.   Day 1 injections are 2 x GSK744 LA 400 mg IM + 1 x TMC278 LA 600 mg 
IM.  At Week 4 and Q4W, injections are 1 x GSK744 LA 400 mg IM + 1 x TMC278 LA 
600 mg IM.  If possible, injections should be spaced approximately 2 cm from one 
another and from the site of any previous injection and or any injection site reaction.  
Bring TMC278 LA to approximately room temperature prior to injecting.   Time and 
location of injection (right or left) as well as needle length used will be collected in the 
eCRF.  IM dosing is expected to occur during the week in which the subject’s 
projected visit falls (as according to the Day 1 visit).  An additional (+ or -) 7 day 
window is allowable for IM dosing but not preferred.  All decisions regarding 
dose interruption/ resumption must be discussed with the medical monitor in 
advance. 
n)
Subjects will receive the selected Extension dosing regimen (either Q8W or Q4W) at 
this visit.  If switching to Q8W, no loading dose is necessary.  Injections are 1 x 
GSK744 LA 600 mg IM + 1 x TMC278 LA 900 mg IM.
o)
Remind subjects of the potential change in study treatment and visit frequency 
beginning at Week 96.
p)
Subjects who WD must enter Long-Term Follow Up (see Section 3.2.6) instead of 
completing the WD visit.  If they cannot enter Long-Term Follow-Up complete WD and 
Follow Up assessments.
q)
Follow Up Visit:  Conduct approximately 4 weeks after the last dose of IP.  Required 
for subjects not entering Long-Term Follow Up and only if the subject has ongoing AEs 
or lab abnormalities at the last on-study visit.  This visit may be conducted by phone.
 
 
 
2018N380094_00

2013N168152_09
CONFIDENTIAL
200056
291
Time and Events Table – Maintenance Period for Oral Regimen (GSK744+ABC/3TC)
Procedures
For Maintenance 
– ORAL regimen
D1
W
4
W
8
W
12
W
16
W
20
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
52
W
56
W
60
W
64
W
68
W
72
W
76
W
80
W
84
W
88
W
92
W
96
W 
100m
W
102m
W
104m
WD q
Verify Eligibility 
X
X l
X 
l, n
Randomization
X
Symptom 
Directed PE & 
Medical 
Assessment a
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X and 
smoking 
status
Vital Signs
(BP, HR) b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight and BMI c
X
X
X
X
X
X
ECG d
X
pre
X
X
X
X
X
X
X
X
X
X
X
X
pre
X
HIV Associated 
Conditions, AE 
and SAE 
Assessment, Con  
Meds 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK Diary 
(D)ispensation 
and (R)eview e
R
D
R
D
R
eC-SSRS f
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
2018N380094_00

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Procedures
For Maintenance 
– ORAL regimen
D1
W
4
W
8
W
12
W
16
W
20
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
52
W
56
W
60
W
64
W
68
W
72
W
76
W
80
W
84
W
88
W
92
W
96
W 
100m
W
102m
W
104m
WD q
HIVTSQ(s) g
X
pre
X
X
X
X
X
HIVTSQ(c) g
X
X
HIVMQ g
X
X
X
X
X g
Clinical 
Chemistry and 
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test 
(S)erum/(U)rine h
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
U
S
HIV-1 RNA &
sample for 
storage i
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X n
X
X
X
CD4+/ CD8+
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
Fasting:  
Glucose, Insulin, 
Cholesterol 
(Total, HDL and 
LDL) and 
Triglycerides j
X
X
X
X
X
X
X
X
PT/PTT/INR
X
X
X
X
X
X
PK Sample k
X 
X
X
S
S
X
 
 
 
2018N380094_00

2013N168152_09
CONFIDENTIAL
200056
293
Procedures
For Maintenance 
– ORAL regimen
D1
W
4
W
8
W
12
W
16
W
20
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
52
W
56
W
60
W
64
W
68
W
72
W
76
W
80
W
84
W
88
W
92
W
96
W 
100m
W
102m
W
104m
WD q
Study Treatment 
Dispensation and 
Accountability o
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xm
X
X
Add
RPV
X
Add 
injection
Visit Reminder 
Contact
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
p
Xm,p
X p
X p
X p
X
Subject Contact 
Confirmation
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xm
X
X
X
X
D=Day     W=Week    Pre=Pre-dosing  PE = Physical Exam   BMI=Body Mass Index
Gray shading indicates telephone safety assessments that will include interviewing the subject 
for adverse events, concomitant medications, HIV associated conditions and any other issues 
including compliance. 
a.
Physical exams should be conducted as part of normal routine clinical care but data will 
not be collected in the eCRF. Medical assessments include any decisions the study staff 
must make for subject management and/or care of the subject.
b.
Measure vital signs after about 5 minutes of rest in a semi-supine position.
c.
BMI collected at Week 104 only.
d.
12-Lead ECG – Conduct pre-dose at Day 1 and Week 104.  At all other visits, it is 
preferable to conduct 2 – 4 hours after dosing.
e.
Review PK diary at the beginning of the visit to verify time of last dose.  PK samples must 
be collected within the window of 20-28 hours after the last dose taken.  Contact the study 
team for guidance in cases when subject’s last dose is not within window.  Visit may need 
to be rescheduled.
f.
Preferably completed at the beginning of the visit.  
g.
Conduct the HIVTSQ(s) at Day 1 prior to dosing and post dosing where possible at all 
other visits.  Conduct the HIVTSQ(c, WD) at WD ONLY if the subject WD between Week 8 
and Week 32.  Conduct the HIVMQ preferably at the beginning of the visit, but may be 
completed at any time during the visit.
h.
Women of childbearing potential only. A (-) urine pregnancy test is required prior to any 
injection and as required by medical monitor after a treatment interruption. A positive urine 
test should be confirmed with a stat serum test.  If positive, subject will need to be WD.
i.
Plasma for storage samples are collected for possible future analyses, as back- up in 
case of lost or damaged in transit to the lab and for geno/pheno analyses for virologic 
failures
j.
Fast overnight; however, a minimum of a 6 hour fast is acceptable.
k.
All PK samples should be taken pre-dose within 20-28 hours after the last dose of IP 
taken.  Subjects will take their dose of IP in the clinic at PK visits. S=Storage
l.
Assess subject’s willingness to continue on to the Extension Period.  If not continuing 
into the Extension Period, this is the subject’s last study visit.
m.
For subjects continuing into the Extension Period only.  
n.
The Week 100 HIV-1 RNA result must be <50 c/mL to be eligible to continue into the 
Extension Period.  See Section 3.2.5.2.    Subjects ineligible for Extension will end their 
study participation at Week 102 (no withdrawal visit needed).
o.
Subjects will discontinue RPV at Day 1 and begin taking 1 x GSK744 + 1 x ABC/3TC 
tablet once daily. At Week 96 and Week 100, while awaiting eligibility for Extension, 
subjects will continue their GSK744+ABC/3TC regimen.  At Week 102, subjects eligible 
to enter the Extension Period will add once daily RPV to their GSK744+ABC/3TC 
regimen and continue to take GSK744+ABC/3TC +RPV once daily through Week 104.  
At Week 104, subjects will take final dose of GSK744+ABC/3TC+RPV in the clinic and 
begin the selected IM regimen (Q8W or Q4W).  See Section 5.1.6 for IM dosing 
administration as loading doses are required.  
p.
Remind subjects of the change in study and assessments for eligibility into Extension.
q.
Follow Up Visit:  Conduct approximately 4 weeks after the last dose of IP.  Required only 
if the subject has ongoing AEs or lab abnormalities at the last on-study visit.  This visit 
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Time and Events Table – Extension Period if Q8W is Selected
Procedures for 
Extension if 
Q8W is Selected
W 
104 a
W 
108b
From Oral 
Arm Only
W 
112
W 
120
W 
128
W
136
W 
144
W
152
W
160
W
168
W
176
W 
184 c
W 
192 c
W 
200 c
WD 
n, o
Notes
Symptom 
Directed 
Physical Exam, 
ISR and 
Medical 
Assessment d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
See footnote “b” for continuation of visit schedule 
after Week 200.  Continue until either locally 
approved and commercially available, the subject 
no longer derives clinical benefit or meets a 
protocol-defined reason for discontinuation or 
until development is terminated.
a.
Subjects switching from the oral regimen will 
complete Week 104 visit as per the Maintenance 
T&E Section 6.4.
b.
Week 108 visit is only for subjects switching from 
the oral arm.
c.
Continue this pattern for visits for the remainder 
of the study.  For example, Week 208 will be 
conducted just like Week 184, Week 216 will be 
conducted just like Week 192 and Week 224 will 
be conducted just like Week 200.
d.
Physical exams should be conducted as part of 
normal routine clinical care but data will not be 
collected in the eCRF. Medical assessments 
include any decisions the study staff must make 
for subject management.
e.
Measure vital signs after about 5 minutes of rest 
in a semi-supine position.
f.
Can be done at any time during the visit.
g.
A (-) urine pregnancy test is required prior to any 
injection and as required by medical monitor 
after a treatment interruption. A (+) urine test 
should be confirmed with a stat serum test.  If 
(+), subject will need to be WD.
Vital Signs
(BP, HR) e
X
X
X
X
X
X
X
X
Weight & BMI
X
X
X
X
X
X
X
X
HIV Associated 
Conditions, AE 
and SAE 
Assessments, 
Con Meds
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG f
X
X
X
X
X
X
X
X
X
Clinical 
Chemistry and 
Hematology
X
X
X
X
X
X
X
X
X
Pregnancy 
Testing
(U)rine g
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
 
 
 
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Procedures for 
Extension if 
Q8W is Selected
W 
104 a
W 
108b
From Oral 
Arm Only
W 
112
W 
120
W 
128
W
136
W 
144
W
152
W
160
W
168
W
176
W 
184 c
W 
192 c
W 
200 c
WD 
n, o
Notes
HIV-1 RNA and 
sample for 
storage h
X
X
X
X
X
X
X
X
h.
Plasma for storage samples are collected for 
possible future analyses, back-up in cases of 
loss/damage in transit and geno/pheno analyses 
for virologic failures.
i.
Fast overnight; minimum of a 6 hour fast is 
acceptable.
j.
Samples should be collected pre-dose.
k.
Subjects will complete a diary only if the subject 
experiences a reaction ((E)pisodic).  Subjects 
will be dispensed a new diary at each visit. Diary 
data will be entered into the eCRF.
l.
Q8W Injections are 1 x GSK744 LA 600 mg IM 
+ 1 x TMC278 LA 900 mg IM.  If possible, 
injections should be spaced approximately 2 cm 
from one another and from the site of any 
previous injection and or any injection site 
reaction.  Bring TMC278 LA to approximately 
room temperature prior to injecting.   Time and 
location of injection (right or left) as well as 
needle length used will be collected in the eCRF.  
IM dosing is expected to occur during the 
week in which the subject’s projected visit 
falls (as according to the Day 1 visit).  An 
additional (+ or -) 7 day window is allowable 
for IM dosing but not preferred.  All decisions 
regarding dose interruption/ resumption 
must be discussed with the medical monitor 
in advance.
m.
Subjects switching from the oral arm will 
receive their 2nd loading dose injection of 
1 x GSK744 LA 600 mg (no TMC278 LA).
CD4+
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
Fasting:  
Glucose, 
Cholesterol 
(Total, HDL and 
LDL) and 
Triglycerides i
X
X
X
X
X
X
X
X
PT/PTT/INR
X
PK Sample 
(S)torage j
S
S
S
S
S
S
S
S
ISR Diary 
Dispensation k
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E 
review
Study Treatment 
Administration l
X a
X m
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
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Procedures for 
Extension if 
Q8W is Selected
W 
104 a
W 
108b
From Oral 
Arm Only
W 
112
W 
120
W 
128
W
136
W 
144
W
152
W
160
W
168
W
176
W 
184 c
W 
192 c
W 
200 c
WD 
n, o
Notes
n.
Or Long-Term Follow Up
o.
Follow Up Visit - Conduct ~4 weeks after the last 
dose of IP if not entering Long-Term Follow Up 
and only if the subject has ongoing AEs or lab 
abnormalities at the last on-study visit.  May be 
conducted by telephone.
Subject Visit 
Reminder 
Contact
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Subject Contact 
Detail 
Confirmation
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
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Time and Events Table – Extension Period if Q4W is Selected
Procedures for 
Extension if Q4W is 
Selected
W 
100 a
W 
104 a
W 
108
W 
112
W
116
W 
120
W
124
W 
128 b
W 
132 b
W 
136 b
W 
140 b
WD 
l, m
Notes
Symptom Directed 
Physical Exam, ISR and 
Medical Assessment c
X
X
X
X
X
X
X
X
X
X
X
X
See footnote “b” for continuation of visit schedule after 
Week 140.  Continue until either locally approved and 
commercially available, the subject no longer derives 
clinical benefit or meets a protocol-defined reason for 
discontinuation or until development is terminated. 
a.
Subjects switching from the oral regimen will complete 
Week 100 and 104 visits as per the Maintenance T&E 
Section 6.4.
b.
Continue this pattern for visits for the remainder of the 
study.  For example, Week 144 will be conducted just like 
Week 128, Week 148 will be conducted just like Week 132, 
Week 152 will be conducted just like Week 136 and Week 
156 will be conducted just like Week 140.
c.
Physical exams should be conducted as part of normal 
routine clinical care but data will not be collected in the 
eCRF. Medical assessments include any decisions the 
study staff must make for subject management.
d.
Measure vital signs after about 5 minutes of rest in a semi-
supine position.
e.
Can be done at any time during the visit.
f.
A (-) urine pregnancy test is required prior to any injection 
and as required by medical monitor after a treatment 
interruption. A (+) urine test should be confirmed with a stat 
serum test.  If (+), subject will need to be WD.
g.
Plasma for storage samples are collected for possible 
future analyses, back-up in cases of loss/damage in transit 
and geno/pheno analyses for virologic failures.
Vital Signs (BP, HR) d
X
X
X
X
X
Weight & BMI
X
X
X
X
X
HIV Associated 
Conditions, AE and SAE 
Assessments, Con 
Meds
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG e
X
X
X
X
X
Clinical Chemistry and 
Hematology
X
X
X
X
X
X
Pregnancy Testing
(U)rine f
U
U
U
U
U
U
U
U
U
U
U
U
HIV-1 RNA and sample 
for storage g
X
X
X
X
X
X
CD4+
X
X
X
X
X
X
 
 
 
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Procedures for 
Extension if Q4W is 
Selected
W 
100 a
W 
104 a
W 
108
W 
112
W
116
W 
120
W
124
W 
128 b
W 
132 b
W 
136 b
W 
140 b
WD 
l, m
Notes
Urinalysis
X
X
X
X
X
h.
Fast overnight; minimum of a 6 hour fast is acceptable.
i.
Samples should be collected pre-dose.
j.
Subjects will complete a diary only if the subject 
experiences a reaction ((E)pisodic).  Subjects will be 
dispensed a new diary at each visit. Diary data will be 
entered into the eCRF.
k.
Q4W Injections are 1 x GSK744 LA 400 mg IM + 1 x 
TMC278 LA 600 mg IM.  If possible, injections should be 
spaced approximately 2 cm from one another and from the 
site of any previous injection and or any injection site 
reaction.  Bring TMC278 LA to approximately room 
temperature prior to injecting.   Time and location of 
injection (right or left) as well as needle length used will be 
collected in the eCRF.  IM dosing is expected to occur 
during the week in which the subject’s projected visit 
falls (as according to the Day 1 visit).  An additional
(+ or -) 7 day window is allowable for IM dosing but not 
preferred.  All decisions regarding dose interruption/ 
resumption must be discussed with the medical 
monitor in advance.
l.
Or Long-Term Follow Up
m.
Follow Up Visit - Conduct ~4 weeks after the last dose of IP 
if not entering Long-Term Follow Up and only if the subject 
has ongoing AEs or lab abnormalities at the last on-study 
visit.  May be conducted by telephone.
Fasting:  Glucose, 
Cholesterol (Total, HDL 
and LDL) and 
Triglycerides h
X
X
X
X
X
PT/PTT/INR
X
PK Sample 
(S)torage  i
S
S
S
S
S
S
ISR Diary Dispensation j
E
E
E
E
E
E
E
E
E
E
E
E 
review
Study Treatment 
Administration k
X a
X a
X
X
X
X
X
X
X
X
X
Subject Visit Reminder 
Contact
X
X
X
X
X
X
X
X
X
X
X
Subject Contact Detail 
Confirmation
X
X
X
X
X
X
X
X
X
X
X
 
 
 
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Time and Events Table – Long-Term Follow Up Period
Procedures for Long-Term Follow Up
Month 1 a
Month 
3
Month 
6
Month 
9
Month 12
WD
Notes
HIV Associated Conditions, AE and 
SAE Assessments, Con Meds
X
X
X
X
X
X
Every effort should be made to enter subjects into the Long-
Term Follow Up if they withdraw from or discontinue the study 
after receiving at least one dose of GSK744 LA and / or 
TMC278 LA.
a)
The start of the 52-week follow up period begins the 
day of the last GSK744 LA and/or TMC278 LA dose.
b)
Women of childbearing potential only.  S = Serum
c)
Fast overnight; however, a minimum of a 6 hour fast 
is acceptable.
d)
Women of childbearing potential should continue to 
receive counselling on the need to use adequate 
contraception for the entirety of the Long-Term 
Follow-Up Period. 
e)
Investigators must discuss choice of HAART 
regimen and timing of initiation with the medical 
monitor before initiating.  This regimen is not 
provided by the study but the Sponsor will 
reimburse sites for cost.
HIV-1 RNA
X
X
X
X
X
X
CD4+
X
X
X
X
X
X
Plasma for Storage
X
X
X
X
X
X
PK Sample for Storage
X
X
X
X
X
X
Clinical Chemistry and Hematology
X
X
X
X
X
X
Pregnancy Testing b
S
S
S
S
S
S
Urinalysis
X
X
X
Fasting:  Glucose, Cholesterol (Total, 
HDL and LDL) and Triglycerides
X
X
PT/PTT/INR
X
X
Contraception Counselling d
X
X
X
X
X
X
HAART Dispensation e
X
X
X
X
X
X
 
 
 
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Section 6.8.1 – Screening
Revised to (changes struck through and underlined).
All clinical and laboratory assessments of eligibility must be performed and reviewed 
within 28 days of initiating the Screening process. All Screening results must be 
available prior to randomization. 
Eligibility criteria must be carefully assessed at the Screening visit and confirmed at the 
first Induction Period visit prior to enrollment.
Subjects may be randomizedenroll and begin the Induction Period as soon as all 
Screening assessments are complete and the results are available and documented.  
Each subject screened Subjects who meet all entry criteria are randomized andwill be 
assigned a randomizationsubject number. Subjects not meeting all inclusion and 
exclusion criteria at initial screen may be re-screened one time with a new subject 
number. Subjects who are enrolled into the trial and subsequently withdrawn from the 
study for any reason may not be rescreened.
At Screening, samples for HIV-1 genotypic and phenotypic resistance testing and plasma 
HIV-1 RNA measurement will be obtained.
Known moderate or severe hepatic impairment (Class B or C) is exclusionary.  Child-
Pugh classification will be assessed at the Screening visit in subjects with a concern for 
hepatic impairment (see Section 11.2).
Section 6.8.2 – Baseline
Revised to (changes struck through and underlined).
Subjects will have “Baseline” assessments completed at either Week (-24) or Week (-16) 
depending on the length of the beginning of the Induction Periodin which they were 
randomized.
Any changes to the eligibility parameters must be assessed and any results required must 
be available and reviewed prior to randomization enrollment (e.g. urine pregnancy test 
for women of child bearing potential).
HIV-1 genotypic resistance testing and plasma HIV-1 RNA measurement results from 
Screening must be available prior to the Baseline visit.
Section 6.9.3 - HIV Associated Conditions
Revised to (changes underlined).
HIV-associated conditions will be recorded as per Time and Events schedule (Section 6).  
HIV-associated conditions will be assessed according to the 1993 CDC Revised 
 
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Classification System for HIV Infection in Adults (see Section 11.1).  Indicators of 
clinical disease progression are defined as:
CDC Category A at enrollment Category B event;
CDC Category A at enrollment Category C event;
CDC Category B at enrollment Category C event;
CDC Category C at enrollment New Category C Event;
CDC Category A, B or C at enrollment Death.
Section 6.10.1 - Clinical evaluations
Revised to (changes struck through and underlined).
The following clinical evaluations will be performed according to the Time and Events 
schedule (see Section 6):

Pregnancy testing.  A negative urine pregnancy test is required prior to initiation of 
IP, any dose of GSK744 LA or TMC278 LA or prior to reinitiating therapy after an 
interruption of GSK744 LA or TMC278 LA > 7 day as required by the medical 
monitor following a treatment interruption(s).

Injection Site Reactions (ISRs) will be assessed for the following clinically as well as 
patient-reported by utilizing a subject diary:

Daily from Day 1 – 7, from Week 24 – Week 25 and again daily from 
Week 2840 to Week 2941:  Pain, tenderness, pruritis, warmth, bruising, 
discoloration, infections, rash, erythema, swelling, induration, and nodules 
(granulomas or cysts). 
Section 6.10.2 – Laboratory Assessments
Removed collection of  Phosphate (inorganic phosphorus) and changed reporting of 
Creatinine clearance and CD8+ cells from Week 24 to Week 32.
Section 6.10.3 - Liver Chemistry Stopping Criteria
Revised to (changes struck through and underlined).
Liver chemistry threshold stopping criteria have been designed to assure subject safety
and to evaluate liver event etiology during administration of IP and the follow-up period. 
IP will be stopped if any of the following liver chemistry criteria are met:

ALT ≥3xULN and bilirubin ≥2xULN (>35% direct bilirubin, bilirubin 
fractionation required).
NOTE: serum bilirubin fractionation should be performed if testing is available. If testing 
is unavailable, record presence of detectable urinary bilirubin on dipstick, indicating 
direct bilirubin elevations and suggesting liver injury.  If testing is unavailable and a 
 
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subject meets the criterion of total bilirubin 2xULN, then the event meets liver stopping 
criteria.

ALT ≥8xULN.

ALT ≥3xULN (if Baseline ALT is < ULN) with symptoms or worsening of 
acute hepatitis or hypersensitivity such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, or eosinophilia, OR;

ALT ≥3x Baseline ALT with symptoms or worsening of acute hepatitis or 
hypersensitivity such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, or eosinophilia;

ALT ≥3xULN with acute hepatitis symptoms or hypersensitivity if Baseline 
ALT≤ULN OR ALT ≥3 fold increase from Baseline with acute hepatitis 
symptoms or hypersensitivity if Baseline ALT>ULN.

ALT ≥5xULN and <8xULN that persists ≥2 weeks (with bilirubin <2 ULN & no 
signs or symptoms of acute hepatitis or hypersensitivity).

ALT ≥5xULN but <8xULN and cannot be monitored weekly for >2 weeks.
NOTE: if serum bilirubin fractionation is not immediately available, withdraw study drug 
for that subject if ALT 3xULN and bilirubin 2xULN. Serum bilirubin fractionation 
should be performed if testing is available. If testing is unavailable, sites should evaluate 
the presence of detectable urinary bilirubin on dipstick, which indicates direct 
bilirubin elevations and suggests liver injury.
Liver Chemistry Stopping Criteria, Subject Management
Subjects who develop ALT ≥5xULN must be followed weekly until resolution or
stabilization (ALT <5xULN on 2 consecutive evaluations).
When any of the liver chemistry stopping critera is met, do the following:

Immediately hold IP.  

Report the event to the medical monitor within 24 hours of learning its 
occurrence (Section 6.10.13, Section 6.10.15).

Complete the liver event eCRF and SAE eCRF, where applicable, (see 
Section 6.10.13).

Complete the liver imaging and/or liver biopsy eCRFs if these tests are 
performed.

Perform liver event follow up assessments (described below), and monitor the 
subject until liver chemistries resolve, stabilize, or return to Baseline values as
described below.

Make every reasonable attempt to have subjects return to clinic within 24 hours 
for repeat liver chemistries, liver event follow up assessments (see below), and 
close monitoring.
 
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
A specialist or hepatology consultation is recommended.

Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline
phosphatase, bilirubin) resolve, stabilize or return to within Baseline values.
Make every attempt to carry out the liver event follow up assessments described below:

Viral hepatitis serology including:
o
Hepatitis A IgM antibody;
o
HBsAg and Hepatitis B Core Antibody (IgM);
o
Hepatitis C RNA;
o
Hepatitis E IgM antibody;

Cytomegalovirus IgM antibody;

Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);

Syphilis screening;

Drugs of abuse screen including alcohol;

Serum acetaminophen test (APAP adduct test). The site must contact GSK 
when this test is required. Please refer to the Quest Laboratory Manual.

Hepatitis E IgM antibody;

Blood sample for pharmacokinetic (PK) analysis, obtained within 60 hours of 
last dose.  Record the date/time of the PK blood sample draw and the date/time 
of the last dose of investigational product prior to blood sample draw on the 
eCRF. 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 SPM.

Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH);

Fractionate bilirubin, if total bilirubin is greater than 1.5xULN;

Obtain complete blood count with differential to assess eosinophilia;

Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver 
kidney microsomal antibodies;

Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to
evaluate liver disease;

Record the appearance or worsening of clinical symptoms of hepatitis, or
hypersensitivity, fatigue, decreased appetite, nausea, vomiting, abdominal pain,
jaundice, fever, or rash as relevant on the AE report form;

Record use of concomitant medications, acetaminophen, herbal remedies, other 
over the counter medications, or putative hepatotoxins, on the concomitant 
 
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medications report form. Record alcohol use on the liver event alcohol intake 
case report form.
Liver Chemistry Stopping Criteria - Rechallenge
Subjects who meet liver toxicity stopping criteria should not be retreated with 
investigational product unless an exemption has been approved by the ViiV Safety and 
Labeling Committee (VSLC).  The guideline for Rechallenge/Restart approved by the 
VSLC, which is maintained as a separate document (See Section 11.4, Appendix 4), must 
be followed.
Drug Restart/Rechallenge Following Liver Events that are Possibly Related to IP
Approval by the VSLC for drug restart can be considered where:

The subject is receiving compelling benefit, benefit of drug restart exceeds risk, 
and no effective alternative therapy is available.  Ethics Committee or 
Institutional Review Board approval of drug restart/rechallenge must be 
obtained, as required.

If the restart/rechallenge is approved by the VSLC in writing, the subject must 
be provided with a clear description of the possible benefits and risks of drug 
administration, including the possibility of recurrent, more severe liver injury or 
death.

The subject must also provide signed informed consent specifically for the IP 
restart/rechallenge.  Documentation of informed consent must be recorded in the 
study chart.

Study drug must be administered at the dose specified by the VSLC.

Subjects approved by the VSLC for rechallenge of IP must return to the clinic 
twice a week for liver chemistry tests for a minimum of one month and 
thereafter for as long as clinically indicated and then laboratory monitoring may 
resume as per protocol.
Drug Restart Following Transient Resolving Liver Events Not Related to IP
Approval by the VSLC for drug restart can be considered where:

Liver chemistries have a clear underlying cause (e.g., biliary obstruction, 
hypotension and liver chemistries have improved to normal or are within 
1.5 x baseline and ALT <3xULN).  Ethics Committee or Institutional Review 
Board approval of drug restart/rechallenge must be obtained, as required.

If restart of drug is approved by the VSLC in writing, the subject must be 
provided with a clear description of the possible benefits and risks of drug 
administration, including the possibility of recurrent, more severe liver injury or 
death.

The subject must also provide signed informed consent specifically for the 
restart.  Documentation of informed consent must be recorded in the study chart.
 
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
Study drug must be administered at the dose specified by the VSLC.
Subjects approved by the VSLC for restarting IP must return to the clinic once a week for 
liver chemistry tests for a minimum of one month and thereafter for as long as clinically 
indicated and then laboratory monitoring may resume as per protocol.  If protocol defined 
stopping criteria for liver chemistry elevations are met, study drug must be stopped.
See Section 11.4, Appendix 4 for further details.
Section 6.10.6.1 - Treatment Interruption Due to an Adverse Event
Revised to (changes struck through and underlined).
No toxicity-related dose reductions of IP will be allowed. IP and background NRTIs 
should be restarted as soon as medically appropriate; in general, this should be no longer 
than 14 days after discontinuation (unless Grade 3 or 4 toxicities persist). Decisions 
regarding sequential reintroduction of IP or temporary interruption of one or more but not 
all drugs within the ART regimen should be made with the understanding that these 
changes may result in incomplete viral suppression and selection of resistant virus.  Any 
interruption in therapy during the Maintenance Period, oral dosing, of greater than 7 
consecutive days must be discussed with and agreed by the medical monitor prior to 
resumption of therapy.  The medical monitor must be contacted upon becoming aware of 
resumption in therapy, if therapy was resumed without prior approval (Section 5.7).  IM 
dosing is expected to occur during the week in which the subject’s projected visit 
falls (as according to the Day 1 visit).  An additional (+ or -) 7 day window is 
allowable for IM dosing but not preferred.  Any interruption outside of this guidance 
MUST be discussed with the medical monitor prior to reinitiating IM IP (see Section 
5.7.2).
Section 6.10.11 - Injection Site Reaction Monitoring
Revised to (changes struck through and underlined).
Subjects on either IM regimen will be monitored closely both clinically and by patient 
report for the following in relation to injection site reactions:

Pain, tenderness, pruritis, warmth, infections, rash, erythema, swelling, 
induration, and nodules (granulomas or cysts).  
Digital photographs will be documented where possible on all subjects who have an 
injection site reaction that is areeither serious or Grade 2 or above that persist beyond 2 
weeks.  Dermatology will be consulted on all subjects who have an injection site reaction 
considered serious, Grade 3 or above, or if clinically significant and persistent beyond 30 
days and others if the Investigator or Medical Monitor feels it is medically necessary.
 
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Section 6.10.12.1 - Pregnancy Testing
Women of childbearing potential must have a negative pregnancy test at Screening, the 
first Induction Period visit and prior to administration of each GSK744 LA and / or 
TMC278 LA injection.   Pregnancy testing will also be conducted as per the Time and 
Events Table (see Section 6) and at anytime during the trial when pregnancy is suspected. 
Additionally, the medical monitor may request that a pregnancy test should also be 
performed in the event of a treatment interruption greater than 7 days.  A negative test 
result is required to reinitiate GSK744 LA and / or TMC278 LA.  
Section 6.11 – Pharmacokinetics
Original text:
Plasma samples for determination of GSK744 and TMC278 concentration will be 
collected throughout the study.  Samples for determination of RPV will be protected from 
light until analyzed.
PK Sample Collection
Blood samples for evaluation of GSK744 (2mL each) and TMC278 (3mL each) plasma 
PK will be collected from all subjects randomized to receive GSK744 LA + TMC278 LA 
for determination of GSK744 and TMC278 concentrations as described in Table 4.  All 
PK samples will be collected prior to LA dosing, except at Weeks 1 and 29 which may be 
collected anytime during the Week 1 and Week 29 visits, respectively.  The exact date 
and time of the PK sample should be recorded in CRF.
For subjects randomized to GSK744, pre-dose samples will be collected as described in 
Table 4. These samples must be collected within the window of 20-28 hours after the last 
dose taken.  Subjects will be expected to complete a PK dosing diary card noting the date 
and time of the last three doses of IP prior to the scheduled clinic visits on Day 1, Weeks 
24, 48 and 96.  The information from the diary card will be recorded in the eCRF.  
Additionally, dosing information on the clinic day, including whether or not the dose was 
administered with food, and the actual date and time of the PK samples, must be recorded 
on the CRF.  Subjects will take their dose of oral IP in the clinic at PK visits.
 
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Table 4
GSK744 and TMC278 Plasma Pharmacokinetic Sample Schedule
Group
Analyte
Week
Sample Times Relative to Dose
LA
GSK744
Day 1 (prior to LA and last 
oral Induction dose), 
Weeks: 1, 4, 8, 12, 16, 20, 
24, 28, 29, 32, 36, 40, 44 
and 48
Pre-Dose:  Day 1, Weeks 4, 8, 12, 16, 
20, 24, 28, 32, 36, 40, 44 and 48
2 Hours Post Dose:  Day 1
1 Week Post Dose:  Weeks 1, 29
TMC278
Day 1 (prior to LA and last 
oral Induction dose), 
Weeks: 1, 4, 8, 12, 16, 20, 
24, 28, 29, 32, 36, 40, 44 
and 48
Pre-Dose:  Day 1, Weeks 4, 8, 12, 16, 
20, 24, 28, 32, 36, 40, 44 and 48
2 Hours Post Dose:  Day 1
1 Week Post Dose:  Weeks 1, 29
Oral 
(Control Arm 
only)
GSK744
Day 1, Weeks: 24, 48 and 
96
Pre-Dose:  Day 1, Weeks 24, 48 and 96
Additional GSK744 and TMC278 PK samples for storage will be collected at Weeks 52, 
56, 60, 64, 68, 72, 76, 80, 84, 88, 92 and 96 for subjects on GSK744 LA+TMC278 LA 
and at Months 1, 3, 6, 9 and 12 for subjects in the Long-Term Follow Up Period.  These 
samples may be analyzed in case of protocol-defined virologic failure or to investigate 
any PK related issues (such as missing dose, missing sample, suspected non-adherence 
etc.).
Revised text:
Plasma samples for determination of GSK1265744 and TMC278 concentration will be 
collected throughout the Maintenance Period of the study.  Additional samples will be 
collected for storage during the Extension and Long-Term Follow Up Period.  Samples 
for determination of RPV will be protected from light until analyzed.
PK Sample Collection
Blood samples for evaluation of GSK1265744 (2mL each) and TMC278 (3mL each) 
plasma PK will be collected from all subjects randomized to receive GSK744 LA + 
TMC278 LA for determination of GSK1265744 and TMC278 concentrations as 
described in Table 4.  All PK samples will be collected prior to IM dosing and may be 
collected at anytime during visits that study treatment is not administered.  The exact date 
and time of the PK sample should be recorded in eCRF.
For subjects randomized to GSK744, pre-dose blood samples for evaluation of 
GSK1265744 (2mL each) and TMC278 (3mL each) will be collected as described in 
Table 4. These samples must be collected within the window of 20-28 hours after the last 
 
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dose taken.  Subjects will be expected to complete a PK dosing diary card noting the date 
and time of the last three doses of IP prior to the scheduled clinic visits on Day 1, Weeks 
32 and 48.  The information from the diary card will be recorded in the eCRF.  
Additionally, dosing information on the clinic day, including whether or not the dose was 
administered with food, if the subject vomited within 4 hours of dosing and the actual 
date and time of the PK samples, must be recorded on the eCRF.  Subjects will take their 
dose of oral IP in the clinic at PK visits.
 
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Table 13 
GSK744 and TMC278 Plasma Pharmacokinetic Sample Schedule
Group
Analyte
Week
Sample Times Relative to Dose
IM
GSK744
Day 1 (prior to LA and 
last oral Induction 
dose), Weeks: 1, 4, 8, 
12, 16, 20, 24, 25, 28,  
32, 36, 40, 41, 44 and 
48
Pre-Dose (Q8W):  Day 1, Weeks 4, 8, 
16, 24, 32, 40 and 48
Pre-Dose (Q4W):  Day 1, Weeks 4, 8, 
12, 16, 20, 24, 28, 32, 36, 40, 44 and 
48
2 Hours Post Dose:  Day 1
1 Week Post Dose:  Week 1, Week 
25 and Week 41
4 Weeks Post Dose (Q8W):  Weeks 
12, 20, 28, 36 and 44
TMC278
Day 1 (prior to LA and 
last oral Induction 
dose), Weeks: 1, 4, 8, 
12, 16, 20, 24, 25, 28, 
32, 36, 40, 41, 44 and 
48
Pre-Dose (Q8W):  Day 1, Weeks 4, 8, 
16, 24, 32, 40 and 48
Pre-Dose (Q4W):  Day 1, Weeks 4, 8, 
12, 16, 20, 24, 28, 32, 36, 40, 44 and 
48
2 Hours Post Dose:  Day 1
1 Week Post Dose:  Week 1, Week 
25 and Week 41
4 Weeks Post Dose (Q8W):  Weeks 
12, 20, 28, 36 and 44
Oral 
(Control Arm 
only)
GSK744
Day 1, Weeks: 32 and
48
Pre-Dose:  Day 1, Weeks 32 and 48
Additional GSK1265744 and TMC278 PK samples for storage will be collected pre-dose 
at Weeks  56,64, 72, 80, and 96 for subjects on GSK744 LA+TMC278 LA as per the 
Time and Events Table (see Section 6.2 and Section 6.3) and in the Extension Period (see 
Section 6.5 and Section 6.6).  Samples for storage will be also be collected at Week 96 
and 104 for subjects on GSK744+ABC/3TC and at Months 1, 3, 6, 9 and 12 for subjects 
in the Long-Term Follow Up Period.  These samples may be analyzed in case of 
protocol-defined virologic failure or to investigate any PK related issues (such as missing 
dose, missing sample, suspected non-adherence etc.).
 
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Section 6.14 – Health Outcomes
Revised to (changes struck through and underlined).
The HIVTSQ(s) will be administered at the following time points: 

Induction: Week -20 (-16) in the 24 Week Induction Period and Week -12 in the 
16 Week Induction Period and Week (-4) (pre-dose if possible) in both Induction 
Periods

Maintenance:  pre-dose at Day 1and post-dose at Week 4, and post-dose (where 
possible in oral dosing arm) Week 8, Week 3224, Week 48 and Week 96 

Withdrawal
The HIVTSQ(c) will be administered at the following time points:  

Maintenance:  Week 32
The HIVTSQ(c, WD) will be administered at the following time points:   

Withdrawal for subjects withdrawn between Week 8 and Week 32
HIVMQ will be administered at the following time points:

Induction: Week (-4)

Maintenance:  Week 8, Week 24 32, Week 48, Week 96 & Withdrawal
o
IM Regimen:  Complete post-injection
o
Oral Regimen:  Preferably completed at the beginning of the visit, but may 
be completed at any time during the visit
Section 8.1 – Hypotheses
Revised to (changes struck through and underlined).
The study is designed to evaluate the efficacy and safety ofa two-drug regimen consisting 
of GSK744 LA + TMC278 LA when both are administered as intramuscular injections 
every 4 weeksGSK744 LA 400 mg IM plus TMC278 LA 600 mg IM every 4 weeks and 
GSK744 LA 600 mg IM plus TMC278 LA 900 mg IM every 8 weeks, relative to 
GSK744 30 mg once daily plus ABC/3TC once daily, through Week 24 32 of the 
Maintenance Period.
Section 8.2 - Sample Size Assumptions
Original text:
 
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LA treatment relative to Oral treatment
The sample size of 50 subjects per arm and 100 subjects combined in LA arms were 
chosen to ensure a high probability that a long-acting two drug treatment with truly poor 
response relative to GSK744 once daily plus NRTIs once daily will not be studied 
further, while allowing for formal considerations of other factors should efficacy be 
similar between the treatment arms.
The study is designed to test the comparability of GSK744 LA plus TMC278 LA two-
drug regimen to GSK744 30 mg once daily plus ABC/3TC. The primary comparison of 
interest will be performed using a Bayesian probability model. If the posterior probability 
that the difference is greater than -10% is large (i.e., 90%), then sufficient statistical 
evidence has been provided for the positive outcome. A response rate of 85% in the 
GSK744 LA plus TMC278 LA two-drug regimen (compared with an GSK744 plus 
ABC/3TC response rate of 95%) would result in a rejection of the null hypothesis with a 
probability of approximately 0.068 (type I error). The given sample size is unlikely to 
select a random sample that would falsely conclude that GSK744 LA plus TMC278 LA 
two-drug regimen is comparable with GSK744 plus ABC/3TC if the response rates are 
truly 85% versus 95%, respectively. If the GSK744 LA plus TMC278 LA two-drug 
regimen yields an response rate of greater than 92%, then there is a high probability of 
rejecting the null hypothesis and correctly concluding that GSK744 LA plus TMC278 LA 
two-drug regimen is at least as good as GSK744 plus ABC/3TC.
Historical response rates of dolutegravir, an integrase compound similar to GSK744, 
were used as reference for the oral control arm.  Response rates for dolutegravir plus 
ABC/3TC ranged from 93% to 96% at Week 48 in studies SPRING-1, SPRING-2 and 
SINGLE among subjects who were suppressed (HIV-1 viral load <50 c/mL) at Week 24. 
The probability of a positive outcome assuming the true response rate for GSK744 LA 
plus TMC278 LA two-drug regimen is presented in Table 5.
Table 5
Probability of Positive Outcome Assuming True Response Rates of LA
True Response Rate for 
GSK744 LA plus TMC278 LA 
two-drug regimen
80%
83%
85%a
86%
89%
92%
95%
98%
Probability of Positive 
Outcomeb
0.4%
2.5%
6.8%
11%
34%
71%
96%
100%
a.
Type I error is <10%.
b.
It is assumed that the response rate for GSK744 plus ABC/3TC is 95%.
 
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Incorporation of prior beliefs and information about population parameters is a required 
part of any Bayesian probability model. The assumptions made will help provide a more 
reliable estimate when the prior beliefs are combined with the observed data than the data 
alone as long as the beliefs are reasonable. Therefore, the trial will utilize a Beta (44, 2.6) 
distribution with the median response rate being 95%, with 99th percentile of 99% and 5th
percentile of 88%.
Furthermore, a non- informative prior belief is assumed for the response rate for GSK744 
LA plus TMC278 LA two-drug regimen. Therefore, the trial will conservatively utilize a 
Beta (1, 1) distribution. These priors are displayed in Figure 5
 
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Figure 5
Plot of Prior Distribution for Response Rate for GSK744 LA plus 
TMC278 LA two-drug regimen and GSK744 plus ABC/3TC
Revised text:
IM treatment relative to Oral treatment
The sample size of 45 subjects in the oral treatment arm and 90 subjects each in the IM
treatment arms were chosen to ensure a high probability that a long-acting two drug 
treatment with truly poor response relative to GSK744 once daily plus ABC/3TC once 
daily will not be studied further, while allowing for formal considerations of other factors 
should efficacy be similar between the treatment arms.  It is assumed that 85% subjects 
enrolled will be suppressed at Week (-16), approximately 265 subjects will be enrolled in 
order to have 225 subjects randomized at Day 1.
The study is designed to test the comparability of GSK744 LA plus TMC278 LA two-
drug regimen to GSK744 30 mg once daily plus ABC/3TC. The primary comparison of 
interest will be performed using a Bayesian probability model. If the posterior probability 
that the difference is greater than -10% is large (i.e., 90%), then sufficient statistical 
evidence has been provided for the positive outcome. A response rate of 82% in the 
GSK744 LA plus TMC278 LA two-drug regimen (compared with an GSK744 plus 
ABC/3TC response rate of 92%) would result in a rejection of the null hypothesis with a 
probability of approximately 0.064 (type I error). The given sample size is unlikely to 
 
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select a random sample that would falsely conclude that GSK744 LA plus TMC278 LA 
two-drug regimen is comparable with GSK744 plus ABC/3TC if the response rates are 
truly 82% versus 92%, respectively. If the GSK744 LA plus TMC278 LA two-drug 
regimen yields an response rate of greater than 92%, then there is a high probability of 
rejecting the null hypothesis and correctly concluding that GSK744 LA plus TMC278 LA 
two-drug regimen is at least as good as GSK744 plus ABC/3TC.
Historical response rates of dolutegravir, an integrase compound similar to GSK744, 
were used as reference for the oral control arm.  Response rates for dolutegravir plus 
ABC/3TC ranged from 92% to 94% at Week 60 in studies SPRING-1, SPRING-2 and 
SINGLE among subjects who were suppressed (HIV-1 viral load <50 c/mL) at Week 24. 
The probability of a positive outcome assuming the true response rate for GSK744 LA 
plus TMC278 LA two-drug regimen is presented in Table 5.
Table 5
Probability of Positive Outcome Assuming True Response Rates of 
GSK744 LA plus TMC278 LA
True Response Rate for 
GSK744 LA plus TMC278 LA 
two-drug regimen (Q4W or 
Q8W)
80%
82%a
86%
90%
92%
94%
96%
Probability of Positive 
Outcomeb
2.8%
6.4%
26%
63%
82%
95%
99%
a.
Type I error is <10%.
b.
It is assumed that the response rate for GSK744 plus ABC/3TC is 92%.
Incorporation of prior beliefs and information about population parameters is a required 
part of any Bayesian probability model. The assumptions made will help provide a more 
reliable estimate when the prior beliefs are combined with the observed data than the data 
alone as long as the beliefs are reasonable. Therefore, the trial will utilize a Beta (23, 2) 
distribution with the mean response rate being 92%, with 97.5th percentile of 99% and 
2.5th percentile of 78%.
Furthermore, a non- informative prior belief is assumed for the response rate for GSK744 
LA plus TMC278 LA two-drug regimen. Therefore, the trial will conservatively utilize a 
Beta (1, 1) distribution. These priors are displayed in Figure 6.
 
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Figure 6
Plot of Prior Distribution for Response Rate for GSK744 LA plus 
TMC278 LA two-drug regimen and GSK744 plus ABC/3TC
Section 8.2.2 – Sample Size Sensitivity
Removed:
If sample size of LA arm decrease to 50 subjects in the event that the two induction 
length arms cannot be combined, the likelihood of establishing comparability is reduced. 
With the smaller sample size, if GSK744 LA plus TMC278 LA two-drug regimen yields 
a response rate of 95%, there would be an 81% probability of rejecting the null 
hypothesis, as compared with a 96% probability with the selected sample size. 
Section 8.3.1 - Analysis Populations
Original text:
The following populations will be assessed:
Intent-to-Treat Exposed Population (ITT-E)
The ITT-E population consists of all randomized subjects who received at least one dose 
of IP. Subjects will be analyzed according to the randomized treatment regardless of what 
treatment was actually received. Unless stated otherwise, the ITT-E population will be 
the primary population for efficacy analyses.  
Intent-to-Treat Maintenance Exposed Population (ITT-ME)
The ITT-ME population consists of all randomized who received at least one dose of IP 
during the Maintenance Period of the study.  Subjects will be analyzed according to the 
 
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randomized treatment regardless of what treatment was actually received. The ITT-ME 
population will be the secondary population for some efficacy analyses.
Per Protocol Population (PP)
This population will consist of subjects in the ITT-E population with the exception of 
major protocol violators (these will be defined in the RAP of this study).  The PP 
population will be a secondary population for efficacy purposes. 
Per Protocol Maintenance Population (PP-M)
This population will consist of subjects in the ITT-ME population with the exception of 
major protocol violators (these will be defined in the RAP of this study).  The PP-M 
population will be a secondary population for efficacy purposes. 
PK Population
The PK Population will include all subjects who received GSK1265744 and / or TMC278 
and undergo PK sampling during the study, and provide evaluable GSK1265744 and /or 
TMC278 plasma concentration data. Subjects in this population will be included in the 
PK analysis. 
Safety Population
The Safety Population consists of all enrolled subjects who were exposed to 
investigational products with the exception of any subjects with documented evidence of 
not having consumed any amount of investigational product.  Subjects will be analyzed 
according to the actual treatments received.  Subjects will not be excluded from this 
population as a result of changes to the background regimen.  The safety population will 
be the primary population for safety analyses.  All safety analyses will be produced using 
the safety population.
Maintenance Safety Population
The Maintenance Safety Population consists of all randomized subjects who were 
exposed to investigational products during the Maintenance Period of the study with the 
exception of any subjects with documented evidence of not having consumed or been 
administered any amount of investigational product during the Maintenance Period of the 
study.  Subjects will be analyzed according to the actual treatments received.  Subjects 
will not be excluded from this population as a result of changes to the background 
regimen.  The maintenance safety population will be an additional population for safety 
analyses.
Revised text:
The following populations will be assessed:
Intent-to-Treat Exposed Population (ITT-E)
 
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The ITT-E population consists of all enrolled subjects who received at least one dose of 
IP. Subjects will be analyzed according to their randomized treatment regardless of what 
treatment was actually received. Those that are not randomized will be summarized 
together under a ‘Not Randomized’ category. The ITT-E population will be the 
secondary population for some efficacy analyses.  
Intent-to-Treat Maintenance Exposed Population (ITT-ME)
The ITT-ME population consists of all randomized who received at least one dose of IP 
during the Maintenance Period of the study.  Subjects will be analyzed according to the 
randomized treatment regardless of what treatment was actually received. Unless stated 
otherwise, the ITT-ME population will be the primary population for efficacy analyses.
Per Protocol Maintenance Population (PP-M)
This population will consist of subjects in the ITT-ME population with the exception of 
major protocol violators (these will be defined in the RAP of this study).  The PP-M 
population will be a secondary population for efficacy purposes. 
PK Population
The PK Population will include all subjects who received GSK1265744 and / or TMC278 
and undergo PK sampling during the study, and provide evaluable GSK1265744 and /or 
TMC278 plasma concentration data. Subjects in this population will be included in the 
PK analysis. 
Safety Population
The Safety Population consists of all enrolled subjects who were exposed to 
investigational products with the exception of any subjects with documented evidence of 
not having consumed any amount of investigational product.  Subjects will be analyzed 
according to the actual treatments received.  Subjects will not be excluded from this 
population as a result of changes to the background regimen.  The safety population will 
be the primary population for safety analyses.  All safety analyses will be produced using 
the safety population.
Section 8.3.3 - Treatment Comparisons
Original text:
Primary Comparisons of Interest
The primary efficacy analysis will be performed at Week 24 based on the proportion of 
subjects in the ITT-E population with plasma HIV-1 RNA <50 c/mL using MSDF 
algorithm. The primary comparison of interest will be performed using a Bayesian 
probability model.  The probability of (Response rate for LA arm Response rate for 
Oral arm -10%) will be calculated.
Other Comparisons of Interest
 
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The secondary efficacy analysis will be performed to evaluate the impact of the duration 
of suppression, based on 16 or 24 weeks of 30 mg GSK744 once daily in combination 
with ABC/3TC on the ability of a regimen of 400 mg IM of GSK744 LA plus 600 mg IM 
of TMC278 LA every 4 weeks to maintain virologic suppression through Week 96.  
Measures of safety and tolerability will be assessed as detailed in the RAP
Revised text:
Primary Comparisons of Interest
The primary efficacy analysis will be performed at Week 32 based on the proportion of 
subjects in the ITT-ME population with plasma HIV-1 RNA <50 c/mL using MSDF 
algorithm. The primary comparison of interest will be the response rate of each IM 
dosing arm to the oral control arm performed using a Bayesian probability model.  The 
probability of (Response rate for IM arm Response rate for Oral arm -10%) will be 
calculated.
Other Comparisons of Interest
The probability of Q8W comparable to Q4W will be provided using the Bayesian 
probability model.
Section 8.3.4 - Interim and Final Analysis
Original text:
The ITT-E population will be primary efficacy population and the safety population will 
be the primary safety population for all analyses.  All available data will be included in 
all interim analyses, including data beyond the designated time point except for the Day 1 
analysis, if preformed, will only include data from the Induction Period.  
At the first interim analysis the IDMC will evaluate the efficacy, safety and tolerability of 
GSK744 to determine if the GSK744 regimen is suboptimal such that it should be 
discontinued before all subjects transition into the Maintenance Period of the study.  Full 
details of the analyses, estimated timing and the decision criteria that will be used to 
determine regimen performance will be pre-specified in the IDMC Charter.
This interim analysis schedule does not require an adjustment for multiplicity since there 
is no possibility of a false positive finding at any of the interim analyses conducted before 
Week 24, and since the Week 48 and 96 analyses will be used to further characterise the 
long-term safety and efficacy profile of GSK744.  As no hypothesis is being tested for 
rejection during the constant monitoring of virologic response, no adjustment for 
multiplicity will be performed.
Futility interim monitoring
Plasma HIV-1 RNA data will be monitored closely as subjects enter the Maintenance 
Period in order to prevent subjects from continuing on a regimen if existing data indicates 
that they are at unacceptable risk of inadequate maintenance of virologic suppression. 
 
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The number of protocol defined virologic failures during the Maintenance Period will be 
monitored in all subjects that had at least 4 weeks of the maintenance dose regimen on 
LA (Week 4). If the number of failures meets or exceeds the thresholds specified in the 
table below (Table 6) this will be considered strong evidence of an inadequate response 
and will trigger a comprehensive IDMC data review and possible discontinuation of that 
treatment arm.  If an inadequate response is seen in the shorter induction length arm and 
it is determined that that arm should be discontinued, then subjects on that treatment arm 
still in the Induction Period can be switched to the longer induction length.
Table 6
Number of protocol-defined virologic failures on Maintenance Period 
that constitute strong evidence of inadequate virologic response
Number of subjects that had 
at least four weeks of 
maintenance dose on LA
Number of protocol-defined 
virologic failures after 
maintenance dose on LA
3-21
>=3
22-32
>=4
33-43
>=5
44-54
>=6
55-65
>=7
66-75
>=8
76-86
>=9
87-97
>=10
98-100
>=11
The thresholds described in this table are derived on the basis of the ratio of the 
likelihoods for the null hypothesis (H0) that there is a subgroup of subjects with 
inadequate maintenance of virologic suppression and the alternative hypothesis (H1) that 
the only failures in the study are due to poor compliance. For this analysis, H0 translates 
to a protocol defined virologic failure rate of 20% or higher (as defined in Section 4.6) 
and H1 translates to an expected 3% rate of protocol defined virologic failures. Further 
details on this method are contained in Section 11.5. Each threshold represents strong 
evidence in favour of H0 over H1 [Royall, 1997].
The scenarios described above are not exhaustive – it is possible that the overall failure 
rate does not meet the threshold but that a subgroup of subjects (e.g. with a given 
combination of mutations or fold resistance to GSK744 above an as yet unknown 
threshold) are consistently failing. GSK will monitor virologic response by Baseline 
genotype and may halt one or more treatment arms if at any time subjects are deemed to 
be at an unacceptable risk of an inadequate response on the basis of such monitoring, 
although the high number of possible genotypic subgroups precludes pre-specification of 
precise thresholds for such action.
IDMC Interim Analyses
The purpose of these analyses is for the Independent Data Monitoring Committee 
(IDMC) to evaluate the efficacy, safety and tolerability of GSK744 at early time points in 
 
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the study.  The IDMC will review at least one analysis before all eligible subjects have 
transitioned from the Induction Period to the Maintenance Period.  Full details of the 
analyses, estimated timing and the decision criteria that will be used to determine 
regimen performance will be pre-specified in the IDMC Charter, with IDMC agreement.  
As subjects enter the Maintenance Period of the study, the protocol defined virologic 
failure rate will be continually monitored. If the number of failures meets or exceeds the 
pre-specified thresholds specified in the IDMC Charter, this will be considered strong 
evidence of an inadequate response and will trigger a comprehensive data review by the 
IDMC.  The IDMC charter will contain details of this continual monitoring of the 
protocol defined virologic failure rates, the specifics around what will trigger a data 
review, and the safety summaries and efficacy analyses that will be provided should a 
data review be required.
Day 1 Interim Analysis
A Day 1 interim analysis may be conducted to support regulatory submissions and/or 
scientific conference presentations once the last randomized subject has completed the 
Day 1 study visit and the database has been cleaned and released for analysis. The results 
of this analysis will be used to evaluate efficacy, safety and tolerability of GSK744 30 mg 
once daily plus ABC/3TC once daily in the Induction Period.  Only data from the 
Induction Period would be summarized in this analysis.
Week 24 Primary Analysis
The Week 24 primary analysis will be conducted once the last randomized subject has 
completed the Week 24 study visit and the database has been cleaned and released for 
analysis.  The results of this analysis will be used to characterize safety, tolerability and 
durability of antiviral response of the long-acting regimen of GSK744 LA + TMC278 
LA.
Week 48 Interim Analysis
The Week 48 interim analysis will be conducted once the last randomized subject has 
completed the Week 48 study visit and the database has been cleaned and released for 
analysis.  The results of this analysis will be used to characterize the safety, tolerability 
and durability of antiviral response of the long- acting regimen of GSK744 LA + 
TMC278 LA.
Week 96 Final Analysis
The Week 96 final analysis will be conducted once the last randomized subject has 
completed the Week 96 study visit and the database has been cleaned and released for 
analysis.  The results of this analysis will be used to fully characterise the long term 
safety and efficacy profile of the long-acting regimen of GSK744 LA + TMC278 LA.
Additional analyses may be performed as needed.  The primary and interim analyses may 
be used to support regulatory submissions and/or scientific conference presentations
Revised text:
 
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The ITT-ME population will be primary efficacy population and the safety population 
will be the primary safety population for all analyses.  All available data will be included 
in all interim analyses, including data beyond the designated time point except for the 
Day 1 analysis, if preformed, will only include data from the Induction Period.  
At the first interim analysis the IDMC will evaluate the efficacy, safety and tolerability of 
GSK744 to determine if the GSK744 regimen is suboptimal such that it should be 
discontinued before all subjects transition into the Maintenance Period of the study.  Full 
details of the analyses, estimated timing and the decision criteria that will be used to 
determine regimen performance will be pre-specified in the IDMC Charter.
This interim analysis schedule does not require an adjustment for multiplicity since there 
is no possibility of a false positive finding at any of the interim analyses conducted before 
Week 32, and since the Week 48 and 96 analyses will be used to further characterise the 
long-term safety and efficacy profile of GSK744.  As no hypothesis is being tested for 
rejection during the constant monitoring of virologic response, no adjustment for 
multiplicity will be performed.
IDMC Interim Analyses
The purpose of these analyses is for the Independent Data Monitoring Committee 
(IDMC) to evaluate the efficacy, safety and tolerability of GSK744 at early time points in 
the study.  The IDMC will review at least one analysis before all eligible subjects have 
transitioned from the Induction Period to the Maintenance Period.  Full details of the 
analyses, estimated timing and the decision criteria that will be used to determine 
regimen performance will be pre-specified in the IDMC Charter, with IDMC agreement.
All the IDMC reviews will be produced by a Statistics and Data Analysis Centre 
(SDAC).  
Futility Interim Monitoring
Continuous monitoring of the number of protocol defined virologic failures during the 
Maintenance Period and a futility interim analysis when 50% subjects have completed 
Week 24 is planned.
Continuous Monitoring
Plasma HIV-1 RNA data will be monitored closely as subjects enter the Maintenance 
Period in order to prevent subjects from continuing on a regimen if existing data indicates 
that they are at unacceptable risk of inadequate maintenance of virologic suppression. 
The number of protocol defined virologic failures during the Maintenance Period will be 
monitored in all subjects that have at least 4 weeks of either of the Maintenance Period 
IM dosing regimens (Week 4). If the number of failures meets or exceeds the thresholds 
specified in the table below (Table 6) this will be considered strong evidence of an 
inadequate response and will trigger a comprehensive IDMC data review and possible 
discontinuation of that treatment arm.  If an inadequate response is seen in any arm and it 
is determined by IDMC that that arm should be discontinued, then subjects on that 
treatment arm can be switched to the remaining IM arm.
 
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Table 6
Number of protocol-defined virologic failures on Maintenance Period 
that constitute strong evidence of inadequate virologic response
Number of subjects that had 
at least four weeks of 
maintenance dose on IM
Number of protocol-defined 
virologic failures after 
maintenance dose on IM
3-21
>=3
22-32
>=4
33-43
>=5
44-54
>=6
55-65
>=7
66-75
>=8
76-86
>=9
87-97
>=10
98-100
>=11
The thresholds described in this table are derived on the basis of the ratio of the 
likelihoods for the null hypothesis (H0) that there is a subgroup of subjects with 
inadequate maintenance of virologic suppression and the alternative hypothesis (H1) that 
the only failures in the study are due to poor compliance. For this analysis, H0 translates 
to a protocol defined virologic failure rate of 20% or higher (as defined in Section 4.6) 
and H1 translates to an expected 3% rate of protocol defined virologic failures.  For the 
first IDMC review, if the true rate of virologic failure is 20% as specified in H0, the 
probability to detect the inadequate virologic suppression is greater than 70%.  If the true 
rate of virologic failure is 3%, the probability to see number of virology failure exceed 
the threshold is less than<1%. Further details on this method are contained in the IDMC 
charter. Each threshold represents strong evidence in favour of H0 over H1 [Royall, 
1997].
The scenarios described above are not exhaustive – it is possible that the overall failure 
rate does not meet the threshold but that a subgroup of subjects (e.g. with a given 
combination of mutations or fold resistance to GSK1265744 above an as yet unknown 
threshold) are consistently failing. GSK will monitor virologic response by Baseline 
genotype and may halt one or more treatment arms if at any time subjects are deemed to 
be at an unacceptable risk of an inadequate response on the basis of such monitoring, 
although the high number of possible genotypic subgroups precludes pre-specification of 
precise thresholds for such action.
 
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Futility Analysis after 50% of subjects complete Week 24
An interim analysis for the purpose of review by the IDMC will be performed after 
approximately 50% of subjects complete Week 24.  A futility rule based on Bayesian
posterior probability approach will be applied to assess the probability that the IM
treatment arm demonstrates the comparability with the oral control arm given the partial 
data set.  Posterior probabilities of success ( Prob (pIM > poral - 0.1 | data)) are provided in 
Table 7 for a subset of possible outcomes that could occur at the interim. Those outcomes 
associated with a posterior probability of success <40% may trigger a comprehensive 
IDMC data review and possible discontinuation of that treatment arm, although all data 
will be taken into consideration for making this decision.
Table 7
Posterior Probability of Successa at the Interim Analysis Under Various 
Scenarios
# Successes in IM arm (out of 45)
# 
Successes 
in Oral 
arm (out 
of 23)
35
(78%)
36 
(80%)
37
(82%)
38
(84%)
39
(87%)
40
(89%)
41
(91%)
42
(93%)
18(78%)
0.564
0.678
0.753
0.850
0.913
0.955
0.979
0.993
19(83%)
0.454
0.558
0.679
0.782
0.859
0.931
0.966
0.986
20(87%)
0.346
0.465
0.574
0.694
0.805
0.890
0.942
0.974
21(91%)
0.244
0.348
0.455
0.584
0.706
0.829
0.907
0.961
22(96%)
0.146
0.231
0.335
0.461
0.604
0.736
0.845
0.926
23(100%)
0.081
0.135
0.218
0.324
0.473
0.612
0.755
0.874
c.
Posterior probability of success is defined as (prob(pIM > poral - 0.1 | data)) with informative prior Beta (23,2) for oral 
arm and non-informative prior Beta (1,1) for IM arm.
d.
Highlighted cells represent outcomes with posterior probability <0.4 that may trigger a comprehensive IDMC data
review.
The proposed the futility analysis has 91% chance to stop the study at the interim analysis
if the true response rates are 92% and 72% for the oral arm and IM arm, respectively.  
The power to stop the study is 46% if the true response rates are 92% and 82% for the 
oral arm and IM arm, respectively. The chance of stopping the study by error is 2% if the 
true response rates are 92% for both the oral arm and IM arm.
Day 1 Interim Analysis
A Day 1 interim analysis may be conducted to support regulatory submissions and/or 
scientific conference presentations once the last randomized subject has completed the 
Day 1 study visit and the database has been cleaned and released for analysis. The results 
of this analysis will be used to evaluate efficacy, safety and tolerability of GSK744 30 mg 
once daily plus ABC/3TC once daily in the Induction Period.  Only data from the 
Induction Period would be summarized in this analysis.
 
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Week 32 Primary Analysis
The Week 32 primary analysis will be conducted once the last randomized subject has 
completed the Week 32 study visit and the database has been cleaned and released for 
analysis.  The results of this analysis will be used to characterize safety, tolerability and 
durability of antiviral response of both IM dosing regimens of GSK744 LA + TMC278 
LA and to select a regimen for further development should both IM dosing regimens be 
comparable to the oral control arm.
Week 48 Interim Analysis
The Week 48 interim analysis will be conducted once the last randomized subject has 
completed the Week 48 study visit and the database has been cleaned and released for 
analysis.  The results of this analysis will be used to characterize the safety, tolerability 
and durability of antiviral response of both IM dosing regimens of GSK744 LA + 
TMC278 LA and to confirm the selected regimen for further development should both 
IM dosing regimens be comparable to the oral control arm.
Week 96 Final Analysis
The Week 96 final analysis will be conducted once the last randomized subject has 
completed the Week 96 study visit and the database has been cleaned and released for 
analysis.  The results of this analysis will be used to fully characterise the long term 
safety and efficacy profile of both IM dosing regimens of GSK744 LA + TMC278 LA.
Follow-up analyses after the Week 96 analysis of data collected after subjects have 
switched to the chosen dose of GSK744 LA may be conducted to more fully characterize 
the long-term safety and efficacy profile of GSK744 LA.
Section 8.3.5 - Key Elements of Analysis Plan
Revised to (changes struck through and underlined).
Efficacy Analyses
All efficacy analyses, except as stated otherwise, will be based on the ITT-ME 
population.
The primary efficacy analysis will be based on the MSDF approach mentioned in 
Section 8.3.2. For the MSDF analysis, any switches in background ART after HIV-1 
RNA has been collected willmay be considered as failures even if the switch was done to 
manage intolerance issues. Plasma HIV-1 RNA will be log10-transformed prior to 
statistical analyses. Data will be allocated to visit windows using actual visit dates rather 
than nominal visit numbers. Data collected from extra visits within a window will be 
listed and will be included in the derivation of the time to loss of virologic response, but 
summary tables using OC datasets will only use the data captured closest to the target 
visit date. Detailed explanations of the derivation of visit windows will be included in the 
RAP. Any deviations from the planned analyses described in this protocol or the RAP 
will be detailed in the clinical study report (CSR).
 
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And:
Original text:
For the analysis of GSK744 LA+TMC278 LA arm (LA arm) response rate relative to 
GSK744 + ABC/3TC (oral arm), let:
XLA = number of responder in LA arm, and 
Xoral = number of responder in oral arm
The binomial distribution is the assumed likelihood of the eRVR data, as follows:
XLA ~ Binomial (100, pLA)  
Xoral ~ Binomial (50, poral)  
Since the true response rate is unknown, prior distributions are placed on these 
parameters of interest to reflect current beliefs and balanced with acceptable decision 
criteria performance. Conjugate beta densities are assumed. The information pertaining to 
the oral arm response rate is well understood and the prior that was chosen reflects the 
belief that the response rate is between 88% and 99% with 94% certainty. There is very 
few information about the response rate for LA arm, therefore, a non-informative prior 
assumed. 
PLA ~ Beta (1, 1)
Poral ~ Beta (44, 2.6)
The posterior probability that the response rate for LA arm demonstrates the 
comparability of oral arm is as follows: 
p1 = P (PLA > poral - 0.1 | data)
A posterior probability of at least 90% (i.e., p1 >0.90) corresponds to “substantial 
evidence of positive outcome” and is chosen as the weight of evidence threshold. 
Sensitivity analyses may be performed to assess the impact of the choice of informative 
prior for oral arm response rate though the analysis described above will remain primary 
for indication of efficacy decision-making purposes. As an alternative to the informative 
prior, a Beta (1, 1) prior distribution for oral arm may be considered. Full details of the 
planned Bayesian analyses will be provided in the RAP.
The proportion of subjects with plasma HIV-1 RNA <50 c/mL as determined by the 
MSDF algorithm will be provided by treatment group and induction length over the 
entire time on study by visit for the ITT-E population and the ITT-ME population. 
In addition, an OC analysis will be performed for supportive purposes.
 
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Revised text:
For the analysis of GSK744 LA+TMC278 LA arms (IM arms) response rate relative to 
GSK744 + ABC/3TC (oral arm), let:
XLA = number of responder in IM arm, and 
Xoral = number of responder in oral arm
The binomial distribution is the assumed likelihood of the response data, as follows:
XLA ~ Binomial (90, pIM)  
Xoral ~ Binomial (45, poral)  
Since the true response rate is unknown, prior distributions are placed on these 
parameters of interest to reflect current beliefs and balanced with acceptable decision 
criteria performance. Conjugate beta densities are assumed. The information pertaining to 
the oral arm response rate is well understood and the prior that was chosen reflects the 
belief that the response rate is between 78% and 99% with 95% certainty. There is very 
few information about the response rate for IM arm, therefore, a non-informative prior 
assumed. 
PLA ~ Beta (1, 1)
Poral ~ Beta (23, 2)
The posterior probability that the response rate for IM arm demonstrates the 
comparability of oral arm is as follows: 
p1 = P (PIM > poral - 0.1 | data)
A posterior probability of at least 90% (i.e., p1 >0.90) corresponds to “substantial 
evidence of positive outcome” and is chosen as the weight of evidence threshold. 
Sensitivity analyses may be performed to assess the impact of the choice of informative 
prior for oral arm response rate though the analysis described above will remain primary 
for indication of efficacy decision-making purposes. As an alternative to the informative 
prior, a Beta (1, 1) prior distribution for oral arm may be considered. Full details of the 
planned Bayesian analyses will be provided in the RAP.
The proportion of subjects with plasma HIV-1 RNA <50 c/mL as determined by the 
MSDF algorithm will be provided by treatment group over the entire time on study by 
visit for the ITT-ME population and the ITT-E population. 
In addition, an OC analysis will be performed for supportive purposes.
For the probability of comparability between two IM arms, a non-informative prior of 
Beta (1, 1) will be used for both IM treatment arms.
 
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Section 8.3.5.2 - Safety Analyses
Added:
Framingham Risk assessment will be calculated as detailed in the RAP and will be 
summarized by treatment arm.
Section 11.2 – Appendix 2
Removed the Child-Pugh Appendix.
Section 11.4 – Appendix 5
Removed the Statistical Method for Plasma HIV-1 RNA Monitoring.  This is now in the 
RAP.
Section 11 – New Appendix 
With the removal and addition of Appendices, this Appendix is now number 4.
Added the following information regarding liver stopping criteria and restarting / 
rechallenging study drug:
VSLC GUIDELINES FOR DRUG RESTART OR RECHALLENGE AFTER STOP 
FOR LIVER CRITERIA
3. Drug rechallenge may be considered for a subject exhibiting compelling benefit 
for a critical medicine following drug-induced liver injury, if favorable benefit: 
risk and no alternative medicine available (Table 8, Figure 7)
4. In Phase III, drug restart may be considered for liver events with a clear 
underlying cause (e.g. biliary, pancreatic events, hypotension, acute viral 
hepatitis), if not associated with drug-induced liver injury, alcoholic hepatitis or 
hypersensitivity, and drug not associated with HLA marker of liver injury, when 
liver chemistries improve to within 1.5xbaseline and ALT<3xULN) (Table 9,
Figure 8).
Background: Following drug-induced liver injury, drug rechallenge is associated with 
a 13% mortality across all drugs in prospective studies.  Clinical outcomes vary by 
drug, with nearly 50% fatality with halothane re-administered in one month of initial 
injury [Andrade , 2009].  However, some drugs seldom result in recurrent liver injury or 
fatality.
Risk factors for a fatal drug rechallenge outcome include:

hypersensitivity with initial liver injury (e.g. fever, rash, eosinophilia) [Andrade 
2009]

jaundice or bilirubin2xULN with initial liver injury 
 
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
prior serious adverse event or fatality has earlier been observed with drug 
rechallenge [Papay , 2009; Hunt, 2010]

evidence of drug-related preclinical liability (e.g. reactive metabolites; 
mitochondrial impairment) [Hunt, 2010] 
VSLC Decision Process for Drug Rechallenge Approval or 
Disapproval (See Figure 7)

Principal Investigator (PI) requests consideration of drug rechallenge for a 
subject receiving compelling benefit from a critical or life-saving drug, who 
exhibits liver chemistry elevation meeting subject stopping criteria, with no 
alternative treatment

By definition treatment naïve subjects will only be considered for rechallenge if 
they were infected with a multi-resistant virus.

Medical Monitor and Global Clinical Safety and Pharmacovigilance (GCSP) 
Physician to review the subject’s rechallenge risk factors (consultation with the 
Hepatotoxicity Panel is available) and complete checklist (Table 8).

The Medical Monitor and GCSP Physician are accountable to review and agree 
on:
–
compelling benefit of the investigational product (IP) for this subject and no 
alternative therapy 
–
must present source data defining the patient’s current resistance profile with 
documented evidence of extensive drug resistance and previous drug history 
–
Relative benefit-risk of drug rechallenge, with consideration of the following 
high risk factors:
Initial liver injury event included: fever, rash, eosinophilia, or 
bilirubin2xULN (or direct bilirubin >35% of total, if available)
subject currently exhibits severe liver injury defined by: ALT 3xULN, 
bilirubin 2xULN (direct bilirubin >35% of total, if available), or INR1.5
SAE or fatality has earlier been observed with IP rechallenge
IP associated with known preclinical hepatic liability/ injury

Relevant physicians must review and agree on request for drug rechallenge:  

Safety Team Leader, VP, or Senior Safety Physician (GSK)

Medicines Development Leader and Project Physician Leader (GSK)

Request is taken to full VSLC for final decision 
 
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Figure 7
VSLC process for drug rechallenge approval or disapproval
The local operating company (LOC) ViiV medical director (and GSK where applicable)
should be informed that study drug rechallenge is under consideration and of the final
decision, whether or not to proceed.
Table 8
Checklist for drug rechallenge for critical medicine  (Following drug-
induced liver injury, drug rechallenge is associated with 13% mortality 
across all drugs in prospective studies)
Yes
No
Compelling benefit of the investigational product (IP) for this subject and no 
alternative therapy.  Provide brief explanation:
Relative benefit-risk favorable for drug rechallenge, after considering the 
following high risk factors:

Initial liver injury event included: 
o
fever, rash, eosinophilia, or hypersensitivity
o
or bilirubin2xULN (direct bilirubin >35% of total)
o
Subject currently exhibits ALT 3xULN, bilirubin 2xULN 
(direct bilirubin >35% of total, if available), or INR1.5
o
SAE or fatality has earlier been observed with IP rechallenge
If yes, please provide brief explanation:
o
IP associated with known preclinical hepatic liability/ injury
o
Source data defining the patients current resistance profile
o
Previous drug history
 
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Drug Restart
Phase II “drug restart” can be approved by the VSLC for transient, defined non-drug-
induced liver injury if no evidence of:
•
immunoallergic injury /HLA association with injury
•
DILI
•
alcoholic hepatitis
Study drug held while labs and evaluation is completed to assess diagnosis.
VSLC Decision Process for Drug Restart Approval or Disapproval 
(Figure 8): 

PI requests consideration of drug re-initiation for a subject stable or improving 
on IP, who exhibits liver chemistry elevation meeting subject stopping criteria, 
which is transient, non-drug-related, and liver chemistries improve to within 
1.5x baseline and ALT< 3xULN. 

GSK Medical Monitor and Clinical Safety Physician to review the subject’s 
diagnosis, restart risk factors and complete checklist (Table 9).
–
must present source data defining the patient’s current resistance profile with 
documented evidence of extensive drug resistance and previous drug history.

The LOC ViiV medical director (and GSK where applicable) should be 
informed that study drug restart is under consideration and of the final decision, 
whether or not to proceed.
Table 9
Checklist for Phase II drug restart after well-explained liver injury (e.g. 
biliary, pancreatic, hypotensive events, congestive heart failure, acute 
viral hepatitis), improving to liver chemistry 1.5x baseline & 
ALT<3xULN
Yes
No
Is subject stable or improving on the investigational product (IP)?
Do not restart if the following risk factors at initial liver injury:

fever, rash, eosinophilia, or hypersensitivity 

drug-induced liver injury 

alcoholic hepatitis (AST>ALT, typically <10xULN)

IP has an HLA genetic marker associated with liver injury (e.g. 
lapatinib, abacavir, amoxicillin/clavulanate)
Source data defining the patients current resistance profile
Previous drug history
 
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
Relevant physicians must review and agree on request for drug restart:  

Safety Team Leader, VP, or Senior Safety Physician

Medicines Development Leader and Project Physician Leader (GSK).

Hepatotoxicity Panel consultation is available.

Justification for drug restart outlining the benefit and risk for this subject must 
be recorded by GCSP Physician and sent to the VSLC Secretary.

VSLC must approve drug re-initiation and dosing regimen
Figure 8
VSLC process for drug restart approval or disapproval
1. Andrade 2009; 2. Papay , 2009; 3. Hunt, 2010
Medical monitor, GCSP Physician and PI actions for Restart or 
Rechallenge following VSLC decision
Medical Monitor and (Global Clinical Safety and Pharmacovigilance) GCSP 
Physician Actions

Medical Monitor must notify PI of VSLC’s rechallenge (or restart) decision and 
recommended dosing regimen in writing and Medical Monitor must record note 
in study files.
 
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
The Safety Review Team must record rechallenge (or restart) outcomes and the 
GCSP Physician must send these to the VSLC

All severe reactions (rechallenge associated with bilirubin>2xULN or jaundice, 
or INR1.5), SAEs or fatalities with drug rechallenge (or restart) must be 
immediately reported to Line Management, VSLC Chair, VP Global Medical 
Strategy (ViiV) and EU Qualified Person for Pharmacovigilance. 
Principal Investigator Actions:

The PI must obtain IRB/EC approval of drug rechallenge or restart, as required. 

If drug re-initiation VSLC-approved, the patient must provide informed consent 
with a clear description of possible benefits and risks of drug administration 
including recurrent, more severe liver injury or possible death.
–
Targeted drug rechallenge or drug restart consent form must be used.

The patient’s informed consent must be recorded in the study chart, and the drug 
administered at agreed dose, as communicated by Medical Monitor.

Liver chemistries must be followed twice weekly for ‘rechallenge’ cases and 
once weekly for ‘restart’ cases for one month or for as long as clinically 
indicated following drug re-initiation.  If subject exhibits protocol-defined liver 
chemistry elevations, IP should be discontinued as protocol specified.
VSLC and the IRB/EC must be informed of the patient’s outcome following drug 
rechallenge or restart.
Rechallenge/restart safety outcomes:

0 = no liver chemistry elevation

1 = recurrent liver chemistry elevation not meeting subject stopping criteria

2 = recurrent liver chemistry elevation meeting subject stopping criteria

3 = serious adverse event

4 = fatality
REFERENCES:
Andrade RJ, Robles M, Lucena MI.  Rechallenge in drug-induced liver injury: the 
attractive hazard.  Expert Opin Drug Saf. 2009;8:709-714.
Hunt, CM.  Mitochondrial and immunoallergic injury increase risk of positive drug 
rechallenge after drug-induced liver injury: A systematic review.  Hepatol. 2010;52:2216-
2222.
Papay JI, Clines D, Rafi R, Yuen N, Britt SD, Walsh JS, Hunt CM.  Drug-induced liver 
injury following positive drug rechallenge.  Regul Tox Pharm. 2009;54:84-90.
 
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Amendment 3
Amendment 3 applies to all countries and all sites.  Primary modifications are as follows:  
Epzicom / Kivexa added as Investigational Product beginning at Day 1 of the 
Maintenance Period; clarification that alternative background therapy (if positive for 
HLA-B*5701) is not counted as the protocol permitted switch for NRTI; clarification 
regarding provision of alternative NRTI therapy; clarification that Exclusion for 
treatment of hepatitis C infection is exclusionary at any time during the study; removed 
example of effective barrier method from Inclusion criteria; change in visit window for 
subjects on the oral dosing arm; excursion temperatures added for Epzicom / Kivexa and 
Edurant; text added for Epzicom / Kivexa overdose; simplified text for results from 
primary analysis; deleted option for subject informed consent by legal representative; 
deleted duplicate text for “lack of efficacy”; added RPV pre-dose pharmacokinetic (PK) 
sample at Day 1 to PK table; updated PK information for LAI116482 subject with 
integrase and NNRTI resistance; updated operating characteristic figure to include legend 
for 94% response; Time and Events Table clarifications: 1) added the collection of HIV 
risk factors at Screening (or a later visit); 2) added collection of plasma for storage at 
time of confirmation of virologic failure; 3) subjects should have PK sample drawn prior
to dosing; 4) safety assessments should be conducted every 16 weeks if every 8 weeks is 
chosen for the extension schedule; 5) simplified ECG assessments for oral Maintenance 
arm; 6) created new row in Table to separate CD4+ and CD8+ cell counts; corrected 
typographical errors, updated and/or corrected list of abbreviations, Trademarks, and
references.
List of Abbreviations – Updated to remove abbreviations not used within the protocol, 
added abbreviation for FTC.
Trademark List – Updated to remove Trademarks not referenced within the protocol.
Protocol Summary and Section 1.2.:  List of Study Terms – updated to include 
Epzicom / Kivexa as IP starting at Day 1 – based on Regulatory feedback from France.
Original Text:

IP = Investigational product; both formulations of GSK1265744 and TMC278.  
Revised Text:

IP = Investigational product; both formulations of GSK1265744 and TMC278.  
Epizcom / Kivexa will also be considered IP beginning at Day 1 of the 
Maintenance Period.
Protocol Summary: Notable Inclusion Criteria –corrected typo for “”
Original Text:

Male or female subjects at least 18 years old that are HIV-1 positive (HIV-1 
RNA > 1000 copies/millilitre [c/mL])
 
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Revised Text:

Male or female subjects at least 18 years old that are HIV-1 positive (HIV-1 
RNA 1000 copies/millilitre [c/mL])
Protocol Summary:  Notable Exclusion Criteria – clarification that treatment for 
hepatitis C infection is not permitted at any time during the study:
Original Text:

History of ongoing or clinically relevant hepatitis within the previous 6 months, 
including chronic hepatitis B virus (HBV) infection (HBsAg positive). 
Asymptomatic individuals with chronic hepatitis C virus (HCV) infection will not
be excluded, however Investigators must carefully assess if therapy specific for 
HCV infection is required; subjects who are anticipated to require such therapy 
during the randomized portion of the study must be excluded.
Revised Text:

History of ongoing or clinically relevant hepatitis within the previous 6 months, 
including chronic hepatitis B virus (HBV) infection (HBsAg positive). 
Asymptomatic individuals with chronic hepatitis C virus (HCV) infection will not 
be excluded, however Investigators must carefully assess if therapy specific for 
HCV infection is required; subjects who are anticipated to require such therapy 
must be excluded.
Protocol Summary:  Study Design:  Maintenance Period AND Section 
3.2.4. Maintenance Period – clarification of timing of dosing windows:  
Original Text:
A (+ or -) 7 day window is allowable for IM dosing but not preferred.  Oral dosing is 
expected to occur during the week in which the subject’s projected visit falls (as 
according to the Baseline visit).
Revised Text:
A (+ or -) 7 day window, from the projected visit date, is allowable for IM dosing but not 
preferred.
Visits for subjects on the oral dosing arm are expected to occur as projected according to 
the Baseline visit.  There is a (+ or -) 3 day visit window, from the projected visit date.  
However, the number of tablets dispensed should be considered when scheduling the next 
visit.
 
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Protocol Summary:  Study Design:  Maintenance Period:  Entering from the 
GSK744 + ABC/3TC Arm – Typo Correction:
Original Text:
At Week 104, subjects will receive their last dose of GSK744 + ABC/3TC + RPV in the 
clinic and will begin IM dosing with the selected the IM regimen.
Revised Text:
At Week 104, subjects will receive their last dose of GSK744 + ABC/3TC + RPV in the 
clinic and will begin IM dosing with the selected IM regimen.
Protocol Summary:  Study Design:  Long-term Follow-Up Period IM Regimens
AND Section 3.2.6. Long-term Follow-Up Period – IM Regimens only - clarification 
on provision of alternative NRTI therapy:
Original Text: 
In order to assure that subjects have access to HAART during the Long-Term Follow-Up 
Period, the Sponsor will reimburse sites for HAART prescribed during this period.
Revised Text:
In order to assure that subjects have access to HAART during the Long-Term Follow-Up 
Period, GSK may supply HAART regionally or reimbursement will be provided during 
this period.
Protocol Summary:  Permitted Treatment Substitutions AND Section 5.6. Protocol 
Permitted Substitutions AND Setion 6.7. Time and Events Table – Long-Term 
Follow-Up – footnote e – clarification regarding provision of alternative NRTI therapy.
Original Text:
This regimen will not be provided by GSK, but the Sponsor will reimburse sites for this 
cost.
Revised Text:
This regimen may be supplied regionally by GSK or reimbursement will be provided.
Protocol Summary:  Primary Analysis – clarification of how analysis will be used.
Original Text:
The results of this analysis will be used to characterize safety, tolerability and durability 
of antiviral response of both IM dosing regimens of GSK744 LA + TMC278 LA and to 
select a regimen for further development should both IM dosing regimens be comparable 
to the oral control arm.
 
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Revised Text:
The results of this analysis will be used to characterize safety, tolerability and durability 
of antiviral response of both IM dosing regimens of GSK744 LA + TMC278 LA and to 
select a regimen for further development.
Section 1.4. GSK1265744 – Long Acting Injectable (GSK744 LA) – correction of typo
Original Text:
GSK744 LA (has been generally well-tolerated as either an IM or SC dose.  
Intramuscular injection site reactions (ISRs) have been predominantly mild or Grade 1 
(85%), self-limited, and have not led to study discontinuation in any subject to date.
Revised Text:
GSK744 LA has been generally well-tolerated as either an IM or SC dose.  Intramuscular 
injection site reactions (ISRs) have been predominantly mild or Grade 1 (85%), self-
limited, and have not led to study discontinuation in any subject to date.
Section 1.5. TMC278 – Oral (RPV) – clarification provided regarding Week 48 
analysis, reference updated.
Original Text:  
The Week 48 efficacy outcome for the pooled data from TMC278-C209 and TMC278-
C215 (N=1360) showed that the proportion of subjects with HIV-1 RNA < 50 c/mL was 
83% for RPV based regimen compared to 80% for the EFV based regimen. The overall 
virologic failure rate was 13% for the RPV compared to 9% for EFV. The proportion of 
patients who discontinued study due to an adverse event or death was 2% for RPV and 
7% for EFV [Edurant Product Information, 2013].
Revised Text:
The Week 48 efficacy outcome for the pooled data from TMC278-C209 and TMC278-
C215 (N=1368) showed that the proportion of subjects with HIV-1 RNA < 50 c/mL was 
83% for RPV based regimen compared to 80% for the EFV based regimen (Snapshot 
algorithm). The overall virologic failure rate was 13% for the RPV compared to 9% for 
EFV. The proportion of patients who discontinued study due to an adverse event or death 
was 2% for RPV and 7% for EFV [Cohen, 2012].
 
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Section 1.7. Study LAI116482 – updated PK information for Subject 
Original Text:
Week 48 PK for this subject is pending. 
Revised Text:
The Week 40 and Week 48 PK for this subject was consistent with Maintenance Phase 
Individual Average pre-dose values determined prior to the reported dates of calorie 
restriction.
Section 1.10.1.2. TMC278, Section 3.3. Discussion of Design, Section 5.1.2. TMC278 
– Tablet (Rilpivirine, RPV) - Updated Reference
Original Text:
[Edurant Product Information, 2013].
Revised Text:
[Edurant Product Information, 2014].
Section 3.2.1. Screening Period – clarification of background switch and provision of 
alternative NRTI therapy.
Original Text:
Subjects who are HLA-B*5701 positive at the Screening visit are allowed to enter the 
study on a dual-NRTI backbone that does not contain abacavir; this would comprise the 
single allowed NRTI switch for this subject.  The cost of the selected dual-NRTI 
backbone will be reimbursed by the Sponsor.
Revised Text:
Subjects who are HLA-B*5701 positive at the Screening visit are allowed to enter the 
study on a dual-NRTI backbone that does not contain abacavir.  The selected dual-NRTI 
backbone may be supplied regionally by GSK or reimbursement will be provided.
Section 4.2. Inclusion Criteria – Criteria 2 – removed example of effective barrier 
method.
Original Text:
ALL subjects participating in the study must be counseled on safer sexual practices 
including the use of effective barrier methods (e.g. male condom/spermicide) to minimize 
risk of HIV transmission.
 
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Revised Text:
ALL subjects participating in the study must be counseled on safer sexual practices 
including the use of effective barrier methods to minimize risk of HIV transmission.
Section 4.3. Exclusion Criteria – Criteria 7 – clarification that hepatitis C treatment 
would be exclusionary at any time during the study.
Original Text:
7.
History of ongoing or clinically relevant hepatitis within the previous 6 months, 
including chronic hepatitis B virus (HBV) infection (HBsAg positive). 
Asymptomatic individuals with chronic hepatitis C virus (HCV) infection will not be 
excluded, however Investigators must carefully assess if therapy specific for HCV 
infection is required; subjects who are anticipated to require such therapy during the 
randomized portion of the study must be excluded.
Revised Text:
7.
History of ongoing or clinically relevant hepatitis within the previous 6 months, 
including chronic hepatitis B virus (HBV) infection (HBsAg positive). 
Asymptomatic individuals with chronic hepatitis C virus (HCV) infection will not be 
excluded, however Investigators must carefully assess if therapy specific for HCV 
infection is required; subjects who are anticipated to require such therapy must be 
excluded.
Section 4.6.2.2. Confirmed Virologic Sample – added plasma sample collection from 
the confirmation visit.
New Text Added:
A plasma sample from the confirmation visit will be obtained for storage.  This sample 
may be used for possible future analyses, e.g. for genotypic and phenotypic analyses of 
subjects who experience virologic failure.
Section 5.1. Investigational Product and Other Study Treatment – Changed Epzicom 
/ Kivexa to IP at Day 1 and clarification regarding other background therapy supplies.
Original Text:
In this study, investigational product (IP) refers to GSK744, GSK744 LA, RPV and 
TMC278 LA.  These will be supplied by GlaxoSmithKline and Janssen Pharmaceuticals, 
respectively.  
Other antiretrovirals administered in the study as dual background NRTIs are not 
considered IP.  However, these will be supplied by GSK or, in some cases,
reimbursement will be provided.
Revised Text:
In this study, investigational product (IP) refers to GSK744, GSK744 LA, RPV and 
TMC278 LA.  These will be supplied by GlaxoSmithKline and Janssen Pharmaceuticals, 
 
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respectively.  Epzicom / Kivexa will also be considered IP from Day 1 of the 
Maintenance Period and will be provided by GSK.  
Other antiretrovirals administered in the study as dual background NRTIs (e.g. for 
subjects who are HLA-B*5701 positive or switch due to toxicity) are not considered IP.  
These may be supplied regionally by GSK or reimbursement will be provided.
Section 5.1.2. TMC278 – Tablet (Rilpivirine, RPV) – Added Excurion temperatures.
Original Text:  
RPV tablets are to be stored at 25°C and protected from light.
Revised Text:
RPV tablets are to be stored at 25°C (excursions permitted to 15°-30°C [59°-86°F]) and 
protected from light.
Section 5.1.3. Background NRTIs – Section title changed, Reference Information 
clarification, excursion temperatures added.
Original Text:
5.1.3. Background NRTIs
ABC/3TC [Epzicom/Kivexa Product Information, 2012] is manufactured by 
GlaxoSmithKline and is supplied as the ABC/3TC fixed dose combination (FDC) oral 
tablet, which contains 600 mg of ABC (as abacavir sulfate) and 300 mg of 3TC. The 
tablets are orange, film-coated, modified capsule-shaped and debossed with GS FC2 on 
one side with no markings on the reverse side. ABC/3TC is packaged in bottles of 
30 tablets. ABC/3TC will be supplied by GSK as commercial product. ABC/3TC tablets 
are to be stored at 25°C.
Revised Text:
5.1.3. Epzicom / Kivexa
ABC/3TC [Epzicom Product Information, 2012] is manufactured by GlaxoSmithKline 
and is supplied as the ABC/3TC fixed dose combination (FDC) oral tablet, which 
contains 600 mg of ABC (as abacavir sulfate) and 300 mg of 3TC. The tablets are 
orange, film-coated, modified capsule-shaped and debossed with GS FC2 on one side 
with no markings on the reverse side. ABC/3TC is packaged in bottles of 30 tablets. 
ABC/3TC will be supplied by GSK as commercial product. ABC/3TC tablets are to be 
stored at 25°C (excursions permitted to 15°-30°C [59°-86°F]).
 
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Section 5.7.1 Oral Dosing – Clarification of Visit Window.
Original Text:
Oral dosing is expected to occur during the week in which the subject’s projected 
visit falls (as according to the Baseline visit).  
Revised Text:
Visits for subjects on the oral dosing arm are expected to occur as projected 
according to the Baseline visit.  There is a (+ or -) 3 day visit window, from the 
projected visit date.  However, the number of tablets dispensed should be considered 
when scheduling the next visit.
Section 5.7.2. IM Dosing AND Section 6.10.6.1. – dosing window clarification.
Original Text:  
An additional (+ or -) 7 day window is allowable for IM dosing but not preferred.  
Revised Text:
An additional (+ or -) 7 day window, from the projected visit date, is allowable for 
IM dosing but not preferred.  
Section 5.8. Discontinuation of Study Treatment – deleted name of IP since different 
between Induction and Maintenance.
Original Text:
Subjects unable to manage drug toxicity or tolerate investigational product (IP, either 
formulations of GSK1265744 or TMC278) must have IP discontinued.
Revised Text:
Subjects unable to manage drug toxicity or tolerate investigational product must have IP 
discontinued.
Section 5.9.2. Prohibited Medications and Non-Drug Therapies – clarifications.
Original Text:
Chronic use of oral glucocorticosteroids must be avoided; however, short treatment 
courses (e.g., 10 days or less) and topical, inhaled or intranasal use of 
glucocorticosteroids will be allowed.
For information on concurrent therapies and interactions suspected to be relevant to other 
antiretroviral therapy in the regimen, please consult the local prescribing information.
 
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Revised Text:
Chronic use of oral glucocorticoids must be avoided; however, short treatment courses 
(e.g., 10 days or less) and topical, inhaled or intranasal use of glucocorticoids will be 
allowed.
Hepatitis C infection treatment will not be permitted during the study.
For information on concurrent therapies and interactions suspected to be relevant to other 
antiretroviral therapy in the regimen (e.g. Epzicom / Kivexa), please consult the local 
prescribing information.
Section 5.10.1. Long-Term Follow-Up Period – clarification regarding provision of 
alternative NRTI therapy.
Original Text:
The Sponsor will not provide this regimen but will reimburse sites for cost.
Revised Text:
GSK may supply HAART regionally or reimbursement will be provided.
Section 5.11. Treatment of Study Treatment Overdose – overdose information 
provided for Epzicom / Kivexa.
New Text Added:  For subjects receiving Epzicom / Kivexa, any tablet intake exceeding 
the protocol defined daily number of tablets (one tablet daily) will be considered an 
overdose.
Section 6.1. Time and Events Table – Induction Period, Section 6.2. Time and 
Events Table – Maintenance Period for IM Regimen (GSK744 LA + TMC278 LA
Q8W), AND Section 6.3. Time and Events Table – Maintenance Period for IM 
Regimen (GSK744 LA + TMC278 LA Q4W) – clarification provided.
Split CD8+ cell count into new row in table.
Section 6.1 Time and Events Table – Induction Period – Footnote a – clarification for 
subjects who begin the Induction Period (no longer randomized at Induction).
Footnote a: Original Text:
Subjects may be randomized and begin the Induction Period as soon as all 
Screening assessments are complete.
Revised Text:
Subjects may begin the Induction Period as soon as all Screening assessments are 
complete.
 
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Demography:  Moved collection from Week (-20) to Screening Period.
Footnote f:  Addition of HIV Risk Factors and clarification of when data is 
reported in InForm 
Original Text:
f.
Collect full routine medical history plus: cardiovascular risk factors
(assessments include smoking status and history, family history of cardiac 
events), recent [6 months] illicit drug use, intravenous drug use, gastrointestinal 
disease, metabolic, psychiatric, renal and neurologic disorders.
Revised Text:
f.
Collect full routine medical history plus (report at Baseline visit): HIV risk 
factors (may be collected at a later study visit), cardiovascular risk factors 
(assessments include smoking status and history, family history of cardiac 
events), recent [6 months] illicit drug use, intravenous drug use, gastrointestinal 
disease, metabolic, psychiatric, renal and neurologic disorders.
HIV-1 RNA and sample for storage:  “and genotype” added for clarification at 
Screening visit.
Section 6.2. Time and Events Table – Maintenance Period for IM Regimen (GSK744 
LA + TMC278 LA Q8W) – clarification.
PK Sample for Storage – changed to “X” at Withdrawal Visit.
Section 6.2. Time and Events Table – Maintenance Period for IM Regimen (GSK744 
LA + TMC278 LA Q8W) AND Section 6.3. Time and Events Table – Maintenance 
Period for IM Regimen (GSK744 LA + TMC278 LA Q4W) – clarification provided.
Footnotes l and m:
Original Text:
l)
Subjects should take GSK744+ABC/3TC+RPV on Day 1 in the clinic 
prior to PK sampling and injections should be administered within 2 hours of this 
where possible.  
m)
............IM dosing is expected to occur during the week in which the 
subject’s projected visit falls (as according to the Day 1 visit).  An additional 
(+ or -) 7 day window is allowable for IM dosing but not preferred.......
Revised Text:
l)
Subjects should take GSK744+ABC/3TC+RPV on Day 1 in the clinic 
after PK sampling and injections should be administered within 2 hours of this 
where possible.  
 
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m)
..........IM dosing is expected to occur during the week in which the 
subject’s projected visit falls (as according to the Day 1 visit).  An additional 
(+ or -) 7 day window, from date of projected visit, is allowable for IM dosing 
but not preferred........  
Section 6.4. Time and Events Table – Maintenance Period for Oral Regimen 
(GSK744 + ABC/3TC) – simplified ECG schedule to be consistent with IM regimens.  
Removed ECGs at Week 56, Week 72, and Week 88.
Section 6.5. Time and Events Table – Extension Period if Q8W is Selected –
clarification for timings in footnote c.
Original Text:
c.
Continue this pattern for visits for the remainder of the study.  For example, 
Week 208 will be conducted just like Week 184, Week 216 will be conducted just like 
Week 192 and Week 224 will be conducted just like Week 200.
Revised Text:
c.
Continue this pattern for visits for the remainder of the study.  For example, 
Week 208 will be conducted just like Week 192, Week 216 will be conducted just like 
Week 200 and Week 224 will be conducted just like Week 192.
Section 6.5. Time and Events Table – Extension Period if Q8W is Selected AND 
Section 6.6. Time and Events Table – Extension Period if Q4W is Selected –
clarifications provided:
PK Sample for Storage:  Changed to “X” at Withdrawal Visit.
Footnote l (Section 6.5.) and Footnote k (Section 6.6.) – Clarification regarding 
dosing window:
Original Text:
..........IM dosing is expected to occur during the week in which the subject’s 
projected visit falls (as according to the Day 1 visit).  An additional (+ or -) 7 
day window is allowable for IM dosing but not preferred........  
Revised Text:
..........IM dosing is expected to occur during the week in which the subject’s 
projected visit falls (as according to the Day 1 visit).  An additional (+ or -) 7 
day window, from date of projected visit, is allowable for IM dosing but not 
preferred........
Section 6.7. Time and Events Table – Long-Term Follow Up Period – clarification 
provided.
PK Sample for Storage:  Changed to “S” at all visits during this period.
 
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Section 6.8. Critical Screening and Baseline Assessments – clarification provided 
regarding legal representative – per French Regulatory request.
Original Text:
Written informed consent must be obtained from each potentially eligible subject (or 
his/her legal representative) by study site personnel prior to the initiation of any 
Screening procedures as outlined in this protocol.
Revised Text:
Written informed consent must be obtained from each potentially eligible subject by 
study site personnel prior to the initiation of any Screening procedures as outlined in this 
protocol.
Section 6.8.2. Baseline – clarification provided.
Original Text:  
In addition to a full routine medical history at Baseline, more detailed information will be 
collected for some disease processes such as:
Revised Text:
In addition to a full routine medical history, more detailed information will be collected 
for some disease processes such as:
Section 6.9.2. Lymphocyte Subsets, CD4+ and CD8+ - additional protocol reference 
added.
Original Text:
Lymphocyte subsets will be collected for assessment by flow cytometry (total 
lymphocyte counts, percentage and absolute CD4+ and CD8+ lymphocyte counts, ratios) 
according to Time and Events schedule (Section 6).
Revised Text:
Lymphocyte subsets will be collected for assessment by flow cytometry (total 
lymphocyte counts, percentage and absolute CD4+ and CD8+ lymphocyte counts, ratios) 
according to Time and Events schedule (Section 6) and Laboratory Assessments 
(Section 6.10.2).
Section 6.10.4.1. Definition of an AE – removed duplicate text.
The signs and symptoms and/or clinical sequelae resulting from lack of efficacy will be 
reported if they fulfill 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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Section 6.10.6.1. Treatment Interruption Due to an Adverse Event – clarification 
provided.
Original Text:
IP and background NRTIs should be restarted as soon as medically appropriate; in 
general, this should be no longer than 14 days after discontinuation (unless Grade 3 or 4 
toxicities persist).
Revised Text:
IP and background NRTIs should be restarted as soon as medically appropriate; in 
general, for oral dosing, this should be no longer than 14 days after discontinuation 
(unless Grade 3 or 4 toxicities persist).
Section 6.10.6.14.1. Essential Patient Information – clarification of brand name.
Original Text:

In order to avoid restarting abacavir, subjects who have experienced a 
hypersensitivity reaction should be asked to return any remaining EPZICOM tablets 
to the Investigator or site staff.

Subjects, who have stopped abacavir for any reason, and particularly due to possible 
adverse reactions or illness, must be advised to contact their doctor before restarting 
EPZICOM as more severe symptoms may recur within hours and may include life-
threatening hypotension and death.

Each subject should be reminded to read the Package Leaflet included in the 
EPZICOM pack. They should be reminded of the importance of removing the Alert 
Card included in the pack, and keeping it with them at all times. 
Revised Text:

In order to avoid restarting abacavir, subjects who have experienced a 
hypersensitivity reaction should be asked to return any remaining EPZICOM / 
KIVEXA tablets to the Investigator or site staff.

Subjects, who have stopped abacavir for any reason, and particularly due to possible 
adverse reactions or illness, must be advised to contact their doctor before restarting 
EPZICOM / KIVEXA as more severe symptoms may recur within hours and may 
include life-threatening hypotension and death.

Each subject should be reminded to read the Package Leaflet included in the 
EPZICOM / KIVEXA pack. They should be reminded of the importance of 
removing the Alert Card included in the pack, and keeping it with them at all times. 
 
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Section 6.11.1. PK Sample Collection – clarification of TMC278 sample at Day 1.
Original Text:
For subjects randomized to GSK744, pre-dose blood samples for evaluation of 
GSK1265744 (2 mL each) and TMC278 (3 mL each) will be collected as described in 
Table 4.
Revised Text:
For subjects randomized to oral GSK744, pre-dose blood samples for evaluation of 
GSK1265744 (2 mL each) and TMC278 (3 mL, Day 1 predose only) will be collected as 
described in Table 4.
New Text Added:  New row in Table 4 showing pre-dose TMC278 collection at Day 1.
Section 8.2.2. Sample Size Sensitivity – Updated Figure 6 legend to include 94% 
response.
Original Figure:
 
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Revised Figure:
Section 8.3.1.1. Intent-to-Treat Exposed Population (ITT-E) – corrected typo.
Original Text:
The ITT-E population consists of all enrolled subjects who received at least one dose of 
IP. 
Revised Text:
The ITT-E population consists of all enrolled subjects who receive at least one dose of IP. 
Section 8.3.1.2. Intent-to-Treat Maintenance Exposed Population (ITT-ME) –
corrected typo.
Original Text:
The ITT-ME population consists of all randomized who received at least one dose of IP
during the Maintenance Period of the study. 
Revised Text:
The ITT-ME population consists of all randomized subjects who receive at least one dose 
of IP during the Maintenance Period of the study.  
 
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Section 8.3.1.4. PK Population – corrected typo.
Original Text:
The PK Population will include all subjects who received GSK1265744 and / or TMC278 
and undergo PK sampling during the study, and provide evaluable GSK1265744 and /or 
TMC278 plasma concentration data. 
Revised Text:
The PK Population will include all subjects who receive GSK1265744 and / or TMC278 
and undergo PK sampling during the study, and provide evaluable GSK1265744 and /or 
TMC278 plasma concentration data. 
Section 10. References – Updated.
Added New Reference:
Cohen C, Molina JM, Cahn P, et at.  Efficacy and Safety of Rilpivirine (TMC278) 
Versus Efavirenz at 48 Weeks in Treatment-Naïve HIV-1-Infected Patients:  
Pooled Results From the Phase 3 Double-Blind Randomized ECHO and THRIVE 
Trials.  JAIDS.  2012; 60 (1):33-42.
Updated Date:
Original Text:
Edurant Product Information (rilpivirine) June, 2013.
Revised Text:
Edurant Product Information (rilpivirine) May, 2014.
Original Text:
Epzicom/Kivexa Product Information (abacavir/lamivudine) May, 2012.
Revised Text:
Epzicom Product Information (abacavir/lamivudine) May, 2012.
Removed duplicate reference:
GlaxoSmithKline Document Number 2011N112455_03:  LAI115428 A 
Randomized, Open Label Study to Investigate the Safety, Tolerability and 
Pharmacokinetics of Repeat Dose Administration of Long-Acting GSK1265744 
and Long-Acting TMC278 Intramuscular and Subcutaneous Injections in Healthy 
Adult Subjects.  Effective Date:  04Feb2013.
 
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Amendment 4
Amendment 4 applies to all countries.  
Amendment 4 was prepared to add the collection of a 2-hour post dose PK sample and 2-
hour post dose ECG at Week 32 and Week 48.  There is no observed safety issue, 
however, preliminary PK data preceeding IDMC review #1 revealed two subjects with 
very high 2-hour post dose concentrations of TMC278.  A thorough review of all data did 
not uncover a rationale for this elevation.  The additional 2-hour post dose PK samples 
will be collected to better understand and characterize the PK profile at a few early 
timepoints.  The post dose ECGs should help to monitor for potential ECG changes post 
dose as there is documentation of some QTc prolongation at higher concentrations of 
TMC278 which theoretically could occur on this study.  Although nothing has been 
observed to date on either study LAI116482 or 200056.
At the time of the development of the Amendment, Week 96 data from LAI116482 was 
available and therefore included for informational purposes.
A more detailed description of how injection site reactions has been included for clarity.
Removed “preliminary” or “ongoing” when describing studies that are now complete.
Finally, several miscellaneous clarifications were made throughout.
Authors
Original authors:
Author (s):  
 (physician lead and medical monitor); 
 
(project statistician), 
 (study statistician); 
 
(pharmacologist); 
 (virologist); 
 (clinical scientist), 
 (pharmacokineticist); 
 (pharmacokineticist); 
 
 (medical development lead); 
 (operations)
Revised to:
Author (s):  
 (physician lead and medical monitor); 
(project statistician), 
(study statistician); 
(pharmacologist); 
 (virologist); 
 (clinical scientist), 
 
(pharmacokineticist); 
 (medical development lead); 
(operations)
Sponsor Information
Changed the medical monitor’s affiliation from GlaxoSmithKline to ViiV Healthcare.  
The medical monitor’s contact information remains the same, including the email 
address.
Changes underlined and struckthrough:
 
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Sponsor Medical Monitor Contact Information: 
 MD, MPH
ViiV Healthcare
GlaxoSmithKline
Research Triangle Park
Five Moore Drive, Research Triangle Park, NC 27709 (USA)
Mobile: 
Office Telephone: 
Fax: 
e-mail: 
Sponsor Serious Adverse Events (SAE) Contact Information:
 MD, MPH
ViiV Healthcare
GlaxoSmithKline
Research Triangle Park
Five Moore Drive, Research Triangle Park, NC 27709 (USA)
Mobile: 
Office Telephone: 
Fax: 
e-mail: 
Protocol Synopsis
Added:
At one-week post dose visits (Week 1, Week 25, and Week 41), there is no defined visit 
window, rather visits should occur approximately 1 week from the last injection.
Visits in Long Term Follow Up are to occur as projected from the last injection with a 
(+ or -) 3 day visit window, from the projected visit date.
Added:
Visits in Long Term Follow Up are to occur as projected from the last injection with a 
(+ or -) 3 day visit window, from the projected visit date.
Added under Key Study Assessments (changes underlined):

PK assessments including 2 hour post dose samples at Day 1, Week 32 and Week 
48
 
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Section 1.4 GSK1265744 – Long Acting Injectable (GSK744 LA)
Revised to (changes struck through and underlined):
GSK744 LA, a long acting injectable formulation of GSK1265744, has been dosed in 
136 healthy subjects.  Subjects have received single or repeat doses of GSK744 LA at 
doses between 100 to 800 mg, either intramuscularly (IM) or subcutaneously (SC) and 
either alone or in combination with TMC 278 LA (completed study LAI114433 [single 
dose LA, n=58], ongoing study LAI115428 [repeat dose LA, n=40], and ongoing study 
LAI116815 [single dose LA, n=38]). The adverse event (AE) profile has been similar to
those of GSK744 (oral).  To date, no studies in HIV-1 infected subjects have been 
conducted with GSK744 LA.  
GSK744 LA has been generally well-tolerated as either an IM or SC dose.  Intramuscular 
injection site reactions (ISRs) have been predominantly mild or Grade 1 (85%), self-
limited, and have not led to study discontinuation in any subject to date. Erythema, 
nodules, induration, and warmth at the injection site were most commonly reported in 
healthy subjects.  Painless nodules were more common following SC injections than IM 
injections.  No treatment emergent serious AEs have been reported in any of the healthy 
volunteer studies involving GSK744 LA.  [Preliminary data from ongoing study
LAI115428 GlaxoSmithKline Document Number 2011N112455_03 and 
GlaxoSmithKline Document Number RM2010/00179/04: LAI114433]. 
Section 1.7 Study LAI116482
Revised to (changes struck through and underlined):
LAI116482 is an ongoing Phase IIb dose-ranging study (GSK744 10 mg, 30 mg, 60 mg) 
evaluating the utility of a two-drug, two-class combination (GSK744 + RPV) when both 
are given as a once daily oral regimen following induction of virologic suppression using 
GSK744 plus 2 investigator selected NRTIs. Eligible subjects enter Maintenance at 
Week 24 where they begin the GSK744 + RPV regimen.  
To date, the study has enrolled 244 subjects, 181 of whom received one of three oral dose 
regimens of GSK744 (10 mg, 30 mg or 60 mg) plus 2 NRTIs. A planned Week 48 96 
(24 weeks on Induction and 2472 weeks on two-drug Maintenance) analysis is complete 
and demonstrated similar antiviral activity across the three dosing arms of GSK744 in 
combination with RPV, which compared favorably to the control regimen of 
EFV 600 mg once daily plus 2 NRTIs. 
Rates of protocol defined virologic failure (PDVF) through Week 48 96 were low across 
all study arms. Three subjects receiving GSK744 (one at each dose) and three subjects 
receiving EFV were characterized as PDVFs during Induction.  During Maintenance, two 
three subjects receiving GSK744 (10 mg, n=2; and 30 mg, n=1) and one two subjects 
receiving EFV were characterized as PDVF.   
During Maintenance, treatment emergent integrase inhibitor (INI) (Q148R) and NNRTI 
(E138Q) resistance mutations were identified in one of the subjects on GSK744 (10 mg).
The subject experienced suspected virologic failure (SVF) at Week 48, which was 
 
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subsequently confirmed.  There was no change in RPV susceptibility, and a 3.08 fold 
change in susceptibility to GSK744.  The subject reported starting an extreme low calorie 
diet prior to SVF.  Week 26 and Week 36 RPV pre-dose concentrations for the subject 
were lower than concentrations seen in the Phase III RPV studies.  The subject also had 
lower GSK744 predose concentrations in Maintenance compared to Induction.  The 
Week 40 and Week 48 PK for this subject was consistent with Maintenance Phase 
Individual Average pre-dose values determined prior to the reported dates of calorie 
restriction. 
One subject on GSK744 (10 mg) developed treatment emergent NNRTI resistance 
NNRTI (K101K/E and E138E/A).  The subject experienced virologic failure at Week 72 
which was subsequently confirmed.   There was no change to GSK744 susceptibility, and 
a 4.6 fold change in susceptibility to TMC278.  There was no treatment-emergent 
integrase resistance.
By Week 16 or at time of IP discontinuation if before Week 16, 63% of subjects were 
treated with Truvada (tenofovir/emtricitibine, TDF/FTC) as their background dual NRTI 
and 37% of the subjects were treated with EPZICOM/KIVEXA™ (abacavir/lamivudine, 
ABC/3TC).  Similar virologic response rates (HIV-1 RNA < 50 c/mL) through 24 weeks 
were seen in subjects taking GSK744 + ABC/3TC (87%) and in subjects taking GSK744 
+ TDF/FTC (86%). Rates continued to be similar through Week 48, 79% for subjects 
taking GSK744 + ABC/3TC and 84% in subjects taking GSK744 + TDF/FTC.
Following induction therapy, GSK744 + RPV (86%) maintained virologic suppression at 
a rate similar to EFV + NRTIs (83%) through 96 weeks.  There was a numerically lower 
response rate of GSK744 10 mg and GSK744 30 mg, relative to GSK744 60 mg, but this 
was largely due to non-virologic discontinuations, with a low PDVF rate across all arms.
The most common treatment-emergent AEs reported for subjects on any of the GSK744 
doses, were upper respiratory tract infections, diarrhea, nausea, and headache.  One 
subject receiving GSK744 60 mg and one subject receiving GSK744 30 mg had a Grade 
3 headache.  The Grade 3 headache for the GSK744 60 mg subject occurred very early, 
study day 3, while the Grade 3 headache for the GSK744 30 mg subject occurred on 
study day 343.  All other AEs were Grade 1 or 2 with the majority of them being Grade 
1.  The majority of AEs were Grade 1 (29%) or Grade 2 (49%) severity.  Six Seven
subjects on GSK744 versus eight nine on EFV withdrew due to an AE, one receiving 10
mg (ECG abnormal and palpitations), one two receiving 30 mg (panic attack, Burkitt’s 
lymphoma) and four receiving 60 mg (hepatitis, transaminases increased, anxiety 
disorder and musculoskeletal pain).  The majority of GSK744 related AEs were Grade 1 
and few of those AEs led to withdrawal through Week 48 96 (n=4 [2%]).  There have 
been no GSK744 drug related SAEs to date.  
Two of the subjects that withdrew due to AE met liver stopping criteria with an alanine 
aminotransferase (ALT)>10x upper limit of normal (ULN) at approximately Week 4 and 
Week 8 after initiating study drug.  Both had pre-existing steatohepatitis and were dosed 
with GSK744 60 mg + ABC/3TC.  Both subjects remained asymptomatic, had normal 
serum bilirubin levels and had resolution of the ALT values after drug discontinuation.  
These 2 subjects were accounted for the only Grade 3-4 ALT abnormalities in this study
 
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to date.  Overall, the rates of any graded ALT or aspartate aminotransferase (AST)
abnormality were similar between GSK744 and EFV dosed subjects through Week 48 96: 
ALT:  17 20% and 21% respectively; AST:  250% and 1821% respectively.
These data from LAI116482 support the conduct of study 200056 by demonstrating the 
antiviral activity of GSK744 when used initially as part of a HAART regimen to induce 
virologic suppression.  In addition, this data confirmed antiviral activity of GSK744 + 
RPV as a two-drug oral Maintenance regimen and provides proof of principle for 
GSK744 LA + TMC278 LA as a maintenance regimen.  
Based upon the results through Week 48 96 of the LAI116482 study [Margolis, 2015], 
and in accordance with the pre-specified dose selection criteria at Week 2448, a 30 mg 
oral dose of GSK744 has been selected to be used in combination with ABC/3TC for 
induction of virologic suppression in study 200056.
All ongoing subjects in the LAI116482 study have entered into Maintenance the Open 
Label Extension phase to continue to receive the two drug regimen of GSK744 30 mg + 
RPV 25 mg where they have completed 24 weeks or more of the two-drug Maintenance 
regimen.  All subjects will have had completed 48 weeks of the Maintenance regimen at 
by the time study 200056 begins began dosing any IM regimen, permitting a robust 
evaluation of the virologic efficacy of the oral two drug regimen of GSK744 and RPV, 
prior to initiating the long acting injectable regimen.  These data will be made available 
to Investigators.
Section 1.10.1 Risk Assessment
Section 1.10.1.1 GSK744 and GSK744 LA
Added:
Inadvertent Intravenous Injection (Accidental Maladministration)
As with any intramuscular injection, it is possible that GSK744 LA can be inadvertently 
administered intravenously instead of intramuscularly resulting in higher than expected 
concentrations of GSK744 LA.  This could be due to administrator error, improper 
injection technique and / or improper needle length used based on body type.    
Mitigation:  Training will be provided to all sites on proper injection technique.  
Laboratory samples for safety parameters and HIV-1 RNA will be closely monitored in 
all subjects.  Additionally, 2 hour post dose PK samples will be obtained at a few early 
timepoints (Day 1, Week 32 and Week 48) for determination of GSK744 concentration 
and possible pharmacokinetic correlation with safety parameters such as ECG changes 
and virologic response.  Should IM maladministration be suspected at any time (e.g. 
suspected under or overdose or inadvertent IV dosing), a post dose ECG or any other 
supportive testing may be obtained at the discretion of the investigator, and the medical 
monitor notified.  Additionally, an unscheduled PK sample may be drawn approximately 
2 hours post dosing for future evaluation of GSK744 and TMC278 concentrations.
 
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Section 1.10.1.3 TMC278 LA
Added:
Inadvertent Intravenous Injection (Accidental Maladministration)
As with any intramuscular injection, it is possible that TMC278 LA can be inadvertently 
administered intravenously instead of intramuscularly resulting in higher than expected 
concentrations of TMC278 LA.  This could be due to administrator error, improper 
injection technique and / or improper needle length used based on body type.  
Mitigation:  Training will be provided to all sites on proper injection technique.  
Laboratory samples for safety parameters and HIV-1 RNA will be closely monitored in 
all subjects.  Additionally, 2 hour post dose PK samples will be obtained at a few early 
timepoints (Day 1, Week 32 and Week 48) for determination of TMC278 concentration 
and possible pharmacokinetic correlation with safety parameters such as ECG changes 
and virologic response.  Should IM maladministration be suspected at any time (e.g. 
suspected under or overdose or inadvertent IV dosing), a post dose ECG or any other 
supportive testing may be obtained at the discretion of the investigator, and the medical 
monitor notified.  Additionally, an unscheduled PK sample may be drawn approximately 
2 hours post dosing for future evaluation of GSK744 and TMC278 concentrations.
Section 1.10.1.6 Efficacy Risk
Changed title of section to “Risk of Treatment Failure”
And added:
Due to administrationor error, it is possible that a subject could receive an inadequate 
dose of GSK744 LA or TMC278 LA.  Sub-therapeutic concentrations of either GSK744 
LA or TMC278 LA could lead to virologic failure and possibly the development of 
resistance.  HIV-1 RNA viral loads will be closely monitored throughout the injection 
period of the study.
Section 1.10.2 Benefit Assessment
Last sentence updated to be through Week 96.  
Revised to (changes struckthrough and underlined):
Efficacy of the two-drug regimen, as oral agents, has been demonstrated through 
Week 48 96 of the ongoing LAI116482 study.  
Section 3.3 Discussion of Design
Added study number to Table 3.
 
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Revised to (changes underlined):
Table 10
LAI116482 Proportion of Subjects with Plasma HIV-1 RNA <50 c/mL at 
Key Visits - Snapshot (MSDF) Analysis (ITT-ME Population)
Visit
GSK744
10 mg
N=52
n (%)
GSK744
30 mg
N=53
n (%)
GSK744
60 mg
N=55
n (%)
GSK744 
Subtotal
N=160
n (%)
EFV 
600 mg
N=47
n (%)
Week 16 - Induction
50 (96)
49 (92)
52 (95)
151 (94)
43 (91)
Week 24 - Induction
50 (96)
50 (94)
53 (96)
153 (96)
45 (96)
Week 48 - Maintenance
48 (92)
48 (91)
53 (96)
149 (93)
44 (94)
Section 4.5 Withdrawal Criteria
Clarified that the change from Baseline QT criteria is an increase in QTc > 60 msec.
Revised to (changes underlined):

The following QT criteria:

QTc >500 msec

Uncorrected QT >600 msec

Change from Baseline: Increase in QTc > 60 msec
Section 5.1.7 Dosing Considerations for GSK744 LA + TMC278 LA
Clarified need for varied needle lengths and added language regarding maladministration.
Revised to (changes struckthrough and underlined):
Variable needle lengths may need to be used to accommodate individual body type.  For 
example, longer needle lengths will may be required for subjects with higher body mass 
indexes (BMIs, example > 30), to ensure that injections are administered intramuscularly 
as opposed to subcutaneously.  BMI and needle length used will be collected in the 
eCRF.
Added:
Should IM maladministration be suspected at any time (e.g. suspected under or overdose 
or inadvertent IV dosing), the investigator may consider requesting the subject stay onsite 
for up to 2 hours post dose for safety monitoring and notifying the medical monitor.  An 
ECG or any other supportive testing may be obtained at the discretion of the investigator.  
Additionally, a PK sample may be drawn approximately 2 hours post dosing for future 
evaluation of GSK744 and TMC278 concentrations.
Section 5.7.1 Oral Dosing
Revised section heading to “Oral Dosing Including Long Term Follow Up.”
 
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Added:
Visits for subjects in Long Term Follow Up are expected to occur as projected according 
to the last injection.  There is a (+ or -) 3 day visit window, from the projected visit date.
Section 5.7.2 IM Dosing
Clarified visit window for one week post dose visits.
Revised to (changes underlined):
IM dosing is expected to occur during the week in which the subject’s projected visit falls 
(as according to the Day 1 visit).  An additional (+ or -) 7 day window, from the projected 
visit date, is allowable for IM dosing but not preferred.  At one-week post dose visits 
(Week 1, Week 25, and Week 41), there is no defined visit window, rather visits should 
occur approximately 1 week from the last injection.
Section 5.11 Treatment of Study Treatment Overdose
Added:
Should IM maladministration be suspected at any time (e.g. suspected under or overdose 
or inadvertent IV dosing), the investigator may consider requesting the subject stay onsite 
for up to 2 hours post dose for safety monitoring and notifying the medical monitor.  An 
ECG or any other supportive testing may be obtained at the discretion of the investigator.  
Additionally, a PK sample may be drawn approximately 2 hours post dosing for future 
evaluation of GSK744 and TMC278 concentrations.
Section 6.2 Time and Events Table – Maintenance Period for IM Regimen (GSK744 
LA + TMC278 LA Q8W)
Added a footnote “c” to ECG line at Week 32 and 48.  Added a footnote “k” to PK line at 
Week 32 and 48.
Procedure
s
For 
Maintenan
ce – Q8W  
regimen
D
1
W
1
W
4
W
8
W
1
2
W
1
6
W
2
0
W
2
4
W
2
5
W
2
8
W
3
2
W
3
6
W
4
0
W
4
1
W
4
4
W
4
8
W
5
2
W
5
6
W
6
0
W
6
4
W
6
8
W
7
2
W
7
6
W
8
0
W
8
4
W
8
8
W
9
2
W
9
6
W
D
p, q
ECG c
X
pr
e
X
X
X
X
X
c
X
c
X
X
X
X
PK 
Sample 
(S)torage k
X 
k
X
X
X
X
X
X
X
X
X X
k
X
X
X
X X
k
S
S
S
S
S
S
X
Revised footnote “c” to (changes underlined):
 
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c)  12-Lead ECG – Conduct pre-dose at Day 1.  At all other visits, the ECG may be done 
at any time during the visit. At Week 32 and Week 48, a second ECG will be obtained 
approximately 2 hours after the last injection and just prior to the 2 hour post dose PK 
sampling.
Revised footnote “k” to (changes underlined):
k) Take PK samples pre-dose except Weeks 1, 12, 20, 25, 28, 36, 41 and 44 which can be 
taken at any time during the visit.  Day 1 PK sample should be taken after review of PK 
diary and pre-dose of GSK744+ABC/3TC+RPV.  A second Day 1, Week 32 and Week 
48 PK sample will be collected approximately 2 hours after the last injection.
Section 6.3 Time and Events Table – Maintenance Period for IM Regimen (GSK744 
LA + TMC278 LA Q4W)
Added a footnote “c” to ECG line at Week 32 and 48.  Added a footnote “k” to PK line at 
Week 32 and 48.  Added table title to first cell.  Changes underlined.
Procedure
s
For 
Maintenan
ce – Q8W  
regimen
D
1
W
1
W
4
W
8
W
1
2
W
1
6
W
2
0
W
2
4
W
2
5
W
2
8
W
3
2
W
3
6
W
4
0
W
4
1
W
4
4
W
4
8
W
5
2
W
5
6
W
6
0
W
6
4
W
6
8
W
7
2
W
7
6
W
8
0
W
8
4
W
8
8
W
9
2
W
9
6
W
D
p, q
ECG c
X
pr
e
X
X
X
X
X
c
X
c
X
X
X
X
PK 
Sample 
(S)torage k
X 
k
X
X
X
X
X
X
X
X
X X
k
X
X
X
X X
k
S
S
S
S
S
S
X
Revised footnote “c” to (changes underlined):
c)  12-Lead ECG – Conduct pre-dose at Day 1.  At all other visits, the ECG may be done 
at any time during the visit. At Week 32 and Week 48, a second ECG will be obtained 
approximately 2 hours after the last injection and just prior to the 2 hour post dose PK 
sampling.
Revised footnote “k” to (changes underlined):
k) Take PK samples pre-dose except Weeks 1, Week 25 and Week 41 which can be taken 
at any time during the visit.  Day 1 PK sample should be taken after review of PK diary 
and pre-dose of GSK744+ABC/3TC+RPV.  A second Day 1, Week 32 and Week 48 PK 
sample will be collected approximately 2 hours after the last injection.
Section 6.7 Time and Events Table – Long-Term Follow Up Period
Missing footnote “c”.  Added (underlined):
 
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Fasting:  Glucose, Cholesterol (Total, 
HDL and LDL) and Triglycerides c
X
X
Section 6.9.1 Plasma HIV-1 RNA
Revised last sentence to (changes struckthrough and underlined):
Plasma for quantitative HIV-1 RNA will be collected according to the Time and Events 
schedule (Section 6).  Methods to be used may include but are not limited to the Abbott 
RealTime HIV-1 Assay lower limit of detection (LLOD) 40 c/mL.  In some cases (e.g., 
where the HIV-1 RNA is below the lower limit of detection for a given assay) additional 
exploratory methods maywill be used to further characterize HIV-1 RNA levels.
Section 6.10.1 Clinical evaluations
Clarified injection site reaction evaluations.
Added:
The investigator should utilize subject diary reports to assist with a clinical assessment 
(using Division of Acquired Immunodeficiency Syndrome [DAIDS] grading scale).  A 
clinical assessment should be performed both before and after an injection to identify 
resolving and new ISRs.  The clinical assessment and interpretation of any ISR, including 
those reported by the subject via diary, will be documented in the ISR AE eCRF.  Daily 
diary data, or subject assessment, will be documented verbatim in the diary eCRF.
Section 6.10.2 Laboratory Assessments, Section 6.10.3.2 Liver Chemistry 
Stopping Criteria, Subject Management and Section 6.12 Viral Genotyping and 
Phenotyping
Changed “Quest Diagnostics” to “central laboratory” throughout.
Section 6.10.2 Laboratory Assessments
Removed reference to Cockgroft-Gault formula as Creatinine Clearance may be derived 
by another formula.  Changes to footnote struck through.
b)
Creatinine clearance will be estimated by the central laboratory using the 
Cockcroft-Gault method [Cockcroft, 1976] and assessed at Screening, Baseline, Week 
(-12), Week (-4), Day 1 and Weeks 4, 16, 32, 48 and 96.
Removed erroneous footnote “h”.
Section 6.10.4.1 Definition of an AE
Added as an event meeting the definition of AE:
 
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•
All injection site reactions.
Section 6.10.6.11 QTc Prolongation
Clarified instances when IP should be discontinued.
Revised to (changes underlined):
Subjects with an average QTc interval > 500 msec or a >60 msec increase from baseline,
from three or more tracings separated by at least 5 minutes should have IP discontinued.
Section 6.10.6.12 Injection Site Reactions (ISRs)
Clarified that ISRs will be managed through investigator assessment and subject diaries.  
Combined this section with original Section 6.10.11 Injection Site Reaction Monitoring.
Revised to (changes struckthrough and underlined):
Injection site reactions will be managed through AE reporting and patient investigator 
assessment and subject diary collection throughout the study.  All Grade 3 or 4 ISRs must 
be discussed with the medical monitor to determine etiology and assess appropriate 
continued study participation.  
Digital photographs will be documented where possible on all subjects who have an 
injection site reaction that is either serious or Grade 2 or above that persist beyond 2 
weeks.  Dermatology will be consulted on all subjects who have an injection site reaction 
considered serious, Grade 3 or above, or if clinically significant and persistent beyond 30 
days and others if the Investigator or Medical Monitor feels it is medically necessary.
Details regarding photo collection and any other follow up will be given by the Medical 
Monitor at the time of assessment.
ISR discomfort can be managed symptomatically (e.g. cold/warm compress, 
acetaminophen, ibuprofen) if the reaction is interfering with the subject’s ability to 
perform activities of daily living.  The required intervention should be documented on the 
appropriate eCRF page.  
Section 6.10.11 Injection Site Reaction Monitoring
Deleted this section and combined with Section 6.10.6.12.
Subjects on either IM regimen will be monitored closely both clinically and by patient 
report for the following in relation to injection site reactions:
•
Pain, tenderness, pruritis, warmth, infections, rash, erythema, swelling, 
induration, and nodules (granulomas or cysts).  
Digital photographs will be documented where possible on all subjects who have an 
injection site reaction that is either serious or Grade 2 or above that persist beyond 2 
 
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weeks.  Dermatology will be consulted on all subjects who have an injection site reaction 
considered serious, Grade 3 or above, or if clinically significant and persistent beyond 30 
days and others if the Investigator or Medical Monitor feels it is medically necessary.
Details regarding photo collection and any other follow up will be given by the Medical 
Monitor at the time of assessment.
Section 6.11.1 PK Sample Collection
Updated PK sampling Table 4 to include a 2 hour post dose sample for GSK1265744 and 
TMC278 at Week 32 and Week 48.
Group
Analyte
Week
Sample Times Relative to Dose
IM
GSK1265744
Day 1 (prior to LA and 
last oral Induction 
dose), Weeks: 1, 4, 8, 
12, 16, 20, 24, 25, 28,  
32, 36, 40, 41, 44 and 
48
Pre-Dose (Q8W):  Day 1, Weeks 4, 8, 
16, 24, 32, 40 and 48
Pre-Dose (Q4W):  Day 1, Weeks 4, 8, 
12, 16, 20, 24, 28, 32, 36, 40, 44 and 
48
2 Hours Post Dose:  Day 1, Week 32 
and Week 48
1 Week Post Dose:  Week 1, Week 
25 and Week 41
4 Weeks Post Dose (Q8W):  Weeks 
12, 20, 28, 36 and 44
TMC278
Day 1 (prior to LA and 
last oral Induction 
dose), Weeks: 1, 4, 8, 
12, 16, 20, 24, 25, 28, 
32, 36, 40, 41, 44 and 
48
Pre-Dose (Q8W):  Day 1, Weeks 4, 8, 
16, 24, 32, 40 and 48
Pre-Dose (Q4W):  Day 1, Weeks 4, 8, 
12, 16, 20, 24, 28, 32, 36, 40, 44 and 
48
2 Hours Post Dose:  Day 1, Week 32 
and Week 48
1 Week Post Dose:  Week 1, Week 
25 and Week 41
4 Weeks Post Dose (Q8W):  Weeks 
12, 20, 28, 36 and 44
Oral 
GSK1265744
Day 1, Weeks: 32 and 
48
Pre-Dose:  Day 1, Weeks 32 and 48
TMC278
Day 1
Pre-Dose:  Day 1
Section 6.11.1 PK Sample Collection and Section 6.11.3 Bioanalysis of 
GSK1265744 and TMC278
Removed reference to SPM.  All PK sampling details are in the central laboratory 
manual.
 
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Section 8.2.2 Sample Size Sensitivity
Corrected spelling of “positive” in Figure 6.
Section 8.3.1.3 Per Protocol Maintenance Population
Clarified this as the Maintenance Exposed Population.  Changed section title to “Per 
Protocol Maintenance Exposed Population (PP-ME).”
Revised to (changes underlined):
The PP-ME population will be a secondary population for efficacy purposes.
Section 8.3.3.1 Primary Comparisons of Interest
Corrected response rate.
Revised to (changes struckthrough and underlined):
The probability of (Response rate for IM arm Response rate for Oral arm -10%) will 
be calculated.
 
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Section 8.3.4.1 IDMC Interim Analysis
Clairified that the first IDMC analysis may not occur before all subjects enter 
Maintenance.
Revised to (changes struckthrough and underlined):
The IDMC will intends to review at least one analysis before all eligible subjects have 
transitioned from the Induction Period to the Maintenance Period, or as soon as 
reasonably possible after subjects begin to enter the Maintenance Period.
Section 8.3.5.2 Safety Analyses
Clarified that injection site reactions will be part of the AE summaries provided.
Revised to (changes underlined):
Exposure to study medication, measured by the number of weeks on study drug, will be 
summarized by treatment arm.  The proportion of subjects reporting adverse events (AEs) 
will be tabulated for each treatment arm.  The following summaries of AEs will be 
provided:
Incidence and severity of All AEs including injection site reactions;
References
Added:
Margolis, D, et al.  Cabotegravir and Rilpivirine As Two-Drug Oral Maintenance 
Therapy: LATTE Week 96 Results.  22nd Conference on Retroviruses and Opportunistic 
Infections; February 23-26, 2015 Poster 554LB
 
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Amendment 5
General
Clarifications of naming conventions of cabotegravir and rilpivirine (both formulations) 
were made throughout to document to be in line with the defined terms in Section 1.2.  In 
addition, the Extension Period was revised throughout the document to allow subjects to 
remain on their randomized IM regimens (rather than switching to a single selected IM 
regimen as originally planned), and to allow subjects randomized to the oral arm in the 
Maintenance Period to switch to one of the optimized Q8W/Q4W regimens, based on 
subject preference
Week 32 and 48 data from 200056 was added.
Various clarifications made throughout the document.
Protocol Synopsis
The Extension Period and IDMC sections were modified to reflect the new design.  Most 
sections had minor revisions.
Section 1.8 200056
Section added to Protocol.
The 200056 study (LATTE-2) evaluated a 20 week induction of HIV-1 RNA suppression 
with a three drug oral antiretroviral regimen consisting of CAB + ABC / 3TC Fixed Dose 
Combination (FDC) followed by randomization to a two-drug regimen consisting of 
intramuscular (IM) long-acting (LA) CAB LA + RPV LA compared to continuation of 
oral CAB + ABC / 3TC for the maintenance of HIV-1 RNA suppression.  A total of 309 
participants were enrolled and treated.
During the Induction Period there was a rapid and sustained decline in HIV-1 RNA, with 
91% of participants (282/309) achieving HIV-1 RNA <50 c/mL through 20 weeks of 
therapy.  There was a single participant (with known compliance issues) with confirmed 
virologic failure during the Induction Period.  Virologic testing revealed no treatment 
emergent phenotypic or genotypic resistance in this participant.
The primary endpoint for 200056 was the Week 32 proportion of participants with HIV-1 
RNA < 50 c/mL (Snapshot, Intent-to-Treat Maintenance Exposed population [ITT-ME]). 
Following virologic suppression on three drug oral therapy in the Induction Period, 
286 participants qualified to enter randomization at the Day 1 visit, and were 
subsequently randomized 2:2:1 onto every 4 week intramuscular (IM) injections with 
CAB LA + RPV LA (Q4W), every 8 week IM injections with CAB LA + RPV LA 
(Q8W) or continuation of oral CAB + NRTIs, respectively.  At the time of randomization 
at Day 1, participants entering one of the IM arms discontinued all oral ART. Through 
32 weeks of two-drug maintenance therapy, 95% (Q8W) and 94% (Q4W) of participants 
on injectable dosing were virologic successes, compared to 91% of participants 
 
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continuing three drug oral CAB + NRTIs, meeting pre-specified criteria for comparability 
between the dosing arms. Through 32 weeks of Maintenance therapy, there was one 
participant each on Q8W and oral dosing with confirmed virologic failure (CVF), without 
any evolution of viral resistance. The CVF on Q8W dosing occurred following an 
aberrant RPV injection, without measurable plasma RPV concentrations 4 weeks post 
dosing.  
Week 48 data was a secondary endpoint for 200056, and permitted the evaluation of the 
two-drug long-acting combinations’ ability to maintain the virologic suppression 
demonstrated at Week 32.  At Week 48, 92% (Q8W) and 91% (Q4W) of participants 
receiving injectable dosing had a sustained virologic response (HIV-1 RNA <50 c/mL) 
compared to 89% of participants continuing oral CAB + 2 NRTIs.  Although the 
proportion of participants with virologic success was similar for Q8W and Q4W dosing, 
the reason for Snapshot failure was different between the arms.  There were more 
Snapshot failures for virologic reasons on the Q8W arm (n=8, 7%) than in the Q4W arm 
(n=1, <1%), and more participants with no virologic data (discontinued due to AE or 
other reasons) on the Q4W arm (n=9, 8%) compared to the Q8W arm (n=1, <1%).  
Between Week 32 and Week 48, one additional participant (Q8W) had confirmed 
virologic failure.  This participant had a Baseline HIV-1 RNA of 444,489 c/mL.  At 
Week 48, the participant was a suspected virologic failure with HIV-1 RNA = 463 c/mL.  
Upon retest, ten days later, the virologic failure was confirmed with HIV-1 RNA of 
205 c/mL.  At the time of CVF, this participant had treatment emergent NNRTI 
resistance K103N, E138G, and K238T, with high level phenotypic resistance to 
delaviridine (>MAX), efavirenz (48 fold change [FC]), nevirapine (>Max), and 
rilpivirine (3.34 FC). The fold change to etravirine (1.91) was below the lower cutoff.
Week 48 integrase genotype had the treatment emergent integrase resistance mutation 
Q148R, with accompanying resistance to raltegravir (29 FC), elvitegravir (138 FC), and 
cabotegravir (6.06 FC). The Week 48 sample was not resistant to dolutegravir (1.38 FC).
Overall, AEs and clinical chemistries were similar to those observed in prior studies with 
CAB, without discernible trends between Q8W, Q4W, and oral. Injections were well 
tolerated with two participants discontinuing due to injection tolerability through 48 
weeks (both on Q8W dosing). The vast majority of injection site reactions were due to 
pain/discomfort with nearly all injection site reactions classified as mild (82%) or 
moderate (17%), with <1% of reactions classified as severe. There was no discernible 
tolerability difference between Q4W (2 mL) dosing and Q8W (3 mL dosing).  The most 
common non-ISR AEs during the Maintenance Phase were nasopharyngitis (24%), 
headache (16%), and diarrhea (13%) on IM arms and nasopharyngitis (30%), headache 
(11%), and diarrhea (5%) on oral CAB.  Through Week 48, SAEs during the 
Maintenance Period occurred in 7% of participants randomized to CAB LA + RPV LA 
and 5% of participants randomized to remain on oral treatment, none were drug related.  
Based on the data from the Week 48 endpoint, Q4W dosing was chosen to progress for 
further clinical development in Phase 3 studies, however, due to continued interest in 
evaluating the potential of Q8W dosing, subjects entering the Extension Period from the 
oral CAB 30 mg + ABC/3TC arm in this study will be given the option to switch to either 
an optimized Q8W or Q4W regimen.  Subjects originally randomized to the IM regimen 
and entering the extension phase will remain on their randomized regimen.
 
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Section 1.9 Study Rationale
Extension Period revised to (changes struck through and underlined):
The Extension Period of this study will allow for a collection of longer term efficacy and 
safety and tolerability data from subjects receiving GSK744 CAB LA and TMC278 RPV
LA.  Only one Both of the current IM dosing regimens, either Q4W or Q8W and Q4W, 
will be taken into the Extension Period of the study (based on criteria described in the 
Reporting and Analysis Plan [RAP])similar efficacy results across each arm (see Section 
1.8)..
Unless subjects meet a study withdrawal criterion, subjects on the oral regimen may elect 
to continue on the Extension Period by switching to the selected GSK744 LA + TMC278 
LA dosing regimen.  If eligible, their regimen will be modified prior to entering 
Extension by adding RPV 25 mg orally once daily for 2 weeks.  This short RPV add on 
will allow eligible subjects to achieve steady state levels of RPV, prior to the 
administration of the GSK744 LA + TMC278 LA. an optimized IM dosing regimen of 
their choice of CAB LA + RPV LA (either Q8W or Q4W).
Section 1.10 Dose Rationale
Added the following sections for CAB LA-Extension and RPV LA-Extension:
CAB LA – Extension Period
CAB concentrations following administration of CAB LA Q8W and Q4W during the 
Maintenance Period of LATTE-2 were lower than predicted by the modelling and 
simulation in the original protocol,  Observed data for both CAB LA regimens in 
LATTE-2 are presented in Figure 3.  The CAB LA population PK model has been 
updated to include data from Phase 2a/b studies, specifically Study 201120 (CAB LA 
PrEP) and Study 200056.  The current model has increased from 93 subjects to 416 
subjects receiving CAB LA single or repeat IM injections.  The rationales for the new 
CAB LA IM dosing regimens are described below.
 
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Figure 3
Observed Mean (SD) Concentration-Time Data following CAB LA 
Q8W and Q4W and Cfollowing 30 mg PO QD through Week 48 (200056, LATTE-
2)
Week
0 1
4
8
12
16
20
2425
28
32
32
36
4041
44
48
48
Plasma CAB (g/mL)
0.1
1
10
800mg IM LD, 600mg IM W4, W8 and Q8W
800mg IM LD, 400mg IM Q4W
30mg PO QD
PA-IC90 (0.166g/mL)
10mg PO QD C (LATTE, 1.35g/mL)
Both predose and 2h post injection concentrations are shown at Time Zero, Week 32, and Week 48.
Extension Phase Rationale for CAB LA Q8W
After the Maintenance Period oral regimen, the first and second CAB LA 600 mg IM 
dose at study visit Week 100 (1st injection day) and Week 104 (2nd injection) of the 
Extension Period of this study was selected so that 50% of subjects are anticipated to be 
above 1.35 g/mL, the geometric mean Cfollowing oral CAB 10 mg once daily, 
throughout treatment which was shown to be efficacious in the LATTE study.  The lower 
bound of the 90% prediction interval is approximately 0.166 g/mL, indicating that 95% 
of subjects on this regimen should remain above the PA-IC90 throughout dosing ().
 
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Figure 4
Simulated* Median (90% Prediction Interval [PI]) CAB Plasma 
Concentrations versus Time for the Optimized CAB LA Q8W Regimen (600 mg IM 
Day 1, Week 4, Q8W thereafter)^
*Note: current simulations based on interim plasma concentration dataset
^Study Time and Events include a 4 week oral lead in.  Therefore, Day 1 = date of first injections (Week 100 study 
visit); Week 4 = second injections (Week 104 study visit)
Model based predicted steady-state CAB concentrations were consistent with observed 
data in this study, where CAB LA 600 mg IM Q8W was given, albeit with a loading dose 
of 800 mg IM on Day 1 and a third dose of 600 mg IM at Week 8 prior to initiating Q8W.  
The mean CAB plasma concentration at Week 32 was 1.53 g/mL (Figure 4).
At steady state, a one week delay in dosing of the Q8W regimen is predicted to result in a 
median steady state Cthat is 15% lower than for dosing that is administered on 
schedule, with 92% remaining above the PA-IC90 (Figure 5).
 
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Figure 5
Impact of 1-week Delay in Dosing at Steady State (Week 44) on 
Simulated* Median (90% PI) CAB Plasma Concentrations versus Time for the 
Optimized CAB LA 600 mg IM Q8W regimen (Day 1, Week 4, and Q8W 
thereafter^)
*Note: current simulations based on interim plasma concentration dataset
^Study Time and Events include a 4 week oral lead in.  Therefore, Day 1 = date of first injections (Week 100 study 
visit); Week 4 = second injections (Week 104 study visit)
Extension Phase Dose Rationale for CAB LA Q4W
The simulation of the predicted median (90% prediction interval [PI]) CAB 
concentration-time profile based on the population PK model is shown in Figure 6.  The 
lower bound of the PI remains approximately at or above 4x PA-IC90 throughout dosing.  
At steady state, 98% of the population is predicted to achieve trough concentrations 
above 4x PA-IC90, and 88% is predicted to achieve trough concentrations above the 
geometric mean trough following the 10 mg oral dose in LATTE of 1.35 g/mL (8x PA-
IC90).  
 
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Figure 6
Simulated* Median (90% Prediction Interval [PI]) CAB Plasma 
Concentrations versus Time for the Optimized CAB LA Q4W Regimen (600 mg IM 
Day 1, then 400 mg IM Q4W thereafter^)
* Note: current simulations based on interim plasma concentration dataset
^Study Time and Events include a 4 week oral lead in.  Therefore, Day 1 = day of first injections (Week 100 study visit); 
Week 4 = second injections (Week 104 study visit)
Medium dashed line at 1.35 g/mL corresponds to the geometric mean Ctrough concentration following oral CAB 10 
mg once daily  (LATTE) and is equivalent to 8x PA-IC90
Dotted line at 0.664 g/mL corresponds to 4x PA-IC90
Long dashed line at 0.166 g/mL corresponds to the PA-IC90.
At steady state, a one week delay in dosing of the Q4W regimen results in approximately 
15% reduction in median CAB trough. With this delay, 95% are predicted to remain 
above 4x PA-IC90, and 79% are predicted to remain above the 10 mg oral target (Figure 
7).  Simulations including delays greater than one week have been explored (not shown), 
with <70% of subjects remaining above the 10 mg oral target.  Therefore, a 1-week delay 
is the maximum allowed per the protocol.  
 
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Figure 7
Impact of 1-week Delay in Dosing at Steady State (Week 40 delayed to 
Week 41) on Simulated* Median (90% PI) CAB Plasma Concentrations versus 
Time for the Optimized CAB LA Q4W regimen (600 mg IM Day 1, then 400 mg IM 
Q4W thereafter^)
* Note: current simulations based on interim plasma concentration dataset
^Study Time and Events include a 4 week oral lead in.  Therefore, Day 1 = day of first injections (Week 100 study visit); 
Week 4 = second injections (Week 104 study visit)
Medium dashed line at 1.35 g/mL corresponds to the geometric mean Cfollowing oral CAB 10 mg once daily 
(LATTE) and is equivalent to 8x PA-IC90
Dotted line at 0.664 g/mL corresponds to 4x PA-IC90
Long dashed line at 0.166 g/mL corresponds to the PA-IC90.
RPV LA – Extension Period
Similar to CAB, RPV concentrations following RPV LA in LATTE-2 were lower than 
predicted by the modelling and simulation in the original protocol.  Observed data for 
both RPV LA regimens in LATTE-2 are presented in Figure 10.  The RPV LA 
population PK model has been updated to include data from LATTE-2.
 
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Figure 10
Observed Mean (SD) Concentration-Time Data following RPV LA 
Q8W and Q4W through Week 48 and Day 1 Cfollowing RPV 25 mg PO QD 
(LATTE-2)
Week
0 1
4
8
12
16
20
2425
28
32
32
36
4041
44
48
48
Plasma RPV (ng/mL)
10
100
1000
900mg IM Q8W
600mg IM Q4W
25mg PO QD
PA-IC90 (12ng/mL)
25mg PO QD (LATTE, 70ng/mL)
Extension Phase Rationale for RPV LA Q8W
The new optimized RPV LA Q8W regimen for this study was selected based on safety 
and efficacy data from this study, 200056 (LATTE-2) and supported by modelling and 
simulation of pharmacokinetic and response data obtained following administration RPV 
LA administration in healthy subjects (Phase 1 studies C158 and LAI115428 
[GlaxoSmithKline Document Number 2011N112455_03]) and in HIV-infected subjects 
(Phase 2 study LATTE-2), the majority of the data coming from 200056 (LATTE-2). 
The predicted median (90% PI) steady-state Cfor the optimized RPV LA Q8W regimen 
is 54 ng/mL (25 – 109 ng/mL) (Figure 11).  With this regimen, 100% of subjects remain 
above the RPV PA-IC90 during the whole dose interval at steady-state.  These data are 
similar to the observed Week 32 median steady-state Cwhich was also 54 ng/mL and 
the mean Cwas 58 ng/mL (Figure 10).  With the 2nd RPV LA dose at Week 104, the 
anticipated median RPV Cat Week 104 is 42 ng/mL (versus 30 ng/mL observed prior to 
second injection at Week 8 in LATTE-2), with >98% of subjects above the RPV PA-
IC90.
 
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Figure 11
Simulated* Median (90% PI) RPV Plasma Concentrations versus 
Time Profile for the Optimized RPV LA Q8W regimen (900 mg IM Day 1, Week 4, 
and Q8W thereafter^)
* Note: current simulations based on interim plasma concentration dataset
^Study Time and Events include a 4 week oral lead in.  Therefore, Day 1 = date of first injections (Week 100 study 
visit); Week 4 = second injections (Week 104 study visit)
At steady-state, a one week delay in dosing for the Q8W regimen is predicted to result in 
a median steady-state Cthat is approximately 13% lower (47 ng/mL) than for dosing 
that is administered on schedule, with >99% of subjects still remaining above the RPV 
PA-IC90 (Figure 12).  This supports allowance of some flexibility in the dosing regimen 
in this study, similar to what is currently practiced in this study.
 
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Figure 12
Simulated* Median (90% PI) RPV Plasma Concentrations versus 
Time Profile for Optimized RPV LA Q8W dosing regimen, impact of 1-week visit 
window (injection at Week 45 instead of Week 44)^
* Note: current simulations based on interim plasma concentration dataset
^Study Time and Events include a 4 week oral lead in.  Therefore, Day 1 = date of first injections (Week 100 study 
visit); Week 4 = second injections (Week 104 study visit)
Extension Phase Rationale for RPV LA Q4W
The optimized RPV LA Q4W regimen for this study was selected based on LATTE-2 
safety and efficacy data as described above and supported by modeling and simulation of 
pharmacokinetic data obtained following administration of RPV LA in healthy 
participants (Phase 1 studies C158 and LAI115428 [GlaxoSmithKline Document Number 
2011N112455_03]) and in HIV-infected participants (Phase 2 study LATTE-2), with the 
majority of the data coming from 200056 (LATTE-2). 
The predicted median (90% PI) steady-state Cfor the proposed regimen is 86.8 ng/mL 
(45.6 – 168 ng/mL) (Figure 13).  With this regimen, >99% of participants remain above 
the 5th percentile of steady state trough values following oral RPV 25 mg (corresponding 
to 2x the PA-IC90).  With a loading dose of 900 mg RPV LA on Day 1, the anticipated 
 
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median RPV Cat Week 4 is 42 ng/mL, with >98% of participants above the RPV PA-
IC90.
Figure 13
Simulated* Median (90% PI) RPV Plasma Concentrations versus 
Time Profile for the Optimized RPV LA Q4W regimen (900 mg IM Day 1, then 600 
mg IM Q4W thereafter^)
* Note: current simulations based on interim plasma concentration dataset
^Study Time and Events include a 4 week oral lead in.  Therefore, Day 1 = day of first injections (Week 100 study visit); 
Week 4 = second injections (Week 104 study visit) 
Horizontal line at 72 ng/mL corresponds to median Cfollowing oral RPV 25mg once daily in LATTE-2 (oral lead-in) 
and is similar to median RPV Cin other studies in HIV-infected patients (LATTE, ECHO/THRIVE)
At steady-state, a one week delay in dosing for the Q4W regimen is predicted to result in 
a median steady-state Cthat remains above the median trough for RPV 25 mg (Figure 
14).  This supports allowance of some flexibility in the dosing regimen.
 
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Figure 14
Impact of 1-week Delay in Dosing at Steady State (Week 40 delayed to 
Week 41) on Simulated* Median (90% PI) RPV Plasma Concentrations versus 
Time for Optimized RPV LA Q4W dosing regimen (900 mg IM Day 1 and then 600 
mg IM Q4W thereafter^)
*Note: current simulations based on interim plasma concentration dataset
^Study Time and Events include a 4 week oral lead in.  Therefore, Day 1 = day of first injections (Week 100 study visit); 
Week 4 = second injections (Week 104 study visit)
Horizontal line at 72 ng/mL corresponds to median Cfollowing oral RPV 25 mg once daily in LATTE-2 (oral lead-in) 
and is similar to median RPV Cin other studies in HIV-infected patients (LATTE, ECHO/THRIVE)
Section 1. 11 Benefit:  Risk Assessment
Revised to (changes struck through and underlined):
Section 1.11.1 Risk AssessmentSection 
1.11.1.1 GSK744 CAB and GSK744 CAB LA
Since GSK744 CAB is at an early stage of clinical development, and exposure in humans 
with or without HIV infection is limited, the clinical safety profile in humans has yet to 
be fully elucidated. The following risks have primarily been identified during routine 
 
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preclinical testing and/or in the clinical trial experience to date and are considered of 
potential relevance to clinical usage in the context of this protocol.  Additional 
information about the clinical experience to date and possible risks associated with 
treatment using CAB can be found in the Summary of Data and Guidance for the 
Investigator section of the IB.
Elevated Liver Transaminases
Two out of 183 subjects in the Induction Phase of ongoing study LAI116482 involving 
treatment naïve HIV patients receiving GSK744 have developed elevated liver enzymes, 
considered probably related to GSK744. Both subjects met protocol defined liver 
stopping criteria and stopped taking GSK744 as a result of these elevations. 
Transaminases returned to pre-treatment levels after stopping drug in both cases. In the 
two subjects, the peak ALT elevation was >10xULN and occurred approximately 4 
weeks and 8 weeks, respectively, after initiating daily GSK744 60 mg+ ABC/3TC. In 
both cases the ALT and AST values were elevated while other liver tests remained 
normal (bilirubin, alkaline phosphatase, albumin).  Neither subject developed clinical 
symptoms of liver dysfunction. No other subjects have required discontinuation of 
GSK744 as a result of a transaminase elevation.  To date approximately 134 healthy 
volunteers have received 100 to 800 mg of GSK744 LA administered as a SC or IM 
injection.  There have been no Grade 3 or Grade 4 ALT elevations while on GSK744 LA.  
There has been a single subject with a transient Grade 2 ALT elevation following the 
three monthly injections with GSK744 LA 400 mg that resolved while remaining on 
GSK744 LA. A small proportion of participants in the CAB program to date (total 
exposure approximately 1198 to 01 April 2016) have developed transaminitis (elevated 
liver transaminases characterised by predominant ALT elevation).  In some of these 
participants’ transient transaminitis were explained by acute hepatitis C infection and 
whilst a small number of others did not have alternative explanations, suggesting a mild 
form of DILI (drug induced liver injury) without hepatic dysfunction which resolved 
upon withdrawal of treatment with CAB. 
Of the five participants with possible or probable cases of DILI identified in Phase 2 
studies, four participants were receiving oral CAB and one participant developed 
probable DILI following CAB LA or Placebo LA administration.
Creatine Phosphokinase (CPK) elevations
Occurrences of asymptomatic, transient instances of elevations of CPK levels have been 
observed in Phase I studies and an ongoing Phase IIb study studies with GSK744 CAB at 
dose levels of 10, 30 and 60 mg (LAI116482) and with CAB LA (200056). These 
generally appeared to be related to physical activity, were not associated with clinical 
symptoms and returned to pre-treatment levels in all cases.  No subject has required a 
discontinuation of GSK744 CAB as a result of a CPK elevation. Rhabdomyolysis of 
uncertain cause has been included in labeling for a currently available integrase inhibitor 
(raltegravir) but has not been seen in any subject receiving GSK744 CAB to date.
 
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Injection Site Reactions 
The occurrence of ISRs was identified in rats and monkeys at all dose levels of GSK744
CAB LA and associated with both the IM and SC route of administration. In humans, 
experience to date has demonstrated ISRs occur in the majority of exposed subjects but 
are generally mild (Grade 1) or moderate (Grade 2) and include tenderness, erythema, or 
nodule formation of several days duration. Reactions have been well tolerated and have 
not to date been associated with only rarely led to subject withdrawal.
Development of Resistance
Residual concentrations of GSK744 CAB would remain in the systemic circulation of 
subjects who stopped participants for prolonged periods (up to 1 year) despite stopping
treatment (e.g. for tolerability issues or treatment failure) for prolonged periods (months). 
Subjects Participants discontinuing a CAB LA regimen may be at risk for developing 
HIV-1 resistance to GSK744 CAB many weeks after discontinuing injectable therapy.
Mitigation:  Alternative oral HAART regimens will be constructed for subjects stopping 
long acting therapy which prescribed within four weeks after participants stop CAB LA.  
This would be anticipated to result in rapid resuppression of HIV-1 RNA thus 
minimization minimizing of the risk of emergent resistance. The Sponsor will continue to 
monitor subjects participants in this study who discontinue a CAB LA regimen for any 
reason will be monitored for a minimum of 52 weeks from the time of the last CAB LA 
injection.
Inadvertent Intravenous Injection (Accidental Maladministration)
As with any intramuscular injection, it is possible that GSK744 CAB LA can be 
inadvertently administered intravenously instead of intramuscularly resulting in higher 
than expected concentrations of GSK744 CAB LA.  This could be due to administrator 
error, improper injection technique and / or improper needle length used based on body 
type.  The clinical consequences of overdose with CAB are currently unknown. HIV-1 
viral suppression may not be effective following accidental maladministration.
Mitigation:  Training will be provided to all sites on proper injection technique.  Should 
IM maladministration be suspected at any time (e.g. suspected under or overdose or 
inadvertent IV dosing), a PK sample, post dose ECG, vital signs or any other supportive 
testing may be obtained at the discretion of the investigator, and the Medical Monitor 
notified.  Laboratory samples for safety parameters and HIV-1 RNA will be closely 
monitored in all subjects.  Additionally, 2 hour post dose PK samples will be obtained at 
a few early timepoints (Day 1, Week 32 and Week 48) for determination of GSK744
CAB concentration and possible pharmacokinetic correlation with safety parameters such 
as ECG changes and virologic response.  Should IM maladministration be suspected at 
any time (e.g. suspected under or overdose or inadvertent IV dosing), a post dose ECG or 
any other supportive testing may be obtained at the discretion of the investigator, and the 
medical monitor notified.  Additionally, an unscheduled PK sample may be drawn 
approximately 2 hours post dosing for future evaluation of GSK744 CAB and TMC278
RPV concentrations.
 
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Section 1.10.1.2 TMC278
1.11.1.2. RPV and RPV LA
For safety and risk mitigation for TMC278 RPV refer to the RPV rilpivirine prescribing 
information [Edurant Product Information, 20145].
1.10.1.3 TMC278 LA
Since TMC278 LA is at an early stage of clinical development, and exposure in humans 
with or without HIV infection is limited, Information about the clinical safety profile in 
humans experience to date and possible risks associated with treatment using RPV LA 
can be found in the Summary of Data and Guidance for the Investigator section of the IB.  
Beyond what has yet to be fully elucidated already been identified with oral RPV, no new 
systemic adverse reactions to RPV LA (same active moiety) have been observed. The 
following risks have primarily been identified during routine preclinical testing and/or in 
the clinical trial experience to date and are considered to be of potential specific clinical
relevance to clinical usage in the context of this protocol IM use:
Inadvertent Intravenous Injection (Accidental Maladministration)
As with any intramuscular injection, it is possible that TMC278 RPV LA can be 
inadvertently administered intravenously instead of intramuscularly resulting in higher 
than expected concentrations of TMC278 RPV LA.  This could be due to administrator 
error, improper injection technique and / or improper needle length used based on body 
type.  The clinical consequences of overdose with RPV LA are currently unknown.  HIV-
1 viral suppression may not be effective following accidental maladministration.
Mitigation:  Training will be provided to all sites on proper injection technique.  Should 
IM maladministration be suspected at any time (e.g. suspected under or overdose or 
inadvertent IV dosing), a PK sample, post dose ECG monitoring and vital signs or any 
other supportive testing may be obtained at the discretion of the investigator, and the 
Medical Monitor notified.  Laboratory samples for safety parameters and HIV-1 RNA 
will be closely monitored in all subjects.  Additionally, 2 hour post dose PK samples will 
be obtained at a few early timepoints (Day 1, Week 32 and Week 48) for determination 
of TMC278 RPV concentration and possible pharmacokinetic correlation with safety 
parameters such as ECG changes and virologic response.  Should IM maladministration 
be suspected at any time (e.g. suspected under or overdose or inadvertent IV dosing), a 
post dose ECG or any other supportive testing may be obtained at the discretion of the 
investigator, and the medical monitor notified.  Additionally, an unscheduled PK sample 
may be drawn approximately 2 hours post dosing for future evaluation of GSK744 CAB
and TMC278 RPV concentrations.
1.10.1.6. 1.11.1.5 Risk of Treatment Failure
This study employs an induction / maintenance approach to the treatment of HIV-1 
infection.  Following virologic suppression, subjects will be transitioned off of a 3 drug 
ART regimen to a 2 drug ART regimen.  Although both GSK744 CAB and TMC278
RPV have demonstrated antiviral activity in large clinical the Phase 2b studies and the
 
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LAI116482 (oral two drug combination has demonstrated antiviral activity in study 
LAI116482, the risk of virologic failure in study treatment) and 200056 is unknown. 
(through 48 weeks LA treatment ).  Viral loads will be closely monitored throughout the 
study.
Doses of the GSK744 CAB LA and TMC278 RPV LA have been selected to achieve 
exposures that are expected to maintain virologic efficacy on the basis of available data 
with the oral formulations.  Neither GSK744 CAB LA or TMC278 nor RPV LA, at any 
dose, has been used in HIV-1 infected subjects.  Plasma samples will be collected 
throughout the Maintenance Period for determination of GSK744 CAB and TMC278
RPV concentration and possible pharmacokinetic correlation with virologic response.  
Due to administration error, it is possible that a subject could receive an inadequate dose 
of GSK744 CAB LA or TMC278 RPV LA.  Sub-therapeutic concentrations of either 
GSK744 CAB LA or TMC278 RPV LA could lead to virologic failure and possibly the 
development of resistance.  HIV-1 RNA viral loads will be closely monitored throughout 
the injection period of the study.
Mitigation:  HIV-1 RNA will be closely monitored throughout the study.  Plasma 
samples will be collected throughout the Maintenance Phase for determination of CAB 
and RPV concentration and possible pharmacokinetic correlation with virologic response.
Section 1.11.2. Other Clinically Relevant Information
New Section added (underlined):
Additional details concerning safety observations from clinical studies and for which a 
causal association has not been established or which are of minimal clinical significance 
may be found in the Investigator’s Brochure.  Please refer to Section 6: ‘Summary of 
Data and Guidance for the Investigator’
Adverse Events of Special Interest:
Seizure:
Four cases of possible or definitive seizures have occurred in the CAB program 
cumulatively through 7 June 2016.  Two of the cases occurred in HIV uninfected subjects 
with a prior history of seizure. Two cases occurred in HIV infected subjects, one case 
involved a subject in this study, 200056, and another case in the LAI116482 study, both 
cases displayed circumstantial and anecdotal evidence of illicit drug use which may have 
contributed to the event, and each case was determined by the Sponsor to not be 
reasonably likely related to CAB or RPV.  Overall, there is insufficient evidence that 
CAB exposure may be causally associated with seizure or with reduction of seizure 
threshold, due to the low frequency of reports, the confounders present in the cases 
received to date and lack of any pre-clinical signal or identified plausible mechanism.  
However, seizure and seizure-like events will be closely monitored in clinical studies, 
including this study (200056).  Any case of seizure or possible seizure must be reported 
to the Sponsor within 24 hours of notification, as detailed in Section 6.10.14.
 
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Section 1.11.3  Benefit Assessment
Added line to section (underlined):
... Efficacy of the two-drug regimen, as oral agents, has been demonstrated through 
Week 96 of the ongoing LAI116482 study.  Efficacy of the two-drug regimen, as LA 
agents, has been demonstrated through Week 48 of the ongoing 200056 study.
Section 2 Objectives and Endpoints
Added the Exploratory Objectives and Endpoints to table (underlined)
 
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Objective
Endpoint
Primary
To select an intramuscular dosing regimen of 
CAB LA plus RPV LA based on a comparison of 
the Week 32 antiviral activity, tolerability, and 
safety of two IM dosing regimens, relative to 
CAB 30 mg plus ABC/3TC orally once daily.
The proportion of subjects with HIV-1 RNA 
<50 c/mL at Maintenance Week 32 based on 
intent to treat-maintenance exposed (ITT-ME) 
population using the Missing, Switch, or 
Discontinuation = Failure (MSDF) algorithm.
Proportion of subjects with protocol defined 
virologic failures over time
Incidence and severity of AEs and laboratory 
abnormalities over time.
Secondary
To evaluate the antiviral activity, tolerability, and 
safety of CAB 30 mg plus ABC/3TC orally once 
daily through the Induction and Maintenance 
Periods.
Proportion of subjects with plasma HIV-1 RNA 
<200 c/mL and <50 c/mL over time.
Absolute values and change from Baseline in 
plasma HIV-1 RNA.
Absolute values and changes from Baseline in 
CD4+ cell counts.
Incidence of disease progression (HIV-
associated conditions, acquired 
immunodeficiency syndrome [AIDS] and death).
Incidence and severity of AEs and laboratory 
abnormalities over time.
Absolute values and changes in laboratory 
parameters over time.
To evaluate the efficacy, tolerability, and safety 
of CAB LA 400 mg IM plus RPV LA 600 mg IM 
every 4 weeks and CAB LA 600 mg IM plus 
RPV LA 900 mg every 8 weeks, relative to CAB
30 mg plus ABC/3TC orally once daily, through 
Week 96 of the Maintenance Period.
Proportion of subjects with plasma HIV-1 RNA 
<200 c/mL and <50 c/mL over time.
Proportion of subjects with protocol defined 
virologic failures over time.
Absolute values and change from Baseline in 
plasma HIV-1 RNA.
Absolute values and changes from Baseline in 
CD4+ cell counts.
Incidence of disease progression (HIV-
associated conditions, acquired 
immunodeficiency syndrome [AIDS] and death.
Incidence and severity of AEs and laboratory 
abnormalities over time.
 
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Objective
Endpoint
Absolute values and changes in laboratory 
parameters over time.
To characterize CAB LA and RPV LA PK and to 
explore PK-PD relationships.  
Plasma PK parameters for CAB LA and RPV LA
(Ctrough and concentrations post dose [~Cmax]) 
during the Maintenance Period.  
Plasma CAB and RPV trough concentrations
will be used to determine when steady state is 
achieved for each CAB LA and RPV LA
regimen.
Relationship between plasma PK parameters 
and plasma HIV-1 RNA, CD4+ cell counts 
and/or occurrence of adverse events [AEs] 
through Week 48 of the Maintenance Period will 
be explored.
To assess the development of viral resistance in 
subjects experiencing protocol defined virologic 
failure.
Incidence of treatment emergent genotypic and 
phenotypic resistance to CAB, RPV, and other 
on-study ART.
To explore the effect of various demographic 
Baseline characteristics and adherence on 
virologic response of CAB and RPV over time.
Proportion of subjects with plasma HIV-1 RNA 
<50 c/mL over time.
To evaluate the treatment satisfaction for 
subjects on the long-acting injectable regimens
with those on the oral regimen through Week 96 
of the Maintenance Period.
Summarize treatment satisfaction using the HIV 
Treatment Satisfaction Questionnaire Status 
(HIVTSQ(s)) over time. 
To evaluate the change in treatment satisfaction 
for subjects in both the long-acting injectable 
and oral regimens through Week 32 of the 
Maintenance Period.
Measure change in treatment satisfaction using 
the HIV Treatment Satisfaction Questionnaire 
Change (HIVTSQ(c)) over time.
To evaluate medication adherence over time.
Summarize subject reported medication 
adherence using the HIV Medication 
Questionnaire (HIVMQ) over time.
Exploratory
To evaluate the efficacy, tolerability, and safety 
of optimized IM dosing regimens CAB LA 400 
mg IM plus RPV LA 600 mg IM every 4 weeks 
and CAB LA 600 mg IM plus RPV LA 900 mg 
every 8 weeks at Weeks 128 and 152 for 
subjects switching from the oral regimen 
therapy at the end of the Maintenace Period.
To evaluate the long term efficacy, tolerability, 
and safety of IM dosing regimens CAB LA 400 
Proportion of subjects with a ‘virologic failure’ 
endpoint as per FDA Snapshot algorithm at 
Week 128 and 152 (Missing, Switch or 
Discontinuation = Failure, Extension Switch 
population)
Proportion of subjects with Plasma HIV-1 RNA 
<50 copies/mL (c/mL) at Week 128 and 152 
using the FDA Snapshot algorithm (Extension 
Switch population)
 
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Objective
Endpoint
mg IM plus RPV LA 600 mg IM every 4 weeks 
and CAB LA 600 mg IM plus RPV LA 900 mg 
every 8 weeks at Week 152 for subjects who 
continued randomized IM dosing in the 
Extension Period.
Proportion of subjects with protocol defined 
virologic failures over time
Proportion of subjects with plasma HIV-1 RNA 
<200 c/mL and <50 c/mL over time.Absolute 
values and changes in CD4+ cell counts over 
time
Incidence of disease progression (HIV-
associated conditions, acquired 
immunodeficiency syndrome [AIDS] and death).
Incidence and severity of AEs and laboratory 
abnormalities over time.
Absolute values and changes in laboratory 
parameters over time.
Section 3.1 Study Design Schematic
Updated the Extension Period of schematic:
Old: 
 
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New:
Section 3.2.5 Extension Period
Redesign of the Extension Period (Old version, strikethrough; New version, underlined):
Old:
A single IM dosing regimen will be selected as according to the RAP to be evaluated in 
the Extension period.
Section 3.2.5.1 Entering From the GSK744 LA + TMC278 LA Arm
All subjects who successfully complete 96 weeks of GSK744 LA + TMC278 LA 
treatment in the Maintenance Period will continue to have access to both GSK744 LA 
and TMC278 LA in the Extension Period until study treatment is either locally approved 
and commercially available, the subject no longer derives clinical benefit, the subject 
meets a protocol-defined reason for discontinuation or until development of either 
GSK744 LA or TMC278 LA is terminated.  
Subjects will be switched to the selected dose at Week 96 and will continue to receive the 
selected IM dosing regimen for the remainder of study participation.  Safety and efficacy 
assessments will be conducted every 16 weeks after the initial switch.  Dosing visits will 
 
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occur according to the selected dosing regimen.  See the Time and Events Schedule 
Section 6.5 and Section 6.6 for more information.
Section 3.2.5.2 Entering From the GSK744 + ABC/3TC Arm
All subjects who successfully complete 96 weeks of GSK744 + ABC/3TC treatment in 
the Maintenance Period will have the option to either continue study participation by 
switching to GSK744 LA + TMC278 LA in the Extension Period, or to complete their 
study participation at Week 96 (no withdraw visit needed).
Subjects who choose to continue on to the Extension Period will need to be assessed for 
eligibility to begin the selected GSK744 LA + TMC278 LA regimen.  Subjects will 
continue on their Maintenance regimen (GSK744 + ABC/3TC) while eligibility is being 
confirmed.  The Week 100 HIV-1 RNA result will be used to determine eligibility and 
subjects will have a visit at approximately (depending on availability of results) 
Week 102 to assess eligibility.  All subjects with an undetectable HIV-1 RNA 
(<50 c/mL) result from the Week 100 visit are eligible to enter the Extension Period.   
Note:  Subjects with an HIV-1 RNA 50 c/mL result from the Week 100 visit may be 
allowed to enter the Extension Period only at the discretion of the medical monitor or 
withdrawn.
Subjects eligible to enter the Extension Period will add a short course (2 weeks) of 
RPV 25 mg orally once daily to their GSK744 + ABC/3TC regimen at Week 102 before 
initiating dosing with the long acting regimen at Week 104.  This allows subjects to 
achieve steady state of RPV prior to beginning the long acting regimen.
At Week 104, subjects will receive their last dose of GSK744 + ABC/3TC + RPV in the 
clinic and will begin dosing with the selected IM regimen.  These subjects will receive 
loading doses as per the requirement of the selected regimen (see Section 5.1.6 for dosing 
regimens).
Subjects will continue study treatment until GSK744 LA and TMC278 LA are either 
locally approved and commercially available, the subject no longer derives clinical 
benefit, the subject meets a protocol-defined reason for discontinuation or until 
development of either GSK744 LA or TMC278 LA is terminated.  Safety and efficacy 
assessments will be conducted every 16 weeks after the initial switch.  Dosing will occur 
according to the selected regimen. See the Time and Events Schedule Section 6.5 and 
Section 6.6 for more information.
Subjects not eligible to enter the Extension Period will end their study participation 
(Week 102 will be the last study visit, no withdraw visit needed).  Sites may be 
reimbursed for up to a one month supply of antiretroviral medication to facilitate 
transition to non-study ART for subjects that do not qualify for the Extension Period.
New:
Both IM dosing regimens (Q8W and Q4W) will continue evaluation in the Extension 
period.  Subjects who successfully complete 96 weeks of CAB 30 mg + ABC/3TC 
treatment in the Maintenance Period will have the option of continuing study 
 
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participation by switching to an optimized IM dosing regimen of their choice (either 
Q8W or Q4W).
Section 3.2.5.1 Entering From the CAB LA + RPV LA Arm
All subjects who successfully complete 96 weeks of CAB LA + RPV LA treatment in the 
Maintenance Period will continue with their current IM dosing regimen of CAB LA and 
RPV LA in the Extension Period until:

study treatment is locally approved and commercially available, 

the subject no longer derives clinical benefit, 

the subject meets a protocol-defined reason for discontinuation  

the development of either CAB LA or RPV LA is terminated.  
Subjects will remain on their current regimen after Week 96 and will continue to receive 
their Maintenance Period IM dosing regimen for the remainder of study participation.  
Safety and efficacy assessments will be conducted every 16 weeks. Dosing visits will 
occur according to the selected dosing regimen.  See the Time and Events Schedule 
Section 6.5 and Section 6.6 for more information.
Section 3.2.5.2 Eligibility for the Extension Period for Subjects Entering From the CAB 
30 mg + ABC/3TC Arm
All subjects with an undetectable HIV-1 RNA (<50 c/mL) at the Week 96 visit are 
eligible to enter the Extension Period. A single repeat to determine eligibility may be 
allowed ONLY after consultation with the medical monitor.  Subjects with HIV-1 
RNA 400 c/mL at Week 96 are not eligible to enter the Extension Period and will not be 
allowed a repeat to determine eligibility.
Result of HIV-1 RNA at Week 96
Action
<50 c/mL
Begin Extension Period
50 c/mL but <400 c/mL
Single repeat allowed only after consultation 
and approval from medical monitor
Single repeat <50 c/mL
Begin Extension Period
Single repeat 50 c/mL
Cannot begin Extension Period and must be 
withdrawn from study; Complete withdrawal 
visit.  
400 c/mL
Cannot begin Extension Period and must be 
withdrawn from study; Complete withdrawal 
visit.
 
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Should a subject be allowed a repeat, results of this repeat must be available prior to next 
visit, therefore the time needed for scheduling the visit, lab draws and lab analysis should 
be considered.  
In addition to the viral load criteria above, if in the opinion of the Investigator, a subject 
experiences a significant safety event while taking either CAB or RPV, Extension 
eligibility will be determined ONLY in consultation with the medical monitor.  
Subjects ineligible for the Extension Period will be withdrawn.  
If the subject is ineligible for the Extension Period, samples will be sent to a central 
laboratory for resistance testing and results provided to the Investigator once available.
Sites may be reimbursed for up to a one month supply of antiretroviral medication to 
facilitate transition to non-study ART for subjects that do not qualify for the Extension 
Period.
Section 3.2.5.3 Entering From the CAB 30 mg + ABC/3TC Arm
All subjects who successfully complete 96 weeks of CAB 30 mg + ABC/3TC treatment 
in the Maintenance Period will have the option to continue study participation by 
switching to the optimized IM dosing regimen of their choice (either Q8W or Q4W) of 
CAB LA + RPV LA in the Extension Period.  Subjects not choosing to switch to an 
optimized long acting regimen will complete their study participation at Week 96.
Subjects who choose to continue on to the Extension Period will be assessed for 
eligibility to begin their selected CAB LA + RPV LA regimen as described in Section 
3.2.5.2.   Subjects will continue on their oral Maintenance regimen (CAB 30 mg + 
ABC/3TC) until Week 100 while eligibility is being confirmed.  
In order to qualify to receive CAB LA + RPV LA injections at Week 100, the HIV-1 
RNA results from the Week 96 visit must be undetectable (<50 c/mL; a single repeat 
HIV-1 RNA test may be allowed prior to Week 100 following consultation with the 
Medical Monitor). 
If the Optimized Q4W IM Dosing Regimen is Selected by the Subject
At visit Week 100, participants will return to the clinic, take the last dose of their oral 
regimen (CAB 30 mg + ABC/3TC), and receive the first CAB LA (600 mg) + RPV LA 
(900 mg) injections (within 2 hours of the final oral dose of CAB + ABC/3TC).  The 
second and third injections (CAB LA 400 mg + RPV LA 600 mg) will be administered at 
Week 104 and Week 108.  There will be a one week dosing window for the second and 
third IM injections such that the second injections occur within the window of Week 103 
to Week 104, but not later than Week 104, and the third injections occur within the 
window of Week 107 to Week 108, but no later than Week 108.  Subsequent injections 
(CAB LA 400 mg + RPV LA 600 mg) will occur every 4 weeks thereafter, from the 
projected visit date, with a (+ or -) 7 day dosing window being allowed (but not 
preferred).  Following the Week 108 injection, the interval between injection visits 
should be limited to a maximum of 5 weeks.  The Medical Monitor must be contacted if 
 
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the length of time between injections exceeds, or is projected to exceed, 5 weeks from the 
previous injection.
If the Optimized Q8W IM Dosing Regimen is Selected by the Subject
At visit Week 100, subjects will return to the clinic, take the last dose of their oral (CAB 
30 mg + ABC/3TC), and receive the first CAB LA (600 mg) + RPV LA (900 mg) 
injections (within 2 hours of the final oral dose of CAB + ABC/3TC).  The second 
loading injections will be administered at Week 104 (CAB LA 600 mg + RPV LA 
900 mg), with subsequent injections (CAB LA 600 mg + RPV LA 900 mg) occurring 
every 8 weeks thereafter.  The dosing window for the second injection allows 
administration between Week 103 and Week 104, but preferably not later than Week 104.
Starting at the Week 112 injection, the interval between injection visits should be limited 
to a maximum of 9 weeks.  If the length of time between injections exceeds, or is 
projected to exceed 9 weeks, the Medical Monitor must be contacted to discuss individual 
subject case management.  After Week 112, a dosing window (7 days) for injections is 
allowed, but not preferred.
Subjects will continue study treatment until: 

study treatment is locally approved and commercially available, 

the subject no longer derives clinical benefit, 

the subject meets a protocol-defined reason for discontinuation  

the development of either CAB LA or RPV LA is terminated..  
Safety and efficacy assessments will be conducted as per the Time and Events schedule 
(Section 6.5 and Section 6.6 for more information).  Dosing will occur according to the 
selected regimen. 
Subjects not eligible to enter the Extension Period will end their study participation.  
Sites may be reimbursed for up to a one month supply of antiretroviral medication to 
facilitate transition to non-study ART for subjects that do not qualify for the Extension 
Period.
If one of the optimized IM dosing regimens (Q8W or Q4W) is discontinued as a result of 
an IDMC review or any subsequent analysis, those subjects who have not met any 
clinical management criteria for discontinuation and who selected a discontinued 
optimized IM dosing regimen may be given the option to discontinue permanently from 
the study or to continue on the remaining IM dosing regimen at the next scheduled visit.
Section 3.2.8 Independent Data Monitoring Committee
Updated section to reflect new IDMC monitoring for Extension Period
... If one of the IM dosing regimens (Q48W or Q84W) is discontinued as a result of an 
IDMC review or any subsequent analysis, those subjects who have not met any clinical 
management criteria for discontinuation and who were randomized to the discontinued 
dosing regimen , or selected a discontinued optimized IM dosing regimen, may be given 
 
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the option to discontinue permanently from the study or to continue on the remaining IM 
dosing regimen at the next scheduled visit. 
As subjects enter the Maintenance Period of the study, if the number of protocol defined 
virologic failures meets or exceeds the pre-specified thresholds specified in the IDMC 
Charter, this will be considered strong evidence of an inadequate response and will 
trigger a comprehensive data review by the IDMC.  Similar thresholds will be used by the 
IDMC to monitor the number of protocol defined virologic failures for subjects switching 
from oral CAB 30 mg + ABC/3TC to an optimized IM dosing regimen during the 
Extension Period.  The IDMC charter will contain details of this continual monitoring of 
the protocol defined virologic failure rates, the specifics around what will trigger a data 
review, and the safety summaries and efficacy analyses that will be provided should a 
data review be required.
Full details of the analyses, estimated timing and the decision criteria that will be used to 
determine regimen performance will be pre-specified in the IDMC Charter.
Section 3.3 Discussion of Design
Added the following wording (underlined):
The Extension Period will allow participants on the oral Maintenance Period regimen 
who successfully complete Week 96 with an HIV-1 RNA viral load <50 c/mL the 
opportunity to choose an optimized IM dosing regimen (Q8W or Q4W).  This will permit 
an evaluation of the ability of the optimized investigational two-drug long acting 
combinations (see Section 5.1.6) to maintain virologic suppression over time.  This 
period will also allow participants currently on a IM Maintenance Period regimen who 
successfully complete Week 96 with an HIV-1 RNA viral load <50 c/mL the ability to 
continue to receive their current IM dosing regimen and to generate additional long-term 
safety and efficacy data for randomized IM dosing regimens.
A planned Week 128 analysis will primarly evaluate the efficacy, tolerability, and safety 
of the optimized IM dosing regimens through 28 weeks of optimized IM treatment in 
subjects switching from oral Maintenance therapy. Long term durability of virologic 
suppression of the randomized long-acting two-drug regimens through Week 128 may 
also be evaluated.
A Week 152 analysis will permit an evaluation of the ability of the randomized and 
optimized investigational two-drug long-acting combinations to showcase long-term 
durability of virologic suppression.  Additional long-term safety and efficacy data for all 
IM dosing regimens will be generated.
Section 4.5 Withdrawal Criteria
Removed the following Withdrawal Criteria (strikethrough):

Change from Baseline: Increase in QTc > 60 msec
 
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Section 5.1.6 Dosage and Administration
Updated Extension Period Dosing 
Old:
Induction Period (Week -20 through Day 1)
Week -20 to Week (-4)
(2 tablets once daily)
Take 1 X ABC 600 mg / 3TC 300 mg tablet once daily 
Take 1 X GSK744 30 mg tablet once daily
Week (-4) to Day 1
(3 tablets once daily)
Take 1 X ABC 600 mg / 3TC 300 mg tablet once daily 
Take 1 X GSK744 30 mg tablet once daily
Take 1 X RPV 25 mg tablet once daily

Take with a meal

Take Day 1 doses in the clinic
Maintenance Period (Day 1 to Week 96*)
GSK744 LA 600 mg + TMC278 LA 900 mg IM every 8 Weeks (Q8W)
Day 1 – loading dose
(3 injections once)
Receive last dose of Induction regimen
Receive GSK744 LA 800 mg given as 2 X 2 mL IM injections 
Receive TMC278 LA 900 mg given as 1 X 3 mL IM injection 
Week 4 – 2nd loading dose
(1 injection once)
Receive GSK744 LA 600 mg given as 1 X 3 mL IM injections 
(No TMC278 LA)
Week 8 to Week 88
(2 injections every 8 weeks)
Receive GSK744 LA 600 mg given as 1 X 3 mL IM injection 
Receive TMC278 LA 900 mg given as 1 X 3 mL IM injection
GSK744 LA 400 mg + TMC278 LA 600 mg IM every 4 Weeks (Q4W)
Day 1 – loading dose
(3 injections once)
Receive last dose of Induction regimen
Receive GSK744 LA 800 mg given as 2 X 2 mL IM injections 
Receive TMC278 LA 600 mg given as 1 X 2 mL IM injection 
Week 4 to Week 92
(2 injections every 4 weeks)
Receive GSK744 LA 400 mg given as 1 X 2 mL IM injection
Receive TMC278 LA 600 mg given as 1 X 2 mL IM injection
 
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GSK744 30 mg + ABC/3TC once daily
Day 1
Receive last dose of Induction regimen
Day 2 to Week 96
(2 tablets once daily)
Take 1 X ABC 600 mg / 3TC 300 mg tablet once daily 
Take 1 X GSK744 30 mg tablet once daily
If continuing to Extension Period:
Week 96 to Week 102
(2 tablets once daily)
Take 1 X ABC 600 mg / 3TC 300 mg tablet once daily 
Take 1 X GSK744 30 mg tablet once daily
If eligible to enter Extension Period:
Week 102 to Week 104
(3 tablets once daily)
Take 1 X ABC 600 mg / 3TC 300 mg tablet once daily 
Take 1 X GSK744 30 mg tablet once daily
Take 1 X RPV 25 mg tablet once daily

Take with a meal
Extension Period (Week 96 plus+) 
If GSK744 LA 600 mg + TMC278 LA 900 mg IM every 8 Weeks is selected:
Week 96 plus+
(2 injections every 8 weeks)
Receive GSK744 LA 600 mg given as 1 X 3 mL IM injection 
Receive TMC278 LA 900 mg given as 1 X 3 mL IM injection
If switching from Oral Arm:
Week 104 – loading dose
(3 injections once)
Receive last dose of Maintenance regimen
Receive GSK744 LA 800 mg given as 2 X 2 mL IM injections 
Receive TMC278 LA 900 mg given as 1 X 3 mL IM injection
Extension Period (Week 96 plus+)
If GSK744 LA 600 mg + TMC278 LA 900 mg IM every 8 Weeks is selected:
Week 108 – 2nd loading dose
(1 injection once)
Receive GSK744 LA 600 mg given as 1 X 3 mL IM injections 
(No TMC278 LA)
Week 112 plus+
Receive GSK744 LA 600 mg given as 1 X 3 mL IM injection 
 
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(2 injections every 8 weeks)
Receive TMC278 LA 900 mg given as 1 X 3 mL IM injection
If GSK744 LA 400 mg + TMC278 LA 600 mg IM every 4 Weeks is selected:
Week 96 plus+
(2 injections every 4 weeks)
Receive GSK744 LA 400 mg given as 1 X 2 mL IM injection 
Receive TMC278 LA 600 mg given as 1 X 2 mL IM injection
If switching from Oral Arm:
Week 104 – loading dose
(3 injections once)
Receive last dose of Maintenance regimen
Receive GSK744 LA 800 mg given as 2 X 2 mL IM injections 
Receive TMC278 LA 600 mg given as 1 X 2 mL IM injection 
Week 108 plus+
(2 injections every 4 weeks)
Receive GSK744 LA 400 mg given as 1 X 2 mL IM injection 
Receive TMC278 LA 600 mg given as 1 X 2 mL IM injection
*Or through Week 104 if eligible to enter the Extension Period.
+until locally approved and commercially available, the subject no longer derives clinical benefit, the subject meets a 
protocol-defined reason for discontinuation or until development of GSK744 or TMC278 is terminated
New (Modifications Underlined):
Induction Period (Week -20 through Day 1)
Week -20 to Week (-4)
(2 tablets once daily)
Take 1 X ABC 600 mg / 3TC 300 mg tablet once daily 
Take 1 X CAB 30 mg tablet once daily
Week (-4) to Day 1
(3 tablets once daily)
Take 1 X ABC 600 mg / 3TC 300 mg tablet once daily 
Take 1 X CAB 30 mg tablet once daily
Take 1 X RPV 25 mg tablet once daily

Take with a meal

Take Day 1 doses in the clinic
Maintenance Period (Day 1 to Week 96*)
CAB LA 600 mg + RPV LA 900 mg IM every 8 Weeks (Q8W)
Day 1 – loading dose
(3 injections once)
Receive last dose of Induction regimen
Receive CAB LA 800 mg given as 2 X 2 mL IM injections 
 
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Receive RPV LA 900 mg given as 1 X 3 mL IM injection 
Week 4 – 2nd loading dose
(1 injection once)
Receive CAB LA 600 mg given as 1 X 3 mL IM injections 
(No RPV LA)
Week 8 to Week 88
(2 injections every 8 weeks)
Receive CAB LA 600 mg given as 1 X 3 mL IM injection 
Receive RPV LA 900 mg given as 1 X 3 mL IM injection
CAB LA 400 mg + RPV LA 600 mg IM every 4 Weeks (Q4W)
Day 1 – loading dose
(3 injections once)
Receive last dose of Induction regimen
Receive CAB LA 800 mg given as 2 X 2 mL IM injections 
Receive RPV LA 600 mg given as 1 X 2 mL IM injection 
Week 4 to Week 92
(2 injections every 4 weeks)
Receive CAB LA 400 mg given as 1 X 2 mL IM injection
Receive RPV LA 600 mg given as 1 X 2 mL IM injection
CAB 30 mg + ABC/3TC once daily
Day 1
Receive last dose of Induction regimen
Day 2 to Week 96
(2 tablets once daily)
Take 1 X ABC 600 mg / 3TC 300 mg tablet once daily 
Take 1 X CAB 30 mg tablet once daily
If continuing to Extension Period:
Week 96 to Week 100
(2 tablets once daily)
Take 1 X ABC 600 mg / 3TC 300 mg tablet once daily 
Take 1 X CAB 30 mg tablet once daily
Extension Period (Week 96 +) 
If subject was randomized to the Q8W regimen during the Maintenance Period:
Week 96 plus+
(2 injections every 8 weeks)
Receive CAB LA 600 mg given as 1 X 3 mL IM injection 
Receive RPV LA 900 mg given as 1 X 3 mL IM injection
If switching from Oral Arm and the Optimized Q8W regimen is selected by subject:
Week 100 – 1st loading dose
(2 injections once)
Receive last dose of Maintenance regimen
Receive CAB LA 600 mg given as 1 X 3 mL IM injections 
Receive RPV LA 900 mg given as 1 X 3 mL IM injection
Week 104  – 2nd loading dose
Receive CAB LA 600 mg given as 1 X 3 mL IM injections 
 
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(2 injection once)
Receive RPV LA 900 mg given as 1 X 3 mL IM injection
Week 112 plus+
(2 injections every 8 weeks)
Receive CAB LA 600 mg given as 1 X 3 mL IM injection 
Receive RPV LA 900 mg given as 1 X 3 mL IM injection
If Subject was Randomized to the Q4W regimen during the Maintenance Period: 
Week 96 plus+
(2 injections every 4 weeks)
Receive CAB LA 400 mg given as 1 X 2 mL IM injection 
Receive RPV LA 600 mg given as 1 X 2 mL IM injection
If switching from Oral Arm and the Optimized Q4W regimen is selected by subject:
Week 100 – 1st loading dose
(2 injections once)
Receive last dose of Maintenance regimen
Receive CAB LA 600 mg given as 1 X 3 mL IM injections 
Receive RPV LA 900 mg given as 1 X 3 mL IM injection 
Week 104 – 2nd loading dose
(2 injections once)
Receive CAB LA 400 mg given as 1 X 2 mL IM injection 
Receive RPV LA 600 mg given as 1 X 2 mL IM injection
Week 108 plus+
(2 injections every 4 weeks)
Receive CAB LA 400 mg given as 1 X 2 mL IM injection 
Receive RPV LA 600 mg given as 1 X 2 mL IM injection
*Or through Week 100 if eligible to enter the Extension Period.
+until locally approved and commercially available, the subject no longer derives clinical benefit, the subject meets a 
protocol-defined reason for discontinuation or until development of CAB or RPV is terminated
Section 5.9.2 Prohibited Medications and Non-Drug Therapies
Modified the following line (removed items, strikethrough; added items underlined):
Hepatitis C infection treatment will not be permitted therapy is allowed during the study, 
but interferon-based HCV therapy is prohibited throughout the entire study.  Options for 
treatment of hepatitis C must be discussed with the Medical Monitor prior to initiation of 
therapy.
Section 6.2 Time and Events Table – Maintenance Period for IM Regimen (CAB LA 
+ RPV LA Q8W)
Removed footnote ‘o’ and modified footnote ‘n’
n) Subjects will continue to receive the selected Extension their Maintenance Period
dosing regimen in the Extension Period (either Q8W or Q4W) at this visit.  If 
 
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switching to Q4W, injections are 1 x GSK744 LA 400 mg IM + 1 x TMC278 LA 600 
mg IM.  Subjects may immediately begin the new regimen at Week 96.
o) Remind subjects of the potential change in study treatment and visit frequency 
beginning at Week 96
Section 6.3 Time and Events Table – Maintenance Period for IM Regimen (CAB LA 
+ RPV LA Q4W)
Removed footnote ‘o’ and modified footnote ‘n’
n) Subjects will continue to receive the selected Extension their Maintenance Period
dosing regimen in the Extension Period (either Q4W or Q4W) at this visit.  If 
switching to Q4W, no loading dose is necessary injections are 1 x GSK744 LA 600 
mg IM + 1 x TMC278 LA 900 mg IM.  
o) Remind subjects of the potential change in study treatment and visit frequency 
beginning at Week 96
 
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Section 6.4 Time and Events Table – Maintenance Period for Oral Regimen (CAB 30 mg + ABC/3TC)
Modified T&E table and footnotes. Removed Weeks 100, 102 and 104 from table:
Old:
Procedures For 
Maintenance –
ORAL regimen
D1
W
4
W
8
W
12
W
16
W
20
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
52
W
56
W
60
W
64
W
68
W
72
W
76
W
80
W
84
W
88
W
92
W
96
W 
100m
W
102m
W
104m
WD q
Verify 
Eligibility 
X
X l
X l, 
n
Randomization
X
Symptom 
Directed PE & 
Medical 
Assessment a
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X and 
smoking 
status
Vital Signs
(BP, HR) b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight and BMI X
X
X
X
X
X
ECG d
X
pre
X
X
X
X
X
X
X
X
X
pre
X
HIV 
Associated 
Conditions, AE 
and SAE 
Assessment, 
Con  Meds 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK Diary 
(D)ispensation 
and (R)eview e
R
D
R
D
R
eC-SSRS f
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
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Procedures For 
Maintenance –
ORAL regimen
D1
W
4
W
8
W
12
W
16
W
20
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
52
W
56
W
60
W
64
W
68
W
72
W
76
W
80
W
84
W
88
W
92
W
96
W 
100m
W
102m
W
104m
WD q
HIVTSQ(s) g
X
pre
X
X
X
X
X
HIVTSQ(c) g
X
X
HIVMQ g
X
X
X
X
X g
Clinical 
Chemistry and 
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test 
(S)erum/(U)rine h
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
U
S
HIV-1 RNA &
sample for 
storage i
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X n
X
X
X
CD4+
X
X
X
X
X
X
X
X
X
X
X
X
X
CD8+
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
Fasting:  
Glucose,
Insulin, 
Cholesterol 
(Total, HDL 
and LDL) and 
Triglycerides j
X
X
X
X
X
X
X
X
PT/PTT/INR
X
X
X
X
X
X
PK Sample k
X 
X
X
S
S
X
Study 
Treatment 
Dispensation 
and 
Accountability o
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xm
X
X
Add
RPV
X
Add 
injection
Visit Reminder 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xp
Xm,p
X p
X p
X p
X
 
 
 
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Procedures For 
Maintenance –
ORAL regimen
D1
W
4
W
8
W
12
W
16
W
20
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
52
W
56
W
60
W
64
W
68
W
72
W
76
W
80
W
84
W
88
W
92
W
96
W 
100m
W
102m
W
104m
WD q
Contact
Subject 
Contact 
Confirmation
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xm
X
X
X
X
D=Day    W=Week    Pre=Pre-dosing  PE = Physical Exam   BMI=Body Mass Index
Gray shading indicates telephone safety assessments that will include interviewing the 
subject for adverse events, concomitant medications, HIV associated conditions and any 
other issues including compliance. 
a.
Physical exams should be conducted as part of normal routine clinical care but data 
will not be collected in the eCRF. Medical assessments include any decisions the 
study staff must make for subject management and/or care of the subject.
b.
Measure vital signs after about 5 minutes of rest in a semi-supine position.
c.
BMI collected at Week 104 only.
d.
12-Lead ECG – Conduct pre-dose at Day 1 and Week 104.  At all other visits, it is 
preferable to conduct 2 – 4 hours after dosing.
e.
Review PK diary at the beginning of the visit to verify time of last dose.  PK samples 
must be collected within the window of 20-28 hours after the last dose taken.  
Contact the study team for guidance in cases when subject’s last dose is not within 
window.  Visit may need to be rescheduled.
f.
Preferably completed at the beginning of the visit.  
g.
Conduct the HIVTSQ(s) at Day 1 prior to dosing and post dosing where possible at 
all other visits.  Conduct the HIVTSQ(c, WD) at WD ONLY if the subject WD between 
Week 8 and Week 32.  Conduct the HIVMQ preferably at the beginning of the visit, 
but may be completed at any time during the visit.
h.
Women of childbearing potential only. A (-) urine pregnancy test is required prior to 
any injection and as required by medical monitor after a treatment interruption. A 
positive urine test should be confirmed with a stat serum test.  If positive, subject will 
need to be WD.
i.
Plasma for storage samples are collected for possible future analyses, as back- up in 
case of lost or damaged in transit to the lab and for geno/pheno analyses for virologic 
failures
j.
Fast overnight; however, a minimum of a 6 hour fast is acceptable.
k.
All PK samples should be taken pre-dose within 20-28 hours after the last dose of IP 
taken.  Subjects will take their dose of IP in the clinic at PK visits. S=Storage
l.
Assess subject’s willingness to continue on to the Extension Period.  If not continuing 
into the Extension Period, this is the subject’s last study visit.
m.
For subjects continuing into the Extension Period only.  
n.
The Week 100 HIV-1 RNA result must be <50 c/mL to be eligible to continue into the 
Extension Period.  See Section 3.2.5.3.    Subjects ineligible for Extension will end 
their study participation at Week 102 (no withdrawal visit needed).
o.
Subjects will discontinue RPV at Day 1 and begin taking 1 x GSK744 + 1 x ABC/3TC 
tablet once daily. At Week 96 and Week 100, while awaiting eligibility for Extension, 
subjects will continue their GSK744+ABC/3TC regimen.  At Week 102, subjects 
eligible to enter the Extension Period will add once daily RPV to their 
GSK744+ABC/3TC regimen and continue to take GSK744+ABC/3TC +RPV once 
daily through Week 104.  At Week 104, subjects will take final dose of 
GSK744+ABC/3TC+RPV in the clinic and begin the selected IM regimen (Q8W or 
Q4W).  See Section 5.1.6 for IM dosing administration as loading doses are required.  
p.
Remind subjects of the change in study and assessments for eligibility into 
Extension.
q.
Follow Up Visit:  Conduct approximately 4 weeks after the last dose of IP.  Required 
only if the subject has ongoing AEs or lab abnormalities at the last on-study visit.  
This visit may be conducted by telephone.
 
 
 
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New:
Procedures For 
Maintenance –
ORAL regimen
D1
W
4
W
8
W
12
W
16
W
20
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
52
W
56
W
60
W
64
W
68
W
72
W
76
W
80
W
84
W
88
W
92
W
96
WD p
Verify Eligibility 
X
X k
Randomization
X
Symptom 
Directed PE & 
Medical 
Assessment a
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X and smoking 
status
Vital Signs
(BP, HR) b
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight and BMI c
X
X
X
X
X
ECG c
X
pre
X
X
X
X
X
X
X
X
X
HIV Associated 
Conditions, AE 
and SAE 
Assessment, Con  
Meds 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK Diary 
(D)ispensation 
and (R)eview d
R
D
R
D
R
D
eC-SSRS e
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
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Procedures For 
Maintenance –
ORAL regimen
D1
W
4
W
8
W
12
W
16
W
20
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
52
W
56
W
60
W
64
W
68
W
72
W
76
W
80
W
84
W
88
W
92
W
96
WD p
HIVTSQ(s) f
X
pre
X
X
X
X
X
HIVTSQ(c) f
X
X
HIVMQ f
X
X
X
X
X f
Clinical Chemistry 
and Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test 
(S)erum/(U)rine g
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
HIV-1 RNA &
sample for 
storage h
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X m
X
CD4+
X
X
X
X
X
X
X
X
X
X
X
CD8+
X
X
X
X
Urinalysis
X
X
X
X
X
X
Fasting:  Glucose, 
Insulin, 
Cholesterol 
(Total, HDL and 
LDL) and 
Triglycerides i
X
X
X
X
X
X
X
PT/PTT/INR
X
X
X
X
X
PK Sample j
X 
X
X
S
X
Study Treatment 
Dispensation and 
Accountability n
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X q
Study Treatment
 
 
 
2018N380094_00

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401
Procedures For 
Maintenance –
ORAL regimen
D1
W
4
W
8
W
12
W
16
W
20
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
52
W
56
W
60
W
64
W
68
W
72
W
76
W
80
W
84
W
88
W
92
W
96
WD p
Administration 
Visit Reminder 
Contact
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xo
Xl,o
X
Subject Contact 
Confirmation
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xl
X
D=Day     W=Week    Pre=Pre-dosing  PE = Physical Exam   BMI=Body Mass Index
Gray shading indicates telephone safety assessments that will include interviewing the subject for 
adverse events, concomitant medications, HIV associated conditions and any other issues 
including compliance. 
a.
Physical exams should be conducted as part of normal routine clinical care but data will not 
be collected in the eCRF. Medical assessments include any decisions the study staff must 
make for subject management and/or care of the subject.
b.
Measure vital signs after about 5 minutes of rest in a semi-supine position.
c.
12-Lead ECG – Conduct pre-dose at Day 1.  At all other visits, it is preferable to conduct 2 – 4 
hours after dosing.
d.
Review PK diary at the beginning of the visit to verify time of last dose.  PK samples must be 
collected within the window of 20-28 hours after the last dose taken.  Contact the study team 
for guidance in cases when subject’s last dose is not within window.  Visit may need to be 
rescheduled.
e.
Preferably completed at the beginning of the visit.  
f.
Conduct the HIVTSQ(s) at Day 1 prior to dosing and post dosing where possible at all other 
visits.  Conduct the HIVTSQ(c, WD) at WD ONLY if the subject WD between Week 8 and 
Week 32.  Conduct the HIVMQ preferably at the beginning of the visit, but may be completed 
at any time during the visit.
g.
Women of childbearing potential only. A (-) urine pregnancy test is required prior to any 
injection and as required by medical monitor after a treatment interruption. A positive urine 
test should be confirmed with a stat serum test.  If positive, subject will need to be WD.
h.
Plasma for storage samples are collected for possible future analyses, as 
back- up in case of lost or damaged in transit to the lab and for geno/pheno 
analyses for virologic failures
i.
Fast overnight; however, a minimum of a 6 hour fast is acceptable.
j.
All PK samples should be taken pre-dose within 20-28 hours after the last 
dose of IP taken.  Subjects will take their dose of IP in the clinic at PK visits. 
S=Storage
k.
Assess subject’s willingness to continue on to the Extension Period.  If not 
continuing into the Extension Period, this is the subject’s last study visit.
l.
For subjects continuing into the Extension Period only.  
m.
The Week 96 HIV-1 RNA result (or single re-test prior to Week 100) must be 
<50 c/mL to be eligible to continue into the Extension Period.  See Section 
3.2.5.2.  Subjects ineligible for Extension will end their study participation at 
Week 96 (withdrawal visit needed).
n.
Subjects will discontinue RPV at Day 1 and begin taking 1 x CAB 30 mg + 1 
x ABC/3TC tablet once daily. At Week 96, while awaiting eligibility for 
Extension, subjects will continue their CAB 30 mg+ABC/3TC regimen.  
o.
Remind subjects of the change in study and assessments for eligibility into 
Extension.
p.
Follow Up Visit:  Conduct approximately 4 weeks after the last dose of IP.  
Required only if the subject has ongoing AEs or lab abnormalities at the last 
on-study visit.  This visit may be conducted by telephone.
q.
Assess Treatment Accountability only
 
 
 
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Section 6.5 Time and Events Table – Extension Period for IM Regimen (CAB LA+ RPV LA-Q8W
Old:
Procedures for 
Extension if 
Q8W is Selected
W 
104 a
W 
108b
From Oral 
Arm Only
W 
112
W 
120
W 
128
W
136
W 
144
W
152
W
160
W
168
W
176
W 
184
W 
192 c
W 
200 c
WD 
n, o
Notes
Symptom 
Directed 
Physical Exam, 
ISR and 
Medical 
Assessment d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
See footnote “b” for continuation of visit schedule 
after Week 200.  Continue until either locally 
approved and commercially available, the subject 
no longer derives clinical benefit or meets a 
protocol-defined reason for discontinuation or 
until development is terminated.
a.
Subjects switching from the oral regimen will 
complete Week 104 visit as per the Maintenance 
T&E Section 6.4.
b.
Week 108 visit is only for subjects switching from 
the oral arm.
c.
Continue this pattern for visits for the remainder 
of the study.  For example, Week 208 will be 
conducted just like Week 192, Week 216 will be 
conducted just like Week 200 and Week 224 will 
be conducted just like Week 192.
d.
Physical exams should be conducted as part of 
normal routine clinical care but data will not be 
collected in the eCRF. Medical assessments 
include any decisions the study staff must make 
for subject management.
e.
Measure vital signs after about 5 minutes of rest 
in a semi-supine position.
f.
Can be done at any time during the visit.
g.
A (-) urine pregnancy test is required prior to any 
injection and as required by medical monitor 
after a treatment interruption. A (+) urine test 
Vital Signs
(BP, HR) e
X
X
X
X
X
X
X
X
Weight & BMI
X
X
X
X
X
X
X
X
HIV Associated 
Conditions, AE 
and SAE 
Assessments, 
Con Meds
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG f
X
X
X
X
X
X
X
X
X
Clinical 
Chemistry and 
Hematology
X
X
X
X
X
X
X
X
X
Pregnancy 
Testing
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
 
 
 
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Procedures for 
Extension if 
Q8W is Selected
W 
104 a
W 
108b
From Oral 
Arm Only
W 
112
W 
120
W 
128
W
136
W 
144
W
152
W
160
W
168
W
176
W 
184
W 
192 c
W 
200 c
WD 
n, o
Notes
(U)rine g
should be confirmed with a stat serum test.  If 
(+), subject will need to be WD.
h.
Plasma for storage samples are collected for 
possible future analyses, back-up in cases of 
loss/damage in transit and geno/pheno analyses 
for virologic failures.
i.
Fast overnight; minimum of a 6 hour fast is 
acceptable.
j.
Samples should be collected pre-dose.
k.
Subjects will complete a diary only if the subject 
experiences a reaction ((E)pisodic).  Subjects 
will be dispensed a new diary at each visit. Diary 
data will be entered into the eCRF.
l.
Q8W Injections are 1 x GSK744 LA 600 mg IM 
+ 1 x TMC278 LA 900 mg IM.  If possible, 
injections should be spaced approximately 2 cm 
from one another and from the site of any 
previous injection and or any injection site 
reaction.  Bring TMC278 LA to approximately 
room temperature prior to injecting.   Time and 
location of injection (right or left) as well as 
needle length used will be collected in the eCRF.  
IM dosing is expected to occur during the 
week in which the subject’s projected visit 
falls (as according to the Day 1 visit).  An 
additional (+ or -) 7 day window from date of 
projected visit is allowable for IM dosing but 
not preferred.  All decisions regarding dose 
interruption/ resumption must be discussed 
with the medical monitor in advance.
m.
Subjects switching from the oral arm will 
receive their 2nd loading dose injection of 
1 x GSK744 LA 600 mg (no TMC278 LA).
HIV-1 RNA and 
sample for 
storage h
X
X
X
X
X
X
X
X
CD4+
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
Fasting:  
Glucose, 
Cholesterol 
(Total, HDL and 
LDL) and 
Triglycerides i
X
X
X
X
X
X
X
X
PT/PTT/INR
X
PK Sample 
(S)torage j
S
S
S
S
S
S
S
X
ISR Diary 
Dispensation k
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E 
review
Study Treatment 
Administration l
X a
X m
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
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2013N168152_09
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Procedures for 
Extension if 
Q8W is Selected
W 
104 a
W 
108b
From Oral 
Arm Only
W 
112
W 
120
W 
128
W
136
W 
144
W
152
W
160
W
168
W
176
W 
184
W 
192 c
W 
200 c
WD 
n, o
Notes
Subject Visit 
Reminder 
Contact
X
X
X
X
X
X
X
X
X
X
X
X
X
X
n.
Or Long-Term Follow Up
o.
Follow Up Visit - Conduct ~4 weeks after the last 
dose of IP if not entering Long-Term Follow Up 
and only if the subject has ongoing AEs or lab 
abnormalities at the last on-study visit.  May be 
conducted by telephone.
Subject Contact 
Detail 
Confirmation
X
X
X
X
X
X
X
X
X
X
X
X
X
X
New:
Added Visits W101 and W121 for subjects switching from oral to the Q8W IM regimen.  
Added labs and procedures for subjects switching from oral to the Q8W IM regimen, denoted with footnote ‘n’.
Removed the following footnotes:
p. Subjects switching from the oral regimen will complete Week 104 visit as per the Maintenance T&E Section 6.4.
q. Week 108 visit is only for subjects switching from the oral arm.
r.
Samples should be collected pre-dose.
m. Subjects switching from the oral arm will receive their 2nd loading dose injection of 
1 x GSK744 LA 600 mg (no TMC278 LA).
Added the following footnotes:
h. Take PK samples pre-dose except Week 101 and Week 121 which can be taken at any time during the visit.  A second Week 100 and 
128 PK sample will be collected approximately 2 hours after the last injection
 
 
 
2018N380094_00

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k. At Week 100, oral Maintenance subjects eligible for extension dosing will take final dose of CAB 30 mg+ABC/3TC in the clinic 
within 2 hours of  the optimized Q8W IM regimen.  See Section 5.1.6 for IM dosing administration as loading doses are required. 
(W100=1st loading dose; W104=2nd loading dose
n. Procedures and visits for subjects who switch from oral to the optimized Q8W IM dosing regimen.
o. First Extension Period visit for subjects continuing Q8W dosing from the Maintenance Period.
Procedures for 
Extension -
Q8W 
W 
100 
n
W 
101 n
W 
104 o
W 
112
W 
120
W 
121 
n
W 
128
W
136
W 
144
W
152
W
160
W
168
W
176
W 
184
W 
192 a
W 
200 
a
WD 
l, m
Notes
Symptom 
Directed 
Physical Exam, 
ISR and 
Medical 
Assessment b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
See footnote “a” for continuation of visit 
schedule after Week 200.  Continue until 
either locally approved and commercially 
available, the subject no longer derives 
clinical benefit or meets a protocol-defined 
reason for discontinuation or until 
development is terminated.
a.
Continue this pattern for visits for the 
remainder of the study.  For example, Week 
208 will be conducted just like Week 192, 
Week 216 will be conducted just like Week 
200 and Week 224 will be conducted just 
like Week 192.
b.
Physical exams should be conducted as 
part of normal routine clinical care but data 
will not be collected in the eCRF. Medical 
assessments include any decisions the 
study staff must make for subject 
management.
c.
Measure vital signs after about 5 minutes of 
rest in a semi-supine position.
d.
Can be done at any time during the visit.
e.
A (-) urine pregnancy test is required prior 
to any injection and as required by medical 
Vital Signs
(BP, HR) c
X
X
X
X
X
X
X
X
X
Weight & BMI
X
X 
X
X
X
X
X
X
X
HIV Associated 
Conditions, AE 
and SAE 
Assessments, 
Con Meds
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG d
X
X
X
X
X
X
X
X
X
Clinical 
Chemistry and 
Hematology
X
X
X
X
X n
X
X
X
X
X
X
X
 
 
 
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Procedures for 
Extension -
Q8W 
W 
100 
n
W 
101 n
W 
104 o
W 
112
W 
120
W 
121 
n
W 
128
W
136
W 
144
W
152
W
160
W
168
W
176
W 
184
W 
192 a
W 
200 
a
WD 
l, m
Notes
Pregnancy 
Testing
(U)rine e
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
monitor after a treatment interruption. A (+) 
urine test should be confirmed with a stat 
serum test.  If (+), subject will need to be 
WD.
f.
Plasma for storage samples are collected 
for possible future analyses, back-up in 
cases of loss/damage in transit and 
geno/pheno analyses for virologic failures.
g.
Fast overnight; however, a minimum of a 6 
hour fast is acceptable.
h.
Take PK samples pre-dose except Week 
101 and Week 121 which can be taken at 
any time during the visit.  A second Week 
100 and 128 PK sample will be collected 
approximately 2 hours after the last 
injection.
i.
Subjects will complete a diary only if the 
subject experiences a reaction ((E)pisodic).  
Subjects will be dispensed a new diary at 
each visit. Diary data will be entered into the 
eCRF.
j.
Q8W Injections are 1 x CAB LA 600 mg 
IM + 1 x RPV LA 900 mg IM.  If possible, 
injections should be spaced approximately 
2 cm from one another and from the site of 
any previous injection and or any injection 
site reaction.  Bring RPV LA to 
approximately room temperature prior to 
injecting.   Time and location of injection 
(right or left) as well as needle length used 
will be collected in the eCRF.  IM dosing is 
expected to occur during the week in 
which the subject’s projected visit falls 
HIV-1 RNA and 
sample for 
storage f
X
X
X
X n
X
X
X
X
X
X
CD4+
X
X
X
X n
X
X
X
X
X
X
Urinalysis
X
X
X
X n
X
X
X
X
X
X
Fasting 
Glucose, 
Cholesterol 
(Total, HDL 
and LDL) and 
Triglycerides g
X
X
X
X n
X
X
X
X
X
X
PT/PTT/INR
X
PK Diary 
(D)ispensation 
and (R)eview
R n
PK Sample 
(S)torage h
S
S
S
S
S n
S
S
S
S
S
S
X
ISR Diary 
Dispensation i
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E 
review
 
 
 
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Procedures for 
Extension -
Q8W 
W 
100 
n
W 
101 n
W 
104 o
W 
112
W 
120
W 
121 
n
W 
128
W
136
W 
144
W
152
W
160
W
168
W
176
W 
184
W 
192 a
W 
200 
a
WD 
l, m
Notes
Study 
Treatment 
Administration j
X k
X k
X
X
X
X
X
X
X
X
X
X
X
X
(as according to the Day 1 visit).  An 
additional (+ or -) 7 day window from 
date of projected visit is allowable for IM 
dosing but not preferred.  All decisions 
regarding dose interruption/ resumption 
must be discussed with the medical 
monitor in advance.
k.
At Week 100, oral Maintenance subjects 
eligible for extension dosing will take final 
dose of CAB 30 mg+ABC/3TC in the clinic 
within 2 hours of  the optimized Q8W IM 
regimen.  See Section 5.1.6 for IM dosing 
administration as loading doses are 
required. (W100=1st loading dose; 
W104=2nd loading dose)
l.
Or Long-Term Follow Up
m.
Follow Up Visit - Conduct ~4 weeks after 
the last dose of IP if not entering Long-Term 
Follow Up and only if the subject has 
ongoing AEs or lab abnormalities at the last 
on-study visit.  May be conducted by 
telephone.
n.
Procedures and visits for subjects who 
switch from oral to the optimized Q8W IM 
dosing regimen.
o.
First Extension Period visit for subjects 
continuing Q8W dosing from the 
Maintenance Period.
Subject Visit 
Reminder 
Contact
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Subject 
Contact Detail 
Confirmation
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
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Section 6.6 Time and Events Table – Extension Period for IM Regimen (CAB LA + RPV LA – Q4W)
Old:
Procedures for 
Extension if Q4W is 
Selected
W 
100
a
W 
104
a
W 
108
W 
112
W
116
W 
120
W
124
W 
128
b
W 
132
b
W 
136
b
W 
140
b
WD 
l, m
Notes
Symptom Directed 
Physical Exam, ISR 
and Medical 
Assessment c
X
X
X
X
X
X
X
X
X
X
X
X
See footnote “b” for continuation of visit schedule after Week 140.  
Continue until either locally approved and commercially available, 
the subject no longer derives clinical benefit or meets a protocol-
defined reason for discontinuation or until development is 
terminated. 
a.
Subjects switching from the oral regimen will complete Week 100 
and 104 visits as per the Maintenance T&E Section 6.4.
b.
Continue this pattern for visits for the remainder of the study.  For 
example, Week 144 will be conducted just like Week 128, Week 
148 will be conducted just like Week 132, Week 152 will be 
conducted just like Week 136 and Week 156 will be conducted just 
like Week 140.
c.
Physical exams should be conducted as part of normal routine 
clinical care but data will not be collected in the eCRF. Medical 
assessments include any decisions the study staff must make for 
subject management.
d.
Measure vital signs after about 5 minutes of rest in a semi-supine 
position.
e.
Can be done at any time during the visit.
f.
A (-) urine pregnancy test is required prior to any injection and as 
required by medical monitor after a treatment interruption. A (+) 
urine test should be confirmed with a stat serum test.  If (+), 
subject will need to be WD.
g.
Plasma for storage samples are collected for possible future 
analyses, back-up in cases of loss/damage in transit and 
Vital Signs (BP, HR) d
X
X
X
X
X
Weight & BMI
X
X
X
X
X
HIV Associated
Conditions, AE and 
SAE Assessments, 
Con Meds
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG e
X
X
X
X
X
Clinical Chemistry and 
Hematology
X
X
X
X
X
X
Pregnancy Testing
(U)rine f
U
U
U
U
U
U
U
U
U
U
U
U
HIV-1 RNA and 
sample for storage g
X
X
X
X
X
X
 
 
 
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Procedures for 
Extension if Q4W is 
Selected
W 
100
a
W 
104
a
W 
108
W 
112
W
116
W 
120
W
124
W 
128
b
W 
132
b
W 
136
b
W 
140
b
WD 
l, m
Notes
CD4+
X
X
X
X
X
X
geno/pheno analyses for virologic failures.
h.
Fast overnight; minimum of a 6 hour fast is acceptable.
i.
Samples should be collected pre-dose.
j.
Subjects will complete a diary only if the subject experiences a 
reaction ((E)pisodic).  Subjects will be dispensed a new diary at 
each visit. Diary data will be entered into the eCRF.  
k.
l.
Q4W Injections are 1 x GSK744 LA 400 mg IM + 1 x TMC278 
LA 600 mg IM.  If possible, injections should be spaced 
approximately 2 cm from one another and from the site of any 
previous injection and or any injection site reaction.  Bring 
TMC278 LA to approximately room temperature prior to injecting.   
Time and location of injection (right or left) as well as needle 
length used will be collected in the eCRF.  IM dosing is 
expected to occur during the week in which the subject’s 
projected visit falls (as according to the Day 1 visit).  An 
additional
(+ or -) 7 day window from date of projected visit is allowable 
for IM dosing but not preferred.  All decisions regarding dose 
interruption/ resumption must be discussed with the medical 
monitor in advance.
m.
Or Long-Term Follow Up
n.
Follow Up Visit - Conduct ~4 weeks after the last dose of IP if not 
entering Long-Term Follow Up and only if the subject has ongoing 
AEs or lab abnormalities at the last on-study visit.  May be 
conducted by telephone.
Urinalysis
X
X
X
X
X
Fasting:  Glucose, 
Cholesterol (Total, 
HDL and LDL) and 
Triglycerides h
X
X
X
X
X
PT/PTT/INR
X
PK Sample 
(S)torage  i
S
S
S
S
S
X
ISR Diary 
Dispensation j
E
E
E
E
E
E
E
E
E
E
E
E 
review
Study Treatment 
Administration k
X a
X a
X
X
X
X
X
X
X
X
X
Subject Visit Reminder 
Contact
X
X
X
X
X
X
X
X
X
X
X
Subject Contact Detail 
Confirmation
X
X
X
X
X
X
X
X
X
X
X
New:  
 
 
 
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Added Visits W101, W121 and W144 for subjects switching from oral to the Q4W IM regimen.  
Added labs and procedures for subjects switching from oral to the Q4W IM regimen, denoted with footnote ‘m’.
Removed the following footnotes:
a.
Subjects switching from the oral regimen will complete Week 100 and 104 visits as per the Maintenance T&E Section 6.4.
h. Samples should be collected pre-dose.
i.
Subjects switching from the oral arm will receive their 2nd loading dose injection of 
1 x GSK744 LA 600 mg (no TMC278 LA).
Added the following footnotes:
h. Take PK samples pre-dose except Week 101 and Week 121 which can be taken at any time during the visit.  A second Week 100 and 
128 PK sample will be collected approximately 2 hours after the last injection
n. At Week 100, oral Maintenance subjects eligible for extension dosing will take final dose of CAB 30 mg+ABC/3TC in the clinic 
within 2 hours of  the optimized Q4W IM regimen.  See Section 5.1.6 for IM dosing administration as loading doses are required. 
m. Procedures and visits for subjects who switch from oral to the optimized Q4W IM dosing regimen.
 
 
 
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Procedures for Extension -
Q4W 
W 100 
W 101 
m
W 
104 
W 
108
W 
112
W
116
W 
120
W 
121 m
W
124
W 
128 
W 
132 
a
W 
136 a
W 
140 a
W 
144 a
WD k, 
l
Notes
Symptom Directed 
Physical Exam, ISR and 
Medical Assessment b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
See footnote “a” for 
continuation of visit 
schedule after Week 144.  
Continue until either locally 
approved and 
commercially available, the 
subject no longer derives 
clinical benefit or meets a 
protocol-defined reason for 
discontinuation or until 
development is terminated. 
a.
Continue this pattern for 
visits for the remainder 
of the study.  For 
example, Week 148 will 
be conducted just like 
Week 132, Week 152 
will be conducted just 
like Week 136, Week 
156 will be conducted 
just like Week 140 and 
Week 160 will be  
conducted just like 
Week 144.
b.
Physical exams should 
be conducted as part of 
normal routine clinical 
care but data will not be 
collected in the eCRF. 
Medical assessments 
include any decisions 
the study staff must 
make for subject 
Vital Signs (BP, HR) c
X
X m
X m
X
X
X
X
Weight & BMI
X
X
X
X
X
X
HIV Associated 
Conditions, AE and SAE 
Assessments, Con Meds
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG d
X
X m
X m
X
X
X
X
Clinical Chemistry and 
Hematology
X
X
X
X
X 
X m
X m
X
X m
X
X
X
Pregnancy Testing
(U)rine e
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
HIV-1 RNA and sample 
for storage f
X
X
X
X
X m
X m
X m
X
X
X
CD4+
X
X
X
X
X m
X m
X m
X
X
X
Urinalysis
X
X m
X m
X
X m
X m
X m
X
X
X
Fasting Glucose, 
Cholesterol (Total, HDL 
X
X m
X m
X
X m
X m
X m
X
X
X
 
 
 
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Procedures for Extension -
Q4W 
W 100 
W 101 
m
W 
104 
W 
108
W 
112
W
116
W 
120
W 
121 m
W
124
W 
128 
W 
132 
a
W 
136 a
W 
140 a
W 
144 a
WD k, 
l
Notes
and LDL) and 
Triglycerides g
management.
c.
Measure vital signs after 
about 5 minutes of rest 
in a semi-supine 
position.
d.
Can be done at any 
time during the visit.
e.
A (-) urine pregnancy 
test is required prior to 
any injection and as 
required by medical 
monitor after a 
treatment interruption. A 
(+) urine test should be 
confirmed with a stat 
serum test.  If (+), 
subject will need to be 
WD.
f.
Plasma for storage 
samples are collected 
for possible future 
analyses, back-up in 
PT/PTT/INR
X
PK Diary 
(D)ispensation and 
(R)eview
R m
PK Sample 
(S)torage  h
S
S
S
S
S
S m
S m
S
S m
S
S
X
ISR Diary Dispensationi
E
E
E
E
E
E
E
E
E
E
E
E
E 
review
Study Treatment 
Administration j
X n
X
X
X
X
X
X
X
X
X
X
X
Subject Visit Reminder 
Contact
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
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Procedures for Extension -
Q4W 
W 100 
W 101 
m
W 
104 
W 
108
W 
112
W
116
W 
120
W 
121 m
W
124
W 
128 
W 
132 
a
W 
136 a
W 
140 a
W 
144 a
WD k, 
l
Notes
Subject Contact Detail 
Confirmation
X
X
X
X
X
X
X
X
X
X
X
X
X
X
cases of loss/damage in 
transit and geno/pheno 
analyses for virologic 
failures.
g.
Fast overnight; 
however, a minimum of 
a 6 hour fast is 
acceptable.
h.
Take PK samples pre-
dose except Week 101 
and Week 121 which 
can be taken at any 
time during the visit.  
Week 100 PK sample 
should be taken after 
review of PK diary and 
pre-dose of CAB 
30 mg+ABC/3TC.  A 
second Week 100 and 
Week 128 PK sample 
will be collected 
approximately 2 hours 
after the last injection.
i.
Subjects will complete a 
diary only if the subject 
experiences a reaction 
((E)pisodic).  Subjects 
will be dispensed a new 
diary at each visit. Diary 
data will be entered into 
the eCRF.
j.
Q4W Injections are 1 x 
CAB LA 400 mg IM + 1 
x RPV LA 600 mg IM.  
 
 
 
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Procedures for Extension -
Q4W 
W 100 
W 101 
m
W 
104 
W 
108
W 
112
W
116
W 
120
W 
121 m
W
124
W 
128 
W 
132 
a
W 
136 a
W 
140 a
W 
144 a
WD k, 
l
Notes
If possible, injections 
should be spaced 
approximately 2 cm 
from one another and 
from the site of any 
previous injection and or
any injection site 
reaction.  Bring RPV LA 
to approximately room 
temperature prior to 
injecting.   Time and 
location of injection 
(right or left) as well as 
needle length used will 
be collected in the 
eCRF.  IM dosing is 
expected to occur 
during the week in 
which the subject’s 
projected visit falls (as 
according to the Day 1 
visit).  An additional
(+ or -) 7 day window 
from date of projected 
visit is allowable for 
IM dosing but not 
preferred.  All 
decisions regarding 
dose interruption/ 
resumption must be
discussed with the 
medical monitor in 
advance.
k.
Or Long-Term Follow 
 
 
 
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Procedures for Extension -
Q4W 
W 100 
W 101 
m
W 
104 
W 
108
W 
112
W
116
W 
120
W 
121 m
W
124
W 
128 
W 
132 
a
W 
136 a
W 
140 a
W 
144 a
WD k, 
l
Notes
Up
l.
Follow Up Visit -
Conduct ~4 weeks after 
the last dose of IP if not 
entering Long-Term 
Follow Up and only if 
the subject has ongoing 
AEs or lab abnormalities 
at the last on-study visit.  
May be conducted by 
telephone.
m.
Procedures and visits 
for subjects who switch 
from oral to the 
optimized Q4W IM 
dosing regimen.
n.
At Week 100, oral 
Maintenance subjects 
eligible for extension 
dosing will take final 
dose of CAB 
30 mg+ABC/3TC in the 
clinic within 2 hours of 
the optimized Q4W IM 
regimen.  See Section 
5.1.6 for IM dosing 
administration as 
loading doses are 
required.
 
 
 
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Section 6.10.3.3 Liver Stopping Criteria - Rechallenge
Added clarifying statements to this section (additions underlined):
Subjects who meet liver toxicity stopping criteria should not be retreated with 
investigational product unless an exemption has been approved by the ViiV Safety and 
Labeling Committee (VSLC).  The guideline for Rechallenge/Restart approved by the 
VSLC, which is maintained as a separate document (See Section 11.4, Appendix 4), must 
be followed.
Drug Restart/Rechallenge Following Liver Events that are Possibly Related to IP
Approval by the VSLC for drug restart or additional IM administration can be considered 
where:

The subject is receiving compelling benefit, benefit of drug restart exceeds risk, 
and no effective alternative therapy is available.  Ethics Committee or 
Institutional Review Board approval of drug restart/rechallenge must be 
obtained, as required.

If the restart/rechallenge is approved by the VSLC in writing, the subject must 
be provided with a clear description of the possible benefits and risks of drug 
administration, including the possibility of recurrent, more severe liver injury or 
death.

The subject must also provide signed informed consent specifically for the IP 
restart/rechallenge.  Documentation of informed consent must be recorded in the 
study chart.

Study drug must be administered at the dose specified by the VSLC.

Subjects approved by the VSLC for rechallenge of IP must return to the clinic 
twice a week for liver chemistry tests for a minimum of one month and 
thereafter for as long as clinically indicated and then laboratory monitoring may 
resume as per protocol.
Drug Restart Following Transient Resolving Liver Events Not Related to IP
Approval by the VSLC for drug restart or additional IM administration can be considered 
where:

Liver chemistries have a clear underlying cause (e.g., biliary obstruction, 
hypotension and liver chemistries have improved to normal or are within 
1.5 x baseline and ALT <3xULN).  Ethics Committee or Institutional Review 
Board approval of drug restart/rechallenge must be obtained, as required.

If restart of drug or continuation of LA dosing is approved by the VSLC in 
writing, the subject must be provided with a clear description of the possible 
benefits and risks of drug administration, including the possibility of recurrent, 
more severe liver injury or death.
 
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
The subject must also provide signed informed consent specifically for the 
restart.  Documentation of informed consent must be recorded in the study chart.

Study drug must be administered at the dose specified by the VSLC.
Subjects approved by the VSLC for restarting or re-dosing IP must return to the clinic 
once a week for liver chemistry tests for a minimum of one month and thereafter for as 
long as clinically indicated and then laboratory monitoring may resume as per protocol.  
If protocol defined stopping criteria for liver chemistry elevations are met, study drug 
must be stopped.
See Section 11.4, Appendix 4 for further details.
Section 6.10.6.16 Seizures
New section added to protocol (underlined)
Seizures that occur on study should be managed according to the local guidelines on 
emergency seizure management which may include treatment with benzodiazepines, 
general supportive treatment, exclusion of metabolic and toxicological abnormalities 
using laboratory tests, and septic workup and excluding underlying structural 
abnormalities with neuroimaging.
Where seizures occur, the Sponsor would like to better characterize these occurrences to 
enable systematic analyses.
Investigators are requested to document and report seizure or possible seizure events 
promptly (within 24 hours of learning of the event) to the Sponsor for evaluation and 
onward reporting.  Data should be documented on the appropriate eCRF page.
Section 6.10.14 Prompt Reporting of Serious Adverse Events and Other Events to 
GSK
Updated table with the following row (Seizure or suspected seizure - underlined):
Initial Reports
Follow-up Information on a Previous 
Report
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
“SAE” data 
collection tool
24 hours
Updated “SAE” 
data collection tool
 
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Initial Reports
Follow-up Information on a Previous 
Report
Type of Event
Time Frame
Documents
Time Frame
Documents
Cardiovascular (CV) 
or death event
Initial and 
follow up 
reports to be 
completed 
within one 
week of when 
the 
cardiovascular 
event or death 
is reported 
“CV events” 
and/or “death” 
data collection 
tool(s) if 
applicable
Initial and follow 
up reports to be 
completed within 
one week of when 
the cardiovascular 
event or death is 
reported
Updated “CV 
events” and/or 
“death” data 
collection tool(s) if 
applicable
PRSAE
1 week
PRSAE data 
collection tool
1 weeks
Updated PRSAE 
data collection tool
Suspected ABC 
HSR3
24 hours
ABC HSR eCRF
1 Week
Updated ABC HSR 
eCRF
Pregnancy
2 weeks
“Pregnancy 
Notification Form”
2 weeks
“Pregnancy Follow-
up Form”
Seizure or suspected 
seizure
24 hours
eCRF
24 hours
eCRF
Non-serious adverse 
events related to 
study treatment
5 calendar 
days
“Adverse 
Reaction” data 
collection tool
2 weeks
Updated “Adverse 
Reaction” data 
collection tool
Liver chemistry abnormalities see Section 6.10.31,2:
ALT≥3xULN plus 
Bilirubin≥2xULN 
(35% direct) 
24 hours 
SAE data 
collection tool 
Liver Event eCRF 
and liver imaging 
and/or biopsy 
eCRFs if 
applicable 
24 hours 
Updated SAE data 
collection tool 
Updated Liver 
Event eCRF 
ALT≥5xULN that 
persists ≥2 weeks 
24 hours 
Liver Event eCRF 
24 hours 
Updated Liver 
Event eCRF 
ALT ≥8xULN 
24 hours 
Liver Event eCRF 
24 hours 
Updated Liver 
Event eCRF 
 
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Initial Reports
Follow-up Information on a Previous 
Report
Type of Event
Time Frame
Documents
Time Frame
Documents
ALT ≥3xULN or ALT 
≥3 fold increase from 
Baseline value with 
appearance or 
worsening of 
symptoms of 
hepatitis or 
hypersensitivity
24 hours 
Liver Event eCRF 
24 hours 
Updated Liver 
Event eCRF 
1.
GSK must be contacted at onset of liver chemistry elevations to discuss subject safety.
2.
Liver Event Documents (i.e., “Liver Event eCRF” and “Liver Imaging eCRF” and/or “Liver Biopsy eCRF”, as 
applicable) should be completed as soon as possible.
3.
ABC HSR eCRF required only if event meets one of the ICH-E2A, 1994 definitions of seriousness (see 
Section 6.10.6.14.2).
Section 6.11 Pharmacokinetics
Updated paragraph (changes struck through and underlined)
Plasma samples for determination of GSK1265744 CAB and TMC278 RPV
concentration will be collected throughout the Maintenance Period and from Week 100 –
Week 128 in the Extension Period of the study for subjects switching from oral 
Maintenance period regimen to the optimized IM dosing regimen of their choice.  
Additional samples will be collected for storage during the Extension and Long-Term 
Follow Up Period.  Samples for determination of RPV will be protected from light until 
analyzed.
Section 6.11.1 PK Sample Collection
Updated table with Extension Period PK collection times (underlined)
 
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Group
Analyte
Week
Sample Times Relative to Dose
IM
GSK1265744
CAB
Day 1 (prior to LA and 
last oral Induction 
dose), Weeks: 1, 4, 8, 
12, 16, 20, 24, 25, 28,  
32, 36, 40, 41, 44 and
48
100* (prior to LA and 
last oral Maintenance 
dose), 104*, 108*, 112*, 
116*, 120*, 124* and 
128*
Pre-Dose (Q8W):  Day 1, Weeks 4, 8, 
16, 24, 32, 40, 48, 100*, 104*, 112*, 
120* and 128*
Pre-Dose (Q4W):  Day 1, Weeks 4, 8, 
12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 
100*, 104*, 108*, 112*, 116*, 120*, 
124* and 128*
2 Hours Post Dose:  Day 1, Weeks 
32, 48, 100*a and 128*a
1 Week Post Dose:  Week 1, Weeks
25, 41, 101*a and Week 121*a
4 Weeks Post Dose (Q8W):  Weeks 
12, 20, 28, 36 and 44
TMC278 RPV
Day 1 (prior to LA and 
last oral Induction 
dose), Weeks: 1, 4, 8, 
12, 16, 20, 24, 25, 28, 
32, 36, 40, 41, 44 and
48
100* (prior to LA and 
last oral Maintenance 
dose), 104*, 108*, 112*, 
116*, 120*, 124* and 
128*
Pre-Dose (Q8W):  Day 1, Weeks 4, 8, 
16, 24, 32, 40, 48, 100*, 104*, 112*, 
120* and 128*
Pre-Dose (Q4W):  Day 1, Weeks 4, 8, 
12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 
100*, 104*, 108*, 112*, 116*, 120*, 
124* and 128*
2 Hours Post Dose:  Day 1, Weeks 
32, 48, 100*a and 128*a
1 Week Post Dose:  Week 1, Weeks
25, 41, 101*a and Week 121*a
4 Weeks Post Dose (Q8W):  Weeks 
12, 20, 28, 36 and 44
Oral 
GSK1265744
CAB
Day 1, Weeks: 32 and 
48
Pre-Dose:  Day 1, Weeks 32 and 48
TMC278 RPV
Day 1
Pre-Dose:  Day 1
* Denotes PK sample times for subjects in the Extension Period.  Samples will be placed in storage.
a.
PK sample time for subjects switching from oral to an optimized IM dosing regimen only.
 
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Section 6.11.2 Rationale of PK Sampling Strategy
Updated paragraph (changes struck through and underlined)
Given that PK data has been collected following oral administration of GSK744 CAB 
and RPV (LAI116482), there will be no sampling during the Induction Period of the 
study.  Blood sampling for GSK1265744 CAB and TMC278 RPV concentrations will be 
performed during the Maintenance Period and Extension Periods of the study to evaluate 
PK in HIV infected subjects.  The proposed PK visits and sampling scheme at each visit 
presented in Table 4 is based on consideration of available PK data to support interim and 
final PK and PK/Pharmacodynamic (PD) analysis planned in this study.
Section 8.3.1.6 Extension Switch Population
Added new section to protocol (underlined)
The Extension Switch population will include all subjects randomized to the oral 30 mg + 
ABC/3TC arm who switch to and receive at least one dose of the optimized IM dosing 
regimen of their choice (either Q8W or Q4W) in the Extension Period.
The Extension Switch population will be used to evaluate safety and efficacy of the 
optimized IM dosing regimens during the Extension Period.
Section 8.3.4 Interim and Final Analysis
Updated section name (changes struck through and underlined)
Interim and Final Planned Analysis
Section 8.3.4.1 IDMC Interim Analyses
Updated paragraph (changes struck through and underlined)
The purpose of these analyses is for the Independent Data Monitoring Committee 
(IDMC) to evaluate the efficacy, safety and tolerability of GSK1265744 CAB at early 
time points in the study. and to monitor the occurrence of protocol defined virologic 
failure in subjects switching from oral CAB 30 mg +ABC/3TC to an optimized IM 
dosing regimens during the Extension Period.  
The IDMC intends to review at least one analysis before all eligible subjects have 
transitioned from the Induction Period to the Maintenance Period, or as soon as 
reasonably possible after subjects begin to enter the Maintenance Period.  Full details of 
the analyses, estimated timing and the decision criteria that will be used to determine 
regimen performance will be pre-specified in the IDMC Charter, with IDMC agreement.
All of the IDMC reviews will be produced by a Statistics and Data Analysis Centre 
(SDAC).  
 
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Section 8.3.4.2 Futility Interim Monitoring
Added the following line (underlined)
Continuous monitoring of the number of protocol defined virologic failures for subjects 
switching from oral CAB 30 mg + ABC/3TC to the optimized IM dosing regimen of their 
choice (Q8W or Q4W) will also be monitored during the Extension Period.
Updated language (changes struck through and underlined)
...If the true rate of virologic failure is 3%, the probability to see that the number of 
virology failure virologic failures observed will exceed the threshold is less than<1%.
Further details on this method are contained in the IDMC charter. Each threshold 
represents strong evidence in favour of H0 over H1 [Royall, 1997].
Added the following paragraph and table to section (underlined)
The number of protocol defined virologic failures will also be monitored in subjects 
switching from oral CAB 30 mg + ABC/3TC to the optimized IM dosing regimen of their 
choice (Q8W or Q4W) during the Extension Period.  For subjects that have at least 4 
weeks of treatment with an optimized IM dosing regimen, if the number of protocol 
defined virologic failures meets or exceeds the thresholds specified in the table below 
(Table 7) prior to all subjects completing Week 152, this will be considered strong 
evidence of an inadequate response and will trigger a comprehensive IDMC data review.  
If an inadequate response is seen in any arm and it is determined by IDMC that that arm 
should be discontinued, then subjects on that treatment arm can be switched to the 
remaining IM dosing regimens.
Table 7  Number of protocol-defined virologic failures for each Extension Period 
optimized IM dosing regimen that constitutes strong evidence of inadequate virologic 
response – Subjects switching from Maintenance oral CAB + ABC/3TC only
Number of subjects with at least four 
weeks of IM dosing
Number of protocol-defined virologic 
failures needed to trigger IDMC review 
3-21
>=3
22-32
>=4
33-43
>=5
44-54
>=6
Section 8.3.4.6 Week 96 Analysis
Changed section name (changes struck through)
Week 96 Final Analysis
 
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Section 8.3.4.7 Week 128 Extension Switch Analysis
Added new section to protocol (underlined)
The Week 128 analysis will be conducted once the last randomized subject has 
completed the Week 128 study visit and the database has been cleaned and released for 
analysis.  The results of this analysis will be used to characterize the efficacy, tolerability, 
and safety of optimized IM dosing regimens for subjects switching from the oral regimen 
therapy at the end of the Maintenace Period.
Section 8.3.4.8 Week 152 Analysis
Added new section to protocol (changes struck through and underlined)
The Week 152 analysis will be conducted once the last randomized subject has 
completed the Week 152 study visit and the database has been cleaned and released for 
analysis.  The results of this analysis will be used to characterize the following: (a) the 
long-term safety and efficacy profile of both IM dosing regimens for subjects who 
continued randomized IM dosing in the Extension Period and (b) the safety, tolerability 
and durability of antiviral response of the optimized IM dosing regimens for subjects 
switching from the oral regimen therapy at the end of the Maintenace Period.
Follow-up analyses after the Week 96 analysis of data collected after subjects have 
switched to the chosen dose of GSK744 LA 152 analysis may be conducted to more fully 
characterize the long-term safety and efficacy profile of GSK744 CAB LA + RPV LA 
dosing regimens.
Section 8.3.5.1 Efficacy Analyses
The following changes were made to the section (changes struck through and underlined)
... Data collected from extra visits within a window will be included in the derivation of 
the time to loss of protocol defined virologic response (TLOVR) failure, but summary 
tables using OC datasets will only use the data captured closest to the target visit date.
... In addition, an OC analysis will may be performed for supportive purposes.
References
Updated the Rilpivirine Investigator’s Brochure effective date from November 2013 to 
April 2016.
 
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Amendment 7
Updated Exploratory Objectives, Primary Analysis, Discussion of Design, Futility Interim 
Monitoring, and Week 160 Interim Analysis sections to support an interim analysis at Week 
160.Section 2 Objectives and EndpointsExploratory
To evaluate the efficacy, tolerability, and safety 
of optimized IM dosing regimens CAB LA 400 
mg IM plus RPV LA 600 mg IM every 4 weeks
and CAB LA 600 mg IM plus RPV LA 900 mg 
every 8 weeks at Weeks 128 and 152 160 for 
subjects switching from the oral regimen 
therapy at the end of the Maintenace Period.
To evaluate the long term efficacy, tolerability, 
and safety of IM dosing regimens CAB LA 400 
mg IM plus RPV LA 600 mg IM every 4 weeks
and CAB LA 600 mg IM plus RPV LA 900 mg 
every 8 weeks at Week 152 160 for subjects 
who continued randomized IM dosing in the 
Extension Period.
Proportion of subjects with a ‘virologic failure’
endpoint as per FDA Snapshot algorithm at 
Week 128 and 152 160 (Missing, Switch or 
Discontinuation = Failure, Extension Switch 
population)
Proportion of subjects with Plasma HIV-1 RNA 
<50 copies/mL (c/mL) at Week 128 and 160 
using the FDA Snapshot algorithm (Extension 
Switch population)
Proportion of subjects with protocol defined 
virologic failures over time
Proportion of subjects with plasma HIV-1 RNA 
<200 c/mL and <50 c/mL over time.Absolute 
values and changes in CD4+ cell counts over 
time
Incidence of disease progression (HIV-
associated conditions, acquired 
immunodeficiency syndrome [AIDS] and death).
Incidence and severity of AEs and laboratory 
abnormalities over time.
Absolute values and changes in laboratory 
parameters over time.
Section 3.2.9 Primary AnalysisThe primary analysis will be conducted when all 
subjects have completed their Maintenance Period Week 32 visit. This analysis will 
characterize the safety, tolerability and durability of antiviral response from both the 
Induction Period and the Maintenance Period. Planned analyses will also be conducted 
at Week 48, Week 96, Week 128 and Week 152 160. Follow-up analyses of data 
collected after subjects have entered into the Extension Period may be conducted to more 
fully characterize the long-term safety and efficacy profile of CAB and RPV.
Section 3.3 Discussion of Design
… A Week 152 160 analysis will permit an evaluation of the ability of the randomized 
and optimized investigational two-drug long-acting combinations to showcase long-term 
durability of virologic suppression.  Additional long-term safety and efficacy data for all 
IM dosing regimens will be generated.
 
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Section 8.3.4.2 Futility Interim Monitoring
…The number of protocol defined virologic failures will also be monitored in subjects 
switching from oral CAB 30 mg + ABC/3TC to the optimized IM dosing regimen of their 
choice (Q8W or Q4W) during the Extension Period.  For subjects that have at least 4 
weeks of treatment with an optimized IM dosing regimen, if the number of protocol 
defined virologic failures meets or exceeds the thresholds specified in the table below 
(Table 7) prior to all subjects completing Week 152 160, this will be considered strong 
evidence of an inadequate response and will trigger a comprehensive IDMC data review.  
If an inadequate response is seen in any arm and it is determined by IDMC that that arm 
should be discontinued, then subjects on that treatment arm can be switched to the 
remaining IM dosing regimens.
Section 8.3.4.8 Week 152 160 Analysis
The Week 152 160 analysis will be conducted once the last randomized subject has 
completed the Week 152 160 study visit and the database has been cleaned and released 
for analysis.  The results of this analysis will be used to characterize the following: (a) the 
long-term safety and efficacy profile of both IM dosing regimens for subjects who 
continued randomized IM dosing in the Extension Period and (b) the safety, tolerability 
and durability of antiviral response of the optimized IM dosing regimens for subjects 
switching from the oral regimen therapy at the end of the Maintenace Period.
Follow-up analyses after the Week 152 160 analysis may be conducted to more fully 
characterize the long-term safety and efficacy profile of CAB LA + RPV LA dosing 
regimens.
 
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