Clinical trial NCT02120352
Conditions: Infection, Human Immunodeficiency Virus HIV Infections
Keywords: bi-monthly GSK744 injectable long acting maintenance abacavir every other month rilpivirine HIV-1 infection integrase inhibitor TMC278 LA RPV non-nucleoside reverse transcriptase inhibitor LA once monthly GSK1265744 induction treatment satisfication once daily lamivudine adherence TMC278 therapy-naive
Sponsor: ViiV Healthcare
Start date: 2014-04-28; Completion date: 2023-04-20
Enrollment: 309 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a Phase IIb, randomized, multicentre, parallel group, open-label, study having an overall objective to evaluate the antiviral activity, tolerability, and safety of two intramuscular (IM) dosing regimens of GSK744 LA plus TMC278 LA, relative to GSK744 30 milligram (mg) plus Abacavir/Lamivudine (ABC/3TC) given orally once daily (QD), in HIV-1 infected antiretroviral-naïve subjects. GSK744 is the oral formulation of GSK1265744 (cabotegravir), GSK744 LA is the long acting injectable formulation of GSK1265744 and TMC278 LA is the long acting injectable formulation of TMC278.

The study will consist of three parts: an Induction Period, Maintenance Period and Extension Period. There is also a Long-Term Follow Up Period for subjects who withdraw from the study and have received at least one dose of GSK744 LA and / or TMC278 LA. In the Induction Period, eligible subjects will receive a combination of an oral regimen of 30 mg of GSK744 and 600/300 mg of ABC/3TC, once daily for 20 weeks. In the Maintenance Period, eligible subjects will be randomized 2:2:1 at Day 1 to receive an IM regimen of GSK744 LA 400 mg + TMC278 LA 600 mg every 4 weeks for 96 weeks (Q4W), an IM regimen of GSK744 LA 600 mg + TMC278 LA 900 mg every 8 weeks for 96 weeks (Q8W), 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). The Extension Period will allow for a collection of longer term efficacy and safety and tolerability data from subjects receiving GSK744 LA and TMC278 LA.

The study will involve sufficient subjects at screening in order to ensure a total of approximately 265 subjects at the beginning of the Induction Period and approximately 225 subjects randomized into the Maintenance Period.

Detailed description:

Arms: arm 1: On Day 1 of the Maintenance period, participants who successfully completed the Induction period, were randomized to receive following intramuscular (IM) doses: Day 1 only: CAB long acting (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); and from Week 8: CAB LA 600 mg IM +RPV LA 900 mg IM every 8 Weeks (Q8W) for 96 weeks. Eligible participants had the option to continue study participation in the Extension Period. arm 2: On Day 1 of the Maintenance period, participants who successfully completed the Induction period, were randomized to receive following IM doses: Day 1 only: CAB LA 800 mg (loading dose delivered as two 400 mg IM injections) + RPV LA 600 mg IM; and from Week 4: CAB LA 400 mg IM + RPV LA 600 mg IM every 4 Weeks (Q4W) for 96 weeks. Eligible participants had the option to continue study participation in the Extension Period. arm 3: In induction period, all participants received an oral regimen of cabotegravir (CAB) 30 milligrams (mg) once daily (QD) plus abacavir/lamivudine (ABC/3TC) 600/300 mg QD for 20 weeks. They also received an oral dose of Rilpivirine (RPV) 25 mg tablet once daily in the last 4 weeks of the Induction Period. arm 4: On Day 1 of the Maintenance period, participants who successfully completed the Induction period, were randomized to receive CAB and ABC/3TC QD for 96 weeks. Eligible participants had the option to continue study participation in Extension Period by switching to an optimized IM CAB LA+ RPV LA regimen of their choice (Q8W or Q4W). arm 5: Participants who completed 96 weeks of CAB 30 mg + ABC/3TC QD regimen in Maintenance Period transitioned to Extension Period and received an optimized loading dose of CAB LA 600 mg+RPV LA 900 mg IM at Week 100 and Week 104 followed by CAB LA 600 mg+RPV LA 900 mg IM-Q8W in the Extension Phase. Participants were followed up until end of Extension Period. arm 6: Participants who completed 96 weeks of CAB 30 mg + ABC/3TC QD regimen in Maintenance Period transitioned to Extension Period and received an optimized loading dose of CAB LA 400 mg+RPV LA 900 mg IM at Week 100 followed by CAB LA 400 mg+RPV LA 900 mg IM-Q8W in the Extension Phase. Participants were followed up until end of Extension Period. arm 7: This group included participants that were withdrawn from CAB LA+RPV LA IM regimens based on protocol criteria and were required to access Highly Active Antiretroviral Therapy (HAART) of choice. Participants were followed up for approximately 52 weeks.
Interventions: intervention 1: CAB Oral Tablets intervention 2: CAB LA intervention 3: ABC/3TC Oral tablets intervention 4: RPV Oral Tablets intervention 5: HAART intervention 6: RPV
Intervention descriptions: intervention 1: White to almost white oval shaped film coated 30 mg tablets for oral administration. intervention 2: Sterile white to slightly colored suspension containing 200 mg/mL of GSK744 as free acid (GSK1265744 free acid), polysorbate 20, polyethylene glycol 3350, mannitol, and water for injection, packaged in a 3 mL USP Type I glass vial, for administration by IM injection intervention 3: ABC/3TC fixed dose combination (FDC) oral tablet, containing 600 mg of ABC (as abacavir sulfate) and 300 mg of 3TC intervention 4: Off-white, round, biconvex, film-coated 25 mg Rilpivirine (RPV) tablets for oral administration. Eligible subjects switching from the oral regimen to the IM regimen in the Extension Period will receive 2 weeks of RPV 25 mg once daily, from Week 102 through Week 104 intervention 5: Higly-active antiretroviral therapy chosen by participant based on investigator recommendations and based on availability. intervention 6: Sterile white suspension containing 300 mg/mL of TMC278 as free base, poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, glucose monohydrate, sodium hydroxide, water for injection, packaged in a 2 mL USP Type I glass vial, for administration by IM injection.

Protocol documents:
Prot_000.pdf: 
2013N168152_09
CONFIDENTIAL
ViiV Healthcare and The GlaxoSmithKline group of companies
200056
1
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.
 
2018N380094_00
PPD


2013N168152_09
CONFIDENTIAL
ViiV Healthcare and The GlaxoSmithKline group of companies
200056
2
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
ViiV Healthcare and The GlaxoSmithKline group of companies
200056
3
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.
 
2018N380094_00


 
2018N380094_00
PPD
PPD
PPD
PPD


2013N168152_09
CONFIDENTIAL
200056
5
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: 
 
2018N380094_00
PPD
PPD
PPD
PPD
PPD
PPD
PPD


2013N168152_09
CONFIDENTIAL
200056
6
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
 
2018N380094_00
PPD
PPD
PPD
PPD
PPD


2013N168152_09
CONFIDENTIAL
200056
7
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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
8
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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
9
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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
10
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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
11
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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
12
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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
13
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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
14
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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
15
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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
16
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
17

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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
18
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.  
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
19

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.  
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
20
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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
21

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:
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
22

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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
23
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
24
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. 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
25

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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
26
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
27
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.  
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
28

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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
29
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
30
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.   
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
31
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
32
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
33
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.  
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
34
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
35
(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).
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
36
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. 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
37
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,
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
38

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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
39
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
40
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
41
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
42
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).
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
43
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).
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
44
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).  
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
45
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.  
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
46
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
47
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].
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
48
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
49
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
50
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
51
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
52
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
53
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
54
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.  
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
55
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
56
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.   
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
57
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
58
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).
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
59
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].
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
60
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.  
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
61
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’
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
62
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
63
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
64
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
65
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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
66
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
67
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
68
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
69
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 
the Extension Period).  
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
70
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
71
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
72
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  
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
73

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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
74
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
75
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
76
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
77
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
78
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
79
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
80
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).
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
81
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
82
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
83
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
84
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
85
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
86
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
87
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
88
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
89
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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
90
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
91
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
92
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
93
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 
following IM injections.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
94
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).
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
95
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
96
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
97
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
98
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
99
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
100
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.
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
101
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
102
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
103
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.
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
104
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
105
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
106
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.
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
107
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
108
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
109
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).
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
110
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
111
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
112
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
113
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
114
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
115
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
116
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.
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
117
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
118
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
119
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).
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
120
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 
reader. The qualified ECG reader will make the non-calculated ECG interpretations.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
121

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”).
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
122
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
123

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:
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
124

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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
125
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. 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
126
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)
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
127

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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
128
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
129
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
130

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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
131
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
132
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
133
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
134
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
135
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
136
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
137
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
138
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)
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
139

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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
140
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
141
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?”
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
142
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
143
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
144
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
145
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
146
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
147
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
148
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
149
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
150
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
151
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
152
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.  
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
153
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-
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
154
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
155
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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
156
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
157
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
158
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
159
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)
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
160
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
161
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
162
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:
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
163
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
164
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
165
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
166
10.
REFERENCES
Arribas J, Clumeck N, Nelson M, Hill A, van Delft Y, Moecklingoff C. The MONET 
trial: week 144 analysis of the efficacy of darunavir/ritonavir (DRV/r) monotherapy 
versus DRV/r plus two nucleoside reverse transcriptase inhibitors, for patients with viral 
load <50 copies/ml at baseline. HIV MED, 2012 Aug;13(7):398-405.
Bierman WF, van Aqtamael MA, Nijhuis M, Danner SA, Boucher CA. HIV 
monotherapy with ritonavir-boosted protease inhibitors: a systematic review. AIDS, 2009; 
23(3):279-91.
Centers for Disease Control and Prevention (CDC) 1993 revised classification system for 
HIV infection and expanded surveillance case definition for AIDS among adolescents 
and adults. MMWR 1992; 41(No. RR-17):1-19.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron 1976; 16:31-41.
Cohen C, Andrade-Villanueva J, Clotet B, et al. Rilpivirine versus efavirenz with two 
background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naïve 
adults infected with HIV-1 (THRIVE): a Phase 3, randomized, non-inferiority trial. 
Lancet. 2011; 378:229-37.
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.
Dube MP, Stein JH, Aberg JA, et al. Guidelines for the evaluation and management of 
dyslipidemia in human immunodeficiency virus (HIV)-infected adults receiving 
antiretroviral therapy: recommendations of the HIV Medical Association of the Infectious 
Disease Society of America and the Adult AIDS Clinical Trials Group. Clin Infect Dis 
2003; 37(5):613-27.
Edurant Product Information (rilpivirine) May, 2015.
Epzicom Product Information (abacavir/lamivudine) May, 2012.
European AIDS Clinical Society (EACS) Guidelines for the clinical management and 
treatment of HIV Infected Adults in Europe, Version 6.1, 2012. Available at 
http://www.europeanaidsclinicalsociety.org/guidelines.asp
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.  Effective Date:  
04Feb2013.  
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
167
GlaxoSmithKline Document Number 2011N117114_01:  ING112276 A Phase IIb study 
to select a once daily oral dose of GSK1349572 administered with either 
abacavir/lamivudine or tenofovir/emtricitabine in HIV-1 infected antiretroviral therapy 
naïve adult subjects.  Effective Date:  16Nov2012
GlaxoSmithKline Document Number 2012N134026_02:  LAI116482 A Phase IIb, dose 
ranging study of oral GSK1265744 in combination with nucleoside reverse transcriptase 
inhibitors for induction of HIV-1 virologic suppression followed by an evaluation of 
maintenance of virologic suppression when oral GSK1265744 is combined with oral 
rilpivirine in HIV-1 infected, antiretroviral therapy naive adult subjects.  Effective Date:  
11June2012.
GlaxoSmithKline Document Number RH2009/00003/03:  GSK1265744 Investigator’s 
Brochure.  Effective Date:   3Sep2013.
GlaxoSmithKline Document Number RM2008/00633/00: ITZ111451 A Double-Blind, 
Parallel, Randomized, Placebo-Controlled, Single and Repeat Dose Escalation First Time 
in Human Study to Investigate the Safety, Tolerability and Pharmacokinetics of 
GSK1265744 in Healthy Male and Female Subjects and Subjects Infected with HIV. 
May 2009.
GlaxoSmithKline Document Number RM2009/00485/00. ITZ112929 A Phase 2a Study 
to Compare Antiviral Effect, Safety, Tolerability and Pharmacokinetics of GSK1265744 
Monotherapy Versus Placebo in HIV-1 Infected Adults.  Effective Date: 14May2010.
GlaxoSmithKline Document Number RM2010/00170/04: LAI114433 An Observer- and 
Subject-Blinded, Randomized, Placebo-Controlled, Single Dose Escalation Study to 
Investigate the Safety, Tolerability and Pharmacokinetics of Intramuscular and 
Subcutaneous Long Acting GSK1265744 in Healthy Subjects.  Effective Date: Oct 2011
Guidance for Industry. Antiretroviral Drugs Using Plasma HIV RNA Measurements -
Clinical Considerations for Accelerated and Traditional Approval. U.S. Department of 
Health and Human Services Food and Drug Administration Center for Drug Evaluation 
and Research (CDER). October 2002.
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E2A/
Step4/E2A_Guideline.pdf, 27 October 1994
International AIDS Society (IAS) Guidelines - Update of the Drug Resistance Mutations 
in HIV-1: March 2013. Topics in Antiviral Medicine; 21(1):4-12.
Lou Y, Chen S.  Analysis of Aggregated Safety Data to Support HIV 744 LAP 
GSK1265744 Phase IIb/III Clinical Development.  53rd ICAAC Interscience Conference 
on Antimicrobial Agents and Chemotherapy September 10-13, 2013
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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
168
Molina JM, Cahn, P, Grinsztejn B, et al. Rilpivirine versus efavirenz with tenofovir and 
emtricitabine in treatment-naive adults infected with HIV-1 (ECHO): a phase 3 
randomised double-blind active-controlled trial. Lancet. 2011;378:238-46.
Oquendo MA, Mann J. Risk Factors for suicidal behaviour: utility and limitations of 
research instruments (2003). In M.B. First [Ed] Standardized Evaluation in Clinical 
Practice, pp 103- 130.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of 
antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and 
Human Services. DHHS 2013 Available at 
http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf.
Rashbaum B, Girard P, et al Initial tolerability of rilpivirine and efavirenz: grade 1 events 
during weeks 0–12 of the Phase III ECHO and THRIVE studies.  XIX International 
AIDS Conference, 2011b.  Poster TUPE024
Rashbaum B, Girard P, et al Rilpivirine (TMC278) tolerability over the first 12 weeks of 
treatmentin the Phase III ECHO and THRIVE studies.  51st Interscience Conference on 
Antimicrobial Agents and Chemotherapy, 2011a.  Poster H2-805
Royall, Richard M. (1997). Statistical Evidence: A Likelihood Paradigm. London:  
Chapman & Hall.
TMC278 [Rilpivirine, oral and parenteral] Integrated Investigator’s Brochure. 2016
Effective Date: April 2016.
UNAIDS:  2012 AIDS Epidemic Update Available at:  
http://www.unaids.org/en/media/unaids/contentassets/documents/epidemiology/2012/gr2
012/20121120_UNAIDS_Global_Report_2012_with_annexes_en.pdf
Woodcock A, Bradley C (2001). Validation of the HIV Treatment Satisfaction 
Questionnaire (HIVTSQ). Quality of Life Research. 10:517-531.
Woodcock A, Bradley C (2006). Validation of the Revised 10-item HIV Treatment 
Satisfaction Questionnaire Status Version and New Change Version. Value in Health.
9:320-333
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
169
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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
170

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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
171

Progressive multifocal leukoencephalopathy

Salmonella septicemia, recurrent

Toxoplasmosis of brain

Wasting syndrome due to HIV

Non-CDC, HIV-associated conditions.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
172
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
173
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)]
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
174
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
175
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)
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
176
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
177
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
178
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)
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
179
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
180
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
181
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
182
CLINICAL
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
183
CLINICAL
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)
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
184
CLINICAL
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.).
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
185
CLINICAL
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
186
CLINICAL
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
187
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
188
CLINICAL
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
189
CLINICAL
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
190
CLINICAL
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).
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
191
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
192
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
193
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
194
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
195
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
196
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] 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
197
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
198
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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
199
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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
200

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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
201
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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
202
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
203
11.5.
Appendix 5: Country Specific Requirements
No country-specific requirements exist. 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
204
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
205
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):
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
206
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
207
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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
208
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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
209
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
210
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
211
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
212
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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
213

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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
214
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: 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
215

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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
216
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
217
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
218
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
219
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
220
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
221
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
222
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
223
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
224
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, 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
225
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
Original text:
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
226
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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
227
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
228
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
229
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).
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
230
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
231
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
232
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
233
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
234
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
235
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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
236
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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
237
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
238
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].
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
239
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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
240
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:
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
241
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
242
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
243
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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
244
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
245
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
246
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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
247
Revised text:
Induction Period
Maintenance and Extension Period
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
248
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
249
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:
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
250
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, 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
251
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)
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
252
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
253
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.  
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
254
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).
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
255
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:
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
256
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
257
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
258
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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
259
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
260
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*
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
261
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)
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
262
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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
263
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
264
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:
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
265
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
266
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
267
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
268
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
269
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
270
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
271
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
272
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
273
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
274
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
275
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.
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
276
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
277
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, 
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
278
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
279
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
280
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
281
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
282
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
283
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
284
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.
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
285
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
286
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
287
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.
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
288
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


2013N168152_09
CONFIDENTIAL
200056
289
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
CONFIDENTIAL
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


2013N168152_09
CONFIDENTIAL
200056
292
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 
may be conducted by telephone.
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
294
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
295
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
296
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
297
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
298
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
299
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
300
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
301
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
302
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
303

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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
304
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
305

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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
306
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
307
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
308
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
309
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.).
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
310
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:
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
311
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%.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
312
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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
313
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
314
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
315
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
316
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)
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
317
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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
318
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. 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
319
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
320
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:
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
321
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
322
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
323
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
324
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).
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
325
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
326
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
327
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
328

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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
329
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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
330
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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
331

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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
332

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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
333
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])
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
334
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
335
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
336
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].
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
337
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.
 
2018N380094_00
PPD


2013N168152_09
CONFIDENTIAL
200056
338
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, 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
339
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]).
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
340
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
341
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
342
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.  
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
343
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
344
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
345
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. 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
346
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:
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
347
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.  
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
348
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
349
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:
 
2018N380094_00
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


2013N168152_09
CONFIDENTIAL
200056
350
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
 
2018N380094_00
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


2013N168152_09
CONFIDENTIAL
200056
351
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
352
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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
353
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
354
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
355
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.”
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
356
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):
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
357
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):
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
358
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:
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
359
•
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
360
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
361
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
362
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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
363
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
364
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
365
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
366
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 ().
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
367
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).
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
368
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).  
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
369
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.  
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
370
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
371
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
372
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
373
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
374
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
375
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
376
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
377
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
378
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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
379
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
380
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)
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
381
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
382
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)
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
383
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: 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
384
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
385
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
386
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
387
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
388
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
389
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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
390
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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
391
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
392
(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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
393
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
394
(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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
395
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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
396
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
397
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
398
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.
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
399
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
400
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


2013N168152_09
CONFIDENTIAL
200056
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
402
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
403
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
404
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


2013N168152_09
CONFIDENTIAL
200056
405
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
406
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
407
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
408
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
409
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:  
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
410
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.
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
411
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
412
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
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
413
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.  
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
414
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 
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
415
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.
 
 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
416
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
417

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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
418
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 
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
419
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)
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
420
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
421
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).  
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
422
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
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
423
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
424
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.
 
2018N380094_00


2013N168152_09
CONFIDENTIAL
200056
425
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.
 
2018N380094_00

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
200056
1
Division: World Wide Development
Retention Category: GRS019
Information Type: Reporting and Analysis Plan
Title:
Reporting and Analysis Plan Amendment 5 for study 200056 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
Effective Date:
05-Mar-2018
Description: This reporting and analysis plan contains a description of all planned 
statistical analyses and data summary for study 200056. 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 Screening Period, 20 
week Induction Period utilizing an oral regimen of GSK744 30 mg once daily plus 
ABC/3TC 600/300 mg once daily, Maintenance Period, Extension Period and a Long-
term Follow-up 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. 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.  
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.  Eligible 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. Subject 
randomization will be stratified by subjects’ HIV-1 RNA prior to Week (-8) (<50 c/mL, 
yes or no).   This fifth amendment includes amendments to the originally approved 
RAP and amendments 1, 2, 3 and 4.
Subject: HIV-1 infection, GSK1265744, integrase inhibitor, abacavir, lamivudine, 
rilpivirine, TMC278, TMC278 LA, non-nucleoside reverse transcriptase inhibitor, 
therapy-naive, induction, maintenance, long-acting, LA, once daily, once monthly, every 
other month, Quality of Life, injectable, injection
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
2018N380094_00


CONFIDENTIAL
The GlaxoSmithKline group of companies
200056
2
Author’s Name, Title and Functional Area: 
, Statistician, Clinical Statistics -Infectious Diseases
, Principal Statistician, Clinical Statistics -Infectious Diseases
, Manager Statistics, Clinical Statistics-Infectious Disease
, Principal Statistician, Clinical Statistics - Infectious Diseases
, Clinical Pharmacology Director, Clinical Pharmacology Modelling and 
Simulation
RAP Team Approvals:
Approver
Date
Approval 
Method
02-Mar-2018
Email
Clinical Pharmacology Director (Clinical Pharmacology 
Modelling and Simulation)
20-Feb-2018
Email
Clinical Development Director (Clinical Virology)
26-Feb-2018
Email
SERM Director (Global Clinical Safety and 
Pharmacovigilance)
22-Feb-2018
Email
Clinical Investigative Lead (Clinical Development)
20-Feb-2018
Email
Project Physician Lead (Clinical Development)
 
27-Feb-2018
Email
Clinical Statistics Director (Clinical Statistics – Infectious 
Diseases)
Email
27-Feb-2018
Email
Clinical Development Manager (Clinical Operations)
27-Feb-2018
Email
Principal Clinical Data Manager (Data Management)
 
2018N380094_00
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL
The GlaxoSmithKline group of companies
200056
3
Clinical Statistics and Clinical Programming Line Approvals:
Approver
Date
Approval 
Method
05-Mar-2018
Email
Manager Statistics (Clinical Statistics -Infectious 
Diseases)
05-Mar-2018
Email
Programming Manager (Clinical Programming -
Infectious Diseases)
 
2018N380094_00
PPD
PPD


CONFIDENTIAL
200056
4
TABLE OF CONTENTS
PAGE
ABBREVIATIONS .........................................................................................................10
1.
INTRODUCTION....................................................................................................13
2.
STUDY OBJECTIVE(S) AND ENDPOINT(S) .........................................................18
2.1.
Statistical Hypotheses.................................................................................20
3.
STUDY DESIGN ....................................................................................................21
3.1.
Study Design Schematic.............................................................................21
3.2.
Study Design ..............................................................................................22
3.2.1.
Screening Period .........................................................................22
3.2.2.
Induction Period...........................................................................23
3.2.3.
Maintenance Period.....................................................................23
3.2.4.
Extension Period..........................................................................23
3.2.5.
Long-term Follow-Up Period – IM Regimens only........................24
3.2.6.
Follow Up Visit.............................................................................24
4.
PLANNED ANALYSES ..........................................................................................24
4.1.
Interim and Final Analysis...........................................................................24
4.2.
IDMC Interim Analyses ...............................................................................25
4.3.
Futility Interim Monitoring............................................................................25
4.4.
Day 1 Interim Analysis ................................................................................28
4.5.
Week 32 Primary Analysis ..........................................................................28
4.6.
Week 48 Interim Analysis ...........................................................................28
4.7.
Week 96 Final Analysis...............................................................................28
4.8.
Week 128 Extension Switch Analysis .........................................................29
4.9.
Week 160 Analysis .....................................................................................29
5.
SAMPLE SIZE CONSIDERATIONS.......................................................................29
5.1.
Sample Size Assumptions ..........................................................................29
5.2.
Sample Size Sensitivity...............................................................................31
5.3.
Sample Size Re-estimation.........................................................................32
6.
ANALYSIS POPULATIONS ...................................................................................32
6.1.
Analysis Populations...................................................................................32
6.1.1.
All Subjects Screened Population ................................................32
6.1.2.
Randomized Population...............................................................32
6.1.3.
Intent-to-Treat Exposed Population (ITT-E) .................................33
6.1.4.
Intent-to-Treat Maintenance Exposed Population (ITT-ME) .........33
6.1.5.
Per Protocol Maintenance Exposed Population (PP-ME).............33
6.1.6.
The PP-ME Population may be used for a supporting 
analysis of the primary endpoint. Such a supporting 
analysis will not be performed if the PP-ME Population 
comprises more than 95% of the ITT-ME Population. Per 
Protocol Extension Switch Population (PP-ES)............................33
6.1.7.
PK Population..............................................................................33
6.1.8.
Safety Population.........................................................................34
6.1.9.
Safety Maintenance Population ...................................................34
6.1.10.
Safety Long-Term Follow-up Population ......................................34
 
2018N380094_00


CONFIDENTIAL
200056
5
6.1.11.
Protocol Defined Virologic Failure (PDVF) Genotypic and 
Phenotypic Populations ...............................................................34
6.1.12.
Protocol Defined Virologic Failure (PDVF) Genotypic and 
Phenotypic Maintenance Exposed Populations ...........................34
6.1.13.
Extension Switch Population........................................................34
6.1.14.
Protocol Defined Virologic Failure (PDVF) Genotypic and 
Phenotypic Extension Switch Population .....................................35
6.2.
Analysis Data Sets......................................................................................35
6.2.1.
Missing, Switch or Discontinuation = Failure (Snapshot)..............35
6.2.2.
Observed Case............................................................................35
7.
TREATMENT COMPARISONS..............................................................................35
7.1.
Primary Comparisons of Interest.................................................................35
7.2.
Other Comparisons of Interest....................................................................36
7.3.
Regimen Selection Criteria .........................................................................37
7.3.1.
Efficacy Criteria............................................................................37
7.3.2.
Safety Criteria..............................................................................38
7.4.
Data Display Treatment and Other Sub-group Descriptors .........................39
8.
GENERAL CONSIDERATIONS FOR DATA ANALYSES.......................................41
8.1.
Multicentre Studies .....................................................................................41
8.2.
Other Strata and Covariates .......................................................................41
8.3.
Examination of Subgroups..........................................................................41
8.4.
Multiple Comparisons and Multiplicity .........................................................42
8.5.
Virology ......................................................................................................42
8.6.
Genotype....................................................................................................42
8.7.
Phenotype ..................................................................................................43
9.
DATA HANDLING CONVENTIONS .......................................................................44
9.1.
Premature Withdrawal and Missing Data ....................................................44
9.1.1.
Methods for Proportion Endpoints Based on Plasma HIV-1 
RNA.............................................................................................45
9.1.1.1.
Missing, Switch or Discontinuation = Failure 
(MSDF).......................................................................45
9.1.1.2.
Observed Case (OC)..................................................45
9.1.1.3.
Time to Event Methods...............................................45
9.1.2.
Methods for Health Outcomes Data.............................................45
9.1.3.
Method for Other Laboratory Data ...............................................45
9.1.4.
Methods for Vital Signs and ECG Data........................................46
9.1.5.
Methods for Missing PK Data.......................................................46
9.1.6.
Methods for Missing Dates ..........................................................46
9.1.6.1.
Date of Birth ...............................................................46
9.1.6.2.
Adverse Events ..........................................................46
9.1.6.3.
Concomitant Medications ...........................................47
9.1.6.4.
IP Exposure................................................................47
9.1.6.5.
HIV Condition .............................................................47
9.2.
Derived and Transformed Data...................................................................47
9.2.1.
Age..............................................................................................47
9.2.2.
Baseline and Change from Baseline............................................47
9.2.3.
Corrected QT Intervals.................................................................48
9.2.4.
Exposure .....................................................................................48
9.2.5.
Framingham Risk Equation..........................................................49
 
2018N380094_00


CONFIDENTIAL
200056
6
9.2.6.
Genotype.....................................................................................50
9.2.6.1.
Treatment-Emergent Mutations ..................................51
9.2.7.
Glomerular Filtration Rate (GFR).................................................51
9.2.8.
Hepatitis Status............................................................................51
9.2.9.
Lab Toxicities...............................................................................52
9.2.10.
Missing, Switch or Discontinuation = Failure (Snapshot) 
Algorithm .....................................................................................52
9.2.11.
PK Parameters ............................................................................53
9.2.12.
Plasma HIV-1 RNA......................................................................53
9.2.13.
CD4 .............................................................................................53
9.2.14.
Post-baseline...............................................................................53
9.2.15.
Induction Period Study Day .........................................................53
9.2.16.
Study Day....................................................................................54
9.2.17.
Long-Term Follow Up Study Day .................................................54
9.2.18.
Extension Period Study Day ........................................................54
9.2.19.
Total Cholesterol / HDL Cholesterol Ratio....................................55
9.3.
Study Periods .............................................................................................55
9.3.1.
Treatment State within Study Periods..........................................60
9.4.
Assessment Windows.................................................................................62
9.4.1.
Assessment Window Assignment ................................................62
9.4.2.
Multiple Assessments ..................................................................67
9.4.3.
Invalid Laboratory Assessments ..................................................68
9.4.4.
Classification of Prior, Concomitant, and Post-Therapy 
Medications .................................................................................68
9.5.
Values of Potential Clinical Importance.......................................................71
10. STUDY POPULATION...........................................................................................71
10.1.
Disposition of Subjects................................................................................71
10.2.
Protocol Deviations.....................................................................................72
10.2.1.
Inclusion / Exclusion Criteria........................................................72
10.2.2.
Important Protocol Deviations......................................................72
10.2.3.
Important Protocol Deviations that exclude subject from 
Per protocol population................................................................72
10.3.
Demographic and Baseline Characteristics.................................................74
10.3.1.
Associations between Baseline Characteristics ...........................75
10.4.
Treatment Compliance................................................................................75
10.5.
Concomitant Medications............................................................................75
10.6.
Prior and Concomitant ART ........................................................................76
11. EFFICACY ANALYSES..........................................................................................76
11.1.
Primary Efficacy Analysis: Proportion of Subjects with Plasma HIV-1 
RNA <50 c/mL ............................................................................................77
11.1.1.
Summaries ..................................................................................77
11.1.2.
Main Analysis ..............................................................................77
11.2.
Secondary Efficacy Analyses......................................................................78
11.2.1.
Proportion of Subjects with Plasma HIV-1 RNA <200 c/mL..........78
11.2.2.
Observed Values and Change from Baseline in Plasma 
HIV-1 RNA (log10 c/mL)................................................................78
11.2.3.
Observed Values and Change from Baseline in CD4+ and 
CD8+ Cell Counts........................................................................78
11.2.4.
Virologic Failure...........................................................................79
11.2.5.
Virologic or Tolerability Failure.....................................................79
 
2018N380094_00


CONFIDENTIAL
200056
7
11.2.6.
HIV Associated Conditions ..........................................................79
11.2.7.
HIV Disease Progression.............................................................79
11.2.8.
Proportion of Subjects with Plasma HIV-1 RNA <50 c/mL: 
Q8W vs. Q4W..............................................................................80
11.3.
Other Efficacy Analyses..............................................................................80
11.3.1.
Exploratory Analyses ...................................................................81
12. SAFETY ANALYSES .............................................................................................81
12.1.
Extent of Exposure .....................................................................................82
12.2.
Adverse Events...........................................................................................82
12.3.
Injection Site Reactions ..............................................................................85
12.4.
Deaths and Serious Adverse Events...........................................................85
12.5.
Adverse Events Leading to Discontinuation of Investigational 
Product and/or Withdrawal from the Study and Other Significant 
Adverse Events...........................................................................................85
12.5.1.
Cardiovascular Events.................................................................85
12.5.2.
Possible Suicidality-Related Adverse Event (PSRAE) .................86
12.5.3.
Columbia Suicide Severity Rating Scale (eCSSRS).....................86
12.6.
Pregnancies (as applicable)........................................................................86
12.7.
Clinical Laboratory Evaluations...................................................................86
12.7.1.
Listings ........................................................................................87
12.7.2.
Summaries ..................................................................................87
12.7.2.1.
Summary Statistics.....................................................87
12.7.2.2.
Toxicities ....................................................................87
12.7.2.3.
Qualitative Urinalysis Results .....................................88
12.7.3.
Figures ........................................................................................88
12.8.
Other Safety Measures...............................................................................89
12.8.1.
12-Lead ECG...............................................................................89
12.8.2.
Vital Signs....................................................................................89
12.8.3.
Abacavir Hypersensitivity Reaction (HSR) ...................................89
12.8.4.
Liver Events.................................................................................89
13. HEALTH OUTCOMES ANALYSES........................................................................90
13.1.
Humanistic Measures .................................................................................90
13.1.1.
Injection Site Reaction and Subject Activity .................................90
13.1.2.
The HIV Treatment Satisfaction Questionnaire (HIVTSQ)............90
13.1.3.
The HIV Medication Questionnaire (HIVMQ) ...............................92
14. CLINICAL PHARMACOLOGY DATA ANALYSES..................................................93
14.1.
Pharmacokinetic Analyses..........................................................................93
14.1.1.
Drug Concentration Measures .....................................................93
14.1.2.
Deriving and Summarizing Pharmacokinetic Parameters.............94
14.1.3.
Statistical Analyses......................................................................95
14.1.3.1.
Assessment of steady state........................................95
14.2.
Population PK Analysis:..............................................................................96
14.3.
Pharmacokinetic/Pharmacodynamic Analyses............................................96
14.3.1.
Exposure-Antiviral Activity Analysis .............................................96
14.3.2.
Exposure-Immunology Analysis...................................................96
14.3.3.
Exposure-Toxicity Analysis ..........................................................96
15. VIRAL GENOTYPING/PHENOTYPING .................................................................97
15.1.
Genotype....................................................................................................97
 
2018N380094_00


CONFIDENTIAL
200056
8
15.2.
Phenotype ..................................................................................................97
16. References.............................................................................................................98
17. ATTACHMENTS ....................................................................................................99
17.1.
Table of Contents for Data Display Specifications – Day 1 .........................99
17.1.1.
Study Population – Day 1 ............................................................99
17.1.1.1.
Tables ......................................................................100
17.1.1.2.
ICH Listings..............................................................100
17.1.1.3.
Other Listings ...........................................................100
17.1.2.
Efficacy –Day 1..........................................................................100
17.1.2.1.
Tables ......................................................................101
17.1.2.2.
Figures .....................................................................101
17.1.2.3.
ICH Listings..............................................................101
17.1.2.4.
Other Listings ...........................................................102
17.1.3.
Safety – Day 1 ...........................................................................102
17.1.3.1.
Tables ......................................................................102
17.1.3.2.
Figures .....................................................................103
17.1.3.3.
ICH Listings..............................................................103
17.1.3.4.
Other Listings ...........................................................104
17.2.
Table of Contents for Data Display Specifications – Week 
32/48/96/128.............................................................................................105
17.2.1.
Study Population – Week 32/48/96/128.....................................105
17.2.1.1.
Tables ......................................................................106
17.2.1.2.
ICH Listings..............................................................108
17.2.1.3.
Other Listings ...........................................................109
17.2.2.
Efficacy – Week 32/48/96/128 ...................................................110
17.2.2.1.
Tables ......................................................................110
17.2.2.2.
Figures .....................................................................115
17.2.2.3.
ICH Listings..............................................................116
17.2.2.4.
Other Listings ...........................................................117
17.2.3.
Safety – Week 32/48/96/128......................................................117
17.2.3.1.
Tables ......................................................................118
17.2.3.2.
Figures .....................................................................130
17.2.3.3.
ICH Listings..............................................................132
17.2.3.4.
Other Listings ...........................................................133
17.2.4.
Health Outcome – Week 32/48/96 .............................................135
17.2.4.1.
Tables ......................................................................136
17.2.4.2.
Figures .....................................................................138
17.2.4.3.
Other Listings ...........................................................138
17.2.5.
PK - Week 32/48/96/128............................................................139
17.2.5.1.
Tables ......................................................................139
17.2.5.2.
Figures .....................................................................141
17.2.5.3.
ICH Listings..............................................................142
17.2.6.
PK/PD- Week 32/48/96/128.......................................................143
17.2.6.1.
Tables ......................................................................143
17.2.6.2.
PK/PD Figures..........................................................144
17.2.7.
Virology- Week 32/48/96/128.....................................................144
17.2.7.1.
Tables ......................................................................144
17.2.7.2.
Other Listings ...........................................................146
17.3.
Table of Contents for Data Display Specifications – Week 160.................147
17.3.1.
Study Population Tables............................................................147
 
2018N380094_00


CONFIDENTIAL
200056
9
17.3.2.
Efficacy Tables ..........................................................................150
17.3.3.
Efficacy Figures .........................................................................153
17.3.4.
Safety Tables.............................................................................154
17.3.5.
Safety Figures ...........................................................................166
17.3.6.
Pharmacokinetic Tables.............................................................168
17.3.7.
Pharmacokinetic Figures ...........................................................169
17.3.8.
Virology Tables..........................................................................170
17.3.9.
ICH Listings ...............................................................................172
17.3.10. Non-ICH Listings........................................................................175
17.4.
Data Display Specifications ......................................................................181
17.5.
MSDF (Snapshot) Algorithm in Detail .......................................................181
 
2018N380094_00


CONFIDENTIAL
200056
10
ABBREVIATIONS
3TC
Lamivudine, Epivir
ABC
Abacavir, Ziagen
AE
Adverse Event
AIC
Akaike Information Criteria
AIDS
Acquired immunodeficiency syndrome
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
ANOVA
Analysis of Variance
ART
Antiretroviral Therapy
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical
AUC
Area Under the Curve
AUC(0 – τ)
Area under the plasma drug concentration-time curve from 
pre-dose to the end of the dosing interval at steady state
BUN
Blood urea nitrogen
C0
Pre-dose Concentration
Cτ
Concentration at the end of a dosing interval
c/mL
Copies/milliliter
CDC
Centers for disease control and prevention
CDM
Clinical Data Management
CI
Confidence Interval
CL/F
Apparent Oral Clearance
Cmax
Maximum plasma drug concentration
Cmin
Minimum plasma drug concentration
CMV
Cytomegalovirus
CNS
Central Nervous System 
CPK
Creatine Phosphokinase
CPMS
Clinical Pharmacology Modeling and Simulation
CSR
Clinical Study Report
CVb
Coefficient of Variation for Geometric Mean
dL
Deciliter
DAIDS
Division of Acquired Immunodeficiency Syndrome
DNA
Deoxyribonucleic acid
DTG
Dolutegravir
eCRF
Electronic case report form
Emax
Maximal Effect
ECG
Electrocardiograph
eCSSRS
Electronic Columbia Suicidality Severity Rating Scale
EFV
Efavirenz
ELV
Elvitegravir
FC
Fold change
FDA
US Food and Drug Administration
FDC
Fixed dose combination
FTC
Emtricitabine, Emtriva
 
2018N380094_00


CONFIDENTIAL
200056
11
GFR
Glomerular Filtration Rate
GI
Gastrointestinal
GSK
GlaxoSmithKline
H0
Null Hypothesis
H1
Alternative Hypothesis
HBV
Hepatitis B Virus
HGB
Hemoglobin
HCV
Hepatitis C Virus
HDL
High Density Lipoprotein
HIV-1
Human Immunodeficiency Virus Type 1
HPD
Highest Posterior Density
HR
Heart Rate
HSR
Abacavir Hypersensitivity Reaction
IAS
International AIDS Society
IB
Investigator’s Brochure
IDSL
Integrated Data Standards Library
INI
Integrase Inhibitor
INR
International Normalized Ratio
IP
Investigational Product
iSRC
Internal Safety Review Committee
ITT-E
Intent-to-Treat Exposed
ITT-ME
Intent-to-Treat Maintenance Exposed
IU
International Unit
kg
Kilogram
L
Liter
LDL
Low Density Lipoprotein
LLQ
Lower Limit of Quantification
LOCF
Last Observation Carried Forward
LVH
Left ventricular hypertrophy
MCV
Mean Corpuscle Volume
MCH
Mean Corpuscle Hemoglobin
MCHC
Mean Corpuscle Hemoglobin Concentration
MedDRA
Medical Dictionary for Regulatory Activities
MSDF
Missing, Switch, Discontinuation equals Failure
mg
Milligram
mL
Milliliter
NCEP
National Cholesterol Education Program
NNRTI
Non-nucleoside reverse transcriptase inhibitor
NQ
Not Quantified
NRTI
Nucleoside reverse transcriptase inhibitor
OC
Observed case
PD
Pharmacodynamic
PI
Protease Inhibitor
PK
Pharmacokinetics
PO
Taken Orally
PP
Per Protocol
 
2018N380094_00


CONFIDENTIAL
200056
12
PP-M
Per Protocol Maintenance
PRO
Protease
PT
Prothrombin Time
PTT
Partial Thromboplastin Time
QTc
Corrected QT interval
RAL
Raltegravir, Isentress, MK-0518
RAP
Reporting analysis plan
RBC
Red Blood Count
REML
Restricted Maximum Likelihood
RNA
Ribonucleic acid
ROC
Receiver Operating Characteristic
RPV
Rilpivirine hydrochloride
RT
Reverse transcriptase
RUCAM
Roussel Uclaf Causality Assessment Method
SAE
Serious adverse event
SD
Standard Deviation
SIA
Suicidal Indication Alert
SOC
System organ class
t1/2
Estimated terminal phase half-life
τ
Dosing interval, time between consecutive doses
TDF
Tenofovir disoproxil fumarate, Viread
tlag
Time between dosing and detectable plasma concentrations
tmax
Time at which Cmax was observed
tmin
Time at which Cmin was observed
TSH
Thyroid Stimulating Hormone
TST
Therapeutic Area Standard
ULN 
Upper limit of normal
US/USA
United States/United States of America
WBC
White Blood Count
WT
Wild type virus
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks 
not 
owned 
by 
the 
GlaxoSmithKline group of companies
EPZICOM
SAS
KIVEXA
WinNonlin
 
2018N380094_00


CONFIDENTIAL
200056
13
1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to provide details of planned 
analyses and data displays for reporting results of study 200056. These analyses may be 
included in regulatory submissions, study reports, and publications.
In the first amendment to the RAP originally effective 19-FEB-2015, the following 
changes were made: adding the pre-specified dose regimen selection criteria for the Week 
32 primary analysis, adding updated data displays for injection site reaction adverse 
events, adding details for the efficacy assessment of the comparability between the IM 
regimens (see Section 8.3.3.2 of the protocol), removing the correlation analysis for 
snapshot response and the HIVMQ response of medication adherence, removing 
subscales for the HIVTSQ questionnaire; added supportive pk concentration data displays 
excluding 
non-evaluable 
concentrations,
and 
other
additional 
miscellaneous 
clarifications.
In the second amendment to RAP amendment #1 effective 18-SEP-2015, the following 
changes were made prior to the Week 48 interim analysis:

Correction to the formula for the CKD-EPI GFR derivation (Section 9.2.7); 
previous formula had ‘min and min’ which has been corrected to ‘min and max’;

Added further subdivision of the second Baseline HIV-1 RNA subgroup (Section 
8.3); replacing ‘100,000’ with ‘100,000 to <200,000; 200,000’;

Addition of a figure to summarize the proportion of subjects with virologic failure
by visit based on the Snapshot (MSDF) algorithm (Section 11.3 and Section 
17.2.2.2);

Addition of an exploratory summary of the proportion of subjects with plasma
HIV-1 RNA <2 copies/mL by visit (observed case dataset) according to the 
BioMontr low-level assay (Section 11.3.1 and Section 17.2.2.1, Section 17.2.2.4)

Removed the following PK table from the Table of Contents for Data Displays 
(Section 17.2.5.1): Summary of Results of GSK1265744 PK Parameters 
Comparison between Induction and Maintenance Phase; 

Added additional tables to summarize PK concentrations using log-transformed 
statistics (Section 14.1.1 and Section 17.2.5).

Removed ‘Listing of Positive eCSSRS Findings’ from Section 17.2.3.4 and added 
the following tables to Section 17.2.3.1: ‘Listing of eCSSRS Suicidal Ideation and 
Behaviour Data For Subjects With at least One Positive Response for Suicidal 
Indication Alert’, ‘Listing of eCSSRS Suicidal Behaviour Details For Subjects 
With at least One Positive Response for Suicidal Indication Alert’, ‘Listing of 
eCSSRS Details of Most Severe Suicidal Ideation For Subjects With at least One 
Positive Response for Suicidal Indication Alert’
 
2018N380094_00


CONFIDENTIAL
200056
14

Removed ‘Listing of Possible Suicidality-Related Adverse Event Data: Event and 
Description’ from Section 17.2.3.4 as this is already included in Section 17.2.3.1. 

Removed ‘Summary of Maintenance Period Adverse Events Leading to 
Withdrawal/Permanent Discontinuation of Investigational Product’ from Section 
17.2.3.1 as this duplicates information contained in the ‘Summary of Adverse 
Events Leading to Withdrawal/Permanent Discontinuation of Investigational 
Product’ table.
The analyses detailed in this document are based on the protocol of study 200056 
effective on 13 June 2014.
In the third amendment to RAP amendment #2 effective 27-JAN-2016, the following 
changes were made prior to the Week 96 interim analysis based on the protocol 
amendment #5 effective on 21-JUN-2016:

Updated study design schematic, objectives, and IDMC monitoring plan to align 
with updates contained within protocol amendment #5 (mostly notably: 
Q8W/Q4W arms to continue into Extension, Oral arm subjects to switch form 
oral treatment to optimized IM regimen treatment for the Extension Period).

Added Extension Switch Population to align with Protocol Amendment #5;

Updates to period slotting and visit slotting to address transition into the 
Extension period;

Updates to certain study population and safety data displays to align with recent 
updates to core IDSL data display standards;

Addition of a limited number of new displays to include Extension period data
(see Section 17.2  Table of Contents for Data Display Specifications – Week 
32/48/96)

Addition of ‘observed case’ efficacy summary of the proportion of subjects with 
plasma HIV-1 RNA level below 50 copies/mL by treatment group and visit;

Addition of data listing of quantitative plasma HIV-1 RNA data for subjects with 
HIV-1 RNA ≥ 50 c/mL at any time during the Maintenance Period or Extension 
Period;

Addition on statistical analysis of HIVTSQs updated total score and individual 
item scores;

Addition of summary of HIVMQ results combining separate responses for CAB 
LA and RPV LA into a combined score;

Addition of limited PK tables/listings of LTFU period data;
 
2018N380094_00


CONFIDENTIAL
200056
15

Addition of fold-changes results for DTG and EVG in summary tables of 
phenotypic data;

Addition of new treatment group descriptors for data displays including extension 
period data;

Updated Section 6.1.8 and Section 6.1.9 to clarify that the Safety Population is 
used for safety analyses of induction period data and that the Safety Maintenance 
Population is used as the primary population for safety analyses (except for 
induction period data).

Other miscellaneous (title updates and re-numbering of data displays) in Section 
17.2  Table of Contents for Data Display Specifications – Week 32/48/96.
In this fourth amendment to RAP amendment #3 effective 09-DEC-2016, the following 
changes were made prior to the Week 128 Extension Switch analysis based on the 
protocol amendment #5 effective on 21-JUN-2016:

Added displays for the W128 Extension Switch reporting effort, focusing on the 
Extension Switch Population during the Extension Period up to Week 128.

Added the definition for “Protocol Defined Virologic Failure (PDVF) Genotypic 
and Phenotypic Extension Switch Population” in Section 6.1.14 for analysis of 
Extension Period On-treatment and treatment-emergent genotype and phenotype.

Added in Table 7 the “Total – Optimized IM” group in Section 7.4

Updated in Section 9 that starting from the Week 96 analysis, SAS Version 9.4 is 
used for data manipulations, tabulations, and calculations.

Added in Section 9.2.2 the definition of baseline value for the Extension Switch 
Population during the Extension Period.

Updated in Section 9.2.4 that a subject’s exposure can be presented in “number of 
injections” to investigational product in addition to in “days”

Updated in Section 9.2.17 the derivation of “Long-Term Follow Up (LTFU) 
Study Day” of an event.

Updated example b in Section 9.3 that the subject is Q4W rather than 
“Q4W/Q8W”.

Updated the Extension Period Assignment rule in Table 15 in Section 9.3.

Update the date rage for study period assignment for Q4W/Q8W randomized 
subjects not receiving Extension period IP injection in Table 16 in Section 9.3.

Updated the rule for Extension Period Day 1 assessment window assignment, and 
removed the “Week 121” nominal visit in Table 23 in Section 9.4.1.
 
2018N380094_00


CONFIDENTIAL
200056
16

Updated the rules for LTFU Assessment Window assignment in Table 25 in 
Section 9.4.1.

Added Table 26 to define the Assessment Windows for summary of snapshot 
(MSDF) data at key analysis time points for the Extension Switch Population.

Updated in Section 12.7.2.2 the definition of Extension Period emergent 
toxicities.

Added sampling windows for evaluable Extension Period PK concentrations for 
the Extension Switch Population in Table 31 in Section 14.1.1.

Updated that for the Week 128 analysis, PK parameters will not be produced, and 
that the steady state analysis will not be performed given the small sample size in 
the Extension Switch Population as well as evidence from the Maintenance Phase 
that achievement of steady state occurred more than 28 weeks on LA treatment.

Updated that the subsequent analysis to the W128 analysis will be at Week 160 
instead of Week 152.
In this fifth amendment to RAP amendment #4 effective 30-Aug-2017, the following 
changes and minor administrative corrections were made prior to the Week 160 analysis 
based on the protocol amendment #7 effective on 16-Nov-2017:

Added displays for the W160 reporting effort to characterize the long-term safety 
and efficacy profile for the randomized Q8W/Q4W IM population during the 
Maintenance and Extension Period, as well as for the Extension Switch 
Population during the Extension Period.

Updated in Section 6.1.7 that the PK population will include all subjects who 
receive IP and undergo PK sampling during the study, and provide available
GSK1265744 and /or TMC278 plasma concentration data.  

Added the definition for “Protocol Defined Virologic Failure (PDVF) Genotypic 
and Phenotypic Maintenance Exposed Population” in Section 6.1.12 for analysis 
of Maintenance and Extension Period genotype and phenotype at the time of 
PDVF.

Updated in Section 7.4 that for the W160 analysis, descriptor “IM – Total” will be 
used instead of “Subtotal – IM” unless otherwise noted.

Updated in Table 26 the assessment windows for summary of snapshot (MSDF) 
data at W160 for the Extension Switch Population.

Added in Table 27 the assessment windows for summary of snapshot (MSDF) 
data at W160 for the randomized IM subjects who continued Q8W/Q4W IM 
dosing during the Extension Period 
 
2018N380094_00


CONFIDENTIAL
200056
17

Updated in Section 9.1.1.2 that the observed case viral load for assessment is the 
value that is closest to the target date.

Updated in Table 23 the assessment window assignment of the Extension Period 
data to the Follow Up Period for the Extension Switch Subjects

Updated in Section 12.7.2.2 the definition of treatment emergence relative to 
induction baseline and relative to maintenance baseline.
This RAP is based on the standard operating procedure SOP_54838 (formerly SOP-
WWD-4000) v03, effective 28 September 2007, regarding the Development, Review and 
Approval of Reporting and Analysis Plans. This RAP was written using the document 
standard INS_51933 (formerly INS-WWD-4000) v04, effective 26 June 2008. Any 
deviation(s) from this RAP will be described in the clinical study report (CSR).
 
2018N380094_00


CONFIDENTIAL
200056
18
2.
STUDY OBJECTIVE(S) AND ENDPOINT(S)
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
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.
 
2018N380094_00


CONFIDENTIAL
200056
19
Objective
Endpoint
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 
PK and to explore PK-PD relationships.  
Plasma PK parameters for GSK744 LA and 
TMC278 LA (Ctrough, 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.
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 
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 
 
2018N380094_00


CONFIDENTIAL
200056
20
Objective
Endpoint
therapy at the end of the Maintenance 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 160 for subjects who 
continued randomized IM dosing in the 
Extension Period.
<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.
2.1.
Statistical Hypotheses
The study is designed to evaluate the efficacy 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 IM every 8 weeks, relative to GSK744 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 for each of the IM 
regimen:
H0: Response rate for GSK744 LA plus TMC278 LA two-drug regimen GSK744 
plus ABC/3TC -10%
H1: Response rate for GSK744 LA plus TMC278 LA two-drug regimen > GSK744 
plus ABC/3TC -10%
 
2018N380094_00


CONFIDENTIAL
200056
21
3.
STUDY DESIGN
3.1.
Study Design Schematic
Induction Period
 
2018N380094_00


CONFIDENTIAL
200056
22
Maintenance and Extension Period
3.2.
Study Design
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 IM subjects only). 
A subject is considered to have completed the study if they complete the Induction and 
Maintenance Period through Week 96.
3.2.1.
Screening Period
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.  
 
2018N380094_00


CONFIDENTIAL
200056
23
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 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. 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.
Maintenance Period
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 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).
3.2.4.
Extension Period
Both IM randomized dosing regimens (Q8W and Q4W) will continue to be evaluated in 
the Extension period.  Subjects who successfully complete 96 weeks of CAB 30 mg + 
ABC/3TC treatment in the Maintenance Period with an undetectable HIV-1 RNA (<50 
c/mL) at the Week 96 visit will have the option of continuing study participation by 
switching to an optimized IM dosing regimen of their choice (either Q8W or Q4W).
Subjects who successfully complete 96 weeks of CAB LA + RPV LA treatment (Q8W or 
Q4W) in the Maintenance Period 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.  
 
2018N380094_00


CONFIDENTIAL
200056
24
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.  See 
protocol for eligibility criteria for the Extension Period for subjects entering from the 
CAB 30 mg + ABC/3TC arm and details regarding the optimized IM dosing regimens.  
Subjects not eligible to enter the Extension Period will end their study participation.
3.2.5.
Long-term Follow-Up Period – IM Regimens only
Any subject who receives at least a single dose of GSK744 LA and/or TMC278 LA and 
discontinues 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.  This period is considered study participation and subjects will be 
followed on study during this time.
3.2.6.
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.  This visit is not required for subjects in the Long-Term Follow Up Period.
4.
PLANNED ANALYSES
4.1.
Interim and Final 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.  
The first IDMC planned in the protocol was based on the estimated enrolment period of 6 
months.  Thus at the first interim analysis the IDMC should evaluate the efficacy, safety 
and tolerability of GSK1265744 to determine if the GSK1265744 regimen is suboptimal 
such that it should be discontinued before all subjects transition into the Maintenance 
Period of the study. Due to the rapid enrolment, study recruitment finished in 3 months, 
the first IDMC review will be after all subjects have transitioned to 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 GSK1265744.  As no hypothesis is being tested 
 
2018N380094_00


CONFIDENTIAL
200056
25
for rejection during the constant monitoring of virologic response, no adjustment for 
multiplicity will be performed.
4.2.
IDMC Interim Analyses
The purpose of these analyses is for the Independent Data Monitoring Committee 
(IDMC) to evaluate the efficacy, safety and tolerability of GSK1265744 at early time 
points in the study. Due to the rapid enrolment of study, the first IDMC review will be 
after all subjects have transitioned to 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, with IDMC agreement.
All of the IDMC reviews will be produced by a Statistics and Data Analysis Centre 
(SDAC).  
4.3.
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 1), 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. 
 
2018N380094_00


CONFIDENTIAL
200056
26
Table 1
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 virologic 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 
protocol 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 
virologic failures 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 virologic 
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 experiencing virologic failure. 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 (Optimized Q8W or Optimized 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 2) prior to all subjects completing Week160, 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. 
 
2018N380094_00


CONFIDENTIAL
200056
27
Table 2
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 a Bayesian 
posterior probability approach will be applied to assess the probability that an 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 3 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 3
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 discontinue the IM treatment arm at the 
interim analysis if the true response rates are 92% and 72% for the oral arm and IM arm, 
respectively.  The power to discontinuing the IM treatment arm is 46% if the true 
response rates are 92% and 82% for the oral arm and IM arm, respectively.  The chance 
 
2018N380094_00


CONFIDENTIAL
200056
28
of discontinue the IM treatment in error is 2% if the true response rates are 92% for both 
the oral arm and IM arm.
4.4.
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. One data cut when all subjects
have completed Day 1 visit will be used for both the first IDMC review and Day 1 
interim analysis, data from the Maintenance Period will be included in the IDMC review 
but will not be summarized or listed for the Day 1 interim analysis.  
4.5.
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.
4.6.
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.
4.7.
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 and 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.
 
2018N380094_00


CONFIDENTIAL
200056
29
4.8.
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 Maintenance Period.
4.9.
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 
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 Maintenance 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.
5.
SAMPLE SIZE CONSIDERATIONS
5.1.
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 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% of subjects 
enrolled will be suppressed at Week (-16), therefore, initially 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 oral 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 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 
 
2018N380094_00


CONFIDENTIAL
200056
30
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 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 4.
Table 4
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 1.
 
2018N380094_00


CONFIDENTIAL
200056
31
Figure 1
Plot of Prior Distribution for Response Rate for GSK744 LA plus 
TMC278 LA two-drug regimen and GSK744 plus ABC/3TC
5.2.
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 2.
 
2018N380094_00


CONFIDENTIAL
200056
32
Figure 2
Operating Characteristic Curve of Probability of Positive Outcome of 
GSK744 LA plus TMC278 LA two-drug regimen and GSK744 plus 
ABC/3TC
5.3.
Sample Size Re-estimation
No sample size re-estimation is planned for this study.
6.
ANALYSIS POPULATIONS
6.1.
Analysis Populations
6.1.1.
All Subjects Screened Population
The All Subjects Screened population will consist of all subjects screened for inclusion in 
the study.
6.1.2.
Randomized Population
The Randomized population will consist of all subjects who are randomized in the study 
and will be used for select Study Population data listings.
 
2018N380094_00


CONFIDENTIAL
200056
33
6.1.3.
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 (i.e., withdrawn from the 
Induction Period or not eligible for randomization into the Maintenance Period) will be 
summarized together under a ‘Not Randomized’ category.  The ITT-E population will be 
the secondary population for some efficacy analyses.  
6.1.4.
Intent-to-Treat Maintenance Exposed Population (ITT-ME)
The ITT-ME population consists of all randomized subjects who receive at least one 
injection or one dose of IP during the Maintenance Period of the study (on or after Day 1 
visit).  Subjects who discontinue during the Induction Period or are not eligible to be 
randomized into the Maintenance Period will not be included in the ITT-ME population. 
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.
6.1.5.
Per Protocol Maintenance Exposed Population (PP-ME)
This population will consist of subjects in the ITT-ME population with the exception of 
those with protocol deviations as described in Section 10.2.3 before a specified analysis 
timepoint.  For example, a subject with such a protocol deviation between Week 32 and 
Week 48 would not be excluded due to this deviation from the Week 32 PP-ME
Population, but would be excluded from the Week 48 PP-ME Population. 
6.1.6.
The PP-ME Population may be used for a supporting analysis of 
the primary endpoint. Such a supporting analysis will not be 
performed if the PP-ME Population comprises more than 95% of 
the ITT-ME Population. Per Protocol Extension Switch Population 
(PP-ES)
This population will consist of subjects in the Extension Switch population with protocol 
deviations as described in Section 10.2.3 on or after the first administration of IM loading 
dose (Week 100).
The PP-ES Population may be used for a supporting analysis of the Week 128 interim
and the Week 160 endpoints. Such a supporting analysis will not be performed if the PP-
ES Population comprises more than 95% of the Extension Switch Population.
6.1.7.
PK Population
The PK Population will include all subjects who receive GSK1265744 and / or TMC278 
and undergo PK sampling during the study, and provide available GSK1265744 and /or 
TMC278 plasma concentration data.  Subjects in this population will be included in the 
PK analysis. 
 
2018N380094_00


CONFIDENTIAL
200056
34
6.1.8.
Safety Population
The Safety Population consists of all enrolled subjects who received at least one dose of 
IP.   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.  
All safety analyses of induction period data will be produced using the safety population.
6.1.9.
Safety Maintenance Population
The Safety Maintenance Population consists of all subjects who entered the Maintenance 
period and received at least one dose of IP. Subjects will be analyzed according to the 
actual treatments received.  The safety maintenance population will be the primary 
population for safety analysis (with the exception of induction period data).  
6.1.10.
Safety Long-Term Follow-up Population
The Safety Long-Term Follow-up Population consists of all subjects receiving at least 
one dose of GSK744 LA and/or TMC278 LA who have discontinued IP/withdrawn from 
maintenance period and have a least one Long-Term Follow-up period clinic visit.  
Subjects will be analyzed according to the actual treatments received during the 
maintenance period.  This population will be used to produce additional safety displays of 
long-term follow-up period data. 
6.1.11.
Protocol Defined Virologic Failure (PDVF) Genotypic and 
Phenotypic Populations
The PDVF Genotypic and Phenotypic populations will consist of all subjects in the ITT-
E population with available On-treatment genotypic and phenotypic resistance data, 
respectively, at time of protocol defined virologic failure. These populations will be used 
for analysis of On-treatment and treatment-emergent genotype and phenotype.
6.1.12.
Protocol Defined Virologic
Failure (PDVF) Genotypic and 
Phenotypic Maintenance Exposed Populations
The PDVF Genotypic and Phenotypic Maintenance Exposed populations will consist of 
all subjects in the ITT-ME population with available genotypic and phenotypic resistance 
data, respectively, at the time of protocol defined virologic failure.  These populations 
will be used for the W160 analysis.
6.1.13.
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.
 
2018N380094_00


CONFIDENTIAL
200056
35
6.1.14.
Protocol Defined Virologic Failure (PDVF) Genotypic and 
Phenotypic Extension Switch Population
The PDVF Genotypic and Phenotypic Extension Switch population will consist of all 
subjects in the Extension Switch population with available on-treatment genotypic and 
phenotypic resistance data, respectively, at time of protocol defined virologic failure
during the Extension Period.  This population will be used for analysis of Extension 
Period on-treatment and treatment-emergent genotype and phenotype.
6.2.
Analysis Data Sets
6.2.1.
Missing, Switch or Discontinuation = Failure (Snapshot)
Subjects’ responses (e.g., <50 c/mL) will be calculated according to the FDA’s snapshot 
algorithm.  This algorithm treats all subjects without HIV-1 RNA data at the visit of 
interest (due to missing data or discontinuation of IP prior to visit window) as non –
responders, as well as subjects who switch their concomitant ART prior to the visit of 
interest as follows:

Background ART substitutions not permitted per protocol;

Background ART substitutions permitted per protocol but prescribed while not 
suppressed (e.g., HIV-1 RNA ≥ 50 copies/mL based on last viral load at time of 
decision to switch), unless the decision to switch is documented as being on or before 
the first on-treatment visit where HIV-1 RNA is assessed.
Otherwise, virologic success or failure will be determined by the last available HIV-1 
RNA assessment while the subject is on-treatment within the visit of interest window 
(Section 9.4).
See Section 9.2.10 for full details of this MSDF algorithm.
6.2.2.
Observed Case
The observed case (OC) dataset uses only the data that is available at a particular 
timepoint, with no imputation for missing values. This data will be used for safety 
analyses, sensitivity analyses and analysis of health outcome endpoints, and certain 
efficacy summaries (e.g. HIV-associated conditions, HIV-1 RNA and CD4 over time).
7.
TREATMENT COMPARISONS
7.1.
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 
 
2018N380094_00


CONFIDENTIAL
200056
36
probability of (Response rate for IM arm Response rate for Oral arm -10%) will be 
calculated.
7.2.
Other Comparisons of Interest
The analysis described in Section 7.1 will also be performed using the PP-ME population 
if the PP-M Population comprises less than 95% of the ITT-ME Population. The results 
will be compared for consistency with the results from the ITT-ME population.  
The probability that the Q8W treatment arm is comparable to Q4W treatment arm will be 
provided using the Bayesian probability model for the proportion of subjects with plasma 
HIV-1 RNA level below 50 c/mL at Week 32 based on the MSDF algorithm. The 
posterior probability of comparability between two IM treatment arms will be produced, 
as follows:
Let:
XQ8W = number of responders in the Q8W IM arm, and 
XQ4W = number of responders in the Q4W IM arm.
The binomial distribution is the assumed likelihood of the response data, as follows:
XQ8W ~ Binomial (NQ8W, PQ8W)  
XQ4W ~ Binomial (NQ4W, PQ4W)  
where XQ8W and XQ4W are the number of responders out of NQ8W or NQ4W subjects 
randomized to the Q8W IM  or Q4W IM arms in the ITT-ME population, respectively, 
and PQ8W and PQ4W are parameters for the response probabilities for each arm.
For this analysis, the posterior probability of comparability in response rates for each IM 
arm is:
P2 = P (|PQ8W  − PQ4W| < 0.1 | data)
where the following non-informative prior conjugate beta densities for the true response 
rates:
PQ8W ~ Beta (1, 1)
PQ4W ~ Beta (1, 1).
A posterior probability of at least 90% (i.e., P2 >0.90) corresponds to “substantial 
evidence of positive outcome” and is chosen as the weight of evidence threshold for 
concluding that the two IM dosing regimens are equivalent.
The probability to meet this equivalence criterion as a function of the true response rates 
and N=110 per arm (updated approximate sample size based on actual enrolment in the 
 
2018N380094_00


CONFIDENTIAL
200056
37
maintenance period) is presented in Table 5.  If the true response rates for Q8W and 
Q4W regimens are both equal to 92%, then the probability of correctly concluding that 
the two IM regimens are equivalent is approximately 0.85.  A response rate of 82% in the 
Q8W regimen compared with response rate of 92% for the Q4W regimen (or vice versa) 
would result in an erroneous conclusion of equivalence with a probability of
approximately 0.10 (type I error).
Table 5
Probability of Concluding Equivalence between Q4W and Q8W IM 
Arms (N=110 per arm)
True Response Rate for Q4W
True Response Rate for Q8W
88%
90%
92%
94%
96%
78%
0.092a
0.043
0.017
0.0049
0.0011
80%
0.18
0.096a
0.044
0.016
0.0042
82%
0.30
0.19
0.10a
0.044
0.014
84%
0.45
0.33
0.21
0.11a
0.044
86%
0.59
0.51
0.37
0.23
0.11a
88%
0.68
0.67
0.57
0.42
0.25
90%
0.68
0.77
0.75
0.64
0.47
92%
0.58
0.76
0.85
0.84
0.72
94%
0.42
0.65
0.84
0.93
0.91
96%
0.25
0.47
0.72
0.91
0.98
a.
Type I error 
7.3.
Regimen Selection Criteria
The Week 32 primary analysis will be used to select an IM dosing regimen for further 
development.  Regimen selection will be based primarily on antiviral activity in 
conjunction with safety, tolerability, treatment satisfaction, virologic resistance and PK 
measures. Data from the Week 48 analysis will be used to confirm regimen selection.
The criteria that follow are guidelines selected to rule out a regimen in the absence of 
unexpectedly strong evidence in its favour from other endpoints. Regimen selection will 
take all efficacy, safety, health outcomes and pharmacokinetic data into consideration. 
However, the number of endpoints collected in this study and therefore being considered 
for regimen-selection preclude the pre-specification of go/no go thresholds for every 
endpoint.  Consequently, these criteria are being pre-specified for a limited number of 
key endpoints: the primary efficacy comparison assessing comparability to the oral 
control arm, and four key measures for assessing the safety profile of the IM dosing 
regimens.  Efficacy and Safety criteria will be assessed using the ITT-ME and Safety-ME 
populations, respectively.
7.3.1.
Efficacy Criteria
An IM dosing regimen failing to demonstrate comparability to the oral arm in the primary 
efficacy analysis (See Section 8.3.3.1 of the protocol) will not be considered for further 
study unless safety or tolerability concerns rule out the other IM regimen or there is 
compelling evidence that the failures were not related to CAB exposure.  Additionally, an 
IM regimen will not be ruled out based on efficacy if the primary comparison of interest 
 
2018N380094_00


CONFIDENTIAL
200056
38
is deemed underpowered due to a lower than expected observed response rate for the oral 
control arm.  
If both IM regimens are shown to be comparable to the oral control arm in the primary 
comparison (or indeterminate for reasons mentioned above), then the Q8W regimen will 
be selected for further evaluation.
7.3.2.
Safety Criteria

The proportion of subjects with Grade 3 or 4 injection site reaction related adverse 
events (AEs) occurring on-treatment during the Maintenance Period.  An IM dosing 
regimen on which ≥ 14% more subjects (approximately 15 or more subjects)
experience such events relative to the other IM regimen will not be considered for 
further study.  

The proportion of subjects Grade 3 or 4 non-injection site reaction related AEs 
occurring on-treatment during the Maintenance Period.  An IM dosing regimen on 
which ≥ 9% more subjects (approximately 10 or more subjects) experience such 
events relative to the other IM dosing regimen will not be considered for further 
study, unless there is compelling evidence that the differences observed were not 
related to CAB exposure (e.g. based on evaluation of exposure/toxicity relationships, 
see Section 14.3.3).

The proportion of subjects with any serious adverse events (SAE) occurring on-
treatment during the Maintenance Period.  An IM dosing regimen on which ≥ 9% 
more subjects (approximately 10 or more subjects) experience any serious adverse 
event relative to the other IM dosing regimen will not be considered for further study, 
unless there is compelling evidence that the SAEs observed were not related to CAB
exposure.

The proportion of subjects with treatment emergent Grade 3-4 ALT toxicities
during the Maintenance Period.  An IM dosing regimen on which  ≥4% more 
subjects (approximately 4 or more subjects) experience such toxicities relative to 
the other IM dosing regimen will not be considered for further study, unless there is 
compelling evidence that the elevations observed were not related to CAB exposure 
(i.e. acute hepatitis, evidence for significant alcohol consumption, dehydration, illicit 
drug use, etc, and ) . 

The proportion of subjects with any treatment emergent Grade 3-4 laboratory 
toxicities during the Maintenance Period.  An IM dosing regimen on which ≥8% 
more subjects (approximately 9 or more subjects) experience such toxicities 
relative to the other IM dosing regimen will not be considered for further study, 
unless there is compelling evidence that the differences observed were not related to 
CAB exposure (i.e. acute hepatitis, evidence for significant alcohol consumption, 
dehydration, illicit drug use, etc).
During the data review, smaller differences between the groups could still result in 
selecting the other IM dosing regimen, depending on the type of events observed.
 
2018N380094_00


CONFIDENTIAL
200056
39
NOTE: The % differences in the safety criteria are chosen so that the chance of seeing a 
safety difference that warrants stopping a dose is less than 1 in 40 (<2.5%) assuming both 
GSK744 LA + TMC278 LA dosing regimens have the same ISR safety profile, i.e. 
chance of false positive is controlled at <2.5%. The figure below (Figure 3) shows the 
chance of declaring false positive with different true AE rates. For example, if the true 
AE rate is equal in both arms and is 3% (green curve), then an observed difference of 5% 
or more (i.e. 5 or more subjects out of 110 subjects) would keep the false positive error 
rate below 2.5% (dotted horizontal line); or if the true AE rate in both arms is 10% (red 
curve), then an observed difference of 9% or more (i.e. 10 or more subjects out of 110 
subjects) will keep the false positive error rate<2.5%.  In addition, for all the efficacy and 
safety criteria above, a clinical review will also be undertaken comparing the GSK744 
LA + TMC278 LA data against the oral control arm data and against historical control 
data.  The GSK1265744 team will assess the totality of the data in order to make the final 
dose selection decision.
Figure 3
Chance of Declaration of False Positive
7.4.
Data Display Treatment and Other Sub-group Descriptors
In data summary displays, treatment groups will be defined as shown in Table 6.
 
2018N380094_00


CONFIDENTIAL
200056
40
Table 6
Data Display Treatment Descriptors
Treatment Group
Descriptor 
for 
non PK
Descriptor 
for 
Maintenance Phase PK
GSK744 30 mg + ABC/3TC once daily
Oral 744
Oral 744
GSK744 LA 600 mg + TMC278 LA 
900 mg IM every 8 Weeks (Q8W)
Q8W IM
Q8W (744 600 mg + 
TMC278 900 mg) IM
GSK744 LA 400 mg + TMC278 LA 
600 mg IM every 4 Weeks (Q4W)
Q4W IM
Q4W (744 400 mg + 
TMC278 600 mg) IM
Combined IM group
Subtotal - IM
NA
Not Randomized
Not Randomized
NA
In data summary displays of Extension Period, data for subjects switching from 
maintenance oral randomized treatment to either of the optimized IM regimens (i.e. 
according to the Extension Switch Population), treatment groups will be defined as 
shown in Table 7. For the W160 analysis, descriptor “IM – Total” will be used instead of 
“Subtotal – IM” unless otherwise noted.
Table 7
Data Display Treatment Descriptors for Extension Switch Population
Treatment Group
Descriptor
Optimized GSK744 LA 600 mg + 
TMC278 LA 900 mg IM every 8 Weeks 
(Q8W)
Optimized Q8W IM
Optimized GSK744 LA 400 mg + 
TMC278 LA 600 mg IM every 4 Weeks 
(Q4W)
Optimized Q4W IM
Combined Optimized IM group
Total – Optimized IM
In data listing displays, study treatment will be denoted by the expanded treatment arm 
descriptors shown in Table 8. 
Table 8
Data Listings Display Treatment Descriptors
Treatment Arm
Descriptor for Data Listings
GSK744 LA 600 mg + TMC278 LA 900 mg 
IM every 8 Weeks (Q8W)
Q8W IM
GSK744 LA 400 mg + TMC278 LA 600 mg 
IM every 4 Weeks (Q4W)
Q4W IM
GSK744 30 mg + ABC/3TC once daily for 
Maintenance Period, selected GSK744 LA 
600 mg + TMC278 LA 900 mg IM every 8 
Weeks (Q8W) for Extension Period
Oral CAB Maintenance/Q8W Extension
GSK744 30 mg + ABC/3TC once daily for 
Maintenance Period, selected GSK744 LA 
400 mg + TMC278 LA 600 mg IM every 4 
Weeks (Q4W) for Extension Period
Oral CAB Maintenance/Q4W Extension
 
2018N380094_00


CONFIDENTIAL
200056
41
Treatment Arm
Descriptor for Data Listings
GSK744 30 mg + ABC/3TC once daily for 
Maintenance Period and did not participate 
in Extension Period
Oral CAB Maintenance/No Extension
Induction Period participation only, not 
randomized into Maintenance Period
Induction Period Only
In the event that subjects switch to another IM regimen from a regimen which is 
discontinued, an amendment to this RAP will be created to detail how such subjects will 
be described in data displays of subsequent analyses.
8.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
8.1.
Multicentre Studies
The randomization for this study was not stratified or blocked by center. A centralized 
randomization schedule was employed.
Data will be summarized for all centres 
combined.
8.2.
Other Strata and Covariates
The randomization is stratified by subjects’ HIV-1 RNA prior to Week (-8) (<50 c/mL, 
yes or no). A single change in background dual NRTI is permitted as described in the 
protocol, which, if necessary, is likely to occur early during therapy. Therefore the initial 
background dual NRTI may not accurately represent the predominant therapy received up 
to the time of analysis. 
Therefore, the subgroup analyses will be based on the 
background dual NRTI at Week -16 or time of IP discontinuation, whichever is earlier.
8.3.
Examination of Subgroups
Summaries of antiviral response will be repeated by subgroups from the following list:

Plasma HIV-1 RNA result prior to Week (-8) (<50 c/mL yes or no); related to 
investigator specified stratification factor but re-derived using laboratory values.

Baseline plasma HIV-1 RNA:
<100,000 or ≥100,000 c/mL;
<1000; 1000 to <10,000; 10,000 to <50,000; 50,000 to <100,000; 
≥100,000 c/mL to <200,000; ≥ 200,000;

First suppressed (HIV-1 RNA <50 c/mL) at Week (-16), (-12), (-8), and (-4).
Summaries of antiviral response will be repeated by subgroups from the following list
only if greater than 20% of the subjects overall fall into more than one subgroup level

Background dual NRTI (ABC/3TC, TDF/FTC, Other) at Week -16 or time of IP 
discontinuation, whichever is earlier;
 
2018N380094_00


CONFIDENTIAL
200056
42

Baseline CD4+ cell count:  <200; 200 to <350; 350 cells/mm3;

Baseline Centers for Disease Control and Prevention (CDC) category (CDC Category 
A, CDC Category B, or CDC Category C);

Race (white or non-white);

Gender (female or male);

Age (<50 or 50);

Age (<65, 65 years)

Known HIV risk factors or mode of transmission (injectable drug user, homosexual 
contact and not injectable drug user, or no homosexual contact and not injectable drug 
user).
8.4.
Multiple Comparisons and Multiplicity
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 GSK1265744.  As no hypothesis is being tested 
for rejection during the constant monitoring of virologic response, no adjustment for 
multiplicity will be performed.
8.5.
Virology
Full sequence reverse transcriptase (RT), protease (PRO), and integrase (INI) data will be 
analyzed at baseline and at time of suspected protocol-defined virologic failure (PDVF)
for baseline mutations and for treatment emergent mutations. These analyses will use the 
PDVF Genotypic population.
Phenotypic changes for approved drugs will be determined at baseline and at time of 
suspected PDVF. Treatment emergent phenotypic changes will be investigated in the 
PDVF Phenotypic population.
8.6.
Genotype
An assessment will be made of every change across all amino acids within the INI 
encoding region at baseline and at time of suspected protocol-defined virologic failure, 
with particular attention paid to specific amino acid changes associated with the 
development of resistance to raltegravir (RAL), elvitegravir (ELV), dolutegravir (DTG) 
or GSK1265744. The known single and multiple INI mutations associated with the 
development of resistance to RAL, ELV, DTG or GSK1265744 are shown in Table 9.
 
2018N380094_00


CONFIDENTIAL
200056
43
Table 9
INI Mutations Associated with Development of Resistance to RAL, 
ELV, DTG or GSK1265744
Amino Acids in 
HIV Integrase 
for Analysis
H51Y, T66A, T66I, T66K, L68V, L68I, L74I, L74M, L74R, E92Q, E92V, Q95K, 
T97A, G118R, E138A, E138K, E138T, G140A, G140C, G140S, Y143C, Y143H,
Y143R, P145S, S147G, Q148H, Q148K, Q148R, V151I, V151L, S153F, S153Y, 
N155H, E157Q, G163R, G163K, G193E, R263K
a.
Note: draft listing; may be modified in case of additional substantive data availability.
b.
IN substitutions listed in bold above were defined from http://hivdb6.stanford.edu with a score of >45. All other 
mutations were detected during INI clinical investigation or during in vitro studies with DTG.
c.
The mutations bolded are referred to ‘primary’ mutations, and those unbolded are referred to ‘secondary’ 
mutations for this reporting and analysis.
Major resistance mutations to other classes (i.e., NRTI, NNRTI, PI) as defined by IAS-
USA and shown in Table 10 will be evaluated at baseline and at time of suspected PDVF.
Table 10
Major Mutations Associated with Resistance to Other Classes
NRTIs
M41L, A62V, K65R/E/N, D67N, 69 insert, K70R/E, L74V, V75I, F77L, Y115F, 
F116Y, Q151M, M184V/I, L210W, T215Y/F, K219Q/E
NNRTIs
L100I, K101E/P, K103N/S, V106A/M, V108I, E138A/G/K/Q/R, V179L, Y181C/I/V, 
Y188C/L/H, G190S/A, H221Y, P225H, F227C, M230I/L
PIs
D30N, V32I, M46I/L, I47A/V, G48V, I50V/L, I54M/L, Q58E, T74P, L76V, 
V82A/T/F/L/S, N83D, I84V, N88S, L90M
Note: the most recent information available from IAS-USA guide [Wensing et al. 2017]will be used. 
8.7.
Phenotype
Phenotypic susceptibility to all licensed antiretroviral drugs and GSK1265744 will be 
determined using PhenoSense HIV assays from Monogram Inc. and will be reported as 
fold change (FC) in IC50 relative to wild-type control virus NL4-3, i.e., FC of sample 
virus = IC50 of sample virus/IC50 of control virus. 
Since the maximum assay limit for FC for each ART varies from subject to subject, FC 
values that are greater than the maximum assay limit (e.g., ‘>100’) will be interpreted as 
having a value equal to the smallest maximum assay limit for that ART in the study 
population for data analysis. Censored values will be presented ‘as is’ in the listings. 
Phenotypic susceptibilities will be categorised according to FC as shown in Table 11
(based on Monogram PhenoSense assay). Clinical cutoffs (where available) or biological 
cutoffs by PhenoSense will be used to define the phenotypic susceptibility of background 
treatment.
Replication capacity is generated as part of standard phenotypic assays.
 
2018N380094_00


CONFIDENTIAL
200056
44
Table 11
Clinical and Biological Cutoff Values for the PhenoSense HIV Drug 
Resistance Assay
Drug
Abbreviation
Class
PhenoSense cutoff
Abacavir
ABC
NRTI
(4.5 – 6.5)a
Lamivudine
3TC
NRTI
3.5 a
Didanosine
ddI
NRTI
(1.3 – 2.2) a
Stavudine
d4T
NRTI
1.7 a
Zidovudine
AZT (ZDV)
NRTI
1.9
Emtricitabine
FTC
NRTI
3.5
Tenofovir
TDF
NRTI
(1.4 – 4) a
Delavirdine
DLV
NNRTI
6.2
Efavirenz
EFV
NNRTI
3
Nevirapine
NVP
NNRTI
4.5
Etravirine
ETR
NNRTI
2.9 a
Rilpivirine
RPV
NNRTI
2
Fosamprenavir/r
FPV/r
PI
4 a
Atazanavir/r
ATV/r
PI
5.2 a
Indinavir/r
IDV/r
PI
10 a
Lopinavir/r
LPV/r
PI
(9 – 55) a
Nelfinavir
NFV
PI
3.6
Saquinavir/r
SQV/r
PI
(2.3 – 12) a
Tipranavir/r
TPV/r
PI
(2 – 8) a
Darunavir/r
DRV/r
PI
(10 – 90) a
Ritonavir
RTV
PI
2.5
Enfuvirtide
T20
FI
6.48
Raltegravir
RAL
INI
1.5
Elvitegravir
ELV
INI
2.5 b
Dolutegravir
DTG
INI
(4 – 13) a
GSK1265744
744
INI
2.5 b
a.
clinical cutoff (lower cutoff – higher cutoff)
b.
standard cutoff used by Monogram Inc. until clinical or biological cutoff has been determined 
9.
DATA HANDLING CONVENTIONS
All data manipulations, tabulations, and calculations will be performed using SAS 
Version 9.3, and SAS Version 9.4 starting from the Week 96 analysis on a system of 
Linux computers. Figures may also be produced using SAS or other clinical graphics 
software on the same system.
9.1.
Premature Withdrawal and Missing Data
The method for dealing with premature withdrawals and missing data will depend on the 
endpoint being analysed.
In the following sections methods are outlined and analysis 
strategies described.
 
2018N380094_00


CONFIDENTIAL
200056
45
9.1.1.
Methods for Proportion Endpoints Based on Plasma HIV-1 RNA
9.1.1.1.
Missing, Switch or Discontinuation = Failure (MSDF)
For each scheduled assessment time, the MSDF (also known as snapshot) response rate 
for a given threshold (e.g., <50 c/mL) is defined as:
population
analysis
in the
subjects
of
Number 
 window
analysis
in that 
responders
of
Number 
Rate
MSDF

In each analysis window, a subject is defined as a responder as per the algorithm 
described in Section 9.2.10.  In particular, if no HIV-1 RNA assessment is available for a 
subject in the assessment window, then that subject will be counted as a non-responder.  
The nature of this missing data will be further classified in MSDF summaries as either 
‘Virologic Failure’ or ‘No Virologic Data at Week X’; see Section 9.2.10 for full details.
9.1.1.2.
Observed Case (OC)
For each scheduled assessment time, the OC rate for a given threshold is defined as:
period
 treatment
 the
during
 window
     visit
          
scheduled
in the
assessment
an 
 with 
population
analysis
in the
subjects
of
Number 
nt
on treatme
still
is
subject 
 the
 where
,
 timepoint
at the
)
 threshold
 the
below
 window
in the
 value
load
al
target vir
-
to
-
closest
 the
(e.g.
response
positive
a
 with 
subjects
of
Number 
OC 
9.1.1.3.
Time to Event Methods
The time to virologic or tolerability failure [protocol defined virologic failure (PDVF) or 
discontinuation due to treatment related reasons (i.e., drug-related AE, protocol defined 
safety stopping criteria, or lack of efficacy)] will be calculated. Subjects who have not 
met PDVF criteria and are ongoing in the study, or who have discontinued for reasons 
other than those related to treatment, will be censored.   Censored observations will be 
addressed in the analysis based on Kaplan-Maier survival analysis methods (See Section 
11.2.5).
9.1.2.
Methods for Health Outcomes Data
No imputations will be made for Health outcomes endpoints.
9.1.3.
Method for Other Laboratory Data
For other laboratory data (HIV-1 RNA as a continuous measure, CD4+ and CD8+ cell 
counts, hematology, and clinical chemistry) no imputation for missing data or premature 
discontinuation will be performed and the observed values will be used.  If more than one 
assessment was collected during the scheduled visit window, then the closest on-
 
2018N380094_00


CONFIDENTIAL
200056
46
treatment assessment to the scheduled visit will be summarized in the summary tables.  If 
two assessments are equidistance and closest to the scheduled visit, then the later of the 
two assessments collected will be summarized in the summary tables.
9.1.4.
Methods for Vital Signs and ECG Data
For other assessments such as vital signs and ECGs no imputation for missing data or 
premature discontinuation will be performed and the observed values will be used.  
9.1.5.
Methods for Missing PK Data
No imputations will be made for missing PK data.
9.1.6.
Methods for Missing Dates
9.1.6.1.
Date of Birth
Due to local privacy regulations, the electronic case report form (eCRF) only collect year 
of birth.  All birth dates will be imputed as 30-Jun for month & day.  
Completely missing dates of birth will remain as missing, with no imputation applied.  
Consequently, the age of the subject will not be calculated and will remain missing.
In listings of demographic data, year of birth as entered will be displayed.
9.1.6.2.
Adverse Events
The eCRF allows for the possibility of partial dates (i.e., only month and year) to be 
recorded for AE start and end dates; that is, the day of the month may be missing. In such 
a case, the following conventions will be applied for calculating the time to onset and the 
duration of the event:

For a missing start day, the 1st of the month will be used unless this is before the start 
date of investigational product; in this case the IP start date will be used (and hence 
the event is considered On-treatment, induction or maintenance, as per Section 9.3.1).

For a missing stop day, the last day of the month (28th, 29th, 30th, or 31st as 
appropriate for the month and year) will be used, unless this is after the stop date of 
IP; in this case the IP stop date will be used.
Completely missing start or end dates will remain missing, with no imputation applied. 
Consequently, time to onset and duration of such events will be missing.
In listings of AE data, the partial start and end dates as entered will be displayed.
 
2018N380094_00


CONFIDENTIAL
200056
47
9.1.6.3.
Concomitant Medications
Missing dates for concomitant medications/ARTs are handled as described in Section 
9.4.4
9.1.6.4.
IP Exposure
A partial date, day of the month may be missing, is allowed for IP exposure stop date.  
The following method will be used to impute the missing day:

For a missing stop day, the last day of the month (28th, 29th, 30th, or 31st as 
appropriate for the month and year) will be used, unless this is after the next start date 
of IP; in this case the next IP start date will be used.
9.1.6.5.
HIV Condition
Partial dates are also allowed for the start date of the subject’s HIV condition.  No 
imputation will be performed on these partial dates.
9.2.
Derived and Transformed Data
9.2.1.
Age
Age, in whole years, will be calculated with respect to the date of the subject’s Screening 
visit.  For subjects with partial date of birth recorded in the eCRF, the imputed date of 
birth (Section 9.1.6) will be used to calculate the subject’s age.  If the date of birth is 
partial and the calculated age of the subject is 17, then the age will be changed to 18 if the 
site has indicated the subject had met the age eligibility requirement for the study (≥18 
years of age).
9.2.2.
Baseline and Change from Baseline
Unless stated otherwise, the baseline value for a parameter (including labs, vital signs, 
ECGs, virology assessments, etc.) for the study is defined as the last Pre-treatment (see 
Section 9.3) value observed. This is generally expected to be from the Week -20 visit, 
although such values may be missing or unscheduled assessments may be performed 
before treatment start.
Electrocardiograms (ECGs) are to be performed in triplicate on Week -20 visit. The 
baseline value for an ECG parameter will be the mean of the last pre-treatment set of 
assessments from the same date.
The baseline value for each period of the study is defined as the last value observed prior 
to the first treatment in each study period. E.g. for baseline for the Maintenance period is 
defined as the last value observed prior to the first injection for IM arms or oral dose at 
Day 1 for Oral arm. 
 
2018N380094_00


CONFIDENTIAL
200056
48
Except for ECGs, the baseline value for the Extension Switch Population during the 
Extension Period is defined as the last value observed up to and including the date of the 
first IM exposure (loading dose) of CAB (if time of assessment is also collected, then
time of assessment must be prior to time of injection).  For ECGs, the baseline value for 
the Extension Switch Population during the Extension Period is defined as the last value 
prior to the date of the first IM exposure (loading dose) of CAB (since W100 ECGs were 
collected at any time during the visit per protocol, which may be before or after the first 
injection on that day). For the Extension Switch Population, any ECG values collected on 
or after the date of the first IM exposure (loading dose) will be considered as Extension 
period data when summarizing values during the Extension Period (e.g. ECG values 
collected on the date of first IM exposure of CAB will be slotted to analysis visit Week 
100).
Change from baseline for a parameter is calculated as (observed value - baseline value).
The percentage change from baseline for a parameter is calculated as:
9.2.3.
Corrected QT Intervals
When not entered directly in the eCRF, corrected QT intervals by Bazett’s (QTcB) and 
Fridericia’s (QTcF) formulas will be calculated, in msec, depending on the availability of 
other measurements.
If RR interval (in msec) is provided then missing QTcB and/or QTcF will be derived as
1000
RR
QT
QTcB 
3
1000
RR
QT
QTcF 
where uncorrected QT interval is also measured in msec.
If RR interval is not provided directly and one of QTcB or QTcF has been entered, then 
RR interval can be obtained from the above formulas and used to calculate the other 
correction method value; i.e.,
QT
QTcF
QTcB
3

3
2
QTcB
QT
QTcF


9.2.4.
Exposure
A subject’s exposure, in days or number of injections, to investigational product will be 
calculated as in the table below:
 
2018N380094_00


CONFIDENTIAL
200056
49
Study Period
Exposure
Induction
Exposure= 744 IP Stop Date – 744 IP Start Date + 1
Maintenance
Oral arm:
Exposure= 744 IP Stop Date – 744 IP Start Date + 1
IM arms:
744 Exposure = Number of 744 LA Injections received during the 
Maintenance Period
TMC278 Exposure = Number of TMC278 LA Injections received
during the Maintenance Period
Extension
744 Exposure = Number of 744 LA Injections received during the 
Extension Period
TMC278 Exposure = Number of TMC278 LA Injections received
during the Extension Period
where 744 IP Stop Date is the date of final oral dose of 744 IP received in the study 
period and 744 IP Start Date is the date of initial dose of 744 IP in the study. If 744 IP 
Stop Date is missing then, for purposes of calculating exposure, it will be imputed using 
the date of last visit or the recorded date of withdrawal/completion, whichever is earlier.
9.2.5.
Framingham Risk Equation
The predicted probability, p, for time (t = 4,,12 years) of coronary heart disease 
according to the Framingham equation [Anderson, 1991] is


u
p
e
exp
1



where




)
log(t
u
, with 
m


4181
.4

and
)
2784
.0
3155
.0
exp(
m





. The 
quantity m is calculated as















female
if
3758
.0
)
74
/
log(
8515
.1
8549
.5
male
if
1759
.0
)
log(
4792
.1
2
d
d
I
age
a
I
age
a
m
where


LVH
s
I
HDL
TC
I
SBP
a









5865
.0
/
log
7181
.0
2767
.0
)
log(
9119
.0
1122
.
11
and
 
2018N380094_00


CONFIDENTIAL
200056
50















otherwise
0
y
hypertroph
icular 
left ventr
for 
ECG 
definite
1
l
cholestero
HDL
serum
l
cholestero
serum
total
(mmHg)
pressure
blood
systolic
otherwise
0
smoker
former 
or 
current 
1
otherwise
0
subject
diabetic
if
1
LVH
s
d
I
HDL
TC
SBP
I
I
with total cholesterol and HDL cholesterol measured in the same units.
A subject is classified as diabetic if current or past is indicated in the medical conditions 
eCRF for Type 1 or Type 2 diabetes mellitus or subject has taken anti-diabetic 
medication at any time during the study. The medical monitor will review the listing of 
unique concomitant medication terms before database freeze and select the anti-diabetic 
medications.
Smoking status is collected in the eCRF on Baseline. A current smoker is defined as 
currently smoking/using tobacco or has smoked/used tobacco within the previous 6 
months; a former smoker is defined as previously smoked/used tobacco products and has 
not smoked/used tobacco products within the previous 6 months.
Definite ECG for left ventricular hypertrophy (LVH) is assessed based on current or past 
indication in the medical conditions eCRF for LVH.
This calculation will not be performed for subjects who have indicated current or past 
myocardial infarction conditions on the eCRF. These subjects will not be included in 
summary statistics of risk, but will be counted in the highest category of risk in the 
summary by category.
9.2.6.
Genotype
A mutation is considered present whenever the encoded amino acid residue differs from 
the amino acid that would have been encoded by the wild-type (e.g., HXB2, NL43) 
comparator gene; e.g., Q148K. If the encoded amino acid is seen as a mixture of wild-
type and mutant amino acid, e.g., Q148Q/K, the mutated amino acid is considered present 
at the codon of interest. If the encoded amino acid is seen as a mixture of two or more 
amino acids, which may or may not include wild type, e.g., Q184K/H or Q184K/H/Q, 
etc., for the purposes of calculating the number of mutated amino acids, only one 
mutation is considered to be present at the codon of interest. Table 12 shows how 
different amino acid changes will be represented.
 
2018N380094_00


CONFIDENTIAL
200056
51
Table 12
Representation of Amino Acid Changes
Mutations
Amino acid change
T69S
Single mutation from amino acid 'T' (vendor reference) to 'S' (sample) at codon '69' 
Q148H/K/R
Mixture of amino acid mutations ‘H’, ‘K’ and ‘R’ (sample)  from amino acid ‘Q’ (vendor 
reference) at codon ‘148’
_69_1T
First insertion of amino acid 'T' (sample) at codon '69' 
_69_2S
Second insertion of amino acid 'S' (sample) at codon '69' 
_69_3S/A
Third insertion of a mixture of amino acids 'S' and 'A' (sample) at codon '69' 
L74L/-
Mixture of amino acid 'L' (sample) and a deletion at codon '74' 
V75-
Single deletion of amino acid (sample) at codon '75' 
9.2.6.1.
Treatment-Emergent Mutations
Treatment-emergent genotypic mutations are defined as mutations that appear between 
baseline and an On-treatment assessment (e.g., at time of protocol defined virologic 
failure).
9.2.7.
Glomerular Filtration Rate (GFR)
The CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) method will be 
used to provide an estimate of GFR, in mL/min, as follows:
Black]
if
  
[1.159
Female]
if
  
[1.018
  
          
0.993
k),1)
/(88.4
max(CRT
k),1)
/(88.4
min(CRT
141
         
Black]
if
  
[1.159
Female]
if
  
[1.018
   
          
0.993
/k,1)
max(CRT
/k,1)
min(CRT
141
GFR
Age
1.209
mol/L
a
mol/L
Age
1.209
mg/dL
a
mg/dL


















where age (in years) are at time of assessment, k is 0.7 for females and 0.9 for males, a is 
-0.329 for females and -0.411 for males, and CRTmol/L is serum creatinine concentration 
in GSK standard units of mol/L. CRTmg/dL is serum creatinine concentration in mg/dL, 
and CRTmol/L=88.4x CRT mg/dL.
9.2.8.
Hepatitis Status
Hepatitis C status will be determined using antibody (IgM or IgG) and/or hepatitis C 
virus (HCV) RNA assessments performed during screening or during the conduct of the 
study.  If both antibody and virus RNA assessments are available, then the latter will take 
precedence and positive/negative status will be based on whether HCV RNA is detectable 
(i.e., 43 IU/mL [1.63 log IU/mL]) or not.
A subject will be considered positive for hepatitis B virus (HBV) if they have a positive 
surface antigen or detectable HBV DNA result during screening or during the conduct of 
the study.
 
2018N380094_00


CONFIDENTIAL
200056
52
Baseline hepatitis status will be based on laboratory assessments collected during the 
Screening Period (see Section 9.3).
9.2.9.
Lab Toxicities
Toxicities will be based on the Division of AIDS (DAIDS) grading system, as specified 
in the protocol. Toxicity grades provided by the central laboratory do not distinguish 
between abnormally high or low criteria, when both are relevant for a particular 
parameter. When summarizing toxicity grades for such parameters, they will be 
categorised as in Table 13 according to whether they are above or below the midpoint of 
normal range.
Table 13
Categorization of Select Lab Parameters Relative to Midpoint of 
Normal Range
Parameter
Below Midpoint
Above Midpoint
Calcium
Hypocalcemia
Hypercalcemia
Fasted glucose
Hypoglycaemia
Hyperglycaemia
Sodium
Hyponatremia
Hypernatremia
Potassium
Hypokalemia
Hyperkalemia
9.2.10.
Missing, Switch or Discontinuation = Failure (Snapshot) 
Algorithm
The FDA’s “snapshot” algorithm is intended to be primarily a virologic assessment of the 
endpoint, and as such follows a “virology first” hierarchy.
Virologic Success (e.g., <50 c/mL) or Virologic Failure within an analysis window (see 
Section 9.4.1) is typically determined by the last available HIV-1 RNA measurement in 
that window while the subject is On-treatment. When no HIV-1 RNA data is available 
within a window, a subject cannot be a Virologic Success.  Depending on the reason for 
lack of data, the subject will be classified as a Virologic Failure or reported as ‘No 
Virologic Data at Week X’; in the latter case, the algorithm further classifies the nature of 
the missing data. Typically, a subject withdrawn (i) due to AE or, (ii) for another reason 
yet was suppressed at the time, will be counted as ‘No Virologic Data at Week X’.  
Should a subject withdraw for reasons other than AE and was not suppressed at the time, 
they will be a Virologic Failure.
A subject may also be considered a Virologic Failure if they make changes to their 
background regimen.  This includes:

background ART substitutions not permitted per protocol;

Background ART substitutions permitted per protocol but prescribed while not 
suppressed (e.g., HIV-1 RNA ≥ 50 copies/mL based on last viral load at time of 
decision to switch), unless the decision to switch is documented as being on or before 
the first on-treatment visit where HIV-1 RNA is assessed.
 
2018N380094_00


CONFIDENTIAL
200056
53
The addition of oral RPV in the induction period at week -4 is not considered switch nor 
substitution of background ART. Full details of the algorithm, including the handling of 
special cases, are included in Section 17.5.
9.2.11.
PK Parameters
For the purposes of calculating summary statistics and for statistical analyses, all PK 
parameters with the exception of tmax will be loge transformed.
Between-subject coefficient of variation (%CVb) will be calculated as follows:
1
-]
SD)
ed
 transform
exp[(log
100
%CVb
2
e


9.2.12.
Plasma HIV-1 RNA
For summaries and analyses which use HIV-1 RNA level as a continuous measure, the 
logarithm to base 10 of the value will be used. In cases where a sample has been retested, 
the retest value will be used.
HIV-1 RNA results may be provided as censored values, such as <40
or 
>9,999,999 c/mL. For the purposes of summary statistics, such values will be replaced by 
the next value beyond the limit of detection, e.g., 39 or 10,000,000 c/mL, respectively, 
for the given examples. Data listings will show the censored values as provided.
9.2.13.
CD4
CD4+ values provided as non-numeric, censored results from the central laboratory (e.g., 
‘<0.02’ in original units of GI/L) will be imputed as e.g. 0.019 so that they are converted 
to standard units of cells/mm3 and included in the CD4 summary statistics. The listing 
will report the censored result as ‘<20’ in the standard units, i.e., equivalent to <0.02 
GI/L.
9.2.14.
Post-baseline
Post-baseline refers to the combined time periods of On-treatment and Post-treatment 
(Section 9.3.1). Post-baseline may be further specified according to phase of the study: 
Randomized or Extension (Section 9.3.1).
9.2.15.
Induction Period Study Day
The Induction Period Study Day of an event (e.g., lab assessment, vital sign, ECG, start 
date of AE or HIV associated condition) will be derived as the number of days between 
the date of the event and the initial start date of IP in the Induction period as follows:
if date of event start date of Induction Period 744 IP, then
 
2018N380094_00


CONFIDENTIAL
200056
54

1
IP
period
Induction 
of
date
start 
-
event 
of
date
Day 
Study 
Period
Induction 


if date of event < start date of Induction Period 744IP, then

IP
period
Induction 
of
date
start 
-
event 
of
date
Day 
Study 
Period
Induction 

Note that the initial start date of Induction period 744 IP is considered to be on Induction 
Period Study Day 1 and the day before this is Induction Period Study Day -1; i.e., there is 
no Induction Period Study Day 0. 
9.2.16.
Study Day
The Study Day of an event (e.g., lab assessment, vital sign, ECG, start date of AE or HIV 
associated condition) will be derived as the number of days between the date of the event 
and the initial start date of 744 IP on Maintenance period as follows:
if date of event start date of IP, then

1
period
e
Maintenanc
on 
IP
744
of
date
start 
-
event 
of
date
Day 
Study 


if date of event < start date of IP, then

period
e
Maintenanc
on 
IP
744
of
date
start 
-
event 
of
date
Day 
Study 

Note that the initial start date of 744 IP on Maintenance period is considered to be on 
Study Day 1 and the day before this is Study Day -1; i.e., there is no Study Day 0.
9.2.17.
Long-Term Follow Up Study Day
The Long-Term Follow Up (LTFU) Study Day of an event (e.g., lab assessment, vital 
sign, ECG, start date of AE or HIV associated condition) will be derived as the number of 
days between the date of the event and the last 744 IM injection, as follows:
if date of event > Last IM Injection, then

Injection
IM
Last 
of
date
-
event 
of
date
Day 
Study 
LTFU

9.2.18.
Extension Period Study Day
The Extension Period Study Day of an event (e.g., lab assessment, vital sign, ECG, start 
date of AE or HIV associated condition) will be derived as the number of days between 
the date of the event and the first IM injection (optimized Q8W/Q4W) for subjects in the 
Extension Switch Population (Section 6.1.13) as follows:
if date of event date of first injection, then
 
2018N380094_00


CONFIDENTIAL
200056
55

Extension Period Study Day = date of event – first IM injection + 1
if date of event < start date of IP, then

Extension Period Study Day = date of event – first IM injection
9.2.19.
Total Cholesterol / HDL Cholesterol Ratio
When both total cholesterol and HDL cholesterol results are available from the same date 
for a subject, then the ratio will be calculated by dividing the total cholesterol result by 
the HDL cholesterol result.
9.3.
Study Periods
AEs and concomitant medications will be assigned to study periods as defined in Table 
14. Concomitant medications will be categorized as being concomitant within each 
treatment period as defined in Table 28 of Section 9.4.4. 
Efficacy Assessments (HIV-1 RNA, CD4, HIV Associated Conditions, and Genotypic 
and Phenotypic Data) will be assigned to study periods as defined in Table 15
Laboratory Assessments, Vital Signs, and ECGs will be assigned to study periods as 
defined in Table 16.
In addition, all assessments/events will be assigned to the long-term follow up period as 
defined in Table 17.
Assessments/events are assigned to periods sequentially, starting from the top of each 
table.  For example, if a subject does not participate in the maintenance period, then the 
date range for the Induction Period has no upper limit and all assessments with ‘Date >= 
Induction Treatment Start date’ (for Table 14) or Date > Induction Period Start Date (for
Table 15 and Table 16) should be assigned to the Induction Period.
Examples:

Maintenance Period Adverse Events: 
a) Q4W subject has injection at W96 and enters Extension period, with first 
extension phase injection at W100: AEs reported up to but not including date 
of W100 injection are assigned to the Maintenance Period
b) Q4Wsubject has last injection at W44, withdraws from Maintenance period, 
and enters LTFU period; starts LTFU ART at LTFUM1 (28 days later): AEs 
reported up to but not including start of LTFU ART are assigned to the 
Maintenance Period
c) Oral arm subject discontinues IP at Week 48 and has follow-up visit 30 days 
later: All AEs reported since the start of maintenance period IP are assigned to 
the Maintenance period, including AEs occurring post-treatment.
 
2018N380094_00


CONFIDENTIAL
200056
56
d) Oral arm subject completes maintenance and has first IM extension period 
injection at Week 100: AEs reported up to but not including date of W100 
injection are assigned to the Maintenance Period.

Maintenance Period Efficacy Assessments (Viral Load, CD4, HIV Associated 
Conditions, Virology): 
a) Q4W subject has injection at W96 and enters Extension period, with first 
extension period injection at W100: HIV associated conditions with onset 
after Week 96 are excluded from Maintenance period, even if within 35 days 
of last maintenance injection;
b) Q4W subject has last injection at W44, withdraws from Maintenance period, 
and enters LTFU period: viral load collected at LTFUM1 (28 days since last 
injection) is excluded from Maintenance period, even though collection is
within 35 days of last maintenance injection.
c) Oral arm subject completes maintenance and has first IM extension period 
injection at Week 100: viral load collected at Week 100 is excluded from the 
maintenance period.
 
2018N380094_00


CONFIDENTIAL
200056
57
Table 14
Assignment of Study Periods for AEs, Concomitant Medications
Study Period
Date range
Screen
Date < Induction Treatment Start Date
Induction
Induction Treatment Start Date ≤ Date < Maintenance Treatment Start Date
Maintenance
Oral Randomized Arm:
Maintenance Treatment Start Date ≤ Date ≤  Date of First Extension Period 
IM injection – 1 or Withdrawn prior to Extension
Q8W or Q4W Randomized Arms:
For subjects not receiving Extension Phase IP Injection:
Maintenance Treatment Start Date ≤ Date ≤  [max(Last Maintenance Period 
Injection Date + X [X=35 if last injection is Q4W, X=63 if last injection is 
Q8W], Date of Last Maintenance Period Oral Bridging Dose + 1)] AND Date < 
LTFU ART Start Date
For subjects receiving Extension Phase IP Injection:
Maintenance Treatment Start Date ≤ Date ≤ Date of First Extension Period 
IM injection – 1 
Extension
Date of First Extension Period IM injection ≤Date ≤  [Max(Date of Extension 
Loading Dose at Week 100 (if switching from oral arm to optimized Q4W) + 
63, Last Extension Period Injection Date + X (X=35 days if last injection is 
Q4W, X=63 if last injection is Q8W), Date of Last Extension Period Oral 
Bridging Dose + 1)] AND Date < LTFU ART Start Date

Date = AE Start date/medication start date

Maintenance Treatment Start Date: Date of first IM injection (i.e. Date of Day 1 IM Injection) 
for subjects randomized to maintenance IM regimen or start date of maintenance period 
investigational product for subject randomized to maintenance oral regimen.
 
2018N380094_00


CONFIDENTIAL
200056
58
Table 15
Assignment of Study Period for HIV-1 RNA, CD4, HIV Associated 
Conditions, and Genotypic and Phenotypic Data
Study Phase
Date range
Screen
Date ≤ Induction Treatment Start Date
Induction
Induction Treatment Start Date < Date ≤ Maintenance Treatment Start Date
Maintenance
Maintenance Treatment Start Date < Date ≤  min(Date subject failed to 
complete Maintenance Period [from Maintenance Period Conclusion form], 
Date of Week 96 Visit)
Extension
If subject participating in the Extension Period:
min(Date subject failed to complete Maintenance Period [from Maintenance 
Phase Conclusion form], Date of Week 96 Visit) < Date ≤ min(Date subject 
failed to complete Extension Period [from Extension Phase Conclusion form], 
Date of Last Extension Phase Visit)
Follow-up
If subject not participating in the Extension Period:
Oral Randomized Arm:
Date > min(Date subject failed to complete Maintenance Period[from 
Maintenance Period Conclusion form], Date of Week 96 Visit) 

Date = Assessment/start date

Maintenance Treatment Start Date: Date of first IM injection (i.e. Date of Day 1 IM Injection) 
for subjects randomized to maintenance IM regimen or start date of maintenance phase study drug 
for subject randomized to the control arm.
 
2018N380094_00


CONFIDENTIAL
200056
59
Table 16
Assignment of Study Period for Laboratory Assessments, Vital 
Signs, and ECGs
Study Period
Date range
Screen
Date ≤ Induction Treatment Start Date
Induction
Induction Treatment Start Date < Date ≤ Maintenance Treatment Start Date
Maintenance
Oral Randomized Arm:
Maintenance Treatment Start Date < Date ≤  Date of First Extension Period 
IM injection (expected to be Week 100 Injection) or Withdrawn prior to 
Extension Period
Q4W or Q8W Randomized Arms:
For subjects receiving Extension Period IP Injection:
Maintenance Treatment Start Date < Date ≤ Date of First Extension Period
IM injection (expected to be Week 100 for Q4W and Week 104 for Q8W).
For subjects not receiving Extension Period IP Injection:
Maintenance Treatment Start Date < Date ≤min(LTFU ART Start Date,
max[Last Maintenance Period Injection Date + X (X=35 days if last injection is 
Q4W, X=63 if last injection is Q8W), Date of Last Maintenance Period Oral 
Bridging Dose + 1])
Extension
Date of First Extension Period IM injection < Date ≤  min(LTFU ART Start 
Date, Max[Date of Extension Loading Dose at Week 100 (if switching from 
oral arm to optimized Q4W) + 63, Last Extension Period Injection Date + X 
(X=35 days if last injection is Q4W, X=63 if last injection is Q8W), Date of 
Last Extension Period Oral Bridging Dose + 1])

Date = AE Start date
Maintenance Treatment Start Date: Date of first IM injection (i.e. Date of Day 1 IM Injection) for 
subjects randomized to maintenance IM regimen or start date of maintenance phase study drug for subject 
randomized to the control arm.
Table 17
Assignment to Long-Term Follow-Up Period
Study Period
Date range
Long-Term 
Follow-Up
Date > max(Last IM Injection Date, Last Oral Bridging End Date)

Date = Assessment/Start Date

If a subject withdraws during oral bridging, then the long-term follow up period is calculated 
using Date > Last IM Injection Date.
Note that the long-term follow-up period and maintenance/extension periods are not 
mutually exclusive by definition and are to be defined with separate period variables in 
the datasets. 
For example, an IM Q4W subject who has Week 92 injection and 
 
2018N380094_00


CONFIDENTIAL
200056
60
withdrawal at Week 96 without receiving Week 96 injection, the “Week 96 withdrawal 
visit” belongs to both the maintenance period and long-term follow-up period.  
9.3.1.
Treatment State within Study Periods
Within each treatment study period (i.e. Induction, Maintenance, and Extension—after 
assignment of study period described in Section 9.3), only those assessments which occur 
within the ranges shown in Table 18 will be considered ‘on-treatment’ for the given 
period.
For adverse events, where a partial start date uses imputation as described in Section 
9.1.6.2. In the case of a completely missing start date, the event will be considered to 
have started during induction treatment unless an end date for the AE is provided which 
is before start of investigational product; then, the AE is assigned as Pre-treatment.
Table 18
Treatment State within Study Periods
Study Perioda
Treatment State
Date Range
Screen
Pre-treatment
All assessments/events within period
Induction
On-treatment
Date ≤ Induction Treatment Stop Date + 1
Post-treatment
Date > Induction Treatment Stop Date + 1
Maintenance
On-treatment
Oral arm:
Date Maintenance IP Stop Date + 1
IM Q8W arm:
Date max(Last Maintenance Injection Date 
+ 63, Last Oral Bridging End Date + 1)
IM Q4W arm: 
Date max(Date of IM Loading Dose at Day 
1+ 63, Date of Last Q4W IM Dose + 35, Last 
Oral Bridging End Date + 1)
Post-treatment
Oral arm:
Date > IP Stop Date + 1
IM Q8W arm:
Date > max(Last Maintenance Injection Date 
+ 63, Last Oral Bridging End Date + 1)
IM Q4W arm: 
Date > max(Date of IM Loading Dose at Day 
1+ 63, Date of Last Maintenance Q4W IM 
Dose + 35, Last Oral Bridging End Date + 1)
Extension
On-treatment
Q8W dosing for Extension (randomized IM 
Q8W arm or Oral arm switching to optimized 
IM Q8W):
Date max(Last Extension Injection Date + 
63, Last Oral Bridging End Date + 1)
Q4W dosing for Extension (randomized IM 
Q4W arm or Oral arm switching to optimized 
IM Q4W):
 
2018N380094_00


CONFIDENTIAL
200056
61
Study Perioda
Treatment State
Date Range
Date max(Date of Extension Loading Dose
at Week 100 (if switching from oral arm) + 
63, Date of Last Extension Q4W IM Dose + 
35, Last Oral Bridging End Date + 1).
Post-treatment
Q8W dosing for Extension (randomized IM 
Q8W arm or Oral arm switching to optimized 
IM Q8W):
Date > max(Last Extension 
Injection Date + 63, Last Oral Bridging End 
Date + 1)
Q4W dosing for Extension (randomized IM 
Q4W arm or Oral arm switching to optimized 
IM Q4W):
Date > max(Date of Extension Loading Dose
at Week 100 (if switching from oral arm) + 63, 
Date of Last Extension Q4W IM Dose + 35, 
Last Oral Bridging End Date + 1).

Note: Treatment State is determined after data has been assigned to the study 
periods as defined in Section 9.3.

Date = Assessment/Start Date.
Table 19
Treatment State for LTFU Period data
Study Perioda
Treatment State
Date Range
Long-Term 
Follow-up
On-treatment
If Last IM Regimen is Q8W:
Date min(LTFU ART start date, max(Last  
Injection Date + 63, Last Oral Bridging End 
Date + 1))
If Last IM Regimen is Q4W: 
Date min(LTFU ART start date, max(Date 
of Extension Loading Dose at Week 100 (if 
switching from oral arm to optimized Q4W) + 
63, Last  Injection Date + 35, Last Oral 
Bridging End Date + 1))
Post-treatment
If Last IM Regimen is Q8W:
Date > min(LTFU ART start date, max(Last  
Injection Date + 63, Last Oral Bridging End 
Date + 1))
If Last IM Regimen is Q4W: 
Date > min(LTFU ART start date, max(Date 
of Extension Loading Dose at Week 100 (if 
switching from oral arm to optimized Q4W) + 
63, Last  Injection Date + 35, Last Oral 
Bridging End Date + 1))
a.
Note: Treatment State is determined after data has been assigned to the study periods as 
defined in Section 9.3.
Date = Assessment/Start Date.
 
2018N380094_00


CONFIDENTIAL
200056
62
9.4.
Assessment Windows
9.4.1.
Assessment Window Assignment
Laboratory data, vital signs, ECGs, health outcomes assessments, and genotypic data will 
be assigned to assessment windows according to actual dates rather than the nominal visit 
labels as recorded on the eCRF or in the laboratory database.
In most cases the window around an assessment will include all dates from the midpoints 
between the target day and that of the previous and the proceeding visits, and, in general, 
the nominal target study day for week w is (7*w)+1.  
Assessments summarized for the ITT-E population (e.g. Day 1 analysis study report 
displays) are assigned as shown in Table 20 based on the Induction Period Study Day 
(see Section 9.2.15) and Study Day (see Section 9.2.16).
For parameters that are not scheduled to be assessed at particular visits, the all-inclusive 
windows defined in will still be used; however, data summaries will only report 
scheduled visits. Assessments at unscheduled visits will be included for ‘any time On-
treatment’ time points and in data listings, as well any algorithms that make use of 
additional data (e.g., MSDF).
Table 20
Assessment Windows for Summary Induction Period Data for the 
ITT-E Population
Day of Assessment
Assessment 
Window
Target 
Induction 
Period 
Study Day 
of Window
Target 
Study 
Day of 
Window
Reporting 
Assessment 
Window
Induction Study Day <-4
Screen
-28
Screen
-3 Induction Study Day 1
Induction Day 1
1
Week -20
2 Induction Study Day 42
Induction Wk 4
29
Week -16 
43 Induction Study Day 70
Induction Wk 8
57
Week -12 
71 Induction Study Day 98
Induction Wk 12
85
Week -8 
99 Induction Study Day 126
Induction Wk 16
113
Week -4 
127 Induction Study Day 
min(Study Day of Last Induction 
Period Dose + 1, Study Day of First 
Maintenance Period Dose)
Induction Wk 20
141
1
Day 1 
Induction Study Day > Study Day of 
Last Induction Period Dose + 1 and 
Subject did not participate in 
Maintenance period
Follow-up
Follow-up
For subjects participating in the maintenance period, induction/maintenance period 
assessments (based on period slotting defined in Section 9.3) are assigned as shown in 
Table 21.
 
2018N380094_00


CONFIDENTIAL
200056
63
Table 21
Assessment Windows for Summary of Induction Period and
Maintenance Period Data
Day of Assessment
Assessment 
Window
Target 
Induction 
Period 
Study Day 
of Window
Target 
Study 
Day of 
Window
Reporting 
Assessment 
Window
Induction Study Day <-4
Screen
-28
Screen
-3 Induction Study Day 1
Induction Day 1
1
Week -20
2 Induction Study Day 42
Induction Wk 4
29
Week -16 
43 Induction Study Day 70
Induction Wk 8
57
Week -12 
71 Induction Study Day 98
Induction Wk 12
85
Week -8 
99 Induction Study Day 126
Induction Wk 16
113
Week -4 
127 
Induction Study Day 
min(Study Day of Last Induction 
Period Dose + 1, Study Day of First 
Maintenance Period Dose)
Induction Wk 20
141
1
Day 1 
2 Study Day 17
Week 1
8
Week 1
18 Study Day 42
Week 4
29
Week 4
43 Study Day 70
Week 8
57
Week 8
71 Study Day 98
Week 12
85
Week 12
99 Study Day 126
Week 16
113
Week 16
127 Study Day 154
Week 20
141
Week 20
155 Study Day 182
Week 24
169
Week 24
183 Study Day 210
Week 28
197
Week 28
211 Study Day 238
Week 32
225
Week 32
239 Study Day 266
Week 36
253
Week 36
267 Study Day 294
Week 40
281
Week 40
295 Study Day 322
Week 44
309
Week 44
323 Study Day 364
Week 48
337
Week 48
365 Study Day 420
Week 56
393
Week 56
421 Study Day 476
Week 64
449
Week 64
477 Study Day 532
Week 72
505
Week 72
533 Study Day 588
Week 80
561
Week 80
589 Study Day 644
Week 88
617
Week 88
645 Study Day 700
Week 96
673
Week 96
(7*w - 27)
Study Day (7*w + 28)
Week w
w = 
104,112,etc.
7*w + 1
Week w
w = 
104,112,etc.
 
2018N380094_00


CONFIDENTIAL
200056
64
Day of Assessment
Assessment 
Window
Target 
Induction 
Period 
Study Day 
of Window
Target 
Study 
Day of 
Window
Reporting 
Assessment 
Window
If Last Dose of Study IP is Oral 
CAB:
Date > (Date of Last Dose +1)
Follow-up
Follow-up
If Last Dose of Study IP is Q4W 
IM:
Date > min(LTFU ART start date, 
max(Date of First IM Loading Dose 
at Day 1+ 63, Date of Week 100 
Loading Dose [subjects switching 
from oral to optimized Q4W], Last  
Injection Date + 35, Last Oral 
Bridging End Date + 1))
If Last Dose of Study IP is Q8W 
IM:
Date > min(LTFU ART start date, 
max(Last  Injection Date + 63, Last 
Oral Bridging End Date + 1))
Extension period assessments (based on period slotting defined in Section 9.3) are 
assigned as shown in Table 22 and Table 23.
Table 22
Assessment 
Windows 
for 
Extension 
Period 
Data: 
Subjects 
Continuing Randomized Q4W/Q8W IM Regimen
Day of Assessment
Assessment Window
Target Extension 
Period Study Day of 
Window
687Study Day 714
Week 100
701
715Study Day 742
Week 104
729
743Study Day 770
Week 108
757
771Study Day 840
Week 112
785
841Study Day 952
Week 128
897
953Study Day 1064
Week 144
1009
(7*w - 55)
Study Day (7*w + 56)
Week w
w = 160, 176,
7*w + 1
 
2018N380094_00


CONFIDENTIAL
200056
65
Table 23
Assessment 
Windows 
for 
Extension 
Period 
Data: 
Subjects 
Switching from Randomized Oral Regimen to Optimized Q8W/Q4W 
IM Dosing
Day of Assessment
Assessment 
Window
Target Extension 
Period Study Day 
of Window
Reporting 
Assessment 
Window
Extension Study Day 1
Day 1
1
Week 100 
2 Extension Study Day 17
Week 1
8
Week 101
18 Extension Study Day 42
Week 4
29
Week 104
43 Extension Study Day 70
Week 8
57
Week 108
71 Extension Study Day 98
Week 12
85
Week 112
99 Extension Study Day 126
Week 16
113
Week 116
127 Extension Study Day 154
Week 20
141
Week 120
155 Extension Study Day 182
Week 24
169
Week 124
183 Extension Study Day 252
Week 28
197
Week 128
253 Extension Study Day 364
Week 44
309
Week 144
(7*w - 55) 
Extension Study Day (7*w + 56)
Week 
w
w = 60,76,
7*w + 1
Week (w + 
100)
If Last Dose of Study IP is Q4W IM:
Date > min(LTFU ART start date, 
max(Date of Extension Loading Dose at 
Week 100 (if switching from oral arm to 
optimized Q4W) + 63, Last  Injection 
Date + 35, Last Oral Bridging End Date + 
1))
Follow-up
Follow-up
If Last Dose of Study IP is Q8W IM:
Date > min(LTFU ART start date, 
max(Last  Injection Date + 63, Last Oral 
Bridging End Date + 1))
Assessment windows for the purposes of the Snaphot(MSDF) algorithm are defined in 
Table 24 based on data assigned to the maintenance period as defined in Section 9.3)
 
2018N380094_00


CONFIDENTIAL
200056
66
Table 24
Expanded Assessment Windows for Summary of Snapshot (MSDF) 
Data (Window at Key Analysis Time points) - Data in Maintenance 
Period Only
Day of Assessment
Reporting
Assessment 
Window
Snapshot Windows
211 Study Day 238
or 
183 Study Day 266
Week 32
2 Week, if no data in 
the 
window, 
expand 
window to 6 week
323 Study Day 364
or
295 Study Day 378
Week 48
-2 and +4 Week, if no 
data in the window, 
expand window to 6 
week
631 Study Day 714
Week 96
6 Week
> Study Day of max[Last Maintenance Q4W 
IM Injection + 35, Last Maintenance Q8W IM 
Injection + 63, min(Maintenance Oral Stop 
Date +1, Week 96 Visit in eCRF )]
Not 
Evaluable
Assessments in the LTFU period will be assigned to assessment windows as shown in 
Table 25.
Table 25
Assessment Windows for Summaries of Long-Term Follow Up 
Period Data
Day of Assessment
Assessment 
Window
Target 
Induction 
Period 
Study Day 
of Window
Target 
Study Day 
of Window
1 LTFU Study Day 60
Month 1
30
61 LTFU Study Day 135
Month 3
90
136 LTFU Study Day 225
Month 6
180
226 LTFU Study Day 315
Month 9
270
316 LTFU Study Day 405
Month 12
360
(30*m - 44)
LTFU Study Day
(30*m + 45)
Month 
m
m = 15, 18, ...
30*m 
Assessment windows for the purposes of the Snapshot(MSDF) algorithm for the 
Extension Switch population are defined in Table 26 based on data assigned to the 
Extension period as defined in Section 9.3).
 
2018N380094_00


CONFIDENTIAL
200056
67
Table 26
Assessment Windows for Summary of Snapshot (MSDF) Data 
(Window at Key Analysis Time points) — Subjects Switching from 
Randomized Oral Regimen to Optimized Q8W/Q4W IM Dosing (Data 
in Extension Period Only)
Day of Assessment
Assessment 
Window
Snapshot Windows
Reporting 
Assessment 
Window
155 Extension Study Day 238
Week 28
6 Week
Week 128
379 Extension Study Day 462
Week 60
6 Week
Week 160
> Extension Study Day of max[Last 
Extension Q4W IM Injection + 35, 
Last Extension Q8W IM Injection + 
63]
Not 
Evaluable
Table 27
Assessment Windows for Summary of Snapshot (MSDF) Data 
(Window at Key Analysis Time points) — Randomized Subjects Who 
Continued Q8W/Q4W IM Dosing during the Extension Period 
Day of Assessment
Reporting
Assessment 
Window
Snapshot Windows
1079 Study Day 1162
Week 160
6 Weeks
> Study Day of max[Last Extension Q4W IM 
Injection + 35, Last Extension Q8W IM 
Injection + 63,  Week 160 Visit in eCRF )]
Not 
Evaluable
*Study day = maintenance study day
9.4.2.
Multiple Assessments
If after window assignment there are multiple valid (see Section 9.4.3) assessments of a 
parameter within the same window, then the following hierarchy will be used to 
determine the value to be used for summary statistics:
1. the assessment closest to the window target Study/Induction/LTFU Day;
2. if there are multiple assessments equidistant from the target day, then the mean of 
these values will be used. 
Except for HIV-1 RNA and laboratory data which will be handled differently depending 
on the method being used to analyse the data.  As stated in Section 9.2.10, if multiple
assessments are collected during the analysis window, then the last on-treatment 
assessment in that window will be used for calculating the Snapshot/MSDF outcome.  
For OC, HIV-1 RNA data as a continuous measure, and laboratory data, if more than one 
assessment was collected during the scheduled visit window, then the closest on-
treatment assessment to the scheduled visit will be used.  If two assessments are 
equidistance and closest to the scheduled visit, then the later of the two assessments 
collected will be used.  
 
2018N380094_00


CONFIDENTIAL
200056
68
Assessments not chosen for use in summary statistics by this algorithm will still appear in 
the associated listings.
9.4.3.
Invalid Laboratory Assessments
Certain laboratory endpoints are required to be collected in a fasting state: glucose, and 
lipids (triglycerides, total cholesterol, HDL, LDL). If these endpoints are collected in a 
non-fasting state, then the results will be excluded from summaries; such results will be 
included in data listings with the fasting status noted.
9.4.4.
Classification 
of 
Prior, 
Concomitant, 
and 
Post-Therapy 
Medications
Prior medications are those taken (i.e., started) before the start date of investigational 
product. Concomitant medications are those taken (i.e., started or continued) at any time 
between the IP start date and end of the on-treatment window, inclusive. Prior 
medications that were continued during this period are also considered as concomitant 
medications. Post-treatment medications are those started after the end of the on-
treatment window. Concomitant medications that were continued during this period are 
also considered as post-treatment medications.
It will be assumed that the medication has been taken on the date in which it is reported 
as started or stopped.  Also, for any medication starting on the same date as IP, it will be 
assumed that the medication was taken after the subject started taking IP.
Table 28 illustrates how a medication is classified as prior, concomitant, or post-
treatment.
 
2018N380094_00


CONFIDENTIAL
200056
69
Table 28
Prior, Concomitant, and Post-treatment Classification of Medications
Pre-
treatment
On-treatment
Post-treatment
Prior
Conco-
mitant
Post
(a)
xx
Induction IP Start Date
End of on-treatment window a
Y
N
N
(b)
x
x
Y
Y
N
(c)
x

x
Y
Y
Y
(d)
xx
N
Y
N
(e)
x
x
N
Y
Y
(f)
xx
N
N
Y
(g)
?x
Y
N
N
(h)
?
x
Y*
Y
N
(i)
?

x
Y*
Y*
Y
(j)
x

?
Y
Y**
Y**
(k)
x
?
N
Y
Y**
(l)
x?
N
N
Y
(m)
?

?
Y***
Y***
Y***
(n)
x
x
Y
Y
N
(o)
?
x
Y
Y
N
(p)
x
x
N
Y
N
(q)
x

x
N
Y
N
(r)
x
x
N
Y
Y
(s)
x
?
N
Y
Y
(t)
x
x
N
N
Y
(u)
x
?
N
N
Y
(v)
x
x
N
Y
Y
 
2018N380094_00


CONFIDENTIAL
200056
70
x = start/stop date of medication
? = missing start/stop date of medication
* If a medication is stopped On-treatment or Post-treatment and no start date is recorded it will be assumed 
that the medication was ongoing from the Pre-treatment phase
** If a medication is started Pre-treatment or On-treatment and no stop date is recorded then usage will be 
assumed to be ongoing for the remainder of the study
*** If a medication has no start or stop date it will be assumed that the medication was ongoing from the 
Pre-treatment phase to the Post-treatment phase
a.
End of on-treatment window:

Oral arm: max(Induction Treatment Stop Date + 1, Maintenance IP Stop Date + 1, Last Extension 
Period Injection Date + X (X=35 days if last injection is optimized Q4W, X=63 if last injection is 
optimized Q8W, Last Oral Bridging End Date + 1 )

IM Q8W arm: max(Induction Treatment Stop Date + 1, Last Injection Date + 63, Last Oral 
Bridging End Date + 1)

IM Q4W arm: max(Induction Treatment Stop Date + 1, Date of IM Loading Dose at Day 1+ 63, 
Date of Last Q4W IM Dose + 35, Last Oral Bridging End Date + 1)
Concomitant medications (as defined above) will be further categorized as being concomitant during 
Induction, Maintenance, and Extension period, respectively, according to whether the medication was taken 
between the following time points:
Concomitant 
during:
Date range
Induction
Induction Treatment Start Date ≤ Medication Taken < Maintenance 
Treatment Start Date
Maintenance
Oral Randomized Arm:
Maintenance Treatment Start Date ≤ Medication Taken ≤  Date of 
First Extension Period IM injection – 1 or Withdrawn prior to 
Extension
Q8W or Q4W Randomized  Arms:
For subjects not receiving Extension Phase IP Injection:
Maintenance Treatment Start Date ≤ Medication Taken ≤  
max(Last Maintenance Period Injection Date + X [X=35 if last 
injection is Q4W, X=63 if last injection is Q8W], Date of Last 
Maintenance Period Oral Bridging Dose + 1) AND Date < LTFU ART 
Start Date
For subjects receiving Extension Phase IP Injection:
Maintenance Treatment Start Date ≤ Medication Taken ≤ Date of 
First Extension Period IM injection – 1 
Extension
Date of First Extension Period IM injection ≤ Medication Taken ≤  
[Max(Date of Extension Loading Dose at Week 100 (if switching 
from oral arm to optimized Q4W) + 63, Last Extension Period 
Injection Date + X (X=35 days if last injection is Q4W, X=63 if last 
injection is Q8W), Date of Last Extension Period Oral Bridging Dose 
+ 1)] AND Date < LTFU ART Start Date
 
2018N380094_00


CONFIDENTIAL
200056
71
If a partial date is recorded in the eCRF, the following convention will be used to assign 
the medication:

if the partial date is a start date, a '01' will be used for missing days and 'Jan' will be 
used for missing months;

if the partial date is a stop date, a '28/29/30/31' will be used for the missing day 
(dependent on the month and year) and 'Dec' will be used for the missing month;  for 
medications recorded separately in the eCRF as prior ART, the earlier of this 
imputed date or the day before IP start will be used.
The recorded partial date will be displayed in listings.
9.5.
Values of Potential Clinical Importance
The DAIDS grading for severity of laboratory toxicities and clinical adverse events is 
included in the protocol (Appendix 2). The central laboratory will flag lab parameter 
toxicities directly in the provided datasets.
10.
STUDY POPULATION
For the Day 1 interim analysis, all displays referred to in this section will be presented for 
the ITT-ME population, unless otherwise indicated.
For the Week 96 study report, all displays referred to in this section will be presented for 
the ITT-ME population, unless otherwise indicated.  Data displays using other 
populations will be detailed in Section 17.2.
For the Week 128 study report, all displays referred to in this section will be presented 
for the Extension Switch population, unless otherwise indicated.  
Starting from RAP amendment #3, certain data summary and data listing displays have 
been updated or added to align with recent updates to IDSL data display standards.  
These changes are indicated in the table of contents of Section 17.2.2.
10.1.
Disposition of Subjects
The total number of subjects in each analysis population will be summarized and a listing 
will present which populations each subject belonged to. The number and percentage of 
subjects who failed screening will be summarized by reason for failure. A listing will 
show subjects screened but not enrolled, along with the reason for discontinuation at this 
stage. A listing will also be produced to show any subjects enrolled but who did not 
receive investigational product.
The treatment number assigned and the corresponding treatment, for all subjects, will be 
listed by country and site number. A listing of subject numbers and randomization 
numbers with assigned and actual randomization strata, treatment assignment, and start 
date of randomized treatment will be presented. This listing will be ordered by country, 
site, and subject number and will also show the investigator name for each subject. 
 
2018N380094_00


CONFIDENTIAL
200056
72
A summary of subject disposition,
i.e., the number and percentage of subjects who
enrolled in and completed each period (e.g, Induction, Maintenance, Extension and long-
term follow-up) of the study, as well as subjects who withdrew from the study as 
recorded in the eCRF Phase Conclusions pages. A subject is considered to have 
completed the study if they did not prematurely discontinue IP prior to Week 96. Subjects 
who have not been recorded as either completing or withdrawing from the study will be 
categorized as “Ongoing at time of the analysis” for summary purposes.  Listings of 
investigational product discontinuation and subject disposition will be provided.
10.2.
Protocol Deviations
10.2.1.
Inclusion / Exclusion Criteria
A listing of subjects and the criteria they deviated from will be produced.
10.2.2.
Important Protocol Deviations
The number and percentage of subjects with important protocol deviations will be 
summarized by treatment group and overall. A listing of subjects and their important 
protocol deviations will be produced.
10.2.3.
Important Protocol Deviations that exclude subject from Per 
protocol population
Important protocol deviations leading to exclusion from Per Protocol population are those 
deviations which may
i.
directly impact the efficacy endpoint of HIV-1 RNA; or
ii.
lead to permanent discontinuation of IP/withdrawal and hence indirectly impact the 
efficacy endpoint by causing data to be missing.
The following criteria define the protocol deviations which, if they occur prior to an 
analysis time point of interest, will lead to exclusion of a subject from the Per-Protocol 
population for that analysis. Potential protocol deviations leading to exclusion from PP 
population will be reviewed by the study team to confirm that they meet these criteria.  
This review will occur before the clinical database has been frozen for analysis. The 
review process will be conducted at the primary and interim analyses (Day 1, Weeks 32, 
48, 96, 128 and 160).

Subject deviates from any inclusion or exclusion criteria, as recorded on the eCRF 
Eligibility Question form;

Subject has non-compliance with investigational product or took/received incorrect IP 
(i.e., other than the one to which they were randomized) for greater than 10% of total 
time on-treatment (shown in Table 29 ) up to an analysis time point visit of interest.
 
2018N380094_00


CONFIDENTIAL
200056
73
Table 29
Total Time On-Treatment for the Calculation
of Dosing Non-
Compliance/Incorrect Investigational Product at Each Analysis Time 
Point
Population
Treatment 
Arms
Analysis Time 
Point
Total Time On-Treatment 
ITT-ME
Oral and 
Randomized 
IM
Week 32, 
Week 48 and 
Week 96
Total time in the Maintenance period up to 
the analysis time point
Extension 
Switch 
Populationa
Optimized
Q8W and 
Optimized 
Q4W
Week 128 and 
Week 160
Total time in the Extension period up to the 
analysis time point
ITT-ME
Randomized 
IM
Week 160
Total time in the Maintenance + Extension 
period up to Week 160

For this purpose, the total number of non-compliant dosing days up to the analysis 
timepoint visit (or date of IP discontinuation/maintenance period withdrawal, 
whichever is earlier), is derived as follows:

Oral Arm:  Interruptions of oral 744 for reasons other than treatment-related 
adverse events/laboratory abnormalities, based on eCRF IP Dosing forms;

IM arm: Time until next injection from the occurrence of any of the following 
(summing across all injections): 

Date of Projected Injection Visit + 7 days, if injection received >7 
days from projected injection visit date (without bridging) with the 
exception for the W104 and W108 visits for the Extension Switch 
populationb;

Date of Dosage/administration deviation potentially resulting in under 
dosage + 7 days;

Date of Dosage/administration deviation potentially resulting in over 
dosage.
a.
For the Extension Switch population at analysis time points Week 128 and 
Week 160, only non-compliant dosing days during the Extension Period will 
be counted.
b. For the Extension Switch population, the second injection should occur within 
3 to 4 weeks after the first loading dose at W100. In addition, for the 
Optimized Q4W subjects, the third injection should occur within the window 
of 7 to 8 weeks relative to the first loading dose. Therefore, the +7 dosing 
window is not allowed for these time points, and therefore the non-compliant 
time until next injection should be calculated directly from the projected 
injection visit. For example, if a W108 injection is late by 2 days from the 
projected W108 visit, then the number of non-compliant dosing days equals 2.
 
2018N380094_00


CONFIDENTIAL
200056
74

Prohibited medications prior to primary timepoint: receiving ART medication other 
than that prescribed by the study or receiving non-ART medication that would impact 
IP or NRTI backbone exposure or response to therapy. The clinical team will review 
the listing of unique concomitant medication terms before database freeze and select 
the prohibited medications (with duration and timing of use taken into account as 
appropriate);

Oral arm: Switch of NRTI backbone for reason other than toxicity management or 
more than 1 switch of NRTI backbone during the first 96 weeks maintenance period
of the study prior to a specified analysis timepoint;

Study withdrawal due to a reason of “Protocol Deviation” (as recorded in the eCRF) 
prior to a specified analysis timepoint.

Other important protocol deviations that exclude subject from Per protocol population 
as recorded in the study team Protocol deviation review documents.
The number and percentage of subjects with important protocol deviations that exclude 
subject from Per protocol population will be summarized by treatment group and overall. 
10.3.
Demographic and Baseline Characteristics
Demographic characteristics (gender, age, age categories, and ethnicity) collected at 
screening, height at baseline BMI at Day 1 will be summarized. Date of birth, the 
screening assessment date, age, gender, and ethnicity will be included in the listing of 
demographic data.
The five high level FDA race categories and designated Asian subcategories will be 
summarized along with all combinations of high level categories which exist in the data. 
The nine race categories collected will be summarized along with categories for mixed 
race. A by-subject listing of race will also be produced.
Baseline Hepatitis B and C status will also be summarized and all Hepatitis B and C 
results will be listed.
Numbers and percentages of subjects with CDC Classification of HIV Infection 
categories A, B, and C at baseline will be summarized and listed. HIV risk factor/mode of 
transmission will be summarized and listed.
Current and past medical conditions at Baseline will be summarized separately, for each 
treatment group and overall. All past and current conditions will be listed. Medical 
conditions will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).
A summary of cardiovascular risk assessments will be produced. The number and 
percentages of subjects with family cardiac history (parent or sibling with heart attack or 
stroke before age 55) and subjects’ smoking history (never, current, former) at Baseline
will be presented; smoking history at time of withdrawal will also be included.  The 
summary will also include a 10-year risk of coronary heart disease, as calculated using 
Baseline values in the Framingham equation (see Section 9.2.5); summary statistics will 
 
2018N380094_00


CONFIDENTIAL
200056
75
be presented along with the number and percentage of subjects with <10%, 10% to 
<20%, and 20% risk. A listing of data related to cardiovascular risk assessments will be 
produced.
The distribution of plasma HIV-1 RNA at Screening and Baseline will be summarized. 
This will include the number and percentage of subjects with plasma HIV-1 RNA (c/mL) 
in the categories specified in Section 8.3, as well as summary statistics of log10 c/mL
values. A similar summary will be produced for CD4+ cell count data (cells/mm3). 
Listings of HIV-1 RNA and CD4+ values will be included in efficacy outputs.
10.3.1.
Associations between Baseline Characteristics
To explore associations between baseline characteristics, cross-tabulations of certain 
subgroups from Section 8.3 may be performed if there are sufficient number of patients 
in the subgroups. The number and percentage of subjects in each combination of 
categories from the following pairs of subgroups will be summarized:
10.4.
Treatment Compliance
A listing of dispensation information (dates and number of tablets dispensed and 
returned) will be produced.
10.5.
Concomitant Medications
For reporting purposes, medications will be classified as prior, concomitant, and/or post-
treatment using the associated start and stop dates recorded in the eCRF and relative to 
the first and last dose dates of investigational product (see Section 9.4.4). Medications 
will be coded using the GSK Drug coding dictionary.
Concomitant medications will be summarized by GSK-Drug Anatomical Therapeutic 
Chemical (ATC) classification level 1 (body system). Drugs will be displayed according 
to the ATC classifications of both their ingredient and combination term. The data will 
also be summarized by ingredient combinations alone.
A summary of the number and percentage of subjects receiving concomitant medications 
will also be displayed using a method that presents multi-ingredient medications 
according to their combination ATC classification rather than the classifications of the 
ingredients. This display will also include single-ingredient medications. Multi-ingredient 
medications will be labelled according to the sum of their ingredients, e.g., “Tylenol Cold 
and 
Flu” 
would 
appear 
as 
“CHLORPHENAMINE 
MALEATE 
+ 
DEXTROMETHORPHAN 
HYDROBROMIDE 
+ 
PARACETAMOL 
+ 
PSEUDOEPHEDRINE HYDROCHLORIDE” under the ATC headings for “Nervous 
System” and “Respiratory System” (the combination’s ATC classifications).
A listing of all medications taken by subjects, including any which are only prior or post-
treatment, will be produced.  The relationship between ATC level 1, ingredients and 
verbatim text for all medications in the study will be listed.
 
2018N380094_00


CONFIDENTIAL
200056
76
10.6.
Prior and Concomitant ART
ART medications will also be classified as prior, concomitant, and/or post-treatment 
according to Section 9.4.4, with the modification that starting on IP stop date will be 
considered as only post-treatment and not concomitant. It is expected that after 
discontinuation of IP, a subject may immediately begin taking another ART. Also, any 
ART entered on the Prior ART eCRF with partial end date will be assumed to have 
finished before Screening.
All summaries of concomitant ART will be presented by treatment group and will be 
summarized by GSK Drug ATC classification level 4 (which will provide ART class) 
and ingredient.
Concomitant ART at Baseline (i.e., selected background NRTI) will be summarized by 
treatment group. Details of any prior ART, since this is a naïve treatment population this 
is expected to be minimal, will be listed separately. A listing will be produced for 
concomitant and Post-treatment ART, with an additional listing for subjects 
receiving more than one concomitant ART (i.e., to identify subjects who switched 
background therapy during the study). The hierarchical relationship between the ATC 
level 4, combination term, and verbatim text will be listed.
11.
EFFICACY ANALYSES
For the Day 1 interim analysis, efficacy analyses will be based on the ITT-E population.  
For the Week 32/48/96 analyses, efficacy analyses will be based on the ITT-ME 
population, unless stated otherwise.Efficacy data displays for the Week 96 analysis report 
will generally only use data from the Induction and/or Maintenance Period (i.e. up to 
Week 96); limited data displays will be produced including Extension Period data since 
this data will be more thoroughly investigated in future planned study reports (i.e. Week 
128 and Week 160analyses).  Refer to Section 17.2.2 for specification of which displays 
will include Extension period data.
For the Week 96 analysis, listings will present all available data, including from the 
Extension period which may not be summarized until future study reports. Listings will 
present data grouped according to the expanded treatment sequence arms of Table 8.
Starting from RAP amendment #3, certain data summary and data listings displays have 
been updated or added to a) include extension period data, and b) to align with recent 
updates to IDSL data display standards.  These changes are indicated in the table of 
contents of Section 17.2.2.
For the Week 128 analysis, efficacy analyses will be based on the Extension Switch 
Population, unless otherwise noted. Data displays will generally only use data from the 
Extension Period up to Week 128.
 
2018N380094_00


CONFIDENTIAL
200056
77
For the Week 160 analysis, efficacy analyses will be summarized in separate displays for 
the “Randomized Q8W/Q4W IM” and the Extension Switch Population. Listings will 
present data grouped according to the expanded treatment sequence arms of Table 8.
11.1.
Primary Efficacy Analysis: Proportion of Subjects with 
Plasma HIV-1 RNA <50 c/mL
The primary efficacy endpoint is the proportion of subjects with HIV-1 RNA <50 c/mL at
Week 32/48 using the MSDF (Snapshot) algorithm (see Section 9.2.10). The ITT-ME 
population will be the primary population for primary efficacy analysis.
11.1.1.
Summaries
The number and proportion of subjects with plasma HIV-1 RNA level below 50 c/mL at 
the time of analysis based on the MSDF algorithm will be summarised by treatment 
group.
A summary of study outcomes (i.e., response below 50 c/mL or reason for no data in the 
window) at the time of analysis (e.g., Day 1, Week 32/48/96), based on the MSDF 
algorithm, will be presented by treatment.  Unadjusted difference in proportions between 
each of IM arm vs oral arm and corresponding two-sided 95% CI will also be presented.  
Study outcomes will also be listed.
In addition, the number and proportion of subjects with plasma HIV-1 RNA level below 
50 c/mL based on the MSDF algorithm will be summarized by treatment group for each 
visit.   Line plots, with 95% confidence intervals for the proportion of subjects below 50
c/mL by treatment group at each visit, will be produced.
To assess the impact of important protocol deviations that exclude subjects from the per 
protocol population, the summary of responders below 50 c/mL at the time of analysis 
(e.g., Day 1, Week 32/48/96) will be repeated using the PP-ME populations. 
11.1.2.
Main Analysis
The ITT-ME population will be used for the main analysis. 
For the analysis of GSK744 LA+TMC278 LA arms (IM arms) response rate relative to 
GSK744 + ABC/3TC (oral arm), let:
XIM = 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:
XIM ~ Binomial (90, pIM)  
Xoral ~ Binomial (45, poral)  
 
2018N380094_00


CONFIDENTIAL
200056
78
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. 
PIM ~ 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.
11.2.
Secondary Efficacy Analyses
11.2.1.
Proportion of Subjects with Plasma HIV-1 RNA <200 c/mL
The outputs detailed in Section 11.1 will also be produced using a responder threshold of 
<200 c/mL.
11.2.2.
Observed Values and Change from Baseline in Plasma HIV-1 
RNA (log10 c/mL)
The observed values and changes from baseline in plasma HIV-1 RNA (log10 copies/mL) 
by week will be presented in summary tables. The data will be listed and profile plots of 
each individual’s observed values will be produced.
11.2.3.
Observed Values and Change from Baseline in CD4+ and CD8+ 
Cell Counts
The observed values and changes from baseline in CD4+ cell count (cells/mm3) by week 
will be presented in summary tables as well as listed. The observed values and changes 
from baseline in CD8+ cell count (cells/mm3) by week will be presented in summary 
tables and listings. The CD4+/CD8+ cell count ratio will be listed.
 
2018N380094_00


CONFIDENTIAL
200056
79
11.2.4.
Virologic Failure
The cumulative proportion of subjects with protocol-defined virologic failure will be 
summarised by visit in terms of virologic non-response, virologic rebound and overall. 
The distribution of quantitative plasma HIV-1 RNA results at the time of suspected and 
confirmation of PDVF will be summarised by treatment group.
A listing of PDVF subjects will be provided.  This will identify the visit of failure, type 
of PDVF(rebound or non-response) and study phase of the confirmation result (Induction 
, Maintenance or Extension). 
11.2.5.
Virologic or Tolerability Failure
The proportion of subjects without virologic or tolerability failure by the analysis 
timepoint (Week 32/48/96) will be estimated using the Kaplan-Meier nonparametric 
method based on the time to protocol defined virologic failure (PDVF) or treatment 
related/efficacy related discontinuation (i.e., drug-related AE/intolerability of injections, 
protocol defined safety stopping criteria, or lack of efficacy).  Subjects who have not met 
PDVF criteria and are ongoing in the study, or who have discontinued for reasons other 
than those related to treatment during the maintenance period, will be censored.
The estimated proportion without failure at the time of analysis (Week 32/48/96) will be 
presented for each treatment group.  The estimated difference in proportion for each IM 
arm relative to the Oral 744 arm will also be presented, along with its associated two-
sided 95% CI. 
The estimate of the standard error used to derive confidence intervals for the difference in 
proportions between treatment groups will be based on Greenwood’s formula 
[Kalbfleisch, 1980].
Kaplan-Meier Plots for time to virologic or tolerability failure will be provided for each 
treatment group for the maintenance period.
11.2.6.
HIV Associated Conditions
A summary of maintenance period HIV associated conditions, including those which are 
a recurrence of a previous condition, will be presented. The summary will be repeated 
excluding those HIV associated conditions which are a recurrence of a previous 
condition. All data will be included in a listing.
11.2.7.
HIV Disease Progression
The number and proportion of subjects experiencing clinical disease progression or death 
during the maintenance period will be presented, with clinical disease progression 
defined as the progression from baseline HIV disease status as follows:

CDC Category A at baseline to CDC Category B event 
 
2018N380094_00


CONFIDENTIAL
200056
80

CDC Category A at baseline to CDC Category C event 

CDC Category B at baseline to CDC Category C event

CDC Category C at baseline to new CDC Category C event

CDC Category A, B or C at baseline to death
11.2.8.
Proportion of Subjects with Plasma HIV-1 RNA <50 c/mL: Q8W 
vs. Q4W
The comparability between the IM dosing arms in terms of the proportion of subjects 
with plasma HIV-1 RNA level below 50 c/mL at the time of analysis (Week 32/48) based 
on the MSDF algorithm will be assessed using the Bayesian probability model described 
in Section 7.2. The posterior probability for comparability, based on an equivalence 
criterion, P2=P (|PQ8W  − PQ4W| < 0.1 | data), will be provided.
A posterior probability of at least 90% (i.e., P2 >0.90) corresponds to “substantial 
evidence of positive outcome” and is chosen as the weight of evidence threshold for 
concluding that the two IM dosing regimens are equivalent.
11.3.
Other Efficacy Analyses
The summary of the proportion of subjects who were responders at the analysis timepoint 
(Week 32, 48 and 96) based on the MSDF algorithm of those subjects in the ITT-ME 
population that first suppressed (<50 c/mL) at Week -4, -8, -12, -16, separately, will be 
presented by treatment group.  The effect of the time to first HIV-1 RNA suppression in 
the Induction period on the response during the Maintenance period may be explored 
using logistic regression including baseline and/or PK covariates in the model.
The summary of the proportion of subjects with plasma HIV-1 RNA level below 
50 copies/mL, using the MSDF algorithm, by treatment group and visit will be repeated 
for certain subgroups, as described in Section 8.3.
The summary of study outcomes at the time of analysis may also be produced for certain 
subgroups, as described in Section 8.3.
A listing of those subjects that switched background NRTIs during the study will provide 
the duration on NRTI, visit and date of switch, what the subject switched to and reason 
for switch.
A listing of quantitative plasma HIV-1 RNA data for subjects classified as having 'data in 
window >50' at any maintenance period visit based on the Snapshot (MSDF) 
classification will be provided.
A listing of quantitative plasma HIV-1 RNA data for subjects with HIV-1 RNA ≥ 50 
c/mL at any time during the Maintenance Period or Extension Period will be provided.
Line plots, with 95% confidence intervals, for the proportion of subjects with virologic 
failure over time for each treatment group based on the Snapshot (MSDF) algorithm 
(HIV-1 RNA threshold of 50 c/mL) will be produced.  
 
2018N380094_00


CONFIDENTIAL
200056
81
The summary of the proportion of subjects with plasma HIV-1 RNA level below 
50 copies/mL, using an observed case dataset, by treatment group and visit will be 
produced.
11.3.1.
Exploratory Analyses
The number and proportion of subjects with plasma HIV-1 RNA < 2 copies/mL 
according to the BIOMNTR low-level assay will be summarized by treatment group for 
each visit using the observe case method (see Section 9.1.1.2).  A listing of BIOMNTR 
viral load results will also be produced.
For the Extension Period Analyses at Week 128 and Week 160, proportion of subjects 
with a ‘virologic failure’ endpoint, as well as the proportion of subjects with plasma HIV-
1 RNA< 50 copies/mL per the FDA MSDF snapshot algorithm will be provided. 
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, and the absolute 
values and changes in CD4+ cell counts over time will also be produced.
12.
SAFETY ANALYSES
Safety displays of induction period data only will use the Safety Population, and all other 
safety displays for Week 32, Week 64 and Week 96 will use the Safety Maintenance 
Population, unless otherwise specified. For the Week 128 safety displays, the Extension 
Switch Population will be used. For the Week 128 safety displays, the Safety 
Maintenance population and the Extension Switch Population will be used.
In general, data displays for the Week 96 analysis report will use data from the Induction 
and/or Maintenance Period (i.e. up to Week 96).  However, a limited set of additional 
safety displays will be generated to include Extension period data as follows:

Combined time period of Induction and Maintenance Periods for subjects 
originally randomized to Q8W/Q4W IM maintenance regimens;

Combined time period Maintenance Period plus Extension period for subjects 
originally randomized to Q8W/Q4W IM maintenance regimens;

Extension period data only for subjects switching from the oral maintenance 
regimen to an optimized Q8W/Q4W IM for the extension period of the study. 
Listings will present all available data, including from the Extension period which may 
not be summarized until future study reports. Listings will present data grouped 
according to the expanded treatment sequence arms of Table 8.
In general, data displays for the Week 128 analysis report will use data from the 
Extension Period (i.e. up to Week 128). Summaries will be produced by the “Optimized 
Q8W IM” and the “Optimized Q4W IM” treatment arms. Listings will in general only 
present available data within the Extension Period for the Extension Switch Population. 
 
2018N380094_00


CONFIDENTIAL
200056
82
For the W160 safety analysis, the Safety Maintenance population (Q8W/Q4W IM) and 
the Extension Switch population will be summarized in separate displays unless 
otherwise noted. In general, maintenance period data for the randomized oral arm will not 
be repeated in the W160 analysis. Listings will present data grouped according to the 
expanded treatment sequence arms of Table 8 unless otherwise noted.
12.1.
Extent of Exposure
The first and last doses and any changes/interruptions in dosing for oral regimen and 
dates of injections for IM arms will be listed for all subjects, together with details of the 
reason for any dose change/interruption.  A separate listing will be generated for subjects 
receiving oral bridging. 
Distribution and summary statistics for the duration of exposure to IP (defined in Section 
9.2.4) will be presented.
12.2.
Adverse Events
Adverse events will be coded using the most recent MedDRA coding dictionary to give a 
preferred term and a system organ class. These preferred terms and system organ classes 
will be used when summarising the data. The verbatim text will be used in listings 
together with the preferred term. A listing of the relationship of preferred term to 
verbatim text will be presented ordered by system organ class.
An AE will be counted in the study period corresponding to the onset date of the event 
(see Section 9.3).
Post-baseline events—including both on-treatment and post-treatment events as defined 
in Section 9.3.1—will be summarized separately for the induction period and induction 
plus maintenance periods combined.  Maintenance period specific tables will summarize 
on-treatment events only.  See Section 17.1.3 and Section 17.2.3 for details of AE 
summaries by period and population.
For displays of injection site reaction adverse events, common events will include pain, 
erythema, nodules and any other ISR with greater or equal to five percent of subjects.
The following adverse event summaries will be tabulated by treatment group:
1.
All AEs by system organ class (SOC) (Induction + Maintenance: Post-baseline; 
Extension: On-treatment);
2.
Common Non-Serious Adverse Events by SOC (Induction + Maintenance: Post-
baseline; Extension: On-treatment; Maintenance + Extension: on-treatment)
3.
Summary of Subjects and Number of Occurrences of Common Non-Serious Adverse 
Events by SOC (Induction + Maintenance: Post-baseline; Extension: On-treatment)
4.
All AEs by overall frequency (Induction + Maintenance: Post-baseline; Induction: 
Post-baseline; Maintenance: On-treatment; Extension: On-treatment; Maintenance + 
Extension: on-treatment) ;
 
2018N380094_00


CONFIDENTIAL
200056
83
5.
All AEs by SOC and maximum toxicity (Induction + Maintenance: Post-baseline; 
Induction: Post-baseline; Maintenance: On-treatment; Extension: On-treatment; 
Maintenance + Extension: on-treatment ) ;
6.
All grade 2-4 AEs by overall frequency(Induction + Maintenance: Post-baseline; 
Extension: On-treatment; Maintenance + Extension: on-treatment);
7.
All drug-related AEs by overall frequency(Induction + Maintenance: Post-baseline; 
Extension: On-treatment; Maintenance + Extension: on-treatment);
8.
All drug-related AEs by SOC and maximum toxicity (Induction + Maintenance: 
Post-baseline; Induction: Post-baseline; Maintenance: On-treatment; Extension: On-
treatment; Maintenance + Extension: on-treatment) ;
9.
All grade 3-4 drug-related AEs by overall frequency (Induction + Maintenance: Post-
baseline; Induction: Post-baseline; Maintenance: On-treatment; Extension: On-
treatment; Maintenance + Extension: on-treatment) ;
10. All grade 3-4 on-treatment non-injection site reaction related AEs by overall 
frequency (Maintenance: On-treatment; Extension: On-treatment; Maintenance + 
Extension: on-treatment);
11. Serious AEs (SAEs) by overall frequency (Induction + Maintenance: Post-baseline; 
Induction: Post-baseline; Maintenance: On-treatment; Extension: On-treatment; 
Maintenance + Extension: on-treatment) ;
12. Drug-related SAEs by overall frequency(Induction + Maintenance: Post-baseline; 
Extension: On-treatment; Maintenance + Extension: on-treatment);
13. AEs leading to withdrawal/permanent discontinuation of investigational product
(Induction + Maintenance; Induction; Maintenance; Extension: On-treatment; 
Maintenance + Extension: on-treatment);
14. Summary of Injection Site Reaction Adverse Events (Event-Level Summary)

Percentages based on total number of ISR events within each treatment 
group); 

Includes distribution of grade, duration, and event characteristics;

Events will be summarized according to the study medication associated 
with each ISR: GSK744, TMC278, GSK744 and/or TMC278.
15. Summary of Subject-Level Characteristics of Injection Site Reaction Adverse Events 
(Overall and by Common ISRs); 

Percentages based on number of subjects within each treatment group; 

Includes distribution of grade and max grade, event characteristics, 
number of events per subject, rate of number of events per injection visit;

Events will be summarized according to the study medication associated 
with each ISR: GSK744, TMC278, GSK744 and/or TMC278
16. Summary of Injection Site Reaction Adverse Events by Visit and Maximum Severity
(Overall and by Common ISRs); 
 
2018N380094_00


CONFIDENTIAL
200056
84

Events will be summarized according to the study medication associated 
with each ISR: GSK744, TMC278, GSK744 and/or TMC278

ISRs will be assigned based on onset date to the most recent planned IM 
injection visit prior or equal to the AE onset date.

A corresponding plot of all grades and a separate plot of grade 3-4 events 
will be produced
17. Summary of Subject-Level Characteristics of Injection Site Reaction Adverse Events 
by Needle Length (Overall and by Common ISRs); 

Needle Length will default to <=1.5 inch, unless subject has at least one 
administration with Needle Length >1.5 inch.
18. Summary of Total Number of Injection Site Reaction Symptoms by Visit

ISRs will be assigned based on onset date to the most recent planned IM 
injection visit prior or equal to the AE onset date.
For AEs reported more than once by a subject, the most severe intensity will be included 
in summaries where applicable.
If more than 10% of subjects who received IM injection enter the long-term follow-up 
period, the following summaries of long-term follow-up period events will be provided
for the Long-Term Follow-up Period Safety Population: 
1.
All AEs by overall Frequency 
2.
All Drug-Related AEs by Overall Frequency 
3.
SAEs by overall Frequency.
Plots of incidence rates and relative risk for common AEs will be presented comparing 
each IM regimen and also for IM arms combined compared to Oral arm for the 
maintenance period.  Onset, Duration, resolution and Severity of Headache AE, Nausea, 
Diarrhoea will be plotted; a similar plot will be produced for ISR events (overall and by 
common ISRs), with stratification according to the study medication associated with each 
ISR (GSK744, TMC278, GSK744 and/or TMC278) and maximum grade. 
The following listings of will be provided:
1.
All AEs;
2.
Fatal AEs;
3.
Non-fatal SAEs;
4.
AEs leading to permanent discontinuation of investigational product and/or 
withdrawal from the study;
Additionally, a listing of subject numbers for the individual adverse events will be 
presented for all Post-baseline AEs.
A listing of AEs potentially related to torsades de pointes (e.g., torsades de pointes, 
sudden death, cardiac death, ventricular tachycardia, ventricular fibrillation and flutter, 
 
2018N380094_00


CONFIDENTIAL
200056
85
syncope, seizures, QT or QTc prolonged) will be provided; an accompanying listing of 
ECG results for subjects with such AEs will also be produced.
12.3.
Injection Site Reactions
Injection site reactions will be managed through AE reporting and patient diary collection 
throughout the study.  Injection site reactions reported as AE will be summarized as part 
of AE data.  Data collected from the patient diary will be reported separately. 
In addition to AE summaries by patient, Injection site reactions reported as AE will be 
summarized by event, the frequency, severity, duration, resolution and intervention of 
injection site reaction AE by event will be provided. 
A listing of grade 2 or higher injection site reaction AE will be provided. 
12.4.
Deaths and Serious Adverse Events
Displays for deaths and SAEs that were reported during the study will be presented as
detailed in Section 17.1.3. A listing of reasons for considering an AE as serious will be 
produced.
12.5.
Adverse 
Events 
Leading 
to 
Discontinuation 
of 
Investigational Product and/or Withdrawal from the Study 
and Other Significant Adverse Events
Adverse events leading to discontinuation of investigational product and/or withdrawal 
from the study and AEs of special interest will be reported as detailed in the Section 12.2.
12.5.1.
Cardiovascular Events
Patient profile listing of subjects who experienced the cardiovascular events during the 
study will be provided. The cardiovascular events are listed below:

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
 
2018N380094_00


CONFIDENTIAL
200056
86
12.5.2.
Possible Suicidality-Related Adverse Event (PSRAE)
A listing of the event and description of the event will be produced for all PSRAEs 
reported in the study.
12.5.3.
Columbia Suicide Severity Rating Scale (eCSSRS)
Positive finding data from the eCSSRS will be listed.
12.6.
Pregnancies (as applicable)
A listing of any subjects becoming pregnant during the study will be provided.  The 
outcomes of any pregnancies will be described in the CSR, where available.
12.7.
Clinical Laboratory Evaluations
The following laboratory evaluations will be collected at regular intervals throughout the 
trial:

Clinical chemistry (italic text denotes parameters of special interest):

fasted lipids: triglycerides, total cholesterol, high density lipoprotein (HDL), low 
density lipoprotein (LDL);

liver chemistries: alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), total bilirubin(BILT), alkaline phosphatase (ALP);

electrolytes: sodium, potassium,  bicarbonate, chloride;

renal chemistries: blood urea nitrogen (BUN), creatinine, creatinine clearance,;

other: creatine kinase (creatine phosphokinase [CPK]), lipase, glucose (fasted), 
albumin,.

Hematology:

hemoglobin, hematocrit, red blood cell (RBC) count, white blood cell (WBC) 
count, platelet count;

RBC indices: mean corpuscle volume (MCV);

WBC differential (count and %): neutrophils, lymphocytes, monocytes, 
eosinophils, basophils;

coagulation tests: prothrombin time (PT), international normalized ratio (INR), 
partial thromboplastin time (PTT).

Urinalysis:

dipstick tests: bilirubin, blood, glucose, ketones, nitrite, pH, protein, specific 
gravity, WBC;

microscopy (when potential abnormalities detected from dipstick): bacteria, 
RBC, RBC casts, WBC, WBC clumps, WBC casts;
 
2018N380094_00


CONFIDENTIAL
200056
87

other: urine albumin/creatinine ratio.
Data not provided in the GSK standard measurement units by the central laboratory will 
be converted by Clinical Data Management (CDM) where necessary. Values for 
quantitative parameters provided as non-numeric, censored results from the central 
laboratory (e.g., ‘>100’, ‘<1.9’) will not be used when calculating summary statistics, but 
such values will be flagged (relative to normal ranges) and used where appropriate.
12.7.1.
Listings
Listings of laboratory data for subject with grade 3/4 post-baseline emergent or grade 3/4 
maintenance period treatment emergent toxicities will be presented by site, subject 
number, and visit. These listings will contain normal range flags, fasting flags, and 
toxicity grades.
12.7.2.
Summaries
12.7.2.1.
Summary Statistics
Summary statistics for changes from baseline at each visit will be presented by treatment 
group. Separate summaries will be produced for chemistry parameters of special interest, 
other chemistry parameters, hematology parameters, and urine concentrations. A further 
summary will be produced for lipids and glucose using mg/dL instead of GSK standard 
units.
12.7.2.2.
Toxicities
A toxicity is considered post-baseline emergent in the induction period, and combined 
induction and maintenance period, if it develops or increases in intensity from baseline 
for the induction period (last available recorded toxicity up to and including the date of 
first induction period IP).  A toxicity is considered treatment emergent relative to 
induction baseline if it develops or increases in intensity from the last available recorded 
toxicity up to and including the date of first induction period IP (typically this would be 
the Week -20 assessment).
A toxicity is considered treatment emergent relative to maintenance baseline if it 
develops or increases in intensity from the last available recorded toxicity up to and 
including the date of first maintenance period IP (typically this would be the Day 1 
assessment).A toxicity is considered treatment emergent in the Extension Period if it 
occurs on-treatment during the Extension Period and develops or increases in intensity 
from the Extension Period baseline (last available recorded toxicity up to and including 
the date of first Extension Period IP exposure).Induction period specific tables will 
summarize the maximum post-baseline emergent grade based solely on assessments 
collected during the induction period.  Maintenance period specific tables will summarize 
the maximum treatment emergent toxicity grade based on assessments collected during 
the maintenance period as well as long-term follow-up period assessments collected 
during the timeframe defined in Table 19. Overall tables for the combined Induction + 
Maintenance period will summarize the maximum post-baseline emergent toxicity grade 
 
2018N380094_00


CONFIDENTIAL
200056
88
based on assessments collected during the induction and maintenance periods combined, 
as well as long-term follow-up period assessments collected during the timeframe defined 
in Table 19. For the W128 and W160 analysis, Extension Period specific tables will 
summarize the maximum treatment emergent toxicity grade based on assessments 
collected during the Extension period. For the W160 analysis, Maintenance + Extension 
Period specific tables will summarize the maximum treatment emergent toxicity grade 
based on assessments collected during the maintenance and the extension period.The 
number and percentage of subjects with maximum toxicities (post-baseline emergent for 
induction,induction plus maintenance period, and extension period tables; treatment 
emergent for maintenance and extension period tables) for each grade (grade 1, grade 2, 
etc.) and grade range (grade 1 to 4, grade 2 to 4, etc.) will be summarized by parameter 
and treatment group. Separate summaries will be produced for chemistry parameters and 
hematology parameters.  
A shift table for chemistry parameters of special interest will be produced, showing 
baseline toxicity versus maximum treatment emergent toxicity for the maintenance 
period.  The following will be considered parameters of special interest, but the list may 
change as the study progresses and data is reviewed; AST, ALT, BILT and total absolute 
neutrophils.
A summary and listing of subjects meeting hepatobiliary laboratory abnormality criteria 
at any post-Baseline emergent visit will also be produced based on FDA Guidance for 
Drug-Induced Liver Injury: Premarketing Clinical Evaluation (July 2009). In addition a 
listing of all liver chemistry data for subjects meeting hepatobiliary laboratory 
abnormality criteria at any post-Baseline emergent visit will also be produced.
A listing of each subject’s maximum ALT and maximum bilirubin will also be produced.
12.7.2.3.
Qualitative Urinalysis Results
Maximum Post-baseline emergent urine dipstick test abnormalities will be summarized.
12.7.3.
Figures
Box plots of maintenance period changes from baseline, by visit, will be produced for 
parameters of special interest (AST, ALT, BILT and total absolute neutrophils) and other 
parameters which may be identified during blinded reviews.
Scatter-plots of maximum maintenance period on-treatment value versus baseline value 
will be presented for ALT. 
Scatter-plots of maximum maintenance period on-treatment value for ALT versus 
maximum maintenance period on-treatment value for total bilirubin will be presented. A 
matrix plot of maximum maintenance period on-treatment liver chemistries and a box 
plot of maximum maintenance period on-treatment liver chemistries by treatment group 
will be produced.
 
2018N380094_00


CONFIDENTIAL
200056
89
The above plots will be reproduced for the Extension Switch Population on-treatment 
during the Extension Period at Week 128, W160, and for the randomized Q8W/Q4W IM 
subjects during the Maintenance + Extension Period at W160. 
By study day liver chemistry (ALT, AST, and BILT) profile plots will be produced for 
subjects with elevations (ALT or AST ≥3xULN or ALP or BILT > 1.5xULN) at any 
post-baseline visit. This plot will be repeated for the Extension Switch Population with 
elevations at any Extension Period Visit (Extension Period data only), and for the 
randomized Q8W/Q4W IM subjects during the Maintenance + Extension Period
Kaplan-Meier plot of time to first treatment-emergent grade 1 or greater elevation in ALT 
and time to maximum treatment-emergent elevation in ALT will be provided for the 
maintenance period.
Other figures (such as line plots, box plots, etc.) of observed or change from baseline 
values over time may be produced, as needed.
12.8.
Other Safety Measures
12.8.1.
12-Lead ECG
ECG findings will be listed. ECG values will be listed for each subject and change from 
baseline will be summarised by visit and by treatment group. Max post-baseline corrected 
QT intervals will also be summarized by category of value (450, >450 to 480, >480 to 
500, and >500 msec) and max change from baseline (increase 30, >30 to 60, and >60 
msec); A separate listing of ECG values for subjects with values of potential clinical 
concern (i.e., QTc above 480 msec or change from baseline above 60 msec) will be 
provided.
A listing of ECG results for subjects with AEs potentially related to torsades de pointes 
will be produced.
12.8.2.
Vital Signs
Vital signs data will be listed for each subject. Summary statistics for change from 
baseline in vital signs will be presented by visit and treatment group.
12.8.3.
Abacavir Hypersensitivity Reaction (HSR)
For patients experiencing an ABC HSR, data recorded on the ABC HSR eCRFs will be 
listed.
12.8.4.
Liver Events
For subjects with liver chemistry results reaching or exceeding protocol-defined IP 
stopping criteria, the following data will be listed:
 
2018N380094_00


CONFIDENTIAL
200056
90

liver event results exceeding the stopping criteria, and the time of the event relative to 
the start of study treatment and to the most recent study treatment;

information on liver events that is used in the calculation of the Roussel Uclaf 
Causality Assessment Method (RUCAM) score;

liver biopsy results;

liver imaging results;

past and current liver disease medical conditions;

serology results from liver event follow-up (e.g., HCV RNA, hepatitis A IgM, CMV 
IgM antibody, etc.).
13.
HEALTH OUTCOMES ANALYSES
Three specific questionnaires used in the study to measure patient views of their 
treatment are Injection site reaction diary card, HIV Treatment Satisfaction Questionnaire 
– HIV TSQ and HIV Medication Questionnaire-HIV MQ. Summaries of health outcomes 
will be performed using the OC dataset.   
13.1.
Humanistic Measures
13.1.1.
Injection Site Reaction and Subject Activity
The number and proportion of subjects with each response (0-3) for Pain, Itching, and 
other symptoms as reported in the diary card will be summarised by treatment group, 
visit and day.  Number and proportion of subjects needed home treatment or medical 
intervention as recorded in the diary card will be summarised by treatment group, visit 
and day.
Mean and median injection area symptom score from the Daily diary card will be plotted.
The number and proportion of subjects who perform cardiovascular activity, strength 
training and other strenuous activity will be summarized overall and by each activity.  
Total weekly duration for cardiovascular activity, strength training and other strenuous 
activity will be summarized by treatment and visit. 
13.1.2.
The HIV Treatment Satisfaction Questionnaire (HIVTSQ)
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 72), excluding items 7b and 9b, and an individual 
satisfaction rating for each item (0 to 6).
 
2018N380094_00


CONFIDENTIAL
200056
91
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 number and proportion of subjects with each response (0-6) to each of the 14 items 
in the HIVTSQ(s) and HIVTSQ(c) will be summarised by visit and treatment group. 
Total satisfaction scores will be summarised by visit and treatment group using the mean, 
SD, median, min and max. Bar charts will be produced showing mean total satisfaction 
scores by treatment group and visit.
The HIVTSQs updated total scores and individual items scores for each IM arm 
compared to the oral arm will be tested using the Wilcoxon rank sum test at Week 32, 
Week 48 and Week 96, without adjustment for multiple testing. Additional scale scores 
(e.g. updated total scale and subscales) may be derived, pending psychometric assessment 
of the HIVTSQ using LATTE-2 data and guidance from the questionnaire authors on 
which items to include in the total scale or any subscales.
Table 30
HIVTSQ Scoring
HIVTSQs
Total Treatment Satisfaction Score

Items 1 to 12 are summed to produce a score with a possible range of 0 to 72. 

Higher scores represent greater treatment satisfaction as compared to the past few weeks.

A maximum of 6 items of these 12 items can be missing, which can be imputed to reflect the 
mean of the completed item scores. If 7 or more items are missing, then the overall treatment 
satisfaction scale score should not be computed and will remain missing.

Note: Items 7b and 9b will not be included in the derivation of the total score 
Updated Total Treatment Satisfaction Score

Items Q1–Q6; Q7a; Q8; Q9a; Q10; Q11 (range: 0-66) will be summed to produced an updated 
Total Treatment Satisfaction score based on guidance from the questionnaire author.

Higher scores represent greater treatment satisfaction as compared to the past few weeks.

A maximum of 5 items of these 11 items can be missing, which can be imputed to reflect the 
mean of the completed item scores. If 6 or more items are missing, then the updated treatment 
satisfaction  score should not be computed and will remain missing.
Individual Item Scores

Items are rated as 6 (very satisfied, convenient, flexible, etc.) to 0 (very dissatisfied, 
inconvenient, inflexible, etc.). 

Higher scores represent greater satisfaction with each aspect of treatment
 
2018N380094_00


CONFIDENTIAL
200056
92
HIVTSQc
Total Treatment Satisfaction Score (change)

Items 1 to 12 (excluding Items 7b and 9b) are summed to produce a score with a possible 
range of -33 to +33. 

The higher the score, the greater the improvement in satisfaction with treatment; the lower the 
score, the greater the deterioration in satisfaction with treatment.  A score of 0 represents no 
change. 

A maximum of 5 of these 11 items can be missing, which can be imputed to reflect the mean of 
the completed item scores. If 6 or more items are missing, then the overall treatment
satisfaction scale score should not be computed and will remain missing.
Individual Treatment Change Item Scores

Items are rated as +3 (‘much more satisfied’, ‘much more convenient’, ‘much more flexible’, 
etc.) to -3 (‘much less satisfied’, ‘much less convenient’, ‘much less flexible’, etc.). 

The higher the score, the greater the improvement in satisfaction with each aspect of treatment 
and the lower the score, the greater the deterioration in satisfaction with each aspect of 
treatment.
13.1.3.
The HIV Medication Questionnaire (HIVMQ)
The HIV Medication Questionnaire (HIVMQ) will be used to assess subject reported 
medication adherence.
The number and proportion of subjects with each response to items a, b, d, e and f in the 
HIVTMQ will be summarised by treatment group, visit and medication. Items d (how 
often take medication as recommended), e ( how often find it inconvenient or difficult to 
take mediation recommended) and f (how much pain/discomfort experienced) scores (0-
6) will be summarised by treatment group, visit and medication using the mean, SD, 
median, min and max. Data from item c as free text entry will not be summarized but will 
be listed.  
Bar charts will be produced showing mean score for items d, e and f by treatment group, 
visit and medication.
For each response to items a, b, d, e, and f,  a combined CAB LA + RPV LA score will 
be derived as follows:

For items a and b, if the responses for separate medications GSK744 LA and 
TMC278 differ and are both non-missing, then the combined response will be 
categorized as ‘discordant response’.  If the response for one or both medications 
is missing, the combined response for that item will be categorized as ‘missing’.

For items c, e, and f, the combined response will be derived as the mean value of 
the individual medication responses.  If the response for one or both medications 
is missing, the combined response for that item will be categorized as ‘missing’.
The combined CAB LA + RPV LA score will be summarized as defined above.
 
2018N380094_00


CONFIDENTIAL
200056
93
14.
CLINICAL PHARMACOLOGY DATA ANALYSES
The GSK Division of Clinical Pharmacology Modelling and Simulation (CPMS) will be 
responsible for the PK analysis of GSK1265744.  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 
TMC278.
All PK and PK/PD displays will be based on the PK Population, except for the W128 
analysis.
For the Week 128 analysis, PK data displays will be based on the Extension Switch 
Population, unless otherwise noted. Data displays will generally only use data from the 
Extension Period up to Week 128.  Refer to Section 17.2.5 for specification of which 
displays will be generated for the Week 128 analysis.
14.1.
Pharmacokinetic Analyses
14.1.1.
Drug Concentration Measures
Plasma GSK1265744 and TMC278 concentration data will be listed and summarized by 
treatment, week, day, and planned sampling time.  Standard summary statistics will be 
calculated (i.e., mean, standard deviation, median, minimum and maximum). 
The 
following summary statistics may also be calculated: geometric mean, coefficient of 
variation on geometric mean, 95% confidence interval for the geometric mean and 
standard deviation of logarithmically transformed data. Refer to the standard operating 
procedure, SOP-CPK-0001, for more information regarding the treatment of plasma 
concentrations below the assay’s lower limit of quantification (NQ).
Individual plasma concentration-time profiles and median/mean profiles by treatment 
will be plotted. Each of the figures will contain one plot on the untransformed scale (i.e., 
a linear plot) and one plot on the log transformed scale (i.e., log-linear plot).  
Additional data displays excluding samples collected outside of sampling windows 
(relative to the last dose) or that are potentially impacted by dosing irregularities will be 
provided.
 
2018N380094_00


CONFIDENTIAL
200056
94
Table 31
Sampling 
Windows 
for 
Evaluable 
Extension 
Period 
PK 
Concentrations for Extension Switch Population
Optimized Q4W
TIMEPOINT
EVALUABLE WINDOW
FOR PROGRAMMING:
PRE-DOSE: 
W100 
only
20-28 hours after last oral 
dose taken
20 Hours ≤ Days Since Last Oral 
Dose ≤ 28 Hours
2-HR-POST: 
W100 
and W128
0.5 hrs
1.5 hr ≤ Hours Since Last Injection 
≤ 2.5 hr
1-WK-POST: 
W101 
and W121
1 day
6d ≤ Days Since Last Injection ≤ 8d
PRE-DOSE: 
W104, 
W108 etc.
2 days
26d ≤ Days Since Last Injection ≤ 
30d
Optimized Q8W
TIMEPOINT
EVALUABLE WINDOW
FOR PROGRAMMING:
PRE-DOSE: 
W100 
only
20-28 hours after last oral 
dose taken
20 Hours ≤ Days Since Last Oral 
Dose ≤ 28 Hours
2-HR-POST: 
W100 
and W128
0.5 hrs
1.5 hr ≤ Hours Since Last Injection 
≤2.5 hr
1-WK-POST: 
W101 
and W121
1 day
6d ≤ Days Since Last Injection ≤ 8d
PRE-DOSE: 
Week 
104
2 days
26d ≤ Days Since Last Injection ≤ 
30d
PRE-DOSE: 
W112, 
120, 128
4 days
52d ≤ Days Since Last Dose ≤ 60d
14.1.2.
Deriving and Summarizing Pharmacokinetic Parameters
PK analysis of the plasma GSK1265744 and TMC278 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. 
 
2018N380094_00


CONFIDENTIAL
200056
95
Additional PK parameters may be calculated. Pharmacokinetic data will be presented in 
graphical and/or tabular form and will be summarized descriptively. All pharmacokinetic 
data will be stored in the Archives, GlaxoSmithKline Pharmaceuticals, R&D.
The following GSK1265744 and TMC278 pharmacokinetic parameters will be estimated 
for IM treatment arms if adequate concentration-time data are available: AUC(0-), 
Cmax, tmax, and Ctrough. Individual Average Ctrough will be calculated. GSK1265744 pre-
dose concentration will be estimated for oral arm.

The first occurrence of the maximum observed plasma concentration (Cmax) and 
the pre-dose (trough) concentration (Ctrough) will be determined directly from the 
raw concentration-time data.

The time at which Cmax is observed will be determined directly from the raw 
concentration-time data (tmax).

The area over the dosing interval at steady state (AUC(0-)) will be determined 
using the linear trapezoidal rule for increasing concentrations and the logarithmic 
trapezoidal rule for decreasing concentrations.
For each of these parameters, except tmax, the following summary statistics will be 
calculated for each treatment group: median, maximum, minimum, arithmetic mean, 
standard deviation, coefficient of variation on arithmetic mean, geometric mean, 
coefficient of variation on geometric mean, 95% confidence interval for the geometric 
mean and standard deviation of logarithmically transformed data. For tmax, median, 
maximum, minimum, arithmetic mean, and standard deviation will be calculated.
PK parameters will also be summarized by treatment and subgroups including:

Patient reported cardiovascular activity, strength training and other strenuous 
activity. (yes, no)

Total weekly duration for cardiovascular activity, strength training and other 
strenuous activity (< median duration, >=median duration)

MSDF response (<50 c/mL) at Week 32 and Week 48

PVDF at Week 32 and Week 48
For the Week 128 analysis, PK parameters will not be produced.
14.1.3.
Statistical Analyses
14.1.3.1.
Assessment of steady state
To examine steady state of IM treatment arms, statistical analysis of plasma 
GSK1265744 and TMC278 trough concentration levels will be performed separately for 
each analyte and treatment after loge-transformation of the concentrations.  Pre-dose 
concentrations on Week 16-48 will be included in the analysis.
 
2018N380094_00


CONFIDENTIAL
200056
96
A mixed effects ANOVA model will be fitted with Week (continuous variable) as a fixed 
effect and subject as a random effect for each analyte and treatment separately. The 
Kenward & Roger (KR) degrees of freedom approach will be used. The coefficient for 
the slope of the day effect on the loge-scale will be used to evaluate steady state for each 
treatment. The 90% confidence intervals for the slope for each treatment will be 
calculated. If it does not appear that steady-state has been demonstrated, early weeks (e.g. 
Week 16, 20, 24, etc...) results will be dropped and the analysis repeated.
Plots of the arithmetic mean pre-dose concentrations against Week will be produced.
For the Week 128 analysis, this steady state analysis will not be performed given the 
relatively small sample size in the Extension Switch population and likelihood that steady 
state will not be achieved within 28 weeks based on analysis of data in the Maintenance 
Phase of the study.
14.2.
Population PK Analysis:
A population-based PK model may be constructed based on the GSK1265744 and/or 
TMC278 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 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 GSK1265744 
and/or TMC278 PK may be explored. Population PK analyses will be done under 
separate Population-PK Reporting and Analysis Plans.
14.3.
Pharmacokinetic/Pharmacodynamic Analyses
14.3.1.
Exposure-Antiviral Activity Analysis
Logistic regression will be used to exam the correlation between MSDF response (<50 
c/mL) at Week 32, Week 48 and Week 96 and GSK1265744 and TMC278 PK 
parameters. Pearson’s correlations between time to virological failure (as obtained from 
the MSDF algorithm) and plasma GSK1265744 and TMC278 PK parameters may be 
presented.
14.3.2.
Exposure-Immunology Analysis
Pearson’s correlations between CD4+ change from baseline and plasma GSK1265744 
and TMC278 PK parameters will be summarized by treatment.
14.3.3.
Exposure-Toxicity Analysis
Relationships between PK parameters and safety parameters may be explored, if needed. 
Pearson’s correlations between PK parameters and safety parameters (occurrence of AEs, 
maximum intensity of AE per subject, and clinical laboratory parameters of special 
 
2018N380094_00


CONFIDENTIAL
200056
97
interest) may be presented. Logistic regression may be used to examine correlation 
between PK parameters and presence or absence of AEs of special interest from selected 
system organ class. 
Additional factors that may be evaluated in the PK/PD analyses as covariates include age, 
weight, gender, race, baseline viral load, HIV risk factors, CDC classification, CD4+ cell 
count, CD4+ T cell activation level, cardiovascular activity, strength training, other 
strenuous activity, and needle length.
15.
VIRAL GENOTYPING/PHENOTYPING
15.1.
Genotype
For each drug class of mutations described in Section 8.6, the prevalence of On-treatment 
mutations will be summarized for the PDVF Genotypic population of subjects with 
results for the applicable DNA region (i.e., integrase or PR/RT). A similar summary will 
be produced for treatment emergent mutations. For the W128 analysis, only the PDVF 
Genotypic Extension Switch population will be used. For the W160 analysis, the PDVF 
Genotypic Maintenance Exposed population and the PDVF Genotypic Extension Switch 
population will be used. 
15.2.
Phenotype
The prevalence of On-treatment resistance to all ART will be summarized, once for 
resistance to each individual drug in each class, and again for resistance to numbers of 
drugs in each class.
Baseline and On-treatment FC in IC50 relative to wild type (WT) virus for GSK1265744, 
Rilpivirine (RPV), Elvitegravir (ELV) , Dolutegravir (DTG), and Raltegravir (RAL) will 
be summarized. A similar summary will be presented for changes in FC from baseline 
(i.e., On-treatment FC/baseline FC).
All phenotype data outputs will use the PDVF Phenotypic population. For the W128 
analysis, only the PDVF Phenotypic Extension Switch population will be used. For the 
W160 analysis, the PDVF Phenotypic Maintenance Exposed population and the PDVF 
Phenotypic Extension Switch population will be used.
 
2018N380094_00


CONFIDENTIAL
200056
98
16.
References
Anderson KM, Wilson PWF, Odell PM, Kannel WB. An updated coronary risk profile. A 
statement for health professionals. Circulation. 1991;83:356-362. 
GlaxoSmithKline Document Number 2013N168152_09, Study ID 200056, 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. Effective Date 16-NOV-2017.
Grundy S.M., et al. Executive summary of the third report of the National Cholesterol 
Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of 
HIgh 
Blood 
Cholesterol 
in 
Adults 
(Adult 
Treatment 
Panel 
III). 
JAMA. 
2001;285(19):2486-2497.
Kalbfleisch J.D., Prentice R.L. The Statistical Analysis of Failure Time Data. 1st ed. New 
York:John Wiley & Sons; 1980. 
Royall R. M. Statistical Evidence: A Likelihood Paradigm. London:Chapman & Hall; 
1997. 
Wensing AM, Calvez V, Günthard HF, Johnson VA, Paredes R, Pillay D, Shafer RW, 
Richman DD. 2017 Update of the Drug Resistance Mutations in HIV-1. Top Antivir 
Med. 2017; 24(4):132-133.
Woodcock A, Bradley C. Validation of the HIV Treatment Satisfaction Questionnaire 
(HIVTSQ). Quality of Life Research. 2001;10:517-531. 
Woodcock A, Bradley C. Validation of the Revised 10-item HIV Treatment Satisfaction 
Questionnaire Status Version and New Change Version. Value in Health. 2006;9:320-
333. 
 
2018N380094_00


CONFIDENTIAL
200056
99
17.
ATTACHMENTS
17.1.
Table of Contents for Data Display Specifications – Day 1
For table and figure numbering in the Clinical Study Report, prepend a ‘6.’ for study 
population outputs, ‘7.’ for efficacy, ‘8.’ for safety, ‘4.’ for PK,  ’5.’ for PK/PD, and ’9.’ 
for viral genotyping and phenotyping.  Listings are categorized as either ‘ICH’ or 
‘Other’, regardless of the section they appear in below, and are numbered within these 
categories.
The table of contents references the GSK Integrated Data Standards Library (IDSL) or 
Therapeutic Area Standard (TST) shells for data displays, where applicable.
17.1.1.
Study Population – Day 1
The ITT-E Population will be used, except where noted.
 
2018N380094_00


CONFIDENTIAL
200056
100
17.1.1.1.
Tables
Num
Title
Details/Comments
IDSL/TST ID
1
Summary of Subject Accountability: Induction Period Conclusion Record
ES1
2
Summary of Demographic Characteristics
DM1
3
Summary of Race and Racial Combinations
DM5
4
Summary of Race and Racial Combinations Details
DM6
5
Summary of Hepatitis Status at Entry
6
Summary of CDC Classification of HIV Infection at Baseline
CDC1
7
Summary of Current Medical Conditions
MH1
8
Distribution of Quantitative Plasma HIV-1 RNA and CD4+ Results at Screening and Baseline and 
Background Dual NRTI
17.1.1.2.
ICH Listings
Num
Title
Details/Comments
IDSL/TST ID
1
Listing of Induction Period Conclusion Record Reasons for Withdrawal
ES2
2
Listing of Demographic Characteristics
DM2
3
Listing of Race
DM9
17.1.1.3.
Other Listings
Num
Title
Details/Comments
IDSL/TST ID
1
Listing of Study Populations
All Subjects 
Screened Population
2
Listing of Subjects with Changes in Concomitant Antiretroviral Therapy
CA5
17.1.2.
Efficacy –Day 1
The ITT-E Population will be used, except where noted.
 
 
 
2018N380094_00


CONFIDENTIAL
200056
101
17.1.2.1.
Tables
Num
Title
Details/Comments
IDSL/TST ID
1
Proportion of Subjects with Plasma HIV-1 RNA <50 copies/mL by Visits - Snapshot (MSDF) Analysis
2
Summary of Study Outcomes (<50 copies/mL) at Day 1 – Snapshot (MSDF) Analysis
3
Proportion of Subjects with Plasma HIV-1 RNA <200 copies/mL by Visit - Snapshot (MSDF) Analysis
4
Summary of Study Outcomes (<200 copies/mL) at Day 1 – Snapshot (MSDF) Analysis
5
Proportion of Subjects with Plasma HIV-1 RNA <50 copies/mL by Visit and Baseline Plasma HIV-1 RNA -
Snapshot (MSDF) Analysis 
6
Cumulative Proportion of Subjects with Protocol Defined Virologic Failure by Visit
7
Summary of Plasma HIV-1 RNA (log10 copies/mL) by Visit
8
Summary of Change from Baseline in Plasma HIV-1 RNA (log10 copies/mL) by Visit
9
Summary of CD4+ Cell Count (cells/mm^3) by Visit
10
Summary of Change from Baseline in CD4+ Cell Count (cells/mm^3) by Visit
17.1.2.2.
Figures
Num
Title
Details/Comments
IDSL/TST ID
1
Proportion (95% CI) of Subjects with Plasma HIV-1 RNA <50 copies/mL by Visit – Snapshot Analysis
17.1.2.3.
ICH Listings
Num
Title
Details/Comments
IDSL/TST ID
4
Listing of Quantitative Plasma HIV-1 RNA Data
5
Listing of Study Outcome (<50 copies/mL) at Week X – Snapshot (MSDF)
6
Listing of Study Outcome (<200 copies/mL) at Week X – Snapshot (MSDF)
 
 
 
2018N380094_00


CONFIDENTIAL
200056
102
17.1.2.4.
Other Listings
Num
Title
Details/Comments
IDSL/TST ID
4
Listing of CD4+ and CD8+ Cell Count Data
17.1.3.
Safety – Day 1
The Safety Population will be used, except where noted.
17.1.3.1.
Tables
Num
Title
Details/Comments
IDSL/TST ID
1
Summary of Extent of Exposure to Investigational Product
2
Summary of All  Induction Period Adverse Events by Overall Frequency for Safety  Population
3
Summary of Drug-Related Induction Period Adverse Events by Overall Frequency  for Safety  Population
4
Summary of  Grade 3/4 Induction Period Adverse Events by Overall Frequency for Safety Population
5
Summary of Serious Induction Period Adverse Events by Overall Frequency for Safety Population
6
Summary of Drug-Related Serious Induction Period Adverse Events by Overall Frequency for Safety 
Population
7
Summary Induction Period Adverse Events Leading to Withdrawal/Permanent Discontinuation of 
Investigational Product for Safety Population
AE1
8
Summary of Chemistry Changes from Baseline by Visit for Safety Population
LB1
9
Summary of Hematology Changes from Baseline by Visit for Safety Population
LB1
10
Summary of Maximum Treatment Emergent Clinical Chemistry Toxicities for Safety Population
11
Summary of Maximum Treatment Emergent Hematology Toxicities for Safety Population
12
Summary of Changes in Liver Chemistry Baseline Toxicity to Maximum On-treatment Toxicity by Baseline 
ALT>ULN for Safety Population
13
Summary of QTc Values by Category for Safety Population
14
Summary of Change from Baseline QTc Values by Category for Safety Population
15
Summary of All Possible Suicidality-Related Adverse Events for Safety Population
 
 
 
2018N380094_00


CONFIDENTIAL
200056
103
17.1.3.2.
Figures
Num
Title
Details/Comments
IDSL/TST ID
1
Scatter Plots of Maximum On-treatment vs. Baseline for ALT
2
Box Plots of Maximum On-treatment Liver Chemistries
3
Matrix Plot of Maximum On-treatment Liver Chemistries
4
Liver Chemistry Profile Plots for Subjects with Elevation at any Post-Baseline Visit by Study Day
5
Scatter Plot of Maximum Post-Baseline [Parameter 1] vs. Maximum Post Baseline [Parameter 2]
DILI plot for ALT v 
BILI only
6
Kaplan-Meier Plot of Time to First Treatment-Emergent Grade 1 or Greater Elevation in ALT
7
Kaplan-Meier Plot of Time to Maximum Treatment-Emergent Elevation in ALT
8
Figure of Onset, Duration, and Severity of Headache Adverse Events
17.1.3.3.
ICH Listings
Num
Title
Details/Comments
IDSL/TST ID
7
Listing of Investigational Product Exposure Data
HIV_IP5
8
Listing of All Adverse Events
Add the days since 
1st maintenance 
dose.
AE8
9
Listing of Fatal Adverse Events
AE8
10
Listing of Non-Fatal Serious Adverse Events
AE8
11
Listing of Adverse Events Leading to Permanent Discontinuation of Investigational Product and/or 
Withdrawal from the Study
AE8
12
Listing of Subject Numbers for Individual Adverse Events
AE7
 
 
 
2018N380094_00


CONFIDENTIAL
200056
104
17.1.3.4.
Other Listings
Num
Title
Details/Comments
IDSL/TST ID
5
Relationship of Adverse Event System Organ Classes, Preferred Terms, and Verbatim Text
AE2
6
Listing of Clinical Chemistry Data for Subjects with Grade 1 or higher Abnormalities
LB5
7
Listing of Hematology Data for Subjects with Grade 1 or higher Abnormalities
LB5
8
Listing of Clinical Chemistry Laboratory Data for Subjects with Grade 3 or 4 Treatment Emergent Toxicities
LB5
9
Listing of Hematology Laboratory Data for Subjects with Grade 3 or 4 Treatment Emergent Toxicities
LB5
10
Listing of Laboratory Data for Subjects with Grade 3 or 4 Treatment Emergent Toxicities
LB5
11
Listing of Urinalysis Data for Subjects with Grade 3 or 4 Treatment Emergent Toxicities
UR2a
12
Listing of Liver Event Results and Time of Event Relative to Treatment
LIVER5
13
Listing of Past and Current Liver Disease Medical Conditions
14
Listing of Serology Results from Liver Event Follow-up
15
Listing of Possible Suicidality-Related Adverse Event Data: Event and Description
16
Listing of AST, ALT, Alkaline Phosphatase, and Total Bilirubin Laboratory Data for Subjects with On-
Treatment ALT at Least Two Times the ULN
17
Listing of All Liver Chemistry Data for Subjects Meeting Hepatobiliary Laboratory Abnormality Criteria at Any 
Post-Baseline Emergent Visit
18
Listing of Each Subject’s Maximum ALT and Maximum Bilirubin
 
 
 
2018N380094_00


CONFIDENTIAL
200056
105
17.2.
Table of Contents for Data Display Specifications – Week 
32/48/96/128
For table and figure numbering in the Clinical Study Report, prepend a ‘6.’ for study 
population outputs, ‘7.’ for efficacy, ‘8.’ for safety, ‘9.’ for PK,  ’10.’ for PK/PD, ’11.’ 
for Health outcome and ’12.’ for viral genotyping and phenotyping.  Listings are 
categorized as either ‘ICH’ or ‘Other’, regardless of the section they appear in below, and 
are numbered within these categories.
The table of contents references the GSK Integrated Data Standards Library (IDSL) or 
Therapeutic Area Standard (TST) shells for data displays, where applicable
17.2.1.
Study Population – Week 32/48/96/128
The ITT-ME Population will be used, except where noted.   
For the Week 32, Week 48 and Week 96 displays, unless stated otherwise, data will be 
summarized by randomized treatment group.  Data listings will display treatment 
sequence for subjects switching from the randomized oral regimen to one of the selected 
optimized IM regimens for the extension period.
The outputs are for the Week 32, Week 48 and Week 96 reports, except where noted. 
Outputs for the Week 128 report will be noted in the “Reports” Column. The W128 
report will only summarize/list subjects switching from the oral regimen to the optimized 
Q8W/Q4W IM arms (See Table 7 for treatment group descriptors).
 
2018N380094_00


CONFIDENTIAL
200056
106
17.2.1.1.
Tables
Number
Title
Details/Comments
IDSL/
TST ID
Reports
Subject Disposition
1.
Summary of Subject Accountability: Maintenance Period Conclusion 
Record
ES1
2.
Summary 
of 
Subject 
Accountability 
(Maintenance 
Period): 
Withdrawal/Permanent Discontinuation of Investigational Product by 
Visit
HIV_ES1
3.
Summary of Subject Accountability: Maintenance and Extension 
Period Conclusion Records
Randomized Q8W/Q4W Arms only
W96
4.
Summary of Subject Accountability: Extension Period Conclusion 
Record (Extension Switch Population)
Optimized Q8W/Q4W Arms Only
ES1
W96/128
5.
Summary 
of 
Subject 
Accountability:
Withdrawal/Permanent 
Discontinuation of Investigational Product by Visit - Extension Period
(Extension Switch Population)
Optimized Q8W/Q4W Arms Only
HIV_ES1
W96/W128
6.
Summary of Subject Disposition at Each Study Epoch
Intent-to-Treat Population
ES4
W96
7.
Summary of Reasons for Withdrawal at Each Epoch
Intent-to-Treat Population
ES5
W96
8.
Summary of Reasons for Withdrawal During the Extension Period
(Extension Switch Population)
Optimized Q8W/Q4W Arms Only
ES5
W128
9.
Summary of Number of Subjects by Country and Site ID
Intent-to-Treat Population
NS1
W32/W48/W96
10.
Summary of Number of Subjects by Country and Site ID (Extension 
Switch Population)
Optimized Q8W/Q4W Arms Only
NS1
W128
Protocol Deviations
11.
Summary of Important Protocol Deviations
Intent-To-Treat 
Maintenance 
Exposed
12.
Summary of Important Protocol Deviations During the Extension 
Period (Extension Switch Population)
Optimized Q8W/Q4W Arms Only
DV1
W128
 
 
 
2018N380094_00


CONFIDENTIAL
200056
107
Number
Title
Details/Comments
IDSL/
TST ID
Reports
Population Analysed
13.
Summary of Study Populations
All Subjects Screened
W32/W48/W96 
14.
Summary of Exclusions from the Per Protocol Maintenance Population
Updated Display Standard
SP2
15.
Summary of Exclusions from the Extension Switch Population
Optimized Q8W/Q4W Arms Only
SP2
W128
Demographic and Baseline Characteristics
16.
Summary of Demographic Characteristics
Optimized Q8W/Q4W Arms Only 
for W128
DM1
W32/W48/W96/ W128
17.
Summary of Race and Racial Combinations
Optimized Q8W/Q4W Arms Only 
for W128
DM5
W32/W48/W96/ W128
18.
Summary of Race and Racial Combinations Details
Optimized Q8W/Q4W Arms Only 
for W128
DM6
W32/W48/W96/ W128
19.
Summary of Age Ranges
Optimized Q8W/Q4W Arms Only 
for W128
DM11
W96/ W128
20.
Summary of Hepatitis Status at Entry
W32/W48/W96/ 
21.
Summary of Cardiovascular Risk Assessments
W32/W48/W96/ 
22.
Summary of CDC Classification of HIV Infection at Baseline
CDC1
W32/W48/W96/ 
23.
Distribution of Quantitative Plasma HIV-1 RNA and CD4+ Results at 
Screening and Baseline and Background Dual NRTI
W32/W48/W96/ 
24.
Summary of HIV Risk Factors
RF1
W32/W48/W96
25.
Summary of Associations between Subject Characteristics
W48
Prior and Concomitant Medications
26.
Summary of Current Medical Conditions
Optimized Q8W/Q4W Arms Only 
for W128
MH1
W32/W48/W96/ W128
27.
Summary of Past Medical Conditions
MH1
W32/W48/W96/ 
28.
Summary of Concomitant Medication During Treatment by Ingredient 
ATC Level 1 – Induction and Maintenance Period
CM1
29.
Summary of Concomitant Medication During Treatment by Ingredient 
ATC Level 1 – Extension Period (Extension Switch Population)
Optimized Q8W/Q4W Arms Only
CM1
W128
30.
Summary of Concomitant Medication by Combination Term ATC Level 
1 – Induction and Maintenance Period
CM1b
 
 
 
2018N380094_00


CONFIDENTIAL
200056
108
Number
Title
Details/Comments
IDSL/
TST ID
Reports
31.
Summary of Concomitant Medication by Combination Term ATC Level 
1 – Extension Period (Extension Switch Population)
Optimized Q8W/Q4W Arms Only
CM1b
W128
32.
Summary of Concomitant Medication Ingredient Combinations –
Induction and Maintenance Period
CM8
33.
Summary of Concomitant Medication Ingredient Combinations –
Extension Period (Extension Switch Population)
Optimized Q8W/Q4W Arms Only
CM8
W128
34.
Summary of Substance Use
SU1
W96
35.
Summary of Screening Status and Reasons for Screen Failures
All Screened Population
ES6
W48/W96
17.2.1.2.
ICH Listings
Number
Title
Details/Comments
IDSL/TST 
ID
Reports
Subject Disposition
1.
Listing of Screen Failure Subjects
W32/W48/W96
2.
Listing of Reasons for Study Withdrawal
ES2
W32/W48/W96
3.
Listing of Reasons for Study Withdrawal During the Extension Period
Optimized Q8W/Q4W Arms Only 
ES2
W128
Protocol Deviations
4.
Listing of Important Protocol Deviations
DV2
W32/W48/W96
5.
Listing of Important Protocol Deviations During the Extension Period
Optimized Q8W/Q4W Arms Only
DV2
W128
6.
Listing of Subjects with Inclusion/Exclusion Criteria Deviations 
IE3
W96
Demographic and Baseline Characteristics
7.
Listing of Demographic Characteristics
Optimized Q8W/Q4W Arms Only 
for W128
DM2
W32/W48/W96/ W128
8.
Listing of Race
Optimized Q8W/Q4W Arms Only 
for W128
DM9
W32/W48/W96/W128
 
 
 
2018N380094_00


CONFIDENTIAL
200056
109
17.2.1.3.
Other Listings
Number
Title
Details/Comments
IDSL/TST 
ID
Reports
1.
Listing of Study Populations
All Subjects Screened Population
W32/W48/W96
2.
Listing of Subject Recruitment by Country and Site Number
All Subjects Screened Population
W32/W48/W96
3.
Listing of Subject Recruitment by Country and Site Number (Extension 
Switch Population)
Optimized Q8W/Q4W Arms Only
W128
4.
Listing of Hepatitis Test Results
W32/W48/W96
5.
Listing of CDC Classification of HIV Infection at Baseline
CDC3
W32/W48/W96/
6.
Listing of HIV Risk Factors
RF2
W32/W48/W96/
7.
Listing of Investigational Product Accountability
Optimized Q8W/Q4W Arms Only for 
W128
W32/W48/W96/W128
8.
Listing of Concomitant Medications
Optimized Q8W/Q4W Arms Only for 
W128
CM2
W32/W48/W96/W128
9.
Listing of Current and Past Medical Conditions at Baseline
Optimized Q8W/Q4W Arms Only for 
W128
MH2
W32/W48/W96/W128
10.
Listing of Prior Antiretroviral Therapy
CA3
W32/W48/W96
11.
Listing of
Extension Period
Concomitant and Post-treatment 
Antiretroviral Therapy (Extension Switch Population)
Optimized Q8W/Q4W Arms Only for 
W128. Extension Period data only.
CA5
W32/W48/W96/W128
12.
Listing of Subjects with Changes in Concomitant Antiretroviral Therapy
Optimized Q8W/Q4W Arms Only for 
W128
CA5
W32/W48/W96/W128
13.
Listing of Randomized and Actual Strata and Treatment Assignment
Randomized Population
TA1
W32/W48/W96
14.
Listing of Cardiovascular Risk Assessment Data
W32/W48/W96
15.
Listing of Relationship Between ATC Level 1, Ingredient and Verbatim 
Text
CM6
W32/W48/W96/W128
16.
Listing of Relationship Between ATC Level 4, Combination, and 
Verbatim Text for ART
CA7
W32/W48/W96/W128
17.
Listing of Subjects Randomized but Not Treated
Randomized Population
 
 
 
2018N380094_00


CONFIDENTIAL
200056
110
17.2.2.
Efficacy – Week 32/48/96/128
Unless otherwise noted, the ITT-ME Population will be used for Week 32/48/96 displays, and the Extension-Switch Population will be 
used for Week 128 displays. The outputs are for the Week 32, Week 48 and Week 96 reports, except where noted. Outputs for the Week 
128 report will be noted in the “Reports” Column. 
17.2.2.1.
Tables
Number
Title
Details/
Comments
IDSL/ TST 
ID
Reports
1.
Summary of Analysis for Proportion of Subjects with Plasma HIV-1 
RNA <50 copies/mL at Week 32/48/96 - Snapshot (MSDF) Analysis
W32/W48/W96
2.
Summary of Study Outcomes (<50 copies/mL) at Week 32/48/96/128 –
Snapshot (MSDF) Analysis
Optimized Q8W/Q4W Arms Only for 
W128
W32/W48/W96/W128
3.
Summary of Bayesian Probability at Week 32/48: Q4W/Q8W vs. Oral 
744
W32/W48
4.
Proportion of Subjects with Plasma HIV-1 RNA <50 copies/mL at Week 
32/48/96 - Snapshot (MSDF) Analysis for the Per-Protocol Maintenance 
Population
PP-ME population
5.
Summary of Study Outcomes (<50 copies/mL) at Week 128 – Snapshot 
(MSDF) Analysis for the Per-Protocol Extension Switch Population
PP- ES population
W128
6.
Summary of Bayesian Probability at Week 32/48: Q8W vs. Q4W
W32/W48
7.
Proportion of Subjects with Plasma HIV-1 RNA <50 copies/mL by Visit -
Snapshot (MSDF) Analysis
Up to Week 96
 
 
 
2018N380094_00


CONFIDENTIAL
200056
111
Number
Title
Details/
Comments
IDSL/ TST 
ID
Reports
8.
Proportion of Subjects with Plasma HIV-1 RNA <50 copies/mL by Visit 
during the Extension Period - Snapshot (MSDF) Analysis 
Optimized Q8W/Q4W Arms Only, 
up to Week 128
W128
9.
Proportion of Subjects with Plasma HIV-1 RNA <200 copies/mL by Visit 
- Snapshot (MSDF) Analysis
Up to Week 96
10.
Proportion of Subjects with Plasma HIV-1 RNA <200 copies/mL by Visit 
during the Extension Period - Snapshot (MSDF) Analysis
Optimized Q8W/Q4W Arms Only, 
up to Week 128
W128
11.
Summary of Study Outcomes (<200 copies/mL) at Week 32/48/96/128
– Snapshot (MSDF) Analysis
Optimized Q8W/Q4W Arms Only for 
W128
W32/W48/W96/W128
12.
Proportion of Subjects with Plasma HIV-1 RNA <50 copies/mL by Visit 
and Baseline Plasma HIV-1 RNA - Snapshot (MSDF) Analysis
Up to Week 96
13.
Proportion of Subjects with Plasma HIV-1 RNA <50 copies/mL by Visit 
and Derived Plasma HIV-1 RNA <50 c/mL Prior to Week -8 - Snapshot 
(MSDF) Analysis
Up to Week 96
14.
Proportion of Responders at Week 32/48/96 based on Snapshot 
(MSDF) Analysis by Week First Suppressed
W32/W48/W96
15.
Cumulative Proportion of Subjects with Maintenance Period Protocol 
Defined Virologic Failure by Visit
16.
Cumulative Proportion of Subjects with Extension Period Protocol 
Defined Virologic Failure by Visit (Extension Switch Population)
Optimized Q8W/Q4W Arms Only, 
up to Week 128
W128
17.
Summary of Kaplan-Meier Estimates of Proportion of Subjects Without 
Virologic or Tolerability Failure at Week 32/48/96 – Maintenance Period
 
 
 
2018N380094_00


CONFIDENTIAL
200056
112
Number
Title
Details/
Comments
IDSL/ TST 
ID
Reports
18.
Distribution of Quantitative Plasma HIV-1 RNA Results at Suspected 
and Confirmation of Maintenance Period Protocol Defined Virologic 
Failure
19.
Distribution of Quantitative Plasma HIV-1 RNA Results at Suspected 
and Confirmation of Extension Period Protocol Defined Virologic Failure
Optimized Q8W/Q4W Arms Only, 
up to Week 128
W128
20.
Summary of Plasma HIV-1 RNA (log10 copies/mL) by Visit
21.
Summary of Change from Baseline in Plasma HIV-1 RNA (log10 
copies/mL) by Visit
22.
Summary of CD4+ Cell Count (cells/mm^3) by Visit
23.
Summary of CD4+ Cell Count (cells/mm^3) by Visit - Extension Period
Optimized Q8W/Q4W Arms Only for 
W128
W128
24.
Summary of Change from Baseline in CD4+ Cell Count (cells/mm^3) by
Visit
25.
Summary of Change from Baseline in CD4+ Cell Count (cells/mm^3) by 
Visit - Extension Period
Optimized Q8W/Q4W Arms Only for 
W128
Note: Baseline is last value up to 
and including the date of first 
extension injection
W128
26.
Summary of CD8+ Cell Count (cells/mm^3) by Visit
27.
Summary of Change from Baseline in CD8+ Cell Count (cells/mm^3) by 
Visit
 
 
 
2018N380094_00


CONFIDENTIAL
200056
113
Number
Title
Details/
Comments
IDSL/ TST 
ID
Reports
28.
Summary of HIV-1 Associated Conditions Including Recurrences -
Maintenance Period
HIV1
29.
Summary of HIV-1 Associated Conditions Including Recurrences -
Extension Period
Optimized Q8W/Q4W Arms Only
HIV1
W128
30.
Summary of HIV-1 Associated Conditions Excluding Recurrences -
Maintenance Period
HIV1
31.
Summary of HIV-1 Associated Conditions Excluding Recurrences -
Extension Period
Optimized Q8W/Q4W Arms Only
HIV1
W128
32.
Summary of HIV-1 Associated Conditions Progression of HIV Disease -
Maintenance Period
HIV2
33.
Summary of HIV-1 Associated Conditions Progression of HIV Disease -
Extension Period
Optimized Q8W/Q4W Arms Only
HIV2
W128
34.
Proportion of Subjects with Plasma HIV-1 RNA <50 copies/mL by Visit 
and [Subgroup] – Snapshot (MSDF) Analysis
See Section 8.2 for criteria on which 
subgroup variables to include (if 
any). 
35.
Summary of Study Outcomes (<50 copies/mL) at Week 32/48/96 by 
[Subgroup] – Snapshot (MSDF) Analysis
As above
W32/W48/W96
36.
Proportion of Subjects with Plasma HIV-1 RNA <2 copies/mL by Visit –
Observed Case Analysis
Based on BIOMNTR data
Up to Week 96 
 
 
 
2018N380094_00


CONFIDENTIAL
200056
114
Number
Title
Details/
Comments
IDSL/ TST 
ID
Reports
37.
Proportion of Subjects with Plasma HIV-1 RNA <2 copies/mL by Visit 
during Extension Period– Observed Case Analysis
Based on BIOMNTR data
Optimized Q8W/Q4W Arms Only for 
W128
W128
38.
Proportion of Subjects with Plasma HIV-1 RNA <50 copies/mL by Visit  
(Observed Case Analysis) – Maintenance and Extension Period
-
Randomized 
Q8W/Q4W 
Arms Only
-
Maintenance and Extension 
periods
W96
39.
Proportion of Subjects with Extension Period Plasma HIV-1 RNA <50 
copies/mL by Visit (Observed Case Analysis) – Extension Switch 
Population
-
Extension Period data for 
Optimized Q8W/Q4W Arms
W96/W128
40.
Cumulative Proportion of Subjects with Protocol Defined Virologic 
Failure by Visit – Maintenance and Extension Period
-
Randomized 
Q8W/Q4W 
Arms Only
-
Data from Maintenance and 
Extension periods
W96
41.
Cumulative Proportion of Subjects in the Extension Period with Protocol 
Defined Virologic Failure by Visit (Extension Switch Population)  
-
Extension Period data for 
Optimized Q8W/Q4W Arms 
Extension periods
W96/W128
 
 
 
2018N380094_00


CONFIDENTIAL
200056
115
17.2.2.2.
Figures
Number
Title
Details/Comments
IDSL/TST 
ID
Reports
1.
Proportion (95% CI) of Subjects with Plasma HIV-1 RNA <50 copies/mL 
by Visit – Snapshot Analysis (Induction and Maintenance Period)
Up to Week 96
2.
Proportion (95% CI) of Subjects with Plasma HIV-1 RNA <50 copies/mL 
by Visit – Snapshot Analysis (Extension Period)
Optimized Q8W/Q4W Arms, up to 
Week 128
W128
3.
Individual Plasma HIV-1 RNA (log10 copies/mL) and CD4+ Cell Count 
Profiles by Visit
4.
Kaplan-Meier Plot of Time to Virologic or Tolerability Failure –
Maintenance Period
5.
Proportion (95% CI) of Subjects with Virologic Failure by Visit –
Snapshot Analysis (Induction and Maintenance Period)
Up to Week 96
6.
Proportion (95% CI) of Subjects with Virologic Failure by Visit 
(Maintenance Period)  – Snapshot Analysis
Day 1 to Week 96
7.
Proportion (95% CI) of Subjects with Virologic Failure by Visit (Extension 
Period) – Snapshot Analysis
Optimized Q8W/Q4W Arms, up to 
Week 128. 
W128
8.
Individual Plasma HIV-1 RNA (log10 copies/mL) Profiles by Visit – Q8W 
IM Subjects
9.
Individual Plasma HIV-1 RNA (log10 copies/mL) Profiles by Visit – Q4W 
IM Subjects
10.
Individual Plasma HIV-1 RNA (log10 copies/mL) Profiles by Visit – Oral 
744 Subjects
Add annotation of extension period 
regimen (optimized Q8W or Q4W)
11.
Individual Plasma HIV-1 RNA (log10 copies/mL) Profiles by Visit -
Extension Period (Extension-Switch Subjects)
Optimized Q8W/Q4W Arms, up to 
Week 128.
W128
 
 
 
2018N380094_00


CONFIDENTIAL
200056
116
17.2.2.3.
ICH Listings
Number
Title
Details/Comments
IDSL/TST 
ID
Reports
7.
Listing of Quantitative Plasma HIV-1 RNA Data
Extension-Switch Subjects during 
Extension Period Only for W128
W32/W48/W96/W128
8.
Listing of Study Outcome (<50 copies/mL) at Week 32/48/96/128
–
Snapshot (MSDF)
Extension-Switch Subjects Only for 
W128
W32/W48/W96/W128
9.
Listing of Study Outcome (<200 copies/mL) at Week 32/48/96/128 –
Snapshot (MSDF)
Extension-Switch Subjects Only for 
W128
W32/W48/W96/W128
 
 
 
2018N380094_00


CONFIDENTIAL
200056
117
17.2.2.4.
Other Listings
Number
Title
Details/Comments
IDSL/TST 
ID
Reports
17.
Listing of CD4+ and CD8+ Cell Count Data
18.
Listing of Extension Period CD4+ Cell Count Data
Optimized Q8W/Q4W Arms, up to 
Week 128
W128
19.
Listing of HIV-1 Associated Conditions
HIV4
20.
Listing of Extension Period HIV-1 Associated Conditions
Optimized Q8W/Q4W Arms, up to 
Week 128
W128
21.
Listing of Background NRTI Switches
22.
Listing of Subjects with Protocol Defined Virologic Failure
23.
Listing of Subjects with Extension Period Protocol Defined Virologic 
Failure
Optimized Q8W/Q4W Arms Only
W128
24.
Listing of Quantitative Plasma HIV-1 RNA Data for Subjects Classified as 
Having 'data in window >50' at any Maintenance Period Visit based on 
the Snapshot Classification
25.
Listing of Quantitative Plasma HIV-1 RNA Data for Extension-Switch 
Subjects Classified as Having 'data in window >50' at any Extension 
Period Visit based on the Snapshot Classification
Optimized Q8W/Q4W Arms Only
W128
26.
Listing of Quantitative Plasma HIV-1 RNA Data for Subjects with HIV-1 
RNA ≥ 50 c/mL at any time during the Maintenance Period or Extension 
Period
W96
27.
Listing of BIOMNTR Viral Load Results
28.
Listing of BIOMNTR Viral Load Results – Extension Period
Optimized Q8W/Q4W Arms Only
W128
17.2.3.
Safety – Week 32/48/96/128
Unless otherwise noted, the Safety-ME Population will be used for Week 32/48/96 displays, and the Extension-Switch Population will be 
used for W128 displays. Outputs for the Week 128 report will be noted in the “Reports” Column in the following tables. 
 
 
 
2018N380094_00


CONFIDENTIAL
200056
118
17.2.3.1.
Tables
Number
Title
Details/Comments
IDSL/TST 
ID
Reports
1.
Summary of Extent of Exposure to Investigational Product (Induction and Maintenance
Period)
2.
Summary of Extent of Exposure to Investigational Product – Maintenance and 
Extension Period
Randomized 
Q8W/Q4W 
Arms Only
3.
Summary of Extent of Exposure to Investigational Product
(Extension Switch 
Population) – Extension Period
Optimized Q8W/Q4W Arms 
Only
W96/W128
Adverse Events (AEs)
4.
Summary of All Post-baseline Adverse Events by System Organ Class – Induction and 
Maintenance Period
AE1
5.
Summary of All Post-baseline Adverse Events by Overall Frequency – Induction and 
Maintenance Period
6.
Summary of All Induction Period Adverse Events by Overall Frequency
7.
Summary of All Maintenance Period On-treatment Adverse Events by Overall 
Frequency 
8.
Summary of All Extension Period On-treatment Adverse Events by Overall Frequency 
(Extension Switch Population)
Optimized Q8W/Q4W Arms 
Only
W128
9.
Summary of All Long-term Follow-up Period Adverse Events by Overall Frequency 
(Safety Long-Term Follow-up Population)
Provide if >10% IM subjects 
enter long term follow up
10.
Summary of All Post-baseline Adverse Events by System Organ Class and Maximum 
Toxicity – Induction and Maintenance Period
AE5 
or 
AE5b
11.
Summary of All Induction Period Adverse Events by System Organ Class and 
Maximum Toxicity 
AE5 
or 
AE5b
12.
Summary of All Maintenance Period On-treatment Adverse Events by System Organ 
Class and Maximum Toxicity 
AE5 
or 
AE5b
 
 
 
2018N380094_00


CONFIDENTIAL
200056
119
Number
Title
Details/Comments
IDSL/TST 
ID
Reports
13.
Summary of All On-Treatment  Adverse Events by System Organ Class and Maximum 
Toxicity – Maintenance and Extension Period
Randomized 
Q8W/Q4W 
Arms Only
AE5 
or 
AE5b
14.
Summary of Extension Period On-treatment Adverse Events by System Organ Class 
and Maximum Toxicity (Extension Switch Population)
Optimized Q8W/Q4W Arms 
Only
AE5 
or 
AE5b
W96/W128
15.
Summary of Common (>=3%) Grade 2-4 Post-baseline Adverse Events by Overall 
Frequency – Induction and Maintenance Period
16.
Summary of Common (>=3%) Grade 2-4 Extension Period Adverse Events by Overall 
Frequency (Extension Switch Population)
Optimized Q8W/Q4W Arms 
Only
W128
17.
Summary of Common (>=5%) Non-Serious Post-baseline Adverse Event by System 
Organ Class and Preferred Term (Number of Subjects and Occurrences) – Induction 
and Maintenance Period
18.
Summary of Common (>=5%) Extension Period Non-Serious Adverse Event by 
System Organ Class and Preferred Term (Number of Subjects and 
Occurrences/Extension Switch Population)
Optimized Q8W/Q4W Arms 
Only
W128
19.
Summary of Grade 3/4 Post-baseline Adverse Events by Overall Frequency –
Induction and Maintenance Period
20.
Summary of Grade 3/4 Maintenance Period On-treatment Adverse Events by Overall
frequency
21.
Summary of Grade 3/4 Extension Period On-treatment Adverse Events by Overall 
Frequency (Extension Switch Population)
Optimized Q8W/Q4W Arms 
Only
W128
22.
Summary of Grade 3/4 Maintenance Period On-treatment Non Injection Site Reaction 
Related Adverse Events by Overall Frequency
23.
Summary of Grade 3/4 Extension Period On-treatment Non Injection Site Reaction 
Related Adverse Events by Overall Frequency (Extension Switch Population)
Optimized Q8W/Q4W Arms 
Only
W128
24.
Summary of Drug-Related Post-baseline Adverse Events by Overall Frequency –
Induction and Maintenance Period
 
 
 
2018N380094_00


CONFIDENTIAL
200056
120
Number
Title
Details/Comments
IDSL/TST 
ID
Reports
25.
Summary of Drug-Related Extension Period On-treatment Adverse Events by Overall 
Frequency (Extension Switch Population)
Optimized Q8W/Q4W Arms 
Only
W128
26.
Summary of All Drug-Related Post-baseline Adverse Events by System Organ Class 
and Preferred Term and Maximum Toxicity – Induction and Maintenance Period
AE5 
or AE5b
27.
Summary of Drug-Related Induction Period Adverse Events by System Organ Class  
and Maximum Toxicity
AE5
or AE5b
28.
Summary of Drug-Related Maintenance Period On-treatment Adverse Events by 
System Organ Class and Maximum Toxicity 
AE5 
or AE5b
29.
Summary of All Drug-Related  On-treatment Adverse Events by System Organ Class 
and Maximum Toxicity – Maintenance and Extension Period
Randomized 
Q8W/Q4W 
Arms Only
AE5 
or 
AE5b
30.
Summary of Drug-Related Extension Period On-treatment Adverse Events by System 
Organ Class and Maximum Toxicity (Extension Switch Population)
Optimized Q8W/Q4W Arms 
Only
AE5 
or 
AE5b
W96/W128
31.
Summary of Long-Term Follow-up Period Drug-Related Adverse Events by Overall 
Frequency (Safety Long-Term Follow-Up Population)
Provide if >10% IM subjects 
enter long term follow up
32.
Summary of Common (>=3%) Drug-Related Grade 2-4 Post-baseline Adverse Events 
by Overall Frequency – Induction and Maintenance Period
33.
Summary of Extension Period Common (>=3%) Drug-Related Grade 2-4 Adverse 
Events by Overall Frequency (Extension Switch Population)
Optimized Q8W/Q4W Arms 
Only
W128
Serious and Other Significant Adverse Events
34.
Summary of Post-baseline Serious Adverse Events by Overall Frequency – Induction 
and Maintenance Period
35.
Summary of Serious Induction Period Adverse Events by Overall 
36.
Summary of Serious Maintenance Period On-treatment Adverse Events by Overall 
Frequency 
 
 
 
2018N380094_00


CONFIDENTIAL
200056
121
Number
Title
Details/Comments
IDSL/TST 
ID
Reports
37.
Summary of Post-baseline Serious  Adverse Events by Overall Frequency –
Maintenance and Extension Period
Randomized 
Q8W/Q4W 
Arms Only
38.
Summary of Serious Extension Period On-treatment Adverse Events by Overall 
Frequency (Extension Switch Population)
Optimized Q8W/Q4W Arms 
Only
W96/W128
39.
Summary of Long-Term Follow-up Period Serious Adverse Events by Overall 
Frequency (Safety Long-Term Follow-up Population)
Provide if >10% IM subjects 
enter long term follow up, 
40.
Summary of Serious Adverse Events by System Organ Class and Preferred Term 
(Number of Subjects and Occurrences) – Induction and Maintenance Period
new
41.
Summary of Extension Period Serious Adverse Events by System Organ Class and 
Preferred Term (Number of Subjects and Occurrences) -Extension Switch Population
Optimized Q8W/Q4W Arms 
Only
W128
42.
Summary of Post-baseline Drug-Related Serious Adverse Events by Overall 
Frequency – Induction and Maintenance Period
43.
Summary of Extension Period Drug-Related Serious Adverse Events by Overall 
Frequency (Extension Switch Population)
Optimized Q8W/Q4W Arms 
Only
W128
44.
Summary of Maintenance Period Adverse Events Leading to Withdrawal/Permanent 
Discontinuation of Investigational Product by System Organ Class 
AE1
45.
Summary of Extension Period Adverse Events Leading to Withdrawal/Permanent 
Discontinuation of Investigational Product by System Organ Class 
Randomized 
Q8W/Q4W 
Arms Only
46.
Summary of Extension Period Adverse Events Leading to Withdrawal/Permanent 
Discontinuation of Investigational Product by System Organ Class (Extension Switch 
Population)
Optimized Q8W/Q4W Arms 
Only
W96/W128
47.
Summary of Drug-Related Grade 3/4 Post-baseline Adverse Events by Overall 
Frequency – Induction and Maintenance Period
 
 
 
2018N380094_00


CONFIDENTIAL
200056
122
Number
Title
Details/Comments
IDSL/TST 
ID
Reports
48.
Summary of Extension Period Drug-Related Grade 3/4 Adverse Events by Overall 
Frequency (Extension Switch Population)
Optimized Q8W/Q4W Arms 
Only
W128
49.
Summary of Grade 3/4 Maintenance Period On-treatment Non Injection Site Reaction 
Related Adverse Events by Overall Frequency - Drug-related
50.
Summary of Grade 3/4 Extension Period Non Injection Site Reaction Related Adverse 
Events by Overall Frequency - Drug-related (Extension Switch Population)
Optimized Q8W/Q4W Arms 
Only
W128
Injection Site Reaction Adverse Events
51.
Summary of Injection Site Reaction Adverse Events (Event-Level Summary) –
Maintenance Period
52.
Summary of Injection Site Reaction Adverse Events (Event-Level Summary) –
Maintenance and Extension Period
Randomized 
Q8W/Q4W 
Arms Only
53.
Summary of Injection Site Reaction Adverse Events (Event-Level Summary) –
Extension Switch Population
Optimized Q8W/Q4W Arms 
Only. 
Summarize 
AEs 
during 
Extension 
Period 
only for W128
W96/W128
54.
Summary of Subject-Level Characteristics of Injection Site Reaction Adverse Events –
Overall and Common (Maintenance Period)
55.
Summary of Subject-Level Characteristics of Injection Site Reaction Adverse Events –
Overall and Common (Maintenance and Extension Period)
Randomized 
Q8W/Q4W 
Arms Only
56.
Summary of Subject-Level Characteristics of Injection Site Reaction Adverse Events –
Overall and Common (Extension Switch Population)
Optimized Q8W/Q4W Arms 
Only.  Summarize AEs 
during 
Extension 
Period 
only for W128
W96/W128
57.
Summary of Injection Site Reaction Adverse Events by Visit and Maximum Severity –
Overall and Common (Maintenance Period)
 
 
 
2018N380094_00


CONFIDENTIAL
200056
123
Number
Title
Details/Comments
IDSL/TST 
ID
Reports
58.
Summary of Extension Period Injection Site Reaction Adverse Events by Visit and 
Maximum Severity – Overall and Common (Extension Switch Population)
Optimized Q8W/Q4W Arms 
Only
W128
59.
Summary of Subject-Level Characteristics of Injection Site Reaction Adverse Events 
by Needle Length – Overall and Common (Maintenance Period)
60.
Summary of Extension Period Subject-Level Characteristics of Injection Site Reaction 
Adverse Events by Needle Length – Overall and Common (Extension Switch 
Population)
Optimized Q8W/Q4W Arms 
Only
W128
61.
Summary of Total Number of Injection Site Reaction Adverse Events by Visit 
(Maintenance Period)
62.
Summary of Extension Period Total Number of Injection Site Reaction Adverse Events 
by Visit (Extension Switch Population)
Optimized Q8W/Q4W Arms 
Only
W128
63.
Summary of Injection Site Reaction Adverse Events (Event-Level Summary) -
GSK1265744
64.
Summary of Extension Period Injection Site Reaction Adverse Events (Event-Level 
Summary) - GSK1265744 (Extension Switch Population)
Optimized Q8W/Q4W Arms 
Only
W128
65.
Summary of Subject-Level Characteristics of Injection Site Reaction Adverse Events -
Overall and Common (GSK1265744)
66.
Summary of Subject-Level Characteristics of Extension Period Injection Site Reaction 
Adverse Events - Overall and Common - GSK1265744 (Extension Switch Population)
Optimized Q8W/Q4W Arms 
Only
W128
67.
Summary of Overall and Common Injection Site Reaction Adverse Events by Visit and 
Maximum Severity - GSK1265744 
68.
Summary of Overall and Common Extension Period Injection Site Reaction Adverse 
Events by Visit and Maximum Severity - GSK1265744 (Extension Switch Population)
Optimized Q8W/Q4W Arms 
Only
W128
69.
Summary of Subject-Level Characteristics of Injection Site Reaction Adverse Events 
by Needle Length - Overall and Common (GSK1265744) 
 
 
 
2018N380094_00


CONFIDENTIAL
200056
124
Number
Title
Details/Comments
IDSL/TST 
ID
Reports
70.
Summary of Total Number of Injection Site Reaction Adverse Events by Visit -
GSK1265744 
71.
Summary of Total Number of Extension Period Injection Site Reaction Adverse Events 
by Visit - GSK1265744 (Extension Switch Population)
Optimized Q8W/Q4W Arms 
Only
W128
72.
Summary of Injection Site Reaction Adverse Events (Event-Level Summary) -
TMC278 
73.
Summary of Extension Period Injection Site Reaction Adverse Events (Event-Level 
Summary) - TMC278(Extension Switch Population) 
Optimized Q8W/Q4W Arms 
Only
W128
74.
Summary of Subject-Level Characteristics of Injection Site Reaction Adverse Events -
Overall and Common (TMC278) 
75.
Summary of Subject-Level Characteristics of Extension Period Injection Site Reaction 
Adverse Events - Overall and Common - TMC278 (Extension Switch Population) 
Optimized Q8W/Q4W Arms 
Only
W128
76.
Summary of Overall and Common Injection Site Reaction Adverse Events by Visit and 
Maximum Severity -TMC278
77.
Summary of Overall and Common Extension Period Injection Site Reaction Adverse 
Events by Visit and Maximum Severity -TMC278 (Extension Switch Population) 
Optimized Q8W/Q4W Arms 
Only
W128
78.
Summary of Subject-Level Characteristics of Injection Site Reaction Adverse Events 
by Needle Length - Overall and Common (TMC278) 
79.
Summary of Total Number of Injection Site Reaction Adverse Events by Visit -
TMC278
80.
Summary of Total Number of Extension Period Injection Site Reaction Adverse Events 
by Visit - TMC278 (Extension Switch Population) 
Optimized Q8W/Q4W Arms 
Only
W128
 
 
 
2018N380094_00


CONFIDENTIAL
200056
125
Number
Title
Details/Comments
IDSL/TST 
ID
Reports
Laboratory: Chemistry and Hematology
81.
Summary of Chemistry Changes from Baseline by Visit – Induction and Maintenance 
Period
Includes lipids and Glucose 
in Conventional Units
LB1
82.
Summary of Chemistry Changes from Baseline by Visit – Extension Period (Extension 
Switch Population)
Optimized Q8W/Q4W Arms 
Only
Note: Baseline is last value 
up to and including the date 
of first extension injection
W128
83.
Summary of Hematology Changes from Baseline by Visit – Induction and Maintenance 
LB1
84.
Summary of Hematology Changes from Baseline by Visit – Extension Period 
(Extension Switch Population)
Optimized Q8W/Q4W Arms 
Only
Note: Baseline is last value 
up to and including the date 
of first extension injection
W128
85.
Summary of Maximum Post-baseline Emergent Clinical Chemistry Toxicities –
Induction and Maintenance Period
86.
Summary of Maximum Maintenance Period Treatment Emergent Clinical Chemistry 
Toxicities – Induction and Maintenance Period
87.
Summary of Maximum Extension Period Treatment Emergent Clinical Chemistry 
Toxicities (Extension Switch Population)
Optimized Q8W/Q4W Arms 
Only
W128
88.
Summary of Maximum Post-baseline Emergent Hematology Toxicities – Induction and 
Maintenance Period
89.
Summary of Maximum Maintenance Period Treatment Emergent Hematology 
Toxicities – Induction and Maintenance Period
90.
Summary of Maximum Extension Period Treatment Emergent Hematology Toxicities 
(Extension Switch Population)
Optimized Q8W/Q4W Arms 
Only
W128
 
 
 
2018N380094_00


CONFIDENTIAL
200056
126
Number
Title
Details/Comments
IDSL/TST 
ID
Reports
91.
Summary of Changes in Clinical Chemistry Baseline Toxicity to Maximum 
Maintenance Period On-Treatment Toxicity  - Parameters of Special Interest
Parameters 
of 
Special 
Interest: 
AST, 
ALT, 
ALP,Total Bilirubin
Note: Baseline is last value 
up to and including the date 
of first extension injection
92.
Summary of Changes in Clinical Chemistry Baseline Toxicity to Maximum Extension
Period On-Treatment Toxicity - Parameters of Special Interest (Extension Switch 
Population)
Parameters 
of 
Special 
Interest: 
AST, 
ALT, 
ALP,Total Bilirubin
Note: Baseline is last value 
up to and including the date 
of first extension injection
W128
Laboratory: Urinalysis
93.
Summary of Post-Baseline Emergent Urinalysis Dipstick Results – Induction and 
Maintenance Period
UR3/LB2
94.
Summary of Urine Concentration Changes from Baseline by Visit – Induction and 
Maintenance Period
Includes Baseline values.
LB1
95.
Summary of Urine Concentration Changes from Baseline by Visit – Extension Period 
(Extension Switch Population)
Optimized Q8W/Q4W Arms 
Only
Note: Baseline is last value 
up to and including the date 
of first extension injection.
LB1
W128
 
 
 
2018N380094_00


CONFIDENTIAL
200056
127
Number
Title
Details/Comments
IDSL/TST 
ID
Reports
Laboratory: Hepatobiliary (Liver)
96.
Listing of Liver Monitoring/Stopping Event Reporting (Updated Display Standard)
Updated Display Standard
LIVER5
97.
Listing of Liver Monitoring/Stopping Event Reporting During the Extension Period 
(Extension Switch Population)
Optimized Q8W/Q4W Arms 
Only
Updated Display Standard
LIVER5
W128
98.
Summary of Subjects Meeting Hepatobiliary Laboratory Abnormality Criteria (Post-
Baseline Emergent) – Induction and Maintenance Period
99.
Listing of Subjects Meeting Hepatobiliary Laboratory Abnormality Criteria at Any Post-
Baseline Emergent Visit 
100.
Summary of Hepatobiliary Laboratory Abnormalities (Updated Display Standard) –
Induction and Maintenance Period
Updated Display Standard
LIVER10
101.
Summary of Hepatobiliary Laboratory Abnormalities (Updated Display Standard) –
Maintenance and Extension Period
Updated Display Standard 
Randomized 
Q8W/Q4W 
Arms Only
LIVER10
W96
102.
Summary of Extension Period Hepatobiliary Laboratory Abnormalities (Updated 
Display Standard) – Extension Switch Population
Updated Display Standard 
Optimized Q8W/Q4W Arms 
Only
LIVER10
W96/W128
103.
Listing of Subjects Meeting Hepatobiliary Laboratory Criteria Post-Baseline (Updated 
Display Standard)
Updated Display Standard
LIVER13
W96
104.
Listing of Subjects Meeting Hepatobiliary Laboratory Criteria during the Extension 
Period – Updated Display Standard (Extension Switch Population)
Optimized Q8W/Q4W Arms 
Only
LIVER13
W128
 
 
 
2018N380094_00


CONFIDENTIAL
200056
128
Number
Title
Details/Comments
IDSL/TST 
ID
Reports
ECG
105.
Summary of Change from Baseline in ECG Values by Visit – Induction and 
Maintenance Period
EG2
106.
Summary of Change from Baseline in ECG Values by Visit – Extension Period 
(Extension Switch Population)
Optimized Q8W/Q4W Arms 
Only
Note: Note: Baseline is last 
value before the date of first 
extension injection.
EG2
W128
107.
Summary of QTc Values by Category – Induction and Maintenance Period
108.
Summary of QTc Values by Category – Extension Period (Extension Switch 
Population)
Optimized Q8W/Q4W Arms 
Only
W128
109.
Summary of Change from Baseline QTc Values by Category – Induction and 
Maintenance Period
110.
Summary of Change from Baseline QTc Values by Category – Extension Period 
(Extension Switch Population)
Optimized Q8W/Q4W Arms 
Only
Note: Note: Baseline is last 
value before the date of first 
extension injection.
W128
Vital Signs
111.
Summary of Change From Baseline in Vital Signs by Visit – Induction and 
Maintenance Period
Include BMI
VS1
112.
Summary of Change from Baseline in Vital Signs by Visit – Extension Period 
(Extension Switch Population)
VS1
W128
113.
Listing of Possible Suicidality-Related Adverse Event Data: Event and Description 
(Section 1 - Section 2)
PSRAE1
114.
Listing of Possible Suicidality-Related Adverse Event Data: Possible Cause(s) 
(Section 3)
PSRAE3
 
 
 
2018N380094_00


CONFIDENTIAL
200056
129
Number
Title
Details/Comments
IDSL/TST 
ID
Reports
115.
Listing of Possible Suicidality-Related Adverse Event Data (Section 4)
PSRAE4
116.
Listing of Possible Suicidality-Related Adverse Event Data (Section 5 - Section 8)
PSRAE5
117.
Listing of eCSSRS Suicidal Ideation and Behaviour Data For Subjects With at least 
One Positive Response for Suicidal Indication Alert
118.
Listing of eCSSRS Suicidal Behaviour Details For Subjects With at least One Positive 
Response for Suicidal Indication Alert
119.
Listing of eCSSRS Details of Most Severe Suicidal Ideation For Subjects With at least 
One Positive Response for Suicidal Indication Alert
 
 
 
2018N380094_00


CONFIDENTIAL
200056
130
17.2.3.2.
Figures
Number
Title
Details/Comments
IDSL/TST ID
Reports
1.
Plot of Common Maintenance Period On-treatment Adverse Events and Relative 
Risk– Q8W vs. Oral
AE10
2.
Plot of Common Maintenance Period On-treatment Adverse Events and Relative 
Risk– Q4W vs. Oral
AE10
3.
Plot of Common Maintenance Period On-treatment Adverse Events and Relative 
Risk– Q8W vs. Q4W
AE10
4.
Plot of Common Maintenance Period On-treatment Adverse Events and Relative 
Risk– IM Subtotal vs. Oral
AE10
5.
Box Plots of Maintenance Period Change from Baseline of Aspartate Amino 
Transferase (AST) ( (IU/L) over Time
Repeat for other Parameters of Special 
Interest: ALT, ALP, Total Bilirubin, total 
absolute neutrophils.  
6.
Scatter Plots of Maximum Maintenance Period On-Treatment vs. Baseline for 
ALT
7.
Scatter Plots of Maximum Extension Period On-Treatment vs. Baseline for ALT
(Extension Switch Population)
Note: Baseline is last value up to and 
including 
date 
of 
first 
extension 
injection.
W128
8.
Box Plots of Maximum Maintenance Period On-treatment Liver Chemistries
9.
Matrix Plot of Maximum Maintenance Period On-treatment Liver Chemistries
10.
Matrix Plot of Maximum Extension Period On-treatment Liver Chemistries
(Extension Switch Population)
W128
11.
Liver Chemistry Profile Plots for Subjects with Elevation at any Post-Baseline 
Visit by Study Day
12.
Liver Chemistry Profile Plots for Subjects with Elevation during the Extension 
Period by Study Day (Extension Switch Population)
Extension Period Only
W128
13.
Scatter Plot of Maximum Maintenance Period On-Treatment Value: [Parameter 
1] vs. [Parameter 2]
DILI plot for ALT v BILI only
14.
Scatter Plot of Maximum Extension Period On-Treatment Value: [Parameter 1] 
vs. [Parameter 2] (Extension Switch Population)
DILI plot for ALT v BILI only
W128
 
 
 
2018N380094_00


CONFIDENTIAL
200056
131
Number
Title
Details/Comments
IDSL/TST ID
Reports
15.
Kaplan-Meier Plot of Time to First Maintenance Period Treatment-Emergent 
Grade 1 or Greater Elevation in ALT
16.
Kaplan-Meier Plot of Time to Maximum Maintenance Period Treatment-
Emergent Elevation in ALT
17.
Figure of Onset, Duration, and Severity of Headache Adverse Events – Induction 
and Maintenance Period
18.
Plot of Common Maintenance Period Injection Site Adverse Events and Relative 
Risk: Q8W vs. Q4W
19.
Figure of Onset, Duration, and Severity of Overall and Common Maintenance 
Period Injection Site Reaction Adverse Events by Maximum Grade:  GSK744 LA 
or TMC278 LA
Repeat parameters for “GSK126574’, 
‘TMC278’ 
20.
Figure of Onset, Duration, and Severity of Overall and Common Extension 
Period Injection Site Reaction Adverse Events by Maximum Grade:  GSK744 LA 
or TMC278 LA (Extension Switch Population)
W128
21.
Figure of Incidence of Maintenance Period Injection Site Reaction Adverse 
Events – Overall and Common —GSK 744 LA or TMC278 LA
Repeat parameters for “GSK126574’, 
‘TMC278’ 
22.
Figure of Incidence of Extension Period Injection Site Reaction Adverse Events –
Overall and Common —GSK 744 LA or TMC278 LA (Extension Switch 
Population)
W128
23.
Figure of Incidence of Grade 3-4 Maintenance Period Injection Site Reaction 
Adverse Events – Overall and Common—GSK 744 LA or TMC278 LA
Repeat parameters for “GSK126574’, 
‘TMC278’
24.
Figure of Incidence of Grade 3-4 Extension Period Injection Site Reaction 
Adverse Events – Overall and Common—GSK 744 LA or TMC278 LA
(Extension Switch Population)
W128
 
 
 
2018N380094_00


CONFIDENTIAL
200056
132
17.2.3.3.
ICH Listings
Number
Title
Details/Comments
IDSL/ TST 
ID
Report
10.
Listing of Investigational Product Exposure Data
HIV_IP5
11.
Listing of Investigational Product Exposure Data during the Extension 
Period (Extension Switch Population)
W128
12.
Listing of All Adverse Events
Add the days since 1st maintenance 
dose.
AE8
13.
Listing of All Extension Period Adverse Events (Extension Switch 
Population)
W128
14.
Listing of Fatal Adverse Events
AE8
15.
Listing of Extension Period Fatal Adverse Events (Extension Switch 
Population)
W128
16.
Listing of Non-Fatal Serious Adverse Events
AE8
17.
Listing of Extension Period Non-Fatal Serious Adverse Events (Extension 
Switch Population)
W128
18.
Listing of Reasons for Considering an AE as Serious
Moved from Other Listings
AE14
W32/W48/W96/W128
19.
Listing of Adverse Events Leading to Permanent Discontinuation of 
Investigational Product and/or Withdrawal from the Study
AE8
20.
Listing of Extension Period Adverse Events Leading to Permanent 
Discontinuation of Investigational Product and/or Withdrawal from the 
Study (Extension Switch Population)
W128
21.
Listing of Subject Numbers for Individual Adverse Events
AE7
22.
Listing of Subject Numbers for Individual Extension Period Adverse 
Events (Extension Switch Population)
W128
23.
Listing of Subjects Who Became Pregnant During the Study
PREG1a
24.
Listing of Extension Switch Subjects Who Became Pregnant during the 
Extension Period 
W128
25.
Listing of ECG Values
EG3
26.
Listing of Extension Period ECG Values (Extension Switch Population)
W128
 
 
 
2018N380094_00


CONFIDENTIAL
200056
133
Number
Title
Details/Comments
IDSL/ TST 
ID
Report
27.
Listing of ECG Values for Subjects with a Value of Potential Clinical 
Concern
EG3
28.
Listing of ECG Values for Subjects with a Value of Potential Clinical 
Concern during the Extension Period (Extension Switch Population)
W128
29.
Listing of ECG Findings
EG5
30.
Listing of Extension Period ECG Findings (Extension Switch Population)
W128
31.
Listings of Vital Signs
VS4
32.
Listings of Extension Period Vital Signs (Extension Switch Population)
Including baseline findings
W128
Laboratory: Hepatobiliary (Liver)
33.
Listing of Medical Conditions for Subjects with Liver Stopping Events
MH2
W96
34.
Listing of Medical Conditions for Subjects with Liver Stopping Events
during the Extension Period (Extension Switch Population)
W128
35.
Listing of Substance Use for Subjects with Liver Stopping Events
SU2
W96
36.
Listing of Substance Use for Subjects with Liver Stopping Events during 
the Extension Period (Extension Switch Population)
W128
17.2.3.4.
Other Listings
Number
Title
Details/ 
Comments
IDSL/TST 
ID
Report
29.
Relationship of Adverse Event System Organ Classes, Preferred Terms, and Verbatim Text
AE2
W32/W48/W96/ 
W128
30.
Listing of Clinical Chemistry Laboratory Data for Subjects with Grade 3/4 Post Baseline Emergent or 
Grade 3/4 Maintenance Period Treatment-Emergent Toxicities
LB5
31.
Listing of Extension Period Clinical Chemistry Laboratory Data for Subjects with Grade 3/4 Extension 
Period Treatment-Emergent Toxicities (Extension Switch Population)
W128
32.
Listing of Hematology Laboratory Data for Subjects with Grade 3/4 Post Baseline Emergent or Grade 
3/4 Maintenance Period Treatment-Emergent Toxicities
LB5
33.
Listing of Extension Period Hematology Laboratory Data for Subjects with Grade 3/4 Extension 
Period Treatment-Emergent Toxicities (Extension Switch Population)
W128
 
 
 
2018N380094_00


CONFIDENTIAL
200056
134
Number
Title
Details/ 
Comments
IDSL/TST 
ID
Report
34.
Listing of Urinalysis Data for Subjects with Grade 3/4 Post Baseline Emergent or Grade 3/4 
Maintenance Period Treatment-Emergent Toxicities
UR2a
35.
Listing of Extension Period Urinalysis Data for Subjects with Grade 3/4 Extension Period Treatment-
Emergent Toxicities (Extension Switch Population)
W128
36.
Listing of Abacavir Hypersensitivity Reaction Record -  Exposure to Abacavir
ABC_HSR
_EXPO2
37.
Listing of Abacavir Hypersensitivity Reaction Record -  Subject History of Drug Allergies
ABC_HSR
_DRUG2
38.
Listing of Abacavir Hypersensitivity Reaction Record -  Subject and Family Conditions
ABC_HSR
COND2
39.
Listing of Abacavir Hypersensitivity Reaction Record -  Skin Rash Details
ABC_HSR
_RASH2
40.
Listing of Abacavir Hypersensitivity Reaction Record -  Symptoms
ABC_HSR
_SYMP4
41.
Listing of Abacavir Hypersensitivity Reaction Record -  Vital Signs
VS4
42.
Listing of Abacavir Hypersensitivity Reaction Record - Individual Symptoms and Diagnostic Category 
Assignments (Excluding Other Symptoms)
ABC_HSR
_SYMP6
43.
Listing of Abacavir Hypersensitivity Reaction Record - Individual Symptoms and Diagnostic Category 
Assignments (Other Symptoms)
ABC_HSR
_SYMP7
44.
Listing of Liver Event Information for RUCAM Score
LIVER6
45.
Listing of Extension Period Liver Event Information for RUCAM Score (Extension Switch Population)
W128
46.
Listing of Liver Biopsy Details
LIVER7
47.
Listing of Extension Period Liver Biopsy Details (Extension Switch Population)
W128
48.
Listing of Liver Imaging Details
LIVER8
49.
Listing of Extension Period Liver Imaging Details (Extension Switch Population)
W128
50.
Listing of Past and Current Liver Disease Medical Conditions
51.
Listing of Past and Current Liver Disease Medical Conditions (Extension Switch Population)
W128
52.
Listing of Serology Results from Liver Event Follow-up
 
 
 
2018N380094_00


CONFIDENTIAL
200056
135
Number
Title
Details/ 
Comments
IDSL/TST 
ID
Report
53.
Listing of Serology Results from Extension Period Liver Event 
Follow-up (Extension Switch 
Population)
W128
54.
Listing of Adverse Events Potentially Related to Torsades de Pointes
AE8
55.
Listing of ECG Values for Subjects with Adverse Events Potentially Related to Torsades de Pointes
EG3
56.
Listing of AST, ALT, Alkaline Phosphatase, and Total Bilirubin Laboratory Data for Subjects with On-
Treatment ALT at Least Two Times the ULN
57.
Listing of Extension Period AST, ALT, Alkaline Phosphatase, and Total Bilirubin Laboratory Data for 
Subjects with Extension Period On-Treatment ALT at Least Two Times the ULN (Extension Switch 
Population)
W128
58.
Listing of Grade 2 or higher Injection Site Reaction AE
59.
Listing of Grade 2 or higher Extension Period Injection Site Reaction AEs (Extension Switch 
Population)
W128
60.
Listing of Patient Profile for Subjects Who Experienced Cardiovascular Event
61.
Listing of All Liver Chemistry Data for Subjects Meeting Hepatobiliary Laboratory Abnormality Criteria 
at Any Post-Baseline Emergent Visit
62.
Listing of All Liver Chemistry Data for Subjects Meeting Hepatobiliary Laboratory Abnormality Criteria 
at Any Extension Period Visit
W128
63.
Listing of Each Subject’s Maximum ALT and Maximum Bilirubin
64.
Listing of Each Subject’s Maximum ALT and Maximum Bilirubin during the Extension Period 
(Extension Switch Population)
W128
65.
Listing of Investigational Product Exposure Data for Subject Receiving Oral Bridging
66.
Listing of Investigational Product Exposure Data for Subject Receiving Oral Bridging during the 
Extension Period (Extension Switch Population)
W128
67.
Patient Profile of Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE)
68.
Patient Profile of Myocardial Infarction (MI)
17.2.4.
Health Outcome – Week 32/48/96
The ITT-ME Population will be used, except where noted.
 
 
 
2018N380094_00


CONFIDENTIAL
200056
136
17.2.4.1.
Tables
Number
Title
Details/Comments
IDSL/TST 
ID
Report
1.
Summary of Individual Response of Injection Site Area Symptom from Diary Card by Visit and Overall
W32/W48
2.
Summary of Home Treatment for Injection Area Symptom as Reported in Diary Card
W32/W48
3.
Summary of Cardiovascular Activity, Strength Training and Other Strenuous Activity
W32/W48
4.
Summary of Total Weekly Duration for Cardiovascular Activity, Strength Training and Other Strenuous 
Activity
W32/W48
5.
Summary of HIV Treatment Satisfaction Questionnaire HIVTSQ(s) Individual Item Scores by Visit
6.
Summary of HIV Treatment Satisfaction Questionnaire HIVTSQ(c) Individual Item Scores by Visit
W32/W48
7.
Summary of HIV Treatment Satisfaction Questionnaire HIVTSQ(s) Total Score by Visit
8.
Summary of HIV Treatment Satisfaction Questionnaire HIVTSQ(c) Total Score by Visit
W32/W48
9.
Summary of HIV Medication Questionnaire (HIVMQ) Individual Item by Visit
10.
Summary of HIV Medication Questionnaire (HIVMQ) Item D, E and F Score by Visit
11.
Summary of HIV Medication Questionnaire (HIVMQ) Individual Item by Visit  - Combined Score for CAB LA 
+ RPV LA
New
W96
 
 
 
2018N380094_00


CONFIDENTIAL
200056
137
Number
Title
Details/Comments
IDSL/TST 
ID
Report
12.
Summary of HIV Medication Questionnaire (HIVMQ) Item D, E and F Score by Visit - Combined Score for 
CAB LA + RPV LA
New
W96
13.
Summary and Statistical Analysis of HIV Treatment Satisfaction Questionnaire HIVTST(s) Updated Total 
Score by Visit  - Observed Case Dataset
New
W96
14.
Summary and Statistical Analysis of HIV Treatment Satisfaction Questionnaire HIVTST(s) Individual Item 
Score  by Visit  - Observed Case Dataset
New
W96
 
 
 
2018N380094_00


CONFIDENTIAL
200056
138
17.2.4.2.
Figures
Number
Title
Details/Comments
IDSL/TST 
ID
Report
1.
Mean Plot of Injection Area Symptom Score by Day from Daily Dairy Card
W32/W48
2.
Median Plot of Injection Area Symptom Score by Day from Daily Dairy Card
W32/W48
3.
Bar Chart of HIV Treatment Satisfaction Questionnaire HIVTSQ(s) Mean 
Total Score by Visit
4.
Bar Chart of HIV Treatment Satisfaction Questionnaire HIVTSQ(s) Mean
Total Score by Visit - Updated Total Score by Visit  
W96
5.
Bar Chart of HIV Treatment Satisfaction Questionnaire HIVTSQ(c) Mean 
Total Score by Visit
W32/W48
6.
Bar Char of HIV Medication Questionnaire Mean Score by Visit and 
Medication
Item d,e, f
17.2.4.3.
Other Listings
Number
Title
Details/Comments
IDSL/TST ID
Report
69.
Listing of Daily Diary Card For Symptoms at Injection Area
70.
Listing of Subject’s Exercise Habits
71.
Listing of HIV Treatment Satisfaction Questionnaire HIVTSQ(s)
72.
Listing of HIV Treatment Satisfaction Questionnaire HIVTSQ(c)
73.
Listing of HIV Medication Questionnaire
 
 
 
2018N380094_00


CONFIDENTIAL
200056
139
17.2.5.
PK - Week 32/48/96/128
The PK Concentration Population will be used, except where noted.
17.2.5.1.
Tables
Number
Title
Details/Comments
IDSL/ TST ID
Report
1.
Summary of Plasma GSK1265744 PK Concentration-Time Data by Treatment 
and Visit
ING112276 Table 9.2
PKCT1
W32/W48
2.
Summary of Plasma GSK1265744 PK Concentration-Time Data by Treatment 
and Visit from Week 100 to Week 128 (Extension Switch Population)
W128
3.
Summary of Plasma TMC278 PK Concentration-Time Data by Treatment and 
Visit
ING112276 Table 9.2
PKCT1
W32/W48
4.
Summary of Plasma TMC278 PK Concentration-Time Data by Treatment and 
Visit from Week 100 to Week 128 (Extension Switch Population)
W128
5.
Summary of Derived Plasma GSK1265744 PK Parameters by Treatment and 
Subgroup 
PKPT4
W32/W48
6.
Summary of Plasma TMC278 PK Parameters by Treatment and Subgroup
ING112276 Table 9.3
PKPT4
W32/W48
7.
Summary of Results of Steady State Assessment
W32/W48
8.
Summary of Results of Steady State Assessment – Evaluable Concentrations
W32/W48
9.
Summary of Evaluable Plasma GSK1265744 PK Concentration-Time Data by 
Treatment and Visit
W32/W48
10.
Summary of Evaluable Plasma TMC278 PK Concentration-Time Data by 
Treatment and Visit
W32/W48
11.
Summary of Plasma GSK1265744 PK Concentration (ug/mL) -Time Data by 
Treatment and Visit – Included Log-transformed Statistics
W32/W48
12.
Summary of Extension Period Plasma GSK1265744 PK Concentration (ug/mL) 
-Time Data by Treatment and Visit– Included Log-transformed Statistics 
(Extension Switch Population)
W128
 
 
 
2018N380094_00


CONFIDENTIAL
200056
140
Number
Title
Details/Comments
IDSL/ TST ID
Report
13.
Summary of Plasma TMC278 PK Concentration (ng/mL) -Time Data by 
Treatment and Visit – Included Log-transformed Statistics
W32/W48
14.
Summary of Extension Period Plasma TMC278 PK Concentration (ug/mL) -
Time Data by Treatment and Visit  – Included Log-transformed Statistics 
(Extension Switch Population)
W128
15.
Summary of Evaluable Plasma GSK1265744 PK Concentration (ug/mL)-Time 
Data by Treatment and Visit – Included Log-transformed Statistics
W32/W48
16.
Summary of Extension Period Evaluable Plasma GSK1265744 PK 
Concentration (ug/mL) -Time Data by Treatment and Visit Statistics – Included 
Log-transformed Statistics (Extension Switch Population)
W128
17.
Summary of Evaluable Plasma TMC278 PK Concentration (ng/mL) -Time Data 
by Treatment and Visit – Included Log-transformed Statistics
W32/W48
18.
Summary of Extension Period Evaluable Plasma TMC278 PK Concentration 
(ug/mL) -Time Data by Treatment and Visit – Included Log-transformed 
Statistics (Extension Switch Population)
W128
19.
Summary of Derived Plasma GSK1265744 PK Parameters by Treatment and 
Exercise Habit Assessment Subgroups
W32/W48
20.
Summary of Derived Plasma TMC278 PK Parameters by Treatment and 
Exercise Habit Assessment Subgroups
W32/W48
21.
Summary of Long-Term Follow-up Period Plasma GSK1265744 PK 
Concentration (ug/mL) -Time Data by Treatment and Visit – Included Log-
transformed Statistics
By arm and IM subtotal
W96
22.
Summary of Long-Term Follow-up Period Plasma TMC278 PK Concentration 
(ng/mL) -Time Data by Treatment and Visit – Included Log-transformed 
Statistics
By arm and IM subtotal
W96
23.
Summary of Evaluable Long-Term Follow-up Period Plasma GSK1265744 PK 
Concentration (ug/mL) -Time Data by Treatment and Visit – Included Log-
transformed Statistics
By arm and IM subtotal
W96
24.
Summary of Evaluable Long-Term Follow-up Period Plasma TMC278 PK 
Concentration (ng/mL) -Time Data by Treatment and Visit – Included Log-
transformed Statistics
By arm and IM subtotal
W96
 
 
 
2018N380094_00


CONFIDENTIAL
200056
141
17.2.5.2.
Figures
Number
Title
Details/Comments
IDSL/TST ID
Report
1.
Individual Plasma GSK1265744 Concentration-Time Plots (Linear and Semi-
Log) 
PKCF1
W32/W48
2.
Individual Extension Period Plasma GSK1265744 Concentration Time Plots 
from (Linear and Semi-Log) – Extension Switch Population
W128
3.
Individual Plasma TMC278 Concentration-Time Plots (Linear and Semi-Log)
PKCF1
W32/W48 
4.
Individual Extension Period Plasma TMC278 Concentration Time Plots (Linear 
and Semi-Log) – Extension Switch Population
W128
5.
Mean (SD) Plasma GSK1265744 Concentration-Time Plots (Linear and Semi-
Log)
ING112276 Figure 9.2
PKCF2
W32/W48
6.
Median Plasma GSK1265744 Concentration-Time Plots (Linear and Semi-Log)
ING112276 Figure 9.3
PKCF3
W32/W48
7.
Mean (SD) Plasma TMC278 Concentration-Time Plots (Linear and Semi-Log)
PKCF2
W32/W48
8.
Median Plasma TMC278 Concentration-Time Plots (Linear and Semi-Log)
PKCF3
W32/W48
9.
Mean (SD) Evaluable Plasma GSK1265744 Concentration-Time Plots (Linear 
and Semi-Log)
ING112276 Figure 9.2
PKCF2
W32/W48
10.
Median Evaluable Plasma GSK1265744 Concentration-Time Plots (Linear and 
Semi-Log)
ING112276 Figure 9.3
PKCF3
W32/W48
11.
Mean (SD) Evaluable Plasma TMC278 Concentration-Time Plots (Linear and 
Semi-Log)
PKCF2
W32/W48 
12.
Median Evaluable Plasma TMC278 Concentration-Time Plots (Linear and 
Semi-Log)
PKCF3
W32/W48
13.
Mean (SD) Evaluable Plasma GSK1265744 Concentration-Time Plots ( Semi-
Log)
W32/W48 
14.
Mean (SD) Extension Period Evaluable Plasma GSK1265744 Concentration-
Time Plots   ( Semi-Log) – Extension Switch Population
W128
15.
Mean (SD) Evaluable Plasma TMC278 Concentration-Time Plots ( Semi-Log)
W32/W48
16.
Mean (SD) Extension Period Evaluable Plasma TMC278 Concentration-Time 
Plots ( Semi-Log) – Extension Switch Population
W128
 
 
 
2018N380094_00


CONFIDENTIAL
200056
142
17.2.5.3.
ICH Listings
Number
Title
Details/Comments
IDSL/TST ID
Report
24.
Listing of Plasma GSK1265744 PK Concentration-Time Data
ING112276 Listing 9.1
PKCL1
W32/W48
25.
Listing of Extension Period Plasma GSK1265744 PK Concentration-Time Data 
(Extension Switch Population)
W128
26.
Listing of Plasma TMC278 PK Concentration-Time Data
PKCL1
W32/W48
27.
Listing of Extension Period Plasma TMC278 PK Concentration-Time Data 
(Extension Switch Population)
W128
28.
Listing of Derived Plasma GSK1265744 PK Parameters
ING112276 Listing 9.2
PKPL1
W32/W48
29.
Listing of Derived Plasma TMC278 PK Parameters
ING112276 Listing 9.2
PKPL1
W32/W48
30.
Listing of Plasma GSK1265744 PK Concentration-Time Data (Safety Long-
Term Follow-up Period Population)
New
PKCL1
W96
31.
Listing of Plasma TMC278 PK Concentration-Time Data (Safety Long-Term 
Follow-up Period Population)
New
PKCL1
W96
 
 
 
2018N380094_00


CONFIDENTIAL
200056
143
17.2.6.
PK/PD- Week 32/48/96/128
17.2.6.1.
Tables
Number
Title
Details/Comments
IDSL/TST ID
Report
1.
Summary of Logistic Regression of MSDF Response  at Week X 
and Plasma GSK1265744 and TMC278 PK Parameters
W32/W48
2.
Summary of Logistic Regression of Virologic Failure (MSDF)  at 
Week X and Plasma GSK1265744 and TMC278 PK Parameters
W32/W48
3.
Summary of Pearson’s Correlations (P-values) of CD4+ Change 
from Baseline and Plasma GSK1265744 and TMC278 PK 
Parameters -- Maintenance Period
W32/W48
4.
Summary of Pearson’s Correlations (p-values) of Maintenance 
Period On-Treatment Safety Parameters and Log-transformed 
Plasma GSK1265744 and TMC278 PK Parameters 
Optional display
5.
Summary of Logistic Regression of Maintenance Period On-
Treatment AEs of Special Interest from Selected System Organ 
Class and Plasma GSK1265744 and TMC278 PK Parameters
Optional display
 
 
 
2018N380094_00


CONFIDENTIAL
200056
144
17.2.6.2.
PK/PD Figures
Number
Title
Details/Comments
IDSL/TST ID
Report
1.
Box plot Plasma GSK1265744 and TMC278 PK Parameters by 
MSDF Response and PDVF at Week X 
W32/W48
2.
Median GSK1265744 Extension Period Conc-Time Profiles for 
W128 Successes and Snapshot Failures with Individual Profiles 
for Failures 
Extension Switch Population
W128
3.
Median TMC278 Extension Period Conc-Time Profiles for W128 
Successes and Snapshot Failures with Individual Profiles for 
Failures 
Extension Switch Population
W128
4.
Troughs for GSK1265744 for Week 128 Non-failures and Failures 
Extension Switch Population
W128
5.
Troughs for TMC278 for Week 128 Non-failures and Failures 
Extension Switch Population
W128
17.2.7.
Virology- Week 32/48/96/128
17.2.7.1.
Tables
Number
Title
Details/Comments
IDSL/TST ID
Report
1.
Summary of the Prevalence of On-treatment INI Mutations –
Maintenance Period
PDVF Genotypic Population
2.
Summary of the Prevalence of Extension Period On-treatment INI 
Mutations 
PDVF Genotypic Extension 
Switch Population
W128
3.
Summary of the Prevalence of Treatment Emergent INI Mutations –
Maintenance Period
PDVF Genotypic Population
4.
Summary of the Prevalence of Extension Period Treatment 
Emergent INI Mutations
PDVF Genotypic Extension 
Switch Population
W128
5.
Summary of the Prevalence of On-treatment Major Mutations of 
Other Classes – Maintenance Period
PDVF Genotypic Population
 
 
 
2018N380094_00


CONFIDENTIAL
200056
145
Number
Title
Details/Comments
IDSL/TST ID
Report
6.
Summary of the Prevalence of Extension Period Major Mutations of 
Other Classes
PDVF Genotypic Extension 
Switch Population
W128
7.
Summary of the Prevalence of Treatment Emergent Major Mutations 
of Other Classes– Maintenance Period
PDVF Genotypic Population
8.
Summary of the Prevalence of Extension Period Treatment 
Emergent Major Mutations of Other Classes
PDVF Genotypic Extension 
Switch Population
W128
9.
Summary of On-treatment Phenotype by Phenotypic Cutoff –
Maintenance Period
PDVF Phenotypic Population
10.
Summary of Extension Period On-treatment Phenotype by 
Phenotypic Cutoff 
PDVF Phenotypic Extension 
Switch Population
W128
11.
Summary of On-Treatment Phenotype: Number of Drugs to Which 
Subjects are Resistant – Maintenance Period
PDVF Phenotypic Population
12.
Summary of Extension Period On-Treatment Phenotype: Number of 
Drugs to Which Subjects are Resistant
PDVF Phenotypic Extension 
Switch Population
W128
13.
Summary of On-treatment Susceptibility to GSK1265744 and 
TMC278 – Maintenance Period
PDVF Phenotypic Population
14.
Summary of On-treatment Susceptibility to GSK1265744 and 
TMC278 – Extension Period
PDVF Phenotypic Extension 
Switch Population
W128
15.
Summary of On-treatment Change from Baseline in Susceptibility to 
GSK1265744 and TMC278 – Maintenance Period
PDVF Phenotypic Population
16.
Summary of On-treatment Change from Baseline in Susceptibility to 
GSK1265744 and TMC278 – Extension Period
PDVF Phenotypic Extension 
Switch Population
W128
17.
Listing of Genotypic Mutation Data at All Timepoints
PDVF Genotypic Population
18.
Listing of Phenotypic Data at All Timepoints
PDVF Phenotypic Population
 
 
 
2018N380094_00


CONFIDENTIAL
200056
146
17.2.7.2.
Other Listings
Number
Title
Details/Comments
IDSL/TST ID
Report
32.
Listing of Genotypic Mutation Data at All Timepoints
PDVF Genotypic Extension 
Switch Population
W128
33.
Listing of Phenotypic Mutation Data at All Timepoints
PDVF Genotypic Extension 
Switch Population
W128
34.
Listing of Genotypic Mutation Data at Baseline and On-treatment
PDVF Genotypic Population
35.
Listing of Treatment Emergent Genotypic Mutations
PDVF Genotypic Population
36.
Listing of Treatment Emergent Genotypic Mutations during the 
Extension Period
PDVF Genotypic Extension 
Switch Population
W128
37.
Listing of All Genotypic Mutation Data
Intent-to-Treat Exposed 
Population
38.
Listing of All Genotypic Mutation Data during the Extension Period
Extension Switch Population
W128
39.
Listing of Phenotypic Data at Baseline and On-treatment
PDVF Phenotypic Population
40.
Listing of Phenotypic Data during the Extension Period
Extension Switch Population
W128
41.
Listing of Replication Capacity
PDVF Phenotypic Population
42.
Listing of Replication Capacity
PDVF Genotypic Extension 
Switch Population
W128
 
 
 
2018N380094_00


CONFIDENTIAL
200056
147
17.3.
Table of Contents for Data Display Specifications – Week 160
17.3.1.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.
ITT-ME
ES1
Summary of Subject Accountability: Maintenance and Extension 
Period Conclusion Records (Randomized Q8W/Q4W)
W96 Table 6.1003. 
W160
2.
ITT-ME
HIV_ES1
Summary of Subject Accountability: Withdrawal/Permanent 
Discontinuation of Investigational Product by Visit –
Maintenance and Extension Period (Randomized Q8W/Q4W)
W96 Table 6.1002
W160
3.
ITT-E
ES4
Summary of Subject Disposition at Each Study Epoch
W96 Table 6.1006
W160
4.
ITT-E
ES5
Summary of Reasons for Withdrawal at Each Epoch
W96 Table 6.1007, follow the 
groups from Table 6.1006
W160
5.
ITT-E
NS1
Summary of Number of Subjects by Country and Site ID
W160
6.
Extension 
Switch
ES1
Summary of Subject Accountability: Extension Period 
Conclusion Record (Extension Switch Population)
W96 Table 6.1004
W160
7.
Extension 
Switch
HIV_ES1
Summary of Subject Accountability: Withdrawal/Permanent 
Discontinuation of Investigational Product by Visit - Extension 
Period (Extension Switch Population)
W160
Protocol Deviation
8.
ITT-ME
DV1
Summary of Important Protocol Deviations During the 
Maintenance and Extension Period (Randomized Q8W/Q4W)
W160
9.
Extension 
Switch
DV1
Summary of Important Protocol Deviations During the Extension 
Period (Extension Switch Population)
W160
 
 
 
2018N380094_00


CONFIDENTIAL
200056
148
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Population Analysed
10.
All Subjects 
Screened
Summary of Study Populations
Add PDVF genotypic and phenotypic 
maintenance exposed, PDVF genotypic 
and phenotypic ES population
W96 Table 6.1010
W160
11.
ITT-ME
SP2
Summary of Protocol Deviations Leading to Exclusion from the 
Per-Protocol ITT-ME Population (Randomized Q8W/Q4W) 
W160
12.
Extension 
Switch
SP2
Summary of Protocol Deviations Leading to Exclusion from the 
Per-Protocol Extension Switch Population 
W160
Demographic and Baseline Characteristics
13.
ITT-ME
DM1
Summary of Demographic Characteristics 
Please use Table 6.1010 as an 
example for treatment groups and 
remove the first 2 columns
W160
14.
ITT-ME
DM5
Summary of Race and Racial Combinations 
W160
15.
ITT-ME
DM6
Summary of Race and Racial Combinations Details 
W160
16.
ITT-ME
DM11
Summary of Age Ranges
W160
Prior and Concomitant Medications
17.
ITT-ME
MH1
Summary of Current Medical Conditions 
Please use Table 6.1010 as an 
example for treatment groups and 
remove the first 2 columns 
W160
18.
ITT-ME
MH1
Summary of Past Medical Conditions 
Please use Table 6.1010 as an 
example for treatment groups and 
remove the first 2 columns
W160
19.
ITT-ME
CM1
Summary of Concomitant Medication During Treatment by 
Ingredient ATC Level 1 – Maintenance and Extension Period 
(Randomized Q8W/Q4W)
W160
 
 
 
2018N380094_00


CONFIDENTIAL
200056
149
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
20.
ITT-ME
CM1b
Summary of Concomitant Medication by Combination Term ATC 
Level 1 – Maintenance and Extension Period (Randomized 
Q8W/Q4W)
W160
21.
ITT-ME
CM8
Summary of Concomitant Medication Ingredient Combinations –
Maintenance and Extension Period (Randomized Q8W/Q4W)
W160
22.
Extension 
Switch
CM1
Summary of Concomitant Medication During Treatment by 
Ingredient ATC Level 1 – Extension Period (Extension Switch 
Population)
W160
23.
Extension 
Switch
CM1b
Summary of Concomitant Medication by Combination Term ATC 
Level 1 – Extension Period (Extension Switch Population)
W160
24.
Extension 
Switch
CM8
Summary of Concomitant Medication Ingredient Combinations –
Extension Period (Extension Switch Population)
W160
Exposure and Treatment Compliance
25.
ITT-ME
Summary of Extent of Exposure to Investigational Product –
Maintenance and Extension Period (Randomized Q8W/Q4W)
W160
26.
Extension 
Switch
Summary of Extent of Exposure to Investigational Product –
Extension Period (Extension Switch Population)
W160
 
 
 
2018N380094_00


CONFIDENTIAL
200056
150
17.3.2.
Efficacy Tables
Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Insert Endpoint Category
1.
ITT-ME
Summary of Study Outcomes (<50 copies/mL) at Week 160 –
Snapshot (MSDF) Analysis (Randomized Q8W/Q4W)
W160
2.
PP-ME
Summary of Study Outcomes (<50 copies/mL) at Week 160 –
Snapshot (MSDF) Analysis for the Per-Protocol Randomized 
Q8W/Q4W Population
If PP-ME Population comprises less 
than 95% of the ITT-ME Population 
(randomized Q8W/Q4W)
W160
3.
ITT-ME
Proportion of Subjects with Plasma HIV-1 RNA <50 copies/mL 
by Visit during the Maintenance and Extension Period -
Snapshot (MSDF) Analysis  (Randomized Q8W/Q4W)
Up to Week 160
W160
4.
ITT-ME
Summary of Study Outcomes (<200 copies/mL) at Week 160 –
Snapshot (MSDF) Analysis(Randomized Q8W/Q4W)
W160
5.
ITT-ME
Proportion of Subjects with Plasma HIV-1 RNA <200 copies/mL 
by Visit during the Maintenance and Extension Period -
Snapshot (MSDF) Analysis (Randomized Q8W/Q4W)
Up to Week 160
W160
6.
ITT-ME
Cumulative Proportion of Subjects with Protocol Defined 
Virologic Failure by Visit - Maintenance and Extension Period 
(Randomized Q8W/Q4W)
W160
7.
ITT-ME
Distribution of Quantitative Plasma HIV-1 RNA Results at 
Suspected and Confirmation of Protocol Defined Virologic 
Failure - Maintenance and Extension Period (Randomized 
Q8W/Q4W)
W160
8.
ITT-ME
Summary of CD4+ Cell Count (cells/mm^3) by Visit –
Maintenance and Extension Period (Randomized Q8W/Q4W)
Show baseline/Week-20,  Day 1, 
W32, W48 and W96 + Extension
W160
 
 
 
2018N380094_00


CONFIDENTIAL
200056
151
Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
9.
ITT-ME
Summary of Change from Baseline in CD4+ Cell Count 
(cells/mm^3) by Visit – Maintenance and Extension Period 
(Randomized Q8W/Q4W)
Induction baseline (study baseline)
W160
10.
ITT-ME
Summary of CD4+ / CD8+ Cell Count Ratios by Visit (Observed 
Case)
Show baseline/Week-20, W-4. Day 
1, Week 32, Week 48 and Week 96. 
W160
11.
ITT-ME
Summary of Change from Baseline in Plasma HIV-1 RNA (log10 
copies/mL) by Visit (Randomized Q8W/Q4W)
Show baseline/Week-20,  Day 1, 
W32, W48 and W96 + Extension
W160
12.
ITT-ME
HIV1
Summary of HIV-1 Associated Conditions Including Recurrences 
-Maintenance and Extension Period (Randomized Q8W/Q4W)
W160
13.
ITT-ME
HIV1
Summary of HIV-1 Associated Conditions Excluding 
Recurrences -Maintenance and Extension Period (Randomized 
Q8W/Q4W)
W160
14.
ITT-ME
HIV2
Summary of HIV-1 Associated Conditions Progression of HIV 
Disease – Maintenance and Extension Period (Randomized 
Q8W/Q4W Arms)
W160
15.
ITT-ME
Proportion of Subjects with Plasma HIV-1 RNA <50 copies/mL 
by Visit (Observed Case Analysis)  Maintenance and Extension 
Period (Randomized Q8W/Q4W)
Include all visits available at the 
time of analysis
W160
16.
Extension 
Switch
Summary of Study Outcomes (<50 copies/mL) at Week 160 –
Snapshot (MSDF) Analysis (Extension Switch Population)
W160
17.
PP-ES
Summary of Study Outcomes (<50 copies/mL) at Week 160 –
Snapshot (MSDF) Analysis for the Per-Protocol Extension 
Switch Population
If PP-ES Population comprises less 
than 95% of the Extension Switch 
Population 
W160
18.
Extension 
Switch
Proportion of Subjects with Plasma HIV-1 RNA <50 copies/mL 
by Visit during the Extension Period - Snapshot (MSDF) 
Analysis (Extension Switch Population)
Up to Week 160
W160
 
 
 
2018N380094_00


CONFIDENTIAL
200056
152
Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
19.
Extension 
Switch
Summary of Study Outcomes (<200 copies/mL) at Week 160 –
Snapshot (MSDF) Analysis (Extension Switch Population)
W160
20.
Extension 
Switch
Proportion of Subjects with Plasma HIV-1 RNA <200 copies/mL 
by Visit during the Extension Period - Snapshot (MSDF) 
Analysis
Up to Week 160
W160
21.
Extension 
Switch
Cumulative Proportion of Subjects with Extension Period 
Protocol Defined Virologic Failure by Visit (Extension Switch 
Population)
W160
22.
Extension 
Switch
Distribution of Quantitative Plasma HIV-1 RNA Results at 
Suspected and Confirmation of Extension Period Protocol 
Defined Virologic Failure (Extension Switch Population)
W160
23.
Extension 
Switch
Summary of CD4+ Cell Count (cells/mm^3) by Visit - Extension 
Period (Extension Switch Population)
See Week128 Table 7.1009
W160
24.
Extension 
Switch
Summary of Change from Baseline in CD4+ Cell Count 
(cells/mm^3) by Visit - Extension Period (Extension Switch 
Population)
Baseline is last value up to and 
including the date of first extension 
injection
W160
25.
Extension 
Switch
Summary of Change from Baseline in Plasma HIV-1 RNA (log10 
copies/mL) by Visit (Extension Switch Population)
Baseline is last value up to and 
including the date of first extension 
injection
W160
26.
Extension 
Switch
HIV1
Summary of HIV-1 Associated Conditions Including Recurrences 
- Extension Period (Extension Switch Population)
W160
27.
Extension 
Switch
HIV1
Summary of HIV-1 Associated Conditions Excluding 
Recurrences - Extension Period (Extension Switch Population)
W160
 
 
 
2018N380094_00


CONFIDENTIAL
200056
153
Efficacy: Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
28.
Extension 
Switch
HIV2
Summary of HIV-1 Associated Conditions Progression of HIV 
Disease - Extension Period (Extension Switch Population)
W160
29.
Extension 
Switch
Proportion of Subjects with Extension Period Plasma HIV-1 RNA 
<50 copies/mL by Visit - Observed Case Analysis) (Extension 
Switch Population)
Include all visits available at the 
time of analysis
W160
17.3.3.
Efficacy Figures
Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Insert Endpoint Category
1.
ITT-ME
Proportion (95% CI) of Subjects with Plasma HIV-1 RNA <50 
copies/mL by Visit during the Maintenance and Extension 
Period– Snapshot Analysis (Randomized Q8W/Q4W)
W96 Figure 7.1001, start from Day 
1
W160
2.
ITT-ME
Proportion (95% CI) of Subjects with Virologic Failure by Visit 
during the Maintenance and Extension Period – Snapshot 
Analysis (Randomized Q8W/Q4W)
W96 Figure 7.1004, start from Day 
1
W160
3.
ITT-ME
Individual Plasma HIV-1 RNA (log10 copies/mL) Profiles by Visit 
during the Maintenance and Extension Period (Randomized 
Q8W/Q4W)
W96 Figure 7.1002, start from 
Baseline
W160
4.
Extension 
Switch
Proportion (95% CI) of Subjects with Plasma HIV-1 RNA <50 
copies/mL by Visit during the Extension Period – Snapshot 
Analysis (Extension Switch Population)
W128 Figure 7.1001
W160
 
 
 
2018N380094_00


CONFIDENTIAL
200056
154
Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
5.
Extension 
Switch
Proportion (95% CI) of Subjects with Virologic Failure by Visit 
during the Extension Period – Snapshot Analysis (Extension 
Switch Population)
W128 Figure 7.1002
W160
6.
Extension 
Switch
Individual Plasma HIV-1 RNA (log10 copies/mL) Profiles by Visit 
during the Extension Period (Extension Switch Population)
W128 Figure 7.1003, use Pink 
background to indicate Non 
Responders based on Week 160 
Snapshot
W160
17.3.4.
Safety Tables
Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
1.
Safety 
Maintenance
Summary of All Maintenance and Extension Period On-
treatment Adverse Events by Overall Frequency (Randomized 
Q8W/Q4W)
W160
2.
Safety 
Maintenance
AE5 or AE5b
Summary of All On-Treatment Adverse Events by System Organ 
Class and Maximum Toxicity – Maintenance and Extension 
Period (Randomized Q8W/Q4W)
W160
3.
Safety 
Maintenance
Summary of Common (>=3%) Grade 2-4 Maintenance and 
Extension Period Adverse Events by Overall Frequency 
(Randomized Q8W/Q4W)
3% of any arm
W160
 
 
 
2018N380094_00


CONFIDENTIAL
200056
155
Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
4.
Safety 
Maintenance
Summary of Common (>=5%) Maintenance and Extension 
Period Non-Serious Adverse Event by System Organ Class and 
Preferred Term - Number of Subjects and Occurrences 
(Randomized Q8W/Q4W)
5% of any arm
W160
5.
Safety 
Maintenance
Summary of Grade 3/4 Maintenance and Extension Period On-
treatment Adverse Events by Overall Frequency (Randomized 
Q8W/Q4W)
W160
6.
Safety 
Maintenance
Summary of Grade 3/4 Maintenance and Extension Period On-
treatment Non Injection Site Reaction Related Adverse Events 
by Overall Frequency (Randomized Q8W/Q4W)
W160
7.
Safety 
Maintenance
Summary of Drug-Related Maintenance and Extension Period 
On-treatment Adverse Events by Overall Frequency 
(Randomized Q8W/Q4W)
W160
8.
Safety 
Maintenance
Summary of All Drug-Related On-treatment Adverse Events by 
System Organ Class and Maximum Toxicity – Maintenance and 
Extension Period (Randomized Q8W/Q4W)
W160
9.
Safety 
Maintenance
Summary of Maintenance and Extension Period Common 
(>=3%) Drug-Related Grade 2-4 Adverse Events by Overall 
Frequency (Randomized Q8W/Q4W)
3% of any arm
W160
10.
Extension 
Switch
Summary of All Extension Period On-treatment Adverse Events 
by Overall Frequency (Extension Switch Population)
W160
11.
Extension 
Switch
Summary of Extension Period On-treatment Adverse Events by 
System Organ Class and Maximum Toxicity (Extension Switch 
Population)
W160
12.
Extension 
Switch
Summary of Common (>=3%) Grade 2-4 Extension Period 
Adverse Events by Overall Frequency (Extension Switch 
Population)
3% of total subjects. 
W160
 
 
 
2018N380094_00


CONFIDENTIAL
200056
156
Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
13.
Extension 
Switch
Summary of Common (>=5%) Extension Period Non-Serious 
Adverse Event by System Organ Class and Preferred Term -
Number of Subjects and Occurrences (Extension Switch 
Population)
5% of total subjects
W160
14.
Extension 
Switch
Summary of Grade 3/4 Extension Period On-treatment Adverse 
Events by Overall Frequency (Extension Switch Population)
W160
15.
Extension 
Switch
Summary of Grade 3/4 Extension Period On-treatment Non 
Injection Site Reaction Related Adverse Events by Overall 
Frequency (Extension Switch Population)
W160
16.
Extension 
Switch
Summary of Drug-Related Extension Period On-treatment 
Adverse Events by Overall Frequency (Extension Switch 
Population)
W160
17.
Extension 
Switch
Summary of Drug-Related Extension Period On-treatment 
Adverse Events by System Organ Class and Maximum Toxicity 
(Extension Switch Population)
W160
18.
Extension 
Switch
Summary of Extension Period Common (>=3%) Drug-Related 
Grade 2-4 Adverse Events by Overall Frequency (Extension 
Switch Population)
3% of total subjects
W160
19.
Safety Long-
Term Follow 
Up
Summary of All Long-term Follow-up Period Adverse Events by 
Overall Frequency (Safety Long-Term Follow-up Population)
Including all subjects in LTFU
W160
20.
Safety Long-
Term 
Follow-Up
Summary of Long-Term Follow-up Period Drug-Related Adverse 
Events by Overall Frequency (Safety Long-Term Follow-Up 
Population)
Including all subjects in LTFU
W160
 
 
 
2018N380094_00


CONFIDENTIAL
200056
157
Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Serious and Other Significant Adverse Events
21.
Safety 
Maintenance
Summary of Maintenance and Extension Period Serious On-
treatment Adverse Events by Overall Frequency (Randomized 
Q8W/Q4W)
W160
22.
Safety 
Maintenance
Summary of Maintenance and Extension Period Serious 
Adverse Events by System Organ Class and Preferred Term -
Number of Subjects and Occurrences (Randomized Q8W/Q4W)
W160
23.
Safety 
Maintenance
Summary of Maintenance and Extension Period Drug-Related 
Serious Adverse Events by Overall Frequency (Randomized 
Q8W/Q4W)
W160
24.
Safety 
Maintenance
AE1
Summary of Maintenance and Extension Period Adverse Events 
Leading to Withdrawal/Permanent Discontinuation of 
Investigational Product by System Organ Class (Randomized 
Q8W/Q4W)
W160
25.
Safety 
Maintenance
Summary of Maintenance and Extension Period Drug-Related 
Grade 3/4 Adverse Events by Overall Frequency (Randomized 
Q8W/Q4W)
W160
26.
Safety 
Maintenance
Summary of Maintenance and Extension Period Drug-related 
Grade 3/4 Non Injection Site Reaction Related Adverse Events 
by Overall Frequency (Randomized Q8W/Q4W)
W160
27.
Extension 
Switch
Summary of Extension Period Serious On-treatment Adverse 
Events by Overall Frequency (Extension Switch Population)
W160
28.
Extension 
Switch
Summary of Extension Period Serious Adverse Events by 
System Organ Class and Preferred Term (Number of Subjects 
and Occurrences)Extension Switch Population
W160
 
 
 
2018N380094_00


CONFIDENTIAL
200056
158
Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
29.
Extension 
Switch
Summary of Extension Period Drug-Related Serious Adverse 
Events by Overall Frequency (Extension Switch Population)
W160
30.
Extension 
Switch
AE1
Summary of Extension Period Adverse Events Leading to 
Withdrawal/Permanent Discontinuation of Investigational 
Product by System Organ Class (Extension Switch Population)
W160
31.
Extension 
Switch
Summary of Extension Period Drug-Related Grade 3/4 Adverse 
Events by Overall Frequency (Extension Switch Population)
W160
32.
Extension 
Switch
Summary of Extension Period Drug-related Grade 3/4 Non 
Injection Site Reaction Related Adverse Events by Overall 
Frequency (Extension Switch Population)
W160
33.
Safety Long-
Term 
Follow-Up
Summary of Long-Term Follow-up Period Serious Adverse 
Events by Overall Frequency (Safety Long-Term Follow-up 
Population)
W160
Injection Site Reaction Adverse Events
34.
Safety 
Maintenance
Summary of Event-Level Injection Site Reaction Adverse Events 
- Maintenance and Extension Period (Randomized Q8W/Q4W)
W160
35.
Safety 
Maintenance
Summary of Overall and Common Subject-Level Characteristics 
of Injection Site Reaction Adverse Events - Maintenance and 
Extension Period (Randomized Q8W/Q4W)
W160
36.
Safety 
Maintenance
Summary of Overall and Common Injection Site Reaction 
Adverse Events by Visit and Maximum Severity - Maintenance 
and Extension Period (Randomized Q8W/Q4W)
W160
 
 
 
2018N380094_00


CONFIDENTIAL
200056
159
Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
37.
Safety 
Maintenance
Summary of Total Number of Injection Site Reaction Adverse 
Events by Visit - Maintenance and Extension Period 
(Randomized Q8W/Q4W)
W160
38.
Safety 
Maintenance
Summary of Overall and Common Subject-Level Characteristics 
of Injection Site Reaction Adverse Events by Needle Length -
Maintenance and Extension Period (Randomized Q8W/Q4W)
W160
39.
Safety 
Maintenance
Summary of Event-Level Maintenance and Extension Period 
Injection Site Reaction Adverse Events - GSK1265744 
(Randomized Q8W/Q4W)
W160
40.
Safety 
Maintenance
Summary of Overall and Common Subject-Level Characteristics 
of Maintenance and Extension Period Injection Site Reaction 
Adverse Events - GSK1265744 (Randomized Q8W/Q4W)
W160
41.
Safety 
Maintenance
Summary of Overall and Common Maintenance and Extension 
Period Injection Site Reaction Adverse Events by Visit and 
Maximum Severity - GSK1265744 (Randomized Q8W/Q4W)
W160
42.
Safety 
Maintenance
Summary of Total Number of Maintenance and Extension Period 
Injection Site Reaction Adverse Events by Visit - GSK1265744 
(Randomized Q8W/Q4W)
W160
43.
Safety 
Maintenance
Summary of Event-Level Maintenance and Extension Period 
Injection Site Reaction Adverse Events - TMC278 (Randomized 
Q8W/Q4W)
W160
 
 
 
2018N380094_00


CONFIDENTIAL
200056
160
Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
44.
Safety 
Maintenance
Summary of Overall and Common Subject-Level Characteristics 
of Maintenance and Extension Period Injection Site Reaction 
Adverse Events - TMC278 (Randomized Q8W/Q4W)
W160
45.
Safety 
Maintenance
Summary of Overall and Common Maintenance and Extension 
Period Injection Site Reaction Adverse Events by Visit and 
Maximum Severity -TMC278 (Randomized Q8W/Q4W)
W160
46.
Safety 
Maintenance
Summary of Total Number of Maintenance and Extension Period 
Injection Site Reaction Adverse Events by Visit - TMC278 
(Randomized Q8W/Q4W)
W160
47.
Extension 
Switch
Summary of Event-Level Injection Site Reaction Adverse Events 
– Extension Period (Extension Switch Population)
W160
48.
Extension 
Switch
Summary of Overall and Common Subject-Level Characteristics 
of Injection Site Reaction Adverse Events - Extension Period 
(Extension Switch Population)
W160
49.
Extension 
Switch
Summary of Overall and Common Injection Site Reaction 
Adverse Events by Visit and Maximum Severity - Extension 
Period (Extension Switch Population)
W160
50.
Extension 
Switch
Summary of Total Number of Injection Site Reaction Adverse 
Events by Visit - Extension Period (Extension Switch Population)
W160
 
 
 
2018N380094_00


CONFIDENTIAL
200056
161
Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
51.
Extension 
Switch
Summary of Overall and Common Subject-Level Characteristics 
of Injection Site Reaction Adverse Events by Needle Length -
Extension Period (Extension Switch Population)
W160
52.
Extension 
Switch
Summary of Event-Level Extension Period Injection Site 
Reaction Adverse Events - GSK1265744 (Extension Switch 
Population)
W160
53.
Extension 
Switch
Summary of Overall and Common Subject-Level Characteristics 
of Extension Period Injection Site Reaction Adverse Events -
GSK1265744 (Extension Switch Population)
W160
54.
Extension
Switch
Summary of Overall and Common Extension Period Injection 
Site Reaction Adverse Events by Visit and Maximum Severity -
GSK1265744 (Extension Switch Population)
W160
55.
Extension 
Switch
Summary of Total Number of Extension Period Injection Site 
Reaction Adverse Events by Visit - GSK1265744 (Extension 
Switch Population)
W160
56.
Extension 
Switch
Summary of Event-Level Extension Period Injection Site 
Reaction Adverse Events - TMC278(Extension Switch 
Population) 
W160
57.
Extension 
Switch
Summary of Overall and Common Subject-Level Characteristics 
of Extension Period Injection Site Reaction Adverse Events -
TMC278 (Extension Switch Population) 
W160
 
 
 
2018N380094_00


CONFIDENTIAL
200056
162
Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
58.
Extension 
Switch
Summary of Overall and Common Extension Period Injection 
Site Reaction Adverse Events by Visit and Maximum Severity -
TMC278 (Extension Switch Population) 
W160
59.
Extension 
Switch
Summary of Total Number of Extension Period Injection Site 
Reaction Adverse Events by Visit - TMC278 (Extension Switch 
Population) 
W160
Laboratory: Chemistry 
60.
Safety 
Maintenance
LB1
Summary of Chemistry Changes from Baseline by Visit –
Maintenance and Extension Period (Randomized Q8W/Q4W)
Display Baseline/W-20, Day1, W32, 
W48, W96 + Extension Period
W160
61.
Safety 
Maintenance
Summary of Maximum Maintenance and Extension Period 
Treatment Emergent Clinical Chemistry Toxicities (Randomized 
Q8W/Q4W) – Relative to Maintenance Baseline
See main RAP for definition of 
“emergent”.
W160
62.
Safety 
Maintenance
Summary of Maximum Maintenance and Extension Period 
Treatment Emergent Clinical Chemistry Toxicities (Randomized 
Q8W/Q4W) – Relative to Induction Baseline
W160
63.
Safety 
Maintenance
Summary of Changes in Clinical Chemistry Baseline Toxicity to 
Maximum Maintenance and Extension Period On-Treatment 
Toxicity  - Parameters of Special Interest (Randomized 
Q8W/Q4W) – Relative to Maintenance Baseline
Baseline is last value up to and 
including Maintenance Day 1
Parameters of Special Interest: 
AST, ALT, ALP and BILT
W160
64.
Safety 
Maintenance
Summary of Changes in Clinical Chemistry Baseline Toxicity to 
Maximum Maintenance and Extension Period On-Treatment 
Toxicity  - Parameters of Special Interest (Randomized 
Q8W/Q4W) – Relative to Induction Baseline
W160
 
 
 
2018N380094_00


CONFIDENTIAL
200056
163
Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
65.
Extension 
Switch
LB1
Summary of Chemistry Changes from Extension Baseline by 
Visit – Extension Period (Extension Switch Population)
Baseline is last value up to and 
including the date of first extension 
injection. W128 Table 8.1030
W160
66.
Extension 
Switch
Summary of Maximum Extension Period Treatment Emergent 
Clinical Chemistry Toxicities (Extension Switch Population)
W160
67.
Extension 
Switch
Summary of Changes in Clinical Chemistry Baseline Toxicity to 
Maximum Extension Period On-Treatment Toxicity - Parameters 
of Special Interest (Extension Switch Population)
W128 Table 8.1034
W160
Laboratory: Hematology
68.
Safety 
Maintenance
LB1
Summary of Hematology Changes from Baseline by Visit –
Maintenance and Extension Period (Randomized Q8W/Q4W )
Display Baseline/W-20, Day1, W32, 
W48, W96 + Extension Period
W160
69.
Safety 
Maintenance
Summary of Maximum Maintenance and Extension Period 
Treatment Emergent Hematology Toxicities (Randomized 
Q8W/Q4W) – Relative to Maintenance Baseline
W160
70.
Safety 
Maintenance
Summary of Maximum Maintenance and Extension Period 
Treatment Emergent Hematology Toxicities (Randomized 
Q8W/Q4W) – Relative to Induction Baseline
W160
71.
Extension 
Switch
LB1
Summary of Hematology Changes from Baseline by Visit –
Extension Period (Extension Switch Population)
Baseline is last value up to and 
including the date of first extension 
injection
W160
72.
Extension 
Switch
Summary of Maximum Extension Period Treatment Emergent 
Hematology Toxicities (Extension Switch Population)
W160
 
 
 
2018N380094_00


CONFIDENTIAL
200056
164
Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Laboratory: Urinalysis
73.
Safety 
Maintenance
LB1
Summary of Urine Concentration Changes from Baseline by 
Visit – Maintenance and Extension Period (Randomized 
Q8W/Q4W)
Display Baseline/W-20, Day 1, 
W32, W48, W96 + Extension
W160
74.
Safety 
Maintenance
UR3/LB2
Summary of Post-Baseline Emergent Urinalysis Dipstick 
Results Maintenance and Extension Period (Randomized 
Q8W/Q4W) – Relative to Induction Baseline
W160
75.
Safety 
Maintenance
UR3/LB2
Summary of Post-Baseline Emergent Urinalysis Dipstick 
Results Maintenance and Extension Period (Randomized 
Q8W/Q4W) – Relative to Maintenance Baseline
W160
76.
Extension 
Switch
LB1
Summary of Urine Concentration Changes from Baseline by 
Visit – Extension Period (Extension Switch Population)
W128 Table 8.1035
W160
77.
Safety 
Maintenance
UR3/LB2
Summary of Extension Period Post-Baseline Emergent 
Urinalysis Dipstick Results (Extension Switch Subjects) 
Extension Baseline
W160
Laboratory: Hepatobiliary (Liver)
78.
Safety 
Maintenance
LIVER10
Summary of Maintenance and Extension Period Hepatobiliary 
Laboratory Abnormalities (Randomized Q8W/Q4W)
W96 Table 8.1072
W160
79.
Extension 
Switch
LIVER10
Summary of Extension Period Hepatobiliary Laboratory 
Abnormalities (Extension Switch Population)
W128 Table 8.1037
W160
 
 
 
2018N380094_00


CONFIDENTIAL
200056
165
Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
ECG
80.
Safety 
Maintenance
EG2
Summary of Change from Baseline in ECG Values by Visit –
Maintenance and Extension Period (Randomized Q8W/Q4W)
Display Baseline/W-20, Day 1, 
W32, W48, W96 + Extension
W160
81.
Safety 
Maintenance
Summary of QTc Values by Category – Maintenance and 
Extension Period (Randomized Q8W/Q4W)
W160
82.
Safety 
Maintenance
Summary of Change from Baseline QTc Values by Category –
Maintenance and Extension Period (Randomized Q8W/Q4W)
Display Baseline/W-20, Day 1, 
W32, W48, W96 + Extension
83.
Extension 
Switch
EG2
Summary of Change from Baseline in ECG Values by Visit –
Extension Period (Extension Switch Population)
Baseline is last value before the 
date of first extension injection. 
W128 Table 8.1040
W160
84.
Extension 
Switch
Summary of QTc Values by Category – Extension Period 
(Extension Switch Population)
W160
85.
Extension 
Switch
Summary of Change from Baseline QTc Values by Category –
Extension Period (Extension Switch Population)
W160
Vital Signs
86.
Safety 
Maintenance
VS1
Summary of Change from Baseline in Vital Signs by Visit –
Maintenance and Extension Period (Randomized Q8W/Q4W)
Display Baseline/W-20, Day 1, 
W32, W48, W96 + Extension
W160
87.
Extension 
Switch
VS1
Summary of Change from Baseline in Vital Signs by Visit –
Extension Period (Extension Switch Population)
Extension baseline. W128Table 
8.1042
W160
 
 
 
2018N380094_00


CONFIDENTIAL
200056
166
17.3.5.
Safety Figures
Safety: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.
Safety 
Maintenance
Figure of Onset, Duration, and Severity of Overall and Common 
Maintenance and Extension Period Injection Site Reaction 
Adverse Events by Maximum Grade:  GSK744 LA or TMC278 
LA (Randomized Q8W/Q4W)
W160
2.
Safety 
Maintenance
Figure of Incidence of Overall and Common Maintenance and 
Extension Period Injection Site Reaction Adverse Events - GSK 
744 LA or TMC278 LA (Randomized Q8W/Q4W)
W160
3.
Safety 
Maintenance
Figure of Incidence of Overall and Common Grade 3-4 
Maintenance and Extension Period Injection Site Reaction 
Adverse Events - GSK 744 LA or TMC278 LA (Randomized 
Q8W/Q4W)
W160
4.
Safety 
Maintenance
Scatter Plots of Maximum Maintenance and Extension Period 
On-Treatment vs. Baseline for ALT (Randomized Q8W/Q4W)
Baseline is last value up to and 
including date of first maintenance 
injection. See W128 Figure 8.1001
W160
5.
Safety 
Maintenance
Matrix Plot of Maximum Maintenance and Extension Period On-
treatment Liver Chemistries (Randomized Q8W/Q4W)
See W128 Figure 8.1002
W160
6.
Safety 
Maintenance
Liver Chemistry Profile Plots for Subjects with Elevation during 
the Maintenance and Extension Period by Study Day 
(Randomized Q8W/Q4W)
Maintenance study day
W160
7.
Safety
Maintenance
Scatter Plot of Maximum Maintenance and Extension Period On-
Treatment Value: ALT vs. BILT (Randomized Q8W/Q4W)
See W128 Figure 8.1004
W160
8.
Extension 
Switch
Figure of Onset, Duration, and Severity of Overall and Common 
Extension Period Injection Site Reaction Adverse Events by 
Maximum Grade:  GSK744 LA or TMC278 LA (Extension Switch 
Population)
W160
 
 
 
2018N380094_00


CONFIDENTIAL
200056
167
Safety: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
9.
Extension 
Switch
Figure of Incidence of Overall and Common Extension Period 
Injection Site Reaction Adverse Events - GSK 744 LA or 
TMC278 LA (Extension Switch Population)
W160
10.
Extension 
Switch
Figure of Incidence of Overall and Common Grade 3-4 
Extension Period Injection Site Reaction Adverse Events - GSK 
744 LA or TMC278 LA (Extension Switch Population)
W160
11.
Extension 
Switch
Scatter Plots of Maximum Extension Period On-Treatment vs. 
Baseline for ALT (Extension Switch Population)
Baseline is last value up to and 
including date of first extension 
injection. See W128 Figure 8.1001 
W160
12.
Extension 
Switch
Matrix Plot of Maximum Extension Period On-treatment Liver 
Chemistries (Extension Switch Population)
W160
13.
Extension 
Switch
Liver Chemistry Profile Plots for Subjects with Elevation during 
the Extension Period by Study Day (Extension Switch 
Population)
Extension Study day
W160
14.
Extension 
Switch
Scatter Plot of Maximum Extension Period On-Treatment Value: 
ALT vs. BILT (Extension Switch Population)
W160
 
 
 
2018N380094_00


CONFIDENTIAL
200056
168
17.3.6.
Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Insert Endpoint Category
1.
PK 
Population
PKCT1
Summary of Maintenance Period Plasma GSK1265744 PK 
Concentration (ug/mL) -Time Data by Treatment and Visit –
Including Log-transformed Statistics
Day 1 to W96, by 3 groups: 
Q8W,Q4W and Oral 
W160
2.
PK 
Population
PKCT1
Summary of Maintenance Period Plasma TMC278 PK 
Concentration (ug/mL) -Time Data by Treatment and Visit –
Including Log-transformed Statistics 
W160
3.
PK 
Population
PKCT1
Summary of Evaluable Maintenance Period Plasma 
GSK1265744 PK Concentration (ug/mL) -Time Data by 
Treatment and Visit – Including Log-transformed Statistics
W160
4.
PK 
Population
PKCT1
Summary of Evaluable Maintenance Period Plasma TMC278 PK 
Concentration (ug/mL) -Time Data by Treatment and Visit  –
Including Log-transformed Statistics
W160
 
 
 
2018N380094_00


CONFIDENTIAL
200056
169
17.3.7.
Pharmacokinetic Figures
Pharmacokinetic: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Insert Endpoint Category
1.
PK
PKCF1
Individual Maintenance Period Plasma GSK1265744 
Concentration Time Plots (Linear and Semi-Log) 
W160
2.
PK
PKCF1
Individual Maintenance Period Plasma TMC278 Concentration 
Time Plots (Linear and Semi-Log)
W160
3.
PK
PKCF2
Mean(SD) Evaluable Maintenance Period Plasma 
GSK1265744 Concentration Time Plots (Linear and Semi-Log)
W160
4.
PK
PKCF2
Mean(SD) Evaluable Maintenance Period Plasma TMC278 
Concentration Time Plots (Linear and Semi-Log)
W160
 
 
 
2018N380094_00


CONFIDENTIAL
200056
170
17.3.8.
Virology Tables
Virology Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Insert Endpoint Category
1.
PDVF 
Genotypic 
Maintenance 
Exposed
See Table 
9.1002 from W96
Summary of the Prevalence of Treatment Emergent Known INI 
Mutations at the time of PDVF (Randomized Q8W/Q4W)
W160
2.
PDVF 
Genotypic 
Maintenance 
Exposed
See Table 
9.1004 from W96
Summary of the Prevalence of Treatment Emergent Major 
Mutations of Other Classes at the time of PDVF (Randomized 
Q8W/Q4W)
W160
3.
PDVF 
Phenotypic 
Maintenance 
Exposed
See Table 
9.1005 from W96
Summary of Phenotype by Phenotypic Cutoff at the Time of 
PDVF (Randomized Q8W/Q4W)
W160
4.
PDVF 
Phenotypic 
Maintenance 
Exposed
See Table 
9.1006 from W96
Summary of Phenotype: Number of Drugs to Which Subjects are 
Resistant (Randomized Q8W/Q4W)
W160
5.
PDVF 
Phenotypic 
Maintenance 
Exposed
See Table 
9.1007 from W96
Summary of Susceptibility to GSK1265744 and TMC278 –
Maintenance and Extension Period (Randomized Q8W/Q4W)
W160
6.
PDVF 
Phenotypic 
Maintenance 
Exposed
See Table 
9.1008 from W96
Summary of Change from Baseline in Susceptibility to 
GSK1265744 and TMC278 (Randomized Q8W/Q4W)
W160
 
 
 
2018N380094_00


CONFIDENTIAL
200056
171
Virology Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
7.
PDVF 
Genotypic 
Extension 
Switch
Summary of the Prevalence of Treatment Emergent INI 
Mutations at the time of PDVF (PDVF Genotypic Extension 
Switch Population)
Note: treatment emergence is 
always derived by comparing to 
study baseline prior to induction
W160
8.
PDVF 
Genotypic 
Extension 
Switch
Summary of the Prevalence of Treatment Emergent Major 
Mutations of Other Classes at the time of PDVF (PDVF 
Genotypic Extension Switch Population)
W160
9.
PDVF 
Phenotypic 
Extension 
Switch
Summary of Phenotype by Phenotypic Cutoff at the time of 
PDVF (Extension Switch Population)
W160
10.
PDVF 
Phenotypic 
Extension 
Switch
Summary of Phenotype: Number of Drugs to Which Subjects are 
Resistant (Extension Switch Population)
W160
11.
PDVF 
Phenotypic 
Extension 
Switch
Summary of Susceptibility to GSK1265744 and TMC278 
(Extension Switch Population)
W160
12.
PDVF 
Phenotypic 
Extension 
Switch
Summary of Change from Baseline in Susceptibility to 
GSK1265744 and TMC278 (Extension Switch Population)
W160
 
 
 
2018N380094_00


CONFIDENTIAL
200056
172
17.3.9.
ICH Listings
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.
ITT-ME
ES2
Listing of Reasons for Study Withdrawal 
W96 Listing 6.1002
W160
Protocol Deviations
2.
ITT-ME
DV2
Listing of Important Protocol Deviations During the Maintenance 
and Extension Period (Randomized Q8W/Q4W)
W160
3.
Extension 
Switch
DV2
Listing of Important Protocol Deviations During the Extension 
Period (Extension Switch Population)
W160
Demographic and Baseline Characteristics
4.
ITT-ME
DM2
Listing of Demographic Characteristics
Include 5 groups: Q8W, Q4W, 
Oral/Q8W, Oral/Q4W, Oral/no 
Extension
W160
5.
ITT-ME
DM9
Listing of Race
Include 5 groups: Q8W, Q4W, 
Oral/Q8W, Oral/Q4W, Oral/no 
Extension
W160
Prior and Concomitant Medications
6.
ITT-ME
CM2
Listing of Concomitant Medications
W96 Listing 6.1013
W160
Exposure and Treatment Compliance
7.
ITT-ME
Listing of Investigational Product Exposure Data 
See Listing 8.1001 from W96
W160
Efficacy
8.
ITT-ME
Listing of Quantitative Plasma HIV-1 RNA Data
See Listing 7.1001 from W96
W160
9.
ITT-ME
Listing of Study Outcome (<50 copies/mL) at Week 160  –
Snapshot (MSDF)
See Listing 7.1002 from W96
W160
 
 
 
2018N380094_00


CONFIDENTIAL
200056
173
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
10.
ITT-ME
Listing of Study Outcome (<200 copies/mL) at Week 160  –
Snapshot (MSDF)
See Listing 7.1003 from W96
W160
11.
Safety LTFU
Listing of Plasma HIV-1 RNA Data for Subjects in Long-term 
Follow up
New listing. See Listing 3 from 
pub_2017_01 
W160
Safety: Adverse Events
12.
Safety 
Maintenance
Listing of All Adverse Events 
See Listing 8.1002 from W96
W160
13.
Safety 
Maintenance
AE7
Listing of Subject Numbers for Individual Adverse Events
See Listing 8.1006 from W96 
W160
14.
Safety 
Maintenance
PREG1a
Listing of Subjects Who Became Pregnant during the Study
See Listing 8.1007 from W96 
W160
Safety: Serious and Other Significant Adverse Events
15.
Safety 
Maintenance
Listing of Fatal Adverse Events 
W160
16.
Safety 
Maintenance
Listing of Non-Fatal Serious Adverse Events 
W160
17.
Safety 
Maintenance
Listing of Reasons for Considering an AE as Serious
W160
18.
Safety 
Maintenance
AE8
Listing of Adverse Events Leading to Permanent Discontinuation 
of Investigational Product and/or Withdrawal from the Study 
W96 Listing 8.1005
W160
Safety: Hepatobiliary (Liver)
19.
Safety 
Maintenance
MH2
Listing of Medical Conditions for Subjects with Liver Stopping 
Events 
5 groups, see Listing 8.1012 from 
W96
W160
20.
Safety 
Maintenance
MH2
Listing of Substance Use for Subjects with Liver Stopping 
Events 
5 groups, see Listing 8.1013 from 
W96
W160
 
 
 
2018N380094_00


CONFIDENTIAL
200056
174
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Safety: ECG
21.
Safety 
Maintenance
Listing of ECG Values 
5 groups, see Listing 8.1008 from 
W96
W160
22.
Safety 
Maintenance
EG3
Listing of ECG Values for Subjects with a Value of Potential 
Clinical Concern
5 groups, see Listing 8.1019 from 
W96
W160
23.
Safety 
Maintenance
EG5
Listing of ECG Findings
5 groups, see Listing 8.1010 from 
W96
W160
Safety: Vital Signs
24.
Safety 
Maintenance
VS4
Listings of Vital Signs 
5 groups, see Listing 8.1011 from 
W96
W160
Pharmacokinetic
25.
PK
PKCL1
Listing of Plasma GSK1265744 PK Concentration - Time Data 
W160
26.
PK
PKCL1
Listing of Plasma TMC278 PK Concentration - Time Data 
W160
 
 
 
2018N380094_00


CONFIDENTIAL
200056
175
17.3.10.
Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Study Population
27.
All Screened
Listing of study Populations
W96 Listing 6.1007. Add PDVF 
genotypic and phenotypic 
maintenance exposed, PDVF 
genotypic and phenotypic ES 
population (remove on-treatment 
geno. Resist and pheno. Resist)
W160
28.
ITT-ME
Listing of Investigational Product Accountability 
W96 Listing 6.1012
W160
29.
ITT-ME
Listing of Concomitant and Post-Treatment Antiretroviral 
Therapy 
W96 Listing 6.1016
W160
30.
ITT-ME
Listing of Subjects with Changes in Concomitant Antiretroviral 
Therapy 
W96 Listing 6.1017
W160
31.
ITT-ME
Listing of Current and Past Medical Conditions at Baseline
W96 Listing 6.1014
W160
32.
ITT-ME
Listing of Relationship Between ATC Level 1, Ingredient and 
Verbatim Text 
W160
33.
ITT-ME
Listing of Relationship Between ATC Level 4, Combination, and 
Verbatim Text for ART 
W160
Efficacy
34.
ITT-ME
Listing of CD4+ Cell Count Data 
W96 Listing 7.1004
W160
35.
ITT-ME
Listing of HIV-1 Associated Conditions 
W96 Listing 7.1005
W160
36.
ITT-ME
Listing of Subjects with Protocol Defined Virologic Failure 
W96 Listing 7.1007
W160
 
 
 
2018N380094_00


CONFIDENTIAL
200056
176
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
37.
ITT-ME
Listing of Quantitative Plasma HIV-1 RNA Data for Subjects 
Classified as Having 'data in window >50' at any Maintenance or 
Extension Period Visit based on the Snapshot Classification 
(Randomized Q8W/Q4W)
W96 Listing 7.1009
W160
38.
Extension 
Switch
Listing of Quantitative Plasma HIV-1 RNA Data for Subjects 
Classified as Having 'data in window >50' at any Extension 
Period Visit based on the Snapshot Classification (Extension 
Switch)
W128 Listing 7.1007
W160
39.
ITT-ME
Listing of Quantitative Plasma HIV-1 RNA Data for Subjects with 
HIV-1 RNA >= 50 c/mL at any time during the Maintenance 
Period or Extension Period 
W96 Listing 7.1010
W160
Safety
40.
Safety 
Maintenance
AE2
Relationship of Adverse Event System Organ Classes, Preferred 
Terms, and Verbatim Text
W160
41.
Safety 
Maintenance
LB5
Listing of Clinical Chemistry Laboratory Data for Subjects with 
Grade 3/4 Maintenance and Extension Period Treatment-
Emergent Toxicities Relative to Maintenance Baseline 
(Randomized Q8W/Q4W)
ICH E3
W160
42.
Safety 
Maintenance
LB5
Listing of Clinical Chemistry Laboratory Data for Subjects with 
Grade 3/4 Maintenance and Extension Period Treatment-
Emergent Toxicities Relative to Induction Baseline (Randomized 
Q8W/Q4W)
W160
43.
Safety 
Maintenance
LB5
Listing of Hematology Laboratory Data for Subjects with Grade 
3/4 Maintenance and Extension Period Treatment-Emergent 
Toxicities Relative to Maintenance Baseline (Randomized 
Q8W/Q4W)
W160
 
 
 
2018N380094_00


CONFIDENTIAL
200056
177
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
44.
Safety 
Maintenance
LB5
Listing of Hematology Laboratory Data for Subjects with Grade 
3/4 Maintenance and Extension Period Treatment-Emergent 
Toxicities Relative to Induction Baseline (Randomized 
Q8W/Q4W)
W160
45.
Safety 
Maintenance
UR2a
Listing of Urinalysis Data for Subjects with Grade 3/4 
Maintenance and Extension Period Treatment-Emergent 
Toxicities (Randomized Q8W/Q4W) – Relative to Maintenance 
Baseline
W160
46.
Safety 
Maintenance
UR2a
Listing of Urinalysis Data for Subjects with Grade 3/4 
Maintenance and Extension Period Treatment-Emergent 
Toxicities (Randomized Q8W/Q4W) – Relative to Induction 
Baseline
W160
47.
Safety 
Maintenance
LIVER5
Listing of Liver Monitoring/Stopping Event Reporting 
Week 96 Table 8.1068, 5 treatment 
groups
W160
48.
Safety 
Maintenance
LIVER13
Listing of Subjects Meeting Hepatobiliary Laboratory 
Abnormality Criteria during the Maintenance or Extension Period
Updated Display Standard, Week 
96 Table 8.1069, 5 treatment 
groups
W160
49.
Safety 
Maintenance
LIVER6
Listing of Liver Event Information for RUCAM Score 
W96 Listing 8.1026, 5 treatment 
groups
W160
50.
Safety 
Maintenance
LIVER7
Listing of Liver Biopsy Details 
W160
51.
Safety 
Maintenance
LIVER8
Listing of Liver Imaging Details 
W160
52.
Safety 
Maintenance
Listing of Past and Current Liver Disease Medical Conditions
W160
 
 
 
2018N380094_00


CONFIDENTIAL
200056
178
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
53.
Safety 
Maintenance
Listing of Serology Results Liver Event Follow-up
W160
54.
Safety 
Maintenance
Listing of AST, ALT, Alkaline Phosphatase, and Total Bilirubin 
Laboratory Data for Subjects with Maintenance or Extension 
Period On-Treatment ALT at Least Two Times the ULN 
(Randomized Q8W/Q4W)
W160
55.
Safety 
Maintenance
Listing of Grade 2 or higher Maintenance or Extension Period 
Injection Site Reaction AEs 
W96 Listing 8.1034, 5 treatment 
groups
W160
56.
Safety 
Maintenance
Listing of Each Subject’s Maximum ALT and Maximum Bilirubin 
during the Maintenance and Extension Period (Randomized 
Q8W/Q4W)
W96 Listing 8.1037
W160
57.
Safety 
Maintenance
Listing of Investigational Product Exposure Data for Subject 
Receiving Oral Bridging during the Maintenance or Extension 
Period 
W96 Listing 8.1038, 5 treatment 
groups
W160
58.
Extension 
Switch
LB5
Listing of Clinical Chemistry Laboratory Data for Subjects with 
Grade 3/4 Extension Period Treatment-Emergent Toxicities 
(Extension Switch Population)
ICH E3
W160
59.
Extension 
Switch
LB5
Listing of Hematology Laboratory Data for Subjects with Grade 
3/4 Extension Period Treatment-Emergent Toxicities (Extension 
Switch Population)
ICH E3
W160
60.
Extension 
Switch
UR2a
Listing of Urinalysis Data for Subjects with Grade 3/4 Extension 
Period Treatment-Emergent Toxicities (Extension Switch 
Population)
W160
61.
Extension 
Switch
Listing of AST, ALT, Alkaline Phosphatase, and Total Bilirubin 
Laboratory Data for Subjects with Extension Period On-
Treatment ALT at Least Two Times the ULN (Extension Switch 
Population)
W160
 
 
 
2018N380094_00


CONFIDENTIAL
200056
179
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
62.
Extension 
Switch
Listing of Each Subject’s Maximum ALT and Maximum Bilirubin 
during the Extension Period (Extension Switch)
W160
Virology
63.
ITT-E
Listing of All Genotypic Mutation Data at All Time Points
By Treatment groups – Induction no 
maintenance, Q8W, 
Q4W,Oral/Q8W, Oral/Q4W, Oral/no 
extension, induction only, Use 
W96cdic Table 9.1009
W160
64.
ITT-E
Listing of All Phenotypic Mutation Data at All Time Points
By Treatment groups – Induction no 
maintenance, Q8W, 
Q4W,Oral/Q8W, Oral/Q4W, Oral/no 
extension, induction only. Use 
W96cdic Table 9.1010
W160
65.
PDVF 
Genotypic 
Maintenance 
Exposed
Listing of Treatment Emergent Genotypic Mutations at the time 
of PDVF (Randomized Q8W/Q4W)
W160
66.
PDVF 
Phenotypic
Maintenance 
Exposed 
Listing of Replication Capacity (Randomized Q8W/Q4W)
See Listing 9.1005 from W96
W160
67.
PDVF 
Genotypic 
Extension 
Switch
Listing of Treatment Emergent Genotypic Mutations at the time 
of PDVF (Extension Switch Population)
W160
 
 
 
2018N380094_00


CONFIDENTIAL
200056
180
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
68.
PDVF 
Phenotypic 
Extension 
Switch 
Listing of Replication Capacity (Extension Switch Population)
W160
 
 
 
2018N380094_00


CONFIDENTIAL
200056
181
17.4.
Data Display Specifications
Data display specifications are available upon request.
17.5.
MSDF (Snapshot) Algorithm in Detail
Consider an arbitrary visit window, Week X.  A subject’s response (i.e., ‘Virologic 
Success’, ‘Virologic Failure’, or ‘No Virologic Data at Week X’) in that window is 
determined as follows:

If there was a non-permitted change in background ART prior to Week X, then 
the subject is a Virologic Failure.
If there was a permitted change in background ART prior to Week X per protocol but 
prescribed while not suppressed (e.g., HIV-1 RNA ≥ 50 copies/mL based on last viral 
load at time of decision to switch), unless the decision to switch is documented as being 
on or before the first on-treatment visit where HIV-1 RNA is assessed., , then the subject 
is a Virologic Failure.
If there is a change in background ART during Week X, and the decision to make this 
change is after the first On-treatment HIV-1 RNA result, and
a.
no HIV-1 RNA result is available during Week X prior to the change, then the 
subject is a Virologic Failure;
there is at least one HIV-1 RNA result available during Week X prior to the 
change, then consider the latest such result:
i.
if <50 c/mL, then the subject is a Virologic Success;
ii.
if 50 c/mL, then the subject is a Virologic Failure.
If there is no change in background ART during Week X or such a change is decided on 
before the first On-treatment HIV-1 RNA result, and at least one HIV-1 RNA result is 
available during Week X, then consider the latest such result:
b. if <50 c/mL, then the subject is a Virologic Success;
c.
if 50 c/mL, then the subject is a Virologic Failure.
If there is no change in background ART during Week X or such a change is decided on 
before the first On-treatment HIV-1 RNA result, and no HIV-1 RNA results are available 
during Week X:
d. if the subject has not withdrawn from the study prior to or during Week X, they 
are categorized as ‘No Virologic Data at Week X’, with a reason of ‘Missing 
data during window but on study’;
if the subject was withdrawn from the study prior to or during Week X due to 
AE or death, they are categorized as ‘No Virologic Data at Week X’, with a 
reason of ‘Discontinued due to AE or Death’;
otherwise, consider the subject’s last available On-treatment HIV-1 RNA result:
 
2018N380094_00


CONFIDENTIAL
200056
182
iii. if <50 c/mL or no result is available, then the subject is categorized as ‘No 
Virologic Data at Week X’, with a reason of ‘Discontinued for Other 
Reasons’;
iv. if 50 c/mL, then the subject is a Virologic Failure.
To view a graphical representation of this algorithm, see Figure 4.
Figure 4
MSDF (Snapshot) Algorithm
(Non-permitted change in ART)
or
(permitted change in ART after first on-trt VL)
While not suppressed prior to Week X window?
Change in ART in 
Week X window
after first on-trt VL?
Week X VL1
available?
Week X VL1
<50 c/mL?
Yes
No
Virologic
Failure
Virologic
Success
Yes
No
WD before/during 
Week X window?
Due to AE or 
Death?
No Virologic
Data at Week X
4
Last VL2 <50 
c/mLor 
missing?
Virologic
Failure
No Virologic
Data at Week X
5
No Virologic
Data at Week X
6
Yes
Yes
Yes
No
No
No
No
Week X VL1 prior to 
change available?
1Week X VL:Last on-treatment (double-blind, if applicable) HIV-1 RNA viral load in Week X window.
2Last VL: last on-treatment (double-blind, if applicable) HIV-1 RNA viral load prior to Week X
Subreasons:4discontinued due to AE or death; 5discontinued for other reasons; missing data but on-treatment
Virologic
Failure
Yes
Yes
Yes
Virologic
Failure
No
No
6
 
2018N380094_00