A Phase III, Randomized, Multicenter, Parallel-group, Non-inferiority, Open-label Study Evaluating the Efficacy, Safety, and Tolerability of Switching to Long-acting Cabotegravir Plus Long-acting Rilpivirine From Current INI- NNRTI-, or PI-based Antiretroviral Regimen in HIV-1-infected Adults Who Are Virologically Suppressed
Phase: PHASE3
Conditions: Infection, Human Immunodeficiency Virus, HIV Infections
Sponsor: ViiV Healthcare

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The GlaxoSmithKline group of companies
201585
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TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A Phase III, randomized, multicenter, parallel-group, non-
inferiority, open-label study evaluating the efficacy, safety, and 
tolerability of switching to long-acting cabotegravir plus long-
acting rilpivirine from current INI- NNRTI-, or PI-based 
antiretroviral regimen in HIV-1-infected adults who are 
virologically suppressed
Compound Number:
GSK1265744
Development Phase:
III
Effective Date:
02-NOV-2017
Protocol Amendment Number:  04
Author (s):
 
 
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
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2015N252007_04
CONFIDENTIAL
The GlaxoSmithKline group of companies
201585
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Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2015N252007_00
2016-MAY-26
Original
2015N252007_01
2016-SEP-16
Amendment No. 1
The purpose of this amendment is to support country-specific requirements for South 
Korea including an update to inclusion criteria age for local regulatory requirements and 
the addition of study investigational product labels within Appendix 8.
2015N252007_02
2016-NOV-02
Amendment No. 2
The purpose of this amendment is to support country-specific requirements for Sweden 
based on local regulatory requirements and to provide additional protocol details and 
clarifications requested by the MPA.
2015N252007_03
2016-DEC-13
Amendment No. 3
The reasons for this amendment were to: update medical monitor/SAE contact 
information; provide additional clarity for assessments to be conducted during the 
Extension Phase; add text to instruct contact of the Medical Monitor upon the occurrence 
of rash during the CAB + RPV oral lead-in period; specify a secondary lipid objective 
and endpoint within the study objectives; provide clarity around dosing at the Day 1 visit; 
allow serum pregnancy testing instead of urine testing in the event that urine testing is not 
available; provide clarification that cabotegravir and rilpivirine exposure may persist for 
more than one year following IM injections, emphasize that participants should continue 
to use HAART for at least one year following the last CAB + RPV injection, and that 
female participants of childbearing potential must continue to use adequate contraception 
for at least one year after the last CAB + RPV injection; expand the allowance of short 
treatment courses of topical, inhaled, or intranasal glucocorticoids to 21 days or less; add 
additional guidance for the definition of a change in ART regimen for inclusion/exclusion 
criteria; provide additional guidance on when to contact the Medical Monitor upon a 
serofast RPR result for screening syphilis test;  clarify language within exclusion criteria 
#9; added text regarding the treatment assignment randomization schedule;  remove a 
requirement to record within the eCRF how frequently IP was taken on average and the 
requirement to record any treatment delays or dose reductions of IP; add text to indicate 
that drugs known to cause Torsade des Pointes (TdP) should be used with caution with 
rilpivirine; remove limits on the duration for use of topical imiquimod; add clarity around 
reflexive testing for HBV DNA for participants with positive anti HBc and negative 
HBsAg and negative anti-HBs results; add temperature collection as part of vital signs to 
the Time and Events table; add requirement that all sites should have a plan in place for 
managing possible risks for suicide related events;  clarify text regarding PK sample 
window collection; clarify text for patient reported outcome endpoints and timings for 
completion of questionnaires relative to other clinical assessments and procedures, add 
clarification for prohibited medication information; remove information in the Appendix 

2015N252007_04
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The GlaxoSmithKline group of companies
201585
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requiring collection of pregnancy information for female partners of male study 
participants; incorporate updates from country-specific amendments No 1, and No 2. into 
a global protocol amendment; add text that additional details of the injection device used 
by sites for IM administration including, but not limited to functional performance, may 
also be collected within the eCRF; clarify that commercially availability of CAB LA + 
RPV LA includes availability through local public/government health sectors; add 
allowance that in exceptional circumstances, local labs can be reviewed and approved by 
the Medical Monitor for consideration of participant eligibility; add information that 
Screening HLA-B*5701 result is not required to inform eligibility status; add other minor 
corrections and edits to protocol text.
2015N252007_04
2017-NOV-02
Amendment No. 4
The reason for amendment 4 is to acknowledge the potential rollover of eligible 201585
(ATLAS) study participants following the Week 52 visit and completion of the primary 
endpoint to the 207966 (ATLAS-2M) study examining the efficacy, safety and 
tolerability of CAB LA + RPV LA administered every 4 weeks (Q4W) compared to CAB 
LA + RPV LA administered every 8 weeks (Q8W). Specifications for the procedural 
rollover of 201585 participants are included within amendment #4.  Due to the planned 
transition of eligible participants to ATLAS-2M following the Week 48 primary 
endpoint, the snapshot virologic response at Week 96 and in the Extension Phase for 
ATLAS is no longer valid and has been replaced with the proportion of participants with 
plasma HIV-1 RNA < 50 c/mL over time including Week 96.  Exploratory analyses 
evaluation the effect of patient characteristics on virologic and immunologic responses in 
the treatment arms are also limited to a Week 48 analysis.  The reporting timeline of 
pregnancy event and follow-up pregnancy form has been updated from 2 weeks to 24 hrs 
of identification of a pregnancy event, and within 24 hrs of investigator awareness of 
pregnancy outcome, respectively.  Updated references for the cabotegravir and rilpivirine 
investigator brochures have been added.

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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information: 
Primary Medical Monitor/SAE Contact Information: 
 MD, MSc
ViiV Healthcare
Research Triangle Park
Five Moore Drive, Research Triangle Park, NC 27709 (USA)
Mobile: 
Office Telephone: 
Fax: 
e-mail:  
Secondary Medical Monitor:
ViiV Healthcare
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, MSc
ViiV Healthcare
Research Triangle Park
Five Moore Drive, Research Triangle Park, NC 27709 (USA)
Mobile: 
Office Telephone: 
Fax: 
e-mail:  
This study is sponsored by ViiV Healthcare.  GlaxoSmithKline is implementing and 
managing all aspects of this study on behalf of ViiV Healthcare. 
Sponsor Legal Registered Address (excluding US): 
ViiV Healthcare 
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Telephone:  
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US IND Sponsor Legal Registered 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).  If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.   
Regulatory Agency Identifying Number(s): 
IND No. 109,678;
EudraCT No. 2016-001647-39
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 201585
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

2015N252007_04
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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 201585......................................................13
2.
INTRODUCTION....................................................................................................26
2.1.
Study Rationale ..........................................................................................26
2.2.
Brief Background ........................................................................................27
3.
OBJECTIVES AND ENDPOINTS...........................................................................31
4.
STUDY DESIGN ....................................................................................................36
4.1.
Overall Design ............................................................................................36
4.2.
Treatment Arms and Duration.....................................................................38
4.2.1.
Screening Phase (Up to 35 days) ................................................38
4.2.2.
Maintenance Phase (Day 1 up to Week 52).................................38
4.2.3.
Extension Phase..........................................................................40
4.2.3.1.
Participants Entering from the CAB LA + RPV 
LA Arm .......................................................................40
4.2.3.2.
Participants Entering from the current ART 
ARM...........................................................................40
4.2.4.
Long-Term Follow-Up (LTFU) Phase – IM Regimen Only............42
4.2.5.
Dose Modifications ......................................................................43
4.3.
207966 (ATLAS-2M) Rollover Option..........................................................43
4.3.1.
201585 (ATLAS) to 207966 (ATLAS-2M) Transition 
Strategy.......................................................................................44
4.4.
Independent Data Monitoring Committee....................................................45
4.5.
Type and Number of Participants................................................................45
4.6.
Design Justification.....................................................................................46
4.7.
Dose Justification........................................................................................47
4.7.1.
Oral Lead-In Phase......................................................................47
4.7.2.
Long Acting Injectable for Maintenance Phase ............................49
4.7.3.
Modeling and Dose Simulations for CAB LA and RPV LA............56
4.7.3.1.
CAB LA ......................................................................56
4.7.3.2.
RPV LA ......................................................................58
4.8.
Benefit:Risk Assessment ............................................................................61
4.8.1.
Risk Assessment .........................................................................61
4.8.1.1.
Other Clinically Relevant Information..........................70
4.8.2.
Benefit Assessment.....................................................................71
4.8.3.
Overall Benefit:Risk Conclusion...................................................71
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............71
5.1.
Inclusion Criteria.........................................................................................71
5.2.
Exclusion Criteria........................................................................................74
5.3.
Additional Eligibility Criteria.........................................................................78
5.4.
Screening/Baseline/Run-in Failures............................................................78
5.5.
Withdrawal/Stopping Criteria.......................................................................79
5.5.1.
Liver Chemistry Stopping Criteria ................................................81
5.5.1.1.
Liver Chemistry Stopping Criteria, Participant 
Management and Follow-Up.......................................82
5.5.1.2.
Liver Event Adjudication Committee...........................83

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5.5.1.3.
Liver Chemistry Stopping Criteria –
Restart/Rechallenge...................................................84
5.5.1.3.1.
Drug Restart/Rechallenge.  
Following Liver Events that are 
Possibly Related to IP.............................84
5.5.1.3.2.
Drug Restart Following Transient 
Resolving Liver Events Not 
Related to IP...........................................84
5.5.2.
QTc Stopping Criteria ..................................................................85
5.5.3.
Virologic Failure...........................................................................85
5.5.4.
Definition of Confirmed Virologic Failure ......................................85
5.5.5.
Managing Virologic Failure ..........................................................85
5.5.5.1.
HIV-1 RNA Blips.........................................................86
5.5.5.2.
Suspected Virologic Failure........................................86
5.5.5.3.
Confirmed Virologic Failure ........................................87
5.6.
Participant and Study Completion...............................................................88
6.
STUDY TREATMENT ............................................................................................88
6.1.
Investigational Product and Other Study Treatment....................................88
6.1.1.
Formulations of CAB + RPV ........................................................89
6.1.1.1.
Cabotegravir Tablets (CAB)........................................89
6.1.1.2.
Rilpivirine Tablets (RPV).............................................89
6.1.1.3.
Cabotegravir Injectable Suspension (CAB LA) ...........90
6.1.1.4.
Rilpivirine Injectable Suspension (RPV LA) ................90
6.2.
Treatment Assignment................................................................................90
6.3.
Dosage and Administration.........................................................................91
6.4.
Blinding.......................................................................................................93
6.5.
Packaging and Labeling..............................................................................93
6.6.
Preparation/Handling/Storage/Accountability..............................................93
6.6.1.
Dosing Considerations for CAB LA + RPV LA..............................94
6.7.
Compliance with Study Treatment Administration.......................................95
6.8.
Protocol Permitted Substitutions.................................................................96
6.8.1.
Oral Bridging................................................................................96
6.9.
Interruption of Study Treatment and Visit/Dosing Windows.........................96
6.9.1.
IM Dosing ....................................................................................96
6.9.2.
Oral Dosing..................................................................................97
6.10.
Discontinuation of Study Treatment ............................................................98
6.11.
Treatment of Study Treatment Overdose....................................................98
6.12.
Treatment After the End of the Study..........................................................99
6.13.
Concomitant Medications and Non-Drug Therapies....................................99
6.13.1.
Permitted Medications and Non-Drug Therapies..........................99
6.13.2.
Prohibited Medications and Non-Drug Therapies.......................100
6.13.2.1.
Concurrent with CAB and/or RPV.............................101
6.13.2.2.
Concurrent with either CAB LA or RPV LA ...............101
6.13.2.3.
Prohibited Medications for Participants 
Receiving Current Regimen......................................102
7.
STUDY ASSESSMENTS AND PROCEDURES ...................................................102
7.1.
Time and Events Table.............................................................................103
7.2.
Screening and Critical Baseline Assessments ..........................................112
7.2.1.
Screening Assessments ............................................................112
7.2.2.
Baseline Assessments...............................................................113

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7.3.
Efficacy.....................................................................................................114
7.3.1.
Plasma HIV-1 RNA....................................................................114
7.3.2.
Lymphocyte Subsets, CD4+ and CD8+ .....................................114
7.3.3.
HIV Associated Conditions ........................................................115
7.4.
Safety .......................................................................................................115
7.4.1.
Clinical Evaluations....................................................................115
7.4.2.
Laboratory Assessments ...........................................................116
7.4.3.
Adverse Events (AE) and Serious Adverse Events (SAEs)........118
7.4.3.1.
Time period and Frequency for collecting AE 
and SAE information.................................................118
7.4.3.2.
Method of Detecting AEs and SAEs .........................118
7.4.3.3.
Follow-up of AEs and SAEs......................................119
7.4.3.4.
Prompt Reporting of Serious Adverse Events 
and Other Events .....................................................119
7.4.3.5.
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ..............121
7.4.3.6.
Regulatory Reporting Requirements for SAEs..........122
7.4.3.7.
Cardiovascular and Death Events ............................122
7.4.3.8.
Death Events............................................................123
7.4.3.9.
Treatment Interruption Due to an Adverse 
Event........................................................................123
7.4.3.10.
Grade 1 or Grade 2 Toxicity/Adverse Event .............124
7.4.3.11.
Grade 3 Toxicity/Adverse Event ...............................124
7.4.3.12.
Grade 4 Toxicity/Adverse Event ...............................125
7.4.4.
Specific Toxicities/Adverse Event Management’........................125
7.4.4.1.
Liver Chemistry Stopping and Follow-up 
Criteria......................................................................125
7.4.4.2.
Diarrhea ...................................................................126
7.4.4.3.
Hypertriglyceridemia/ Hypercholesterolemia.............126
7.4.4.4.
Seizures ...................................................................126
7.4.4.5.
Creatine Phosphokinase (CPK) Elevation ................127
7.4.4.6.
Lipase Elevations and Pancreatitis...........................127
7.4.4.7.
Decline in Renal Function.........................................128
7.4.4.7.1.
Proximal Renal Tubule 
Dysfunctions.........................................129
7.4.4.8.
Proteinuria................................................................129
7.4.4.9.
QTc Prolongation .....................................................130
7.4.4.10.
Injection Site Reactions (ISRs) .................................130
7.4.4.11.
Allergic reaction........................................................130
7.4.4.12.
Abacavir Hypersensitivity Reaction (ABC HSR)........131
7.4.4.12.1.
Essential Patient Information ................131
7.4.4.12.2.
Reporting of Hypersensitivity 
Reactions .............................................132
7.4.4.13.
Rash Without ABC HSR Symptoms .........................132
7.4.5.
Suicidal Risk Monitoring.............................................................134
7.4.6.
Pregnancy .................................................................................135
7.4.6.1.
Pregnancy testing.....................................................135
7.4.6.2.
Time Period for Collecting Pregnancy 
Information ...............................................................135
7.4.6.3.
Action to be Taken if Pregnancy Occurs...................135
7.4.7.
Physical Exams .........................................................................136
7.4.8.
Vital Signs..................................................................................137

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7.4.9.
Electrocardiogram (ECG)...........................................................137
7.5.
Pharmacokinetics .....................................................................................137
7.5.1.
PK Sample Collection ................................................................137
7.5.2.
Rationale of PK Sampling Strategy............................................140
7.5.3.
Sample Analysis ........................................................................140
7.5.3.1.
CAB Sample Analysis...............................................140
7.5.3.2.
RPV Sample Analysis...............................................140
7.6.
Biomarker(s).............................................................................................140
7.7.
Genetics ...................................................................................................141
7.8.
Viral Genotyping and Phenotyping............................................................141
7.8.1.
HIV-1 Polymerase Viral Genotyping and Phenotyping ...............141
7.8.2.
HIV-1 Exploratory Analysis ........................................................141
7.9.
Value Evidence and Outcomes.................................................................141
7.9.1.
Value Evidence and Outcomes Endpoints (Secondary).............143
7.9.2.
Value Evidence and Outcomes Endpoints (Exploratory)............144
8.
DATA MANAGEMENT .........................................................................................144
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES ...............................145
9.1.
Hypotheses...............................................................................................145
9.2.
Sample Size Considerations.....................................................................145
9.2.1.
Sample Size Assumptions .........................................................145
9.2.1.1.
Rationale for non-inferiority margin...........................146
9.2.1.2.
Assumption for Virologic Failure Rate at Week 
48 (Primary Endpoint)...............................................146
9.2.1.2.1.
Control Arm ..........................................146
9.2.1.2.2.
CAB LA + RPV LA arm.........................147
9.2.1.3.
Assumption for Response Rate at Week 48 
(Secondary Endpoint)...............................................148
9.2.2.
Sample Size Sensitivity..............................................................148
9.2.3.
Sample Size Re-estimation or Adjustment.................................150
9.3.
Data Analysis Considerations ...................................................................151
9.3.1.
Analysis Populations..................................................................151
9.3.1.1.
Intent-to-Treat Exposed (ITT-E)................................151
9.3.1.2.
Per-Protocol Population (PP)....................................151
9.3.1.3.
PK Population...........................................................151
9.3.1.4.
Safety Population .....................................................151
9.3.2.
Treatment Comparisons ............................................................151
9.3.2.1.
Primary Comparison of Interest ................................151
9.3.2.2.
Other Comparisons of Interest..................................151
9.3.2.3.
Secondary comparisons ...........................................152
9.3.2.4.
Planned Analyses.....................................................152
9.4.
Key Elements of Analysis Plan .................................................................152
9.4.1.
Primary Analyses.......................................................................153
9.4.2.
Secondary Analyses ..................................................................154
9.4.3.
Pharmacokinetic Analyses.........................................................155
9.4.4.
Population PK Analysis:.............................................................155
9.4.5.
Pharmacokinetic/Pharmacodynamic Analyses...........................156
9.4.6.
Viral Genotyping/Phenotyping Analyses ....................................156
9.4.7.
Health Outcomes Analyses........................................................156
9.4.8.
Genetic Analyses.......................................................................156
9.4.9.
Other Analyses ..........................................................................157

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10. STUDY GOVERNANCE CONSIDERATIONS......................................................157
10.1.
Posting of Information on Publicly Available Clinical Trial Registers..........157
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ......................................................................................157
10.3.
Quality Control (Study Monitoring) ............................................................158
10.4.
Quality Assurance.....................................................................................158
10.5.
Study and Site Closure .............................................................................159
10.6.
Records Retention....................................................................................159
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication ...............160
10.8.
Review Committees..................................................................................160
10.8.1.
Independent Data Monitoring Committee...................................160
11. REFERENCES.....................................................................................................161
12. APPENDICES......................................................................................................166
12.1.
Appendix 1:  Abbreviations and Trademarks.............................................166
12.2.
Appendix 2:  Division of AIDS Table for Grading the Severity of 
Adult and Pediatric Adverse Events Version 2.0, November 2014 ............170
12.3.
Appendix 3:  Liver Safety – Study Treatment Restart or Rechallenge 
Guidelines.................................................................................................194
12.4.
Appendix 4:  CDC Classification for HIV-1 Infection (2014).......................203
12.5.
Appendix 5:  Genetic Research ................................................................205
12.6.
Appendix 6:  Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events ..........................208
12.6.1.
Definition of Adverse Events......................................................208
12.6.2.
Definition of Serious Adverse Events.........................................209
12.6.3.
Definition of Cardiovascular Events ...........................................211
12.6.4.
Recording of AEs and SAEs ......................................................211
12.6.5.
Evaluating AEs and SAEs..........................................................212
12.6.6.
Reporting of SAEs to GSK.........................................................213
12.7.
Appendix 7:  Pregnancy Information .........................................................215
12.7.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in FRP and Collection of Pregnancy 
Information.................................................................................215
12.7.2.
Collection of Pregnancy Information ..........................................216
12.7.3.
Study Duration...........................................................................216
12.8.
Appendix 8: Country Specific Requirements.............................................217
12.8.1.
South Korea Investigational Product Labels...............................217
12.9.
Appendix 9: Protocol Changes..................................................................219
12.9.1.
Summary of Changes in Protocol Amendment 01 and 
Rationale ...................................................................................219
12.9.2.
Summary of Changes in Protocol Amendment 02 and 
Rationale ...................................................................................223
12.9.3.
Summary of Changes in Protocol Amendment 03 and 
Rationale ...................................................................................227
12.9.4.
Protocol Amendment 4 Summary of Changes Table .................250

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1.
PROTOCOL SYNOPSIS FOR STUDY 201585
Rationale
The 201585 (Antiretroviral Therapy as Long Acting Suppression-ATLAS study) is being 
conducted to establish if human immunodeficiency virus type 1 (HIV-1) infected adult 
participants with current viral suppression on a regimen with 2 nucleoside reverse 
transcriptase inhibitors (NRTIs) plus a third agent, remain suppressed upon switching to a 
two-drug intramuscular (IM) long-acting (LA) regimen of cabotegravir (CAB) and 
rilpivirine (RPV).  This study is designed to demonstrate the non-inferior antiviral 
activity of switching to CAB LA 400 mg + RPV LA 600 mg every 4 weeks (monthly) for 
48 weeks (4 weeks oral CAB + RPV, 44 weeks LA therapy) compared to continuation of 
current antiretroviral therapy (current ART). 201585 (ATLAS) will also provide 
important long-term antiviral activity, safety, tolerability and patient satisfaction through 
Week 96. Additionally, participants initially randomized to continue current ART will be 
given an option to switch to LA therapy at Week 52.  Eligible participants (HIV-1 RNA 
<50 c/mL at Week 48) will transition to LA dosing, beginning with 4 weeks oral CAB + 
RPV therapy at Week 52, and receive the first IM CAB LA + RPV LA injections at 
Week 56.
201585 (ATLAS) is being conducted in parallel with the 201584 (the First Long-Acting 
Injectable Regimen- FLAIR study) with the aim to pool data generated from the current 
study with study 201584, in order to evaluate key program objectives.
Objectives/Endpoints
Objectives
Endpoints
Primary
To demonstrate the non-inferior antiviral activity 
of switching to intramuscular CAB LA + RPV LA 
every 4 weeks (monthly) compared to 
continuation of current first line antiretroviral 
regimen over 48 weeks in HIV-1 infected 
antiretroviral therapy (ART)-experienced 
participants

Proportion of participants with a ‘virologic 
failure’ endpoint as per Food and Drug 
Administration (FDA) Snapshot algorithm at 
Week 48 (Intent-to-Treat Exposed [ITT-E] 
population).
Secondary
To demonstrate the antiviral and immunologic 
activity of switching to intramuscular CAB LA + 
RPV LA every 4 weeks (monthly) compared to 
continuation of current ART

Proportion of participants with Plasma HIV-
1 RNA <50 copies/mL (c/mL) at Week 48 
using the FDA Snapshot algorithm (Missing,
Switch or Discontinuation = Failure, Intent-
to-Treat Exposed [ITT-E] population).

Proportion of participants with plasma HIV-1 
RNA <200 c/mL at Week 48 using the 

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Objectives
Endpoints
Snapshot algorithm (ITT-E population)

Proportion of participants with confirmed 
virologic failure (two consecutive plasma 
HIV-1 RNA levels 200 c/mL after prior 
suppression to <200 c/mL) at Week 48

Absolute values and change from Baseline 
in plasma HIV-1 RNA (log10 c/mL) at Week 
48.

Absolute values and change from Baseline 
in CD4+ lymphocyte count at Week 48

Incidence of disease progression (HIV-
associated conditions, acquired 
immunodeficiency syndrome [AIDS] and 
death over 48 Weeks
To evaluate the safety and tolerability of 
switching to CAB LA + RPV LA every 4 weeks 
(monthly) compared to continuation of current 
ART

Incidence and severity of adverse events 
(AEs) and laboratory abnormalities over 
time including Week 48

Proportion of participants who discontinue 
treatment due to AEs over time including 
Week 48

Absolute values and changes in laboratory 
parameters over time including Week 48
To evaluate the effects of CAB LA + RPV LA 
every 4 weeks on fasting lipids over time 
compared to continuation of current ART over 
time.

Change from Baseline in fasting lipids over 
time including Week 48 and Week 96.
To assess viral resistance in participants 
experiencing protocol-defined virologic failure 

Incidence of treatment emergent genotypic 
and phenotypic resistance to CAB, RPV 
and other on-study ART at Week 48
To assess the impact of Baseline third agent 
treatment class (INI, NNRTI, or PI) on efficacy, 
safety, tolerability, and viral resistance of CAB 
LA + RPV LA compared to continuation of 
current ART
By Baseline third agent treatment class:

Proportion of participants with a ‘virologic 
failure’ endpoint as per FDA Snapshot 
algorithm at Week 48 (Intent-to-Treat 
Exposed [ITT-E] population).

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Objectives
Endpoints

Proportion of participants with Plasma HIV-
1 RNA <50 c/mL at Week 48 using the FDA 
Snapshot algorithm (Intent-to-Treat 
Exposed [ITT-E] population)

Incidence and severity of select AEs and 
laboratory abnormalities over time including 
Week 48

Proportion of participants who discontinue 
treatment due to AEs over time including 
Week 48

Absolute values and changes in select 
laboratory parameters over time including 
Week 48

Incidence of observed genotypic and 
phenotypic resistance to current 
antiretroviral regimen and to CAB or RPV 
for participants meeting confirmed virologic 
failure
To characterize CAB and RPV concentrations 
and population pharmacokinetics and identify 
important determinants of variability.

Plasma PK parameters for CAB LA and 
RPV LA (when evaluable, Ctrough,
concentrations post dose [~Cmax], and 
area under the curve [AUC])

Demographic parameters including, but not 
limited to, age, sex, race, body weight, body 
mass index, and relevant laboratory 
parameters will be evaluated as potential 
predictors of inter- and intra-participant 
variability for pharmacokinetic parameters
To evaluate the antiviral and immunologic 
effects, safety, tolerability, and viral resistance 
of CAB LA + RPV LA for participants during the 
Extension Phase

For participants randomized to CAB 
LA+ RPV LA at Day 1

For participants electing to transition to 
CAB LA + RPV LA in the Extension 

Proportion of participants with plasma HIV-1 
RNA <50 c/mL over time including week 96 
(Observed Case).

Proportion of participants with confirmed 
virologic failure (two consecutive plasma 
HIV-1 RNA levels 200 c/mL after prior 
suppression to <200 c/mL) through Week 
96

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Objectives
Endpoints
Phase

Absolute values and change from Baseline 
in plasma HIV-1 RNA over time including 
Week 96

Absolute values and changes from Baseline 
in CD4+ cell counts over time including 
Week 96

Incidence of disease progression (HIV-
associated conditions, acquired 
immunodeficiency syndrome [AIDS] and 
death)

Incidence and severity of AEs and 
laboratory abnormalities over time including 
Week 96

Proportion of participants who discontinue 
treatment due to AEs over time including 
Week 96

Absolute values and changes in laboratory 
parameters over time including Week 96

Incidence of treatment emergent genotypic 
and phenotypic resistance to CAB, RPV, 
and other on study ART at Week 96
To assess the acceptance of pain and injection 
site reactions following injections 

Change from Week 5 in Dimension scores 
(“Bother of ISRs”, “Leg movement”, “Sleep”, 
and “Injection Acceptance”) and individual 
item scores assessing pain during injection, 
anxiety before and after injection, 
willingness to be injected in the future and 
overall satisfaction with mode of 
administration over time using the 
Perception of iNjection questionnaire (PIN) 

Proportion of participants considering pain 
and local reactions following injection to be 
extremely or very acceptable based on the 
acceptability score over time using the 
Perception of iNjection questionnaire (PIN)
To assess degree of health-related quality of life 
Change from Baseline in HR QoL using the 

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Objectives
Endpoints
(HRQoL) 
HIV/AIDS-targeted quality of life 
questionnaire (HAT QoL) short form at 
Week 24, Week 48, Week 96 (or 
Withdrawal).
To assess the health status

Change from Baseline in health status at 
Week 24, Week 48, and Week 96 (or 
Withdrawal) using the 12-item Short Form 
Survey (SF-12). .
To assess treatment satisfaction of CAB LA + 
RPV LA compared to continuation of current 
ART

Change from baseline in total “treatment 
satisfaction” score, and individual items 
scores of the HIVTSQs at Weeks 4b, 24, 
44, 96 (or Withdrawal)

Change in treatment satisfaction over time 
using the HIVTSQc at Week 48 (or 
Withdrawal)
To assess treatment acceptance 

Change from Baseline in treatment 
acceptance at Week 8, Week 24, Week 48, 
Week 96 (or Withdrawal) using the “General 
acceptance” dimension of the Chronic 
Treatment Acceptance (ACCEPT) 
questionnaire
To assess tolerability of injections 

Change from Week 4b in tolerability of 
injection at Week 5, Week 40, Week 41, 
and Week 96 using the Numeric Rating 
Scale (NRS) within the CAB + RPV LA arm.
Overall Design
201585 (ATLAS) is a Phase III, randomized, open-label, active-controlled, multicenter, 
parallel-group, non-inferiority study designed to assess the antiviral activity and safety of 
a two drug regimen of CAB LA + RPV LA compared with maintenance of current ART.  
Approximately 570 adult HIV-1 infected patients who are on a stable ARV regimen 
containing 2 NRTIs plus an INI, NNRTI, or a PI will be randomized 1:1 to continue 
current ART or be switched to the CAB LA + RPV LA regimen through 52 weeks. The 
randomized portion of the study will continue with an Extension Phase up to at least 96 
weeks.
Participants will be randomized (1:1) at Day 1 to either continue on current ART or to 
discontinue current ART and begin oral therapy with CAB 30 mg + RPV 25 mg once 
daily to determine individual safety and tolerability prior to administration of CAB LA + 

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RPV LA.  Current ART dosing on Day 1 is recommended to occur after randomization to 
avoid overlap of regimens (in the event that the participant is assigned to the CAB LA + 
RPV LA treatment arm).  However, if the participant takes current ART prior to coming 
into the clinic, randomization and initiation of oral CAB and RPV should continue as 
planned for Day 1. 
At the Week 4a visit, safety assessments (including e.g., clinical chemistries) will be 
performed as per the Time and Events Table.  At visit Week 4b, participants will return to 
the clinic, take the last dose of oral CAB + RPV, and receive the first CAB LA (600 mg) 
+ RPV LA (900 mg) injections (within 2 hours of the final oral dose of CAB + RPV).  
The first injection visit with IM CAB LA 600 mg and RPV LA 900 mg (Week 4b) can be 
performed once central lab results are available and safety parameters are reviewed.  The 
second and third IM injections with CAB LA 400 mg and RPV LA 600 mg will be 
performed at Week 8 and Week 12.  There will be a one week dosing window for the 
second and third IM injections such that the second injection occurs within the window of 
Week 7 and Week 8 but no later than Week 8 and the third injection occurs within the 
window of Week 11 and Week 12 but no later than Week 12.  Subsequent injections with 
CAB LA 400 mg and RPV LA 600 mg will occur every 4 weeks thereafter (7 days from 
the visit schedule) allowed but not preferred.  In addition, starting after the Week 12 
injection, efforts should be made to limit time between injection visits 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.
Randomization will be stratified by baseline third agent class (PI, INI, or NNRTI), and 
gender at birth  The primary endpoint for the study is the proportion of participants who 
meet the Snapshot virologic failure criteria at Week 48 using the Intent-to-Treat Exposed 
(ITT-E) population.  The proportion of participants with plasma HIV-1 RNA <50 c/mL at 
Week 48 using the FDA Snapshot algorithm (Missing, Switch or Discontinuation = 
Failure, ITT-E population) is a key secondary endpoint comparison.  
The sample size of 285 per arm is such that the study has approximately 97% power to 
demonstrate non-inferiority in the proportion of participants with snapshot virologic 
failure at Week 48 using a 6% margin, assuming a true 3% failure rate for CAB LA + 
RPV LA and a 2% failure rate for the current ART control arm and using a 2.5% one-
sided alpha level.  This sample size is primarily chosen so that the pooled analysis of data 
from this study and study 201584 (combined sample size of 570 per arm) will have 90% 
power to show non-inferiority for the proportion of participants with Snapshot virologic 
failure at Week 48 using a 4% non-inferiority margin, under the assumptions described 
above.

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201585 (ATLAS) Study Design Schematic
PI, NNRTI or 
INI Based 
Regimen 
with 2 NRTI 
Backbone#
Day 1
Wk 96
Randomization 
1:1
N= 570
CAB LA + RPV LA¥ 
Wk 48
1o
Endpoint
Wk 4b
Oral CAB
+ RPV
2o
Endpoint
Oral CAB
+ RPV
Wk 52
Extension Phase¥
Screening Phase
Maintenance Phase
†Extension Phase
Wk 4a
Wk 56a
Wk 56b
PI, NNRTI or INI 
Current ART
Q4 Weeks
Q4 Weeks
N=570, randomized 1:1 to each arm and stratified by baseline 3rd Agent class and gender at birth.
# Must be on uninterrupted current regimen (either the initial or second cART regimen) for at least 6 months prior to 
Screening.Documented evidence of at least two plasma HIV-1 RNA measurements <50 c/mL in the 12 months prior 
to Screening: one within the 6 to 12 month window, and one within 6 months prior to Screening.  No history of 
virologic failure.  No evidence of viral resistance based on the presence of any resistance-associated major INI, or 
NNRTI mutation (except K103N) from prior genotype assay results. No current or prior history of etravirine use.
INI based regimen excludes abacavir/dolutegravir/lamivudine (TRIUMEQ), and INI therapy will be capped at 
approximately 40% of study enrolment for current ART 
†Optional Extension Phase to CAB LA + RPV LA at Wk 52 for participants randomized to current ART
¥Participants who withdraw from IM arm must go into 52 week long term follow up phase
Treatment Arms and Duration
Screening Phase (Up to 35 days)
Informed consent must be obtained prior to any study procedures, including any 
Screening assessment.
Participants will be involved in a screening period of up to 35 days.  Participants may be 
re-screened once.  Participants who are randomized into the trial and subsequently 
withdrawn from the study, for any reason, may not be re-screened.  Participants may be 
randomized as soon as all eligibility requirements have been confirmed at the site.
Maintenance Phase (Day 1 up to Week 52)
At Day 1, Eligible participants will be randomized 1:1 to:

Oral CAB 30 mg + RPV 25 mg once daily for four weeks (participants will be 
assessed for safety and tolerability after four weeks).  At Week 4a, participants 
will have the assessments completed as per the Time and Events Table including 
clinical chemistries At visit Week 4b, participants will return to the clinic, take 
the last dose of oral CAB + RPV, and receive the first CAB LA (600 mg) + RPV 
LA (900 mg) injections (within 2 hours of the final oral dose of CAB + RPV).  
The first injection visit with IM CAB LA 600 mg and RPV LA 900 mg (Week 
4b) can be performed once central lab results are available and safety parameters 

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are reviewed.  The second and third IM injections with CAB LA 400 mg and RPV 
LA 600 mg will be performed at Week 8 and Week 12 with a one week dosing 
window allowed for the second and third IM injections such that the second 
injection occurs within the window of Week 7 and Week 8 but no later than Week 
8 and the third injection occurs within the window of Week 11 and Week 12 but 
no later than Week 12.  Subsequent injections with CAB LA 400 mg and RPV LA 
600 mg will occur every 4 weeks thereafter with a two week dosing window (7 
days from the visit schedule) allowed but not preferred.  In addition, starting after 
the Week 12 injection, efforts should be made to limit time between injection 
visits 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.
OR

Continue on current ART regimen for at least 52 weeks.  Participants who 
successfully complete Week 52 (without meeting study defined withdrawal 
criteria and who remain virologically suppressed (HIV-1 RNA <50 c/mL) will be 
given the option to switch to CAB LA + RPV LA in the Extension Phase, or be 
withdrawn from the study.
Randomization will be stratified by baseline third agent class (INI, NNRTI, or PI), and 
gender at birth. 
Extension Phase
Participants Entering from the CAB LA + RPV LA Arm
All participants who successfully complete 52 weeks of treatment in the Maintenance 
Phase will continue to have access to both CAB LA and RPV LA in the Extension Phase 
until study treatment is either locally approved and commercially available, the 
participant no longer derives clinical benefit, the participant meets a protocol-defined 
reason for discontinuation or until development of either CAB LA or RPV LA is 
terminated.  Visits will continue to occur every 4 weeks as per the Time and Events 
Schedule 
Participants Entering from the Current ART Arm
Participants randomized to continue on current ART will have the option to either 
continue study participation by switching to CAB LA + RPV LA in the Extension Phase, 
or to complete their study participation at Week 52 (no withdrawal visit needed).
Participants who choose to continue on to the Extension Phase will need to be assessed 
for eligibility to begin the CAB LA + RPV LA regimen. Participants will continue on 
their current ART Maintenance regimen while eligibility is being confirmed. All 
participants with an undetectable HIV-1 RNA (<50 c/mL) result from the Week 48 visit 
are eligible to enter the Extension Phase.  A single repeat of HIV-1 RNA for any 
participant with a HIV-1 RNA 50 c/mL and < 400 c/mL at Week 48 must be performed.
The retest should be scheduled as soon as possible (but no later than 4 weeks from the 
Week 48 visit). Participants with HIV-1 RNA <50 c/mL upon retest are eligible to enter 

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the Extension Phase.  Participants with HIV-1 RNA ≥400 c/mL at Week 48 are not 
eligible to enter the Extension Phase, will not be allowed a repeat to determine eligibility, 
and will therefore be withdrawn from the study.
Participants eligible to enter the Extension Phase will begin a 4 week lead-in of oral CAB 
30 mg + oral RPV 25 mg once daily at Week 52.  At Week 56a, participants will have 
assessments completed as per the Time and Events Table including clinical chemistries.  
At visit Week 56b, participants will return to the clinic, take the last dose of oral CAB + 
RPV, and receive the first CAB LA (600 mg) + RPV LA (900 mg) injections (within 2 
hours of the final oral dose of CAB + RPV).  The first injections can be performed as 
soon as central lab results from the Week 56a visit become available and safety 
parameters are reviewed.  The second and third IM injections with CAB LA 400 mg and 
RPV LA 600 mg will be performed at Week 60 and Week 64.  There will be a one week 
dosing window for the second and third IM injections such that the second injection 
occurs within the window of Week 59 and Week 60 but no later than Week 60 and the 
third injection occurs within the window of Week 63 and Week 64 but no later than 
Week 64.  Subsequent injections with CAB LA 400 mg and RPV LA 600 mg will occur 
every 4 weeks thereafter (7 days from the visit schedule allowed but not preferred).  
Following the Week 64 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.
Participants will continue study treatment until CAB LA and RPV LA are either locally 
approved and commercially available, the participant no longer derives clinical benefit, 
the participant meets a protocol-defined reason for discontinuation or until development 
of either CAB LA or RPV LA is terminated. Visits will continue to occur every 4 weeks 
as per the Time and Events Schedule.
Participants not eligible to enter the Extension Phase will end their study participation 
(Week 52 will be the last study visit, no withdrawal visit needed).  Sites may be 
reimbursed for up to a one month supply of antiretroviral medication to facilitate 
transition to non-study ART for participants that do not qualify for the Extension Phase.
Long-Term Follow-Up Phase – IM Regimen Only
Any participant 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 
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.  
Investigators must discuss the choice of the follow-up HAART regimen with the 
Medical Monitor prior to initiating the new regimen with the participant.  HAART 
therapy should be initiated within 4 weeks of the last injection.  The LTFU will begin 
the day of the last CAB LA and/or RPV LA dose and continue for 52 weeks, or until 
CAB LA + RPV LA is locally approved and commercially available.  These participants 
will not complete a Withdrawal visit, but will instead move directly into the Long-Term 
Follow-Up Phase as per the Time and Events Schedule.  In addition, for participants who 
withdraw during the Long-Term Follow-Up Phase, the final visit will be considered the 
study withdrawal visit. 

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Participants will be assessed with clinic visits at months 1, 3, 6, 9 and 12 during the 
Follow-Up Phase.  Female participants 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 participants have access to HAART during the Long-Term Follow-
Up Phase, GSK may supply HAART regionally or reimbursement will be provided as 
needed during this phase.  The Long-Term Follow-Up Phase may be shortened at any 
time during the study for various reasons, e.g., better understanding of risks of 
development of resistance as CAB and RPV exposures decline, regulatory approval and 
commercial availability, end of study timings, etc.
This phase is considered study participation and participants will be followed on study 
during this time.  A withdrawal visit is not required for participants who do not complete 
the Long-Term Follow-Up Phase.  The participants’ last on study visit will be considered 
as their withdrawal visit.
Dose Modifications:
No dose reductions, modifications, or changes in the frequency of any components of 
each regimen will be allowed during the study beyond what is allowed within the 
protocol. Protocol waivers or exemptions are not allowed. Therefore, adherence to the 
study design requirements is essential and required for study conduct.
In exceptional circumstances, and in consultation with the Medical Monitor, Investigators 
may provide oral CAB and/or RPV as a short-term “bridging” strategy for participants 
who have begun CAB LA + RPV LA.  Should a participant need “oral bridging”, sites 
must contact the Medical Monitor for guidance on treatment strategies prior to a missed 
CAB LA + RPV LA dose.  Should a participant not notify the site in advance, the 
Medical Monitor must be contacted for further treatment guidance.
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM), which is available on 
the online Study Web Portal. The SPM will provide the site personnel with administrative 
and detailed technical information.
207966 (ATLAS-2M) Rollover Option
The 207966 (ATLAS-2M) study is being conducted in approximately 1020 participants 
to establish if human immunodeficiency virus type 1 (HIV-1) infected adults with current 
viral suppression (HIV-1 RNA 50 c/mL) remain suppressed upon administration of a 
two-drug intramuscular (IM) long-acting (LA) regimen of cabotegravir (CAB) and 
rilpivirine (RPV) administered every 8 weeks (Q8W; every 2 months).  The ATLAS-2M 
study is designed to demonstrate the non-inferior antiviral activity of CAB LA 600 mg + 
RPV LA 900 mg administered every 8 weeks compared with CAB LA 400 mg + RPV 
LA 600 mg administered every 4 weeks (Q4W; monthly) over a 48-week treatment 
period.  ATLAS-2M will also provide comparative data on antiviral activity, safety, 
tolerability, and patient satisfaction through Week 96.  It is anticipated that the majority 
of ATLAS participants will transition to the ATLAS-2M study. 

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Upon local approval and implementation of the ATLAS-2M trial, investigators will 
approach all potentially eligible ATLAS participants with the optional consent for 
ATLAS-2M participation and potential randomization to the CAB LA + RPV LA Q4W 
or Q8W regimen. If a participant can not or chooses not to transition to the ATLAS-2M 
trial, or is otherwise determined to be ineligible for ATLAS-2M, the participant can elect 
to continue participation in ATLAS trial without limitations and according to the 
approved protocol design.  
Eligibility to transition to ATLAS-2M at Week 52 (at the earliest) will be determined 
once the final central lab results from ATLAS, following (at minimum) completion of the 
ATLAS Week 48 visit are available and safety parameters have been reviewed.  Separate 
Screening Labs will be utilized to inform eligibility for ATLAS-2M; however, in some 
occasions and upon consultation with the Medical Monitor, individual lab results and 
safety data from the final visit of the ATLAS study can be considered towards informing 
eligibility for the ATLAS-2M study as long as all other screening and eligibility criteria 
are met.  Following randomization to ATLAS-2M, participants will follow all schedules 
and activities of the ATLAS-2M trial and no withdrawal or additional follow-up activities 
for the ATLAS study are required.
Study Completion
Participants are considered to have completed the study if they remain on therapy (i.e., 
have not permanently discontinued IP) and satisfy one of the following:

Randomly assigned to either treatment group, completed the randomized 
Maintenance Phase including the Week 52 visit, and did not enter the Extension 
Phase;

Randomly assigned to either treatment group, completed the randomized 
Maintenance Phase including the Week 52 visit, and entered and completed the 
Extension Phase (defined as remaining on study until commercial supplies of 
CAB LA + RPV LA become locally available or development of CAB LA + RPV 
LA is terminated or participant rolls over into ATLAS 2M).
Independent Data Monitoring Committee
An Independent Data Monitoring Committee (IDMC) will be instituted to ensure external 
objective medical and/or statistical review of efficacy and safety in order to protect the 
ethical interests and well-being of subjects and to protect the scientific validity of this 
study and study 201584. 
The IDMC will evaluate accumulating efficacy, tolerability, safety and PK of CAB LA + 
RPV LA at predetermined times during the study.  An interim analysis will be performed 
for the IDMC to evaluate the efficacy of CAB LA + RPV LA prior to the final analysis.  
Full details of the methods, timing, decision criteria and operating characteristics will be 
pre-specified in the IDMC Charter.

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The interim futility analysis will be performed with the intent of having approximately 
50% of participants reaching Week 24 and providing sufficient lead time to allow the 
IDMC to review the data prior to any participants reaching the Week 48 visit.  A futility 
rule based on Bayesian posterior predictive probability approach will be applied to assess 
the probability that CAB LA + RPV LA injectable regimen demonstrate non-inferiority 
to the continued current ART arm given the partial data set.  The sponsor will remain 
blinded to this analysis.
In addition, the IDMC may also monitor the incidence of participants meeting Confirmed 
Virologic Failure (CVF) criteria through Week 48 to ensure that participants are not 
being sub-optimally treated in the CAB LA + RPV LA arm.
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.
Type and Number of Participants
The target population to be enrolled is virologically suppressed participants with HIV-1 
infection on stable antiretroviral therapy (ART).
Assuming 30% screen failure rate, approximately 815 HIV-1-infected adult participants 
will be screened to achieve 570 randomized participants for a total of 285 participants per 
treatment group. Participants will be enrolled from multiple countries which may include 
Argentina, Canada, France, Germany, Italy, Mexico, Russia, South Africa, South Korea, 
Spain, Sweden, and the United States. 
Randomization will be stratified by baseline third agent class (PI, INI, or NNRTI) and 
gender at birth.  The 201585 (ATLAS) study will exclude enrolment of participants 
treated with abacavir/dolutegravir/lamivudine (TRIUMEQ) and will aim to limit 
enrolment of participants on an INI to approximately 40%.  TRIUMEQ comparator data 
along with the majority of INI comparator data for the CAB LA + RPV LA program will 
be generated from 201584 (FLAIR) and will be included within a planned pooled 
analysis with 201585 (ATLAS) results.  A goal of this study is to enrol populations who 
are underrepresented in clinical studies including approximately 25% women.  To 
provide sufficient data to determine whether either gender is correlated with treatment 
response, sites are expected to take into account gender in their screening strategies. 
Analysis
The primary analysis at Week 48 will take place after the last participant has had their 
Week 48 viral load assessed, including a retest if required.  The primary analysis method 
for the proportion of participants defined as Snapshot virologic failures at Week 48 will 
be a Cochran-Mantel Haenszel test stratified by randomization stratification factors. A 
non-inferiority margin of 6% will be used for this comparison, where if the upper limit of 
the 95% confidence interval (CI) of the difference in failure rate between the two study 
arms is less than 6%, non-inferiority will be demonstrated.
Assuming the true virologic failure rate is 3% for the CAB LA + RPV LA injectable 
regimen and 2% for the current ART arm, this would provide approximately 97% to 

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show non-inferiority at a 2.5% one-sided significance level.  If we observe a 2% failure 
rate for the current ART arm, then non-inferiority would be declared if we observe a 5% 
or lower failure rate for the CAB LA + RPV LA arm (i.e. an observed treatment 
difference less than 3 percentage points for [CAB LA + RPV LA] – current ART).
A key secondary analysis will evaluate the proportion of responders (HIV-1 RNA <50 
c/mL per Snapshot) at Week 48 using a Cochran-Mantel Haenszel test stratified by 
randomization stratification factors. A non-inferiority margin of -10% will be used for 
this secondary comparison, where if the lower limit of the 95% confidence interval (CI) 
of the difference in responder rate between the two study arms is greater than -10%, non-
inferiority will be demonstrated.  Assuming true response rates for the CAB LA + RPV 
LA arm and current ART arm are both 87%, the sample size of 285 per arm will provide 
at least 94% power to show non-inferiority at a 2.5% one-sided significance level.
In addition, the data from this study, together with data from a separate study, 201584, 
will be combined to assess non-inferiority using a 4% non-inferiority margin.  The 
combined sample size from both studies (570 pooled per arm) will provide 90% power, 
under the assumptions described above, to show non-inferiority for the proportion of 
participants with virologic failure (per FDA’s snapshot algorithm for assessing HIV-1 
RNA 50 c/mL) at Week 48.
201585 (ATLAS) is being conducted in parallel with study 201584 (FLAIR) with the aim 
to pool data generated from the current study with study 201584, in order to evaluate key 
program objectives.

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2.
INTRODUCTION
While advances in the development of new antiretroviral therapies (ART) provide 
extensive insights into the management of Human immunodeficiency- (HIV)infected 
individuals, chronic HIV infection 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, safety and tolerability, and 
convenience of all antiretroviral classes.  
Fixed-dose combinations (FDCs) have greatly advanced HIV treatment by allowing 
simplification of dosing and reducing pill burden.  However, adherence to therapy is 
essential to achieve viral suppression and prevent emergence of resistance mutations.  
Among regimens of comparable efficacy, physicians and HIV-1-infected patients who 
receive ART rate total pill burden, dosing frequency, and safety concerns among the 
greatest obstacles to achieving adherence.  Drug resistant virus eventually emerges in 
most patients who struggle with consistent adherence.  Different HIV treatment 
modalities are being developed to help improve adherence and patient outcomes, and 
prevent resistance and transmission of the virus. 
There is also an increasing desire to develop nucleoside reverse transcriptase inhibitor 
(NRTI)-sparing regimens for long-term treatment of HIV infection as an approach to 
avoid known NRTI-associated adverse drug reactions and long-term toxicities.  In 
addition, while there are no currently approved two-drug regimens to maintain 
suppression, simplifying treatment has long been a goal to increase treatment compliance 
and improve the quality of life for patients with HIV.  
Cabotegravir (CAB) is a potent integrase inhibitor that possesses attributes that allow 
formulation and delivery as a long-acting (LA) parenteral product.  Rilpivirine (RPV), 
also formulated as a LA product, 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.  A two-drug combination therapy with CAB 
LA plus RPV LA may offer a better tolerability and resistance profile, as well as 
improved adherence and treatment satisfaction in virologically suppressed patients.
2.1.
Study Rationale
The overall objective of the CAB LA + RPV LA clinical development program is to 
develop a highly effective, well tolerated two drug long-acting injectable regimen which 
has the potential to offer improved treatment convenience, compliance and improved 
quality of life for individuals with HIV compared to current standard of care.  201585 
(ATLAS) is being conducted to establish if human immunodeficiency virus type 1 (HIV-
1) infected adult participants with current viral suppression on a regimen with 2 
nucleoside reverse transcriptase inhibitors (NRTIs) plus a third agent, remain suppressed 
upon switching to a two-drug intramuscular (IM) long-acting (LA) regimen of 
cabotegravir (CAB) and rilpivirine (RPV).  This study is designed to demonstrate the 
non-inferior antiviral activity of switching to CAB LA 400 mg + RPV LA 600 mg every 

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4 weeks for 48 weeks (4 weeks oral CAB + RPV, 44 weeks LA therapy) compared to 
continuation of current antiretroviral therapy (current ART). This study will also provide 
important long-term antiviral activity, safety, tolerability and patient satisfaction data on 
CAB LA 400 mg + RPV LA 600 mg through at least Week 96. Additionally, participants 
initially randomized to continue current ART will be given an option to switch to LA 
therapy at Week 52.  Eligible participants (HIV-1 RNA <50 c/mL at Week 48) will 
transition to LA dosing, beginning with 4 weeks oral CAB + RPV therapy at Week 52, 
and will receive the first IM CAB LA + RPV LA injections at Week 56 (See Section 6.3
for additional details).
2.2.
Brief Background
It is estimated that 36.9 million people are currently living with HIV/AIDS and that the 
worldwide epidemic continues to grow at a rate of two million new infections and cause 
1.2 million deaths per year [UNAIDS, 2015]. 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 a need for continuous improvement on the durability, 
tolerability and convenience of all antiretroviral classes.
A study by the Antiretroviral Therapy Cohort Collaboration [ART-CC, 2013] found that 
of more than 21,000 patients in a European and North American cohort on their first 
combination antiretroviral therapy (cART) regimen (either PI or NNRTI-based), 51% 
modified or interrupted their first cART regimen during a median of 28 months of 
follow-up with one third of interruptions occurring within the first 6 months of starting 
therapy.  Forty percent of all treatment interruptions were due to the secondary side 
effects or toxicities of cART, 17% were due to the desire for simplification of the 
regimen and 14% were due to patient choice. These observations have led to numerous 
“switch” ART studies, designed to understand the efficacy, safety, and tolerability of 
switching patients from one regimen to another.
Previous studies have evaluated switches to ritonavir-boosted PI monotherapy in 
virologically suppressed patients [Bierman, 2009 and Arribas, 2012].  These studies 
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 participants studied who 
have effectively maintained viral suppression.  In the OLE study, virologically 
suppressed (HIV-1 RNA <50 c/mL) HIV-1 infected participants receiving a lopinavir-
ritonavir (LPV/r) + lamivudine (3TC) or emtricitabine (FTC) based NRTI regimen 
simplified to a dual regimen of LPV/r + 3TC or FTC.  In a modified Intent-to-Treat (m-
ITT) analysis, dual therapy with LPV/r + 3TC demonstrated non-inferiority efficacy and 
comparable safety to LPV/r + 2 NRTIs [Arribas, 2015].  
Two Phase IIb studies (LAI116482 GlaxoSmithKline Document number 
2014N216014_00, Study LAI116482  [LATTE] and (20056 GlaxoSmithKline Document 
Number  2013N168152_05, Study [LATTE-2])]) have been conducted with oral CAB 

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and/or intramuscular (IM) CAB LA and oral RPV and/or IM RPV LA, evaluating an 
induction / maintenance simplification approach.  In LAI116482 (LATTE), participants 
were randomized to oral CAB 10, 30, or 60 mg + two nucleoside reverse transcriptase 
inhibitors (NRTIs) compared to efavirenz (EFV) + 2 NRTIs.  The study enrolled and 
treated 243 participants, 181 of whom received one of the three regimens of CAB plus 2 
NRTIs and 62 of whom received EFV 600 mg once daily plus 2 NRTIs.  Following 24 
weeks of Induction therapy, participants receiving CAB who had achieved a HIV-1 RNA 
< 50 copies/mL (c/mL) simplified their ART regimen by discontinuing the NRTIs, 
initiating rilpivirine (RPV), and continuing on two drug ART (CAB + RPV).  A robust 
virologic response (HIV-1 RNA <50 c/mL) was observed across all CAB plus NRTI 
treatment groups by the end of the 24-week induction phase (CAB subtotal: 156/181 
[86%] vs EFV: 46/62 [74%] (ITT-E), with a shorter time to viral suppression for the 
CAB groups compared with the EFV group (each p<0·001; log-rank test)
(GlaxoSmithKline Document Number 2014N216014_00).  A planned Week 48 analysis 
(24 weeks of CAB + 2 NRTIs Induction, followed by 24 weeks of CAB + RPV 
Maintenance) demonstrated the proportion of participants with plasma HIV-1 RNA <50 
c/mL (Snapshot algorithm), in each of the CAB plus RPV groups remained numerically 
higher than the EFV plus dual NRTI group at Week 48 (CAB: 149 [82%] vs EFV: 44 
[71%]).  Similar antiviral activity was observed across the three dosing arms of CAB in 
combination with RPV (10 mg:  80%; 30 mg: 80%; 60 mg:  87%, ITT-E, MSD=F), 
which compared favourably to EFV 600 mg plus 2 NRTIs (71%; ITT-E, MSD=F).
Following 72 weeks of two-drug maintenance therapy (Week 96), 137 (76%) of CAB 
plus RPV patients and 39 (63%) of EFV plus dual NRTI patients remained virologically 
suppressed (ITT-E, MSD=F).
An efficacy analysis of the ITT-Maintenance Exposed (ITT-ME) population which 
excludes participants who did not enter the Maintenance Phase, and assessed the ability 
of the two-drug regimen to maintain viral suppression was also performed at Week 96.  
In this population, virologic response (HIV-1 RNA <50 c/mL) was high across all 
treatment arms at Week 96, demonstrating a comparable durability of virologic response 
between treatments (CAB: 137/160 [86%]; EFV: 39/47 [83%]) with numerically higher 
values observed for the CAB 30 mg (45/53 [85%]) and 60 mg (51/55 [93%]) groups 
compared with the 10 mg group (41/52 [79%]).  
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 two-class regimen 
consisting of intramuscular (IM) long-acting (LA) CAB LA + RPV LA compared to 
continuation of therapy with oral CAB + ABC / 3TC for the maintenance of HIV-1 RNA 
suppression.  A total of 309 participants were enrolled and treated.
During the Induction Phase 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.

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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 Phase, 286 
participants qualified to enter randomization at the Day 1 visit, and were subsequently 
randomized 2:2:1 onto once every 4 weeks intramuscular (IM) injections with CAB LA + 
RPV LA every 4 weeks (Q4W), once every 8 weeks (Q8W) IM injections with CAB LA 
+ RPV LA 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 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 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 E238T, 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%), 

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headache (16%), and diarrhea (13%) on IM arms and nasopharyngitis (30%), headache 
(11%), and diarrhea (5%) on oral CAB.  Through Week 48, serious adverse events 
(SAEs) during the Maintenance Phase 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.  
Long-acting two class therapy consisting of CAB LA + RPV LA as an IM regimen has 
the benefit of being a NRTI-sparing regimen for long-term treatment of HIV infection 
which will avoid known NRTI-associated adverse drug reactions and long-term 
toxicities.  Additionally, a two-drug combination therapy with CAB LA plus RPV LA 
may offer a better tolerability and resistance profile, as well as improved adherence and 
treatment satisfaction in virologically suppressed participants improving the quality of 
life for patients with living with HIV.  
The primary objective of this study will be to demonstrate the non-inferior antiviral 
activity of switching to intramuscular CAB LA + RPV LA compared to continuation of 
current first line antiretroviral regimen (current ART) over 48 weeks in HIV-1 infected 
antiretroviral therapy (ART)-experienced participants.
This study is being conducted in parallel with 201584 (the First Long-Acting Injectable 
Regimen- FLAIR study) with the aim to pool data generated from the current study with 
study 201584, in order to evaluate key program objectives.

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3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
To demonstrate the non-inferior antiviral activity 
of switching to intramuscular CAB LA + RPV LA 
every 4 weeks (monthly) compared to 
continuation of current first line antiretroviral 
regimen over 48 weeks in HIV-1 infected 
antiretroviral therapy (ART)-experienced 
participants

Proportion of participants with a ‘virologic 
failure’ endpoint as per Food and Drug 
Administration (FDA) Snapshot algorithm at 
Week 48 (Intent-to-Treat Exposed [ITT-E] 
population).
Secondary
To demonstrate the antiviral and immunologic 
activity of switching to intramuscular CAB LA + 
RPV LA every 4 weeks (monthly) compared to 
continuation of current ART

Proportion of participants with Plasma HIV-
1 RNA <50 copies/mL (c/mL) at Week 48 
using the FDA Snapshot algorithm (Missing, 
Switch or Discontinuation = Failure, Intent-
to-Treat Exposed [ITT-E] population).

Proportion of participants with plasma HIV-1 
RNA <200 c/mL at Week 48 using the 
Snapshot algorithm (ITT-E population)

Proportion of participants with confirmed 
virologic failure (two consecutive plasma 
HIV-1 RNA levels 200 c/mL after prior 
suppression to <200 c/mL) at Week 48

Absolute values and change from Baseline 
in plasma HIV-1 RNA (log10 c/mL) at Week 
48.

Absolute values and change from Baseline 
in CD4+ lymphocyte count at Week 48

Incidence of disease progression (HIV-
associated conditions, acquired 
immunodeficiency syndrome [AIDS] and 
death over 48 Weeks
To evaluate the safety and tolerability of 
switching to CAB LA + RPV LA every 4 weeks 
(monthly) compared to continuation of current 
ART

Incidence and severity of adverse events 
(AEs) and laboratory abnormalities over 
time including Week 48

Proportion of participants who discontinue 

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Objectives
Endpoints
treatment due to AEs over time including 
Week 48

Absolute values and changes in laboratory 
parameters over time including Week 48
To evaluate the effects of CAB LA + RPV LA 
every 4 weeks on fasting lipids over time 
compared to continuation of current ART over 
time.

Change from Baseline in fasting lipids over 
time including Week 48 and Week 96.
To assess viral resistance in participants 
experiencing protocol-defined virologic failure 

Incidence of treatment emergent genotypic 
and phenotypic resistance to CAB, RPV 
and other on-study ART at Week 48
To assess the impact of Baseline third agent 
treatment class (INI, NNRTI, or PI) on efficacy, 
safety,  tolerability, and viral resistance of CAB 
LA + RPV LA compared to continuation of 
current ART
By Baseline third agent treatment class:

Proportion of participants with a ‘virologic 
failure’ endpoint as per FDA Snapshot 
algorithm at Week 48 (Intent-to-Treat 
Exposed [ITT-E] population).

Proportion of participants with Plasma HIV-
1 RNA <50 c/mL at Week 48 using the FDA 
Snapshot algorithm ( Intent-to-Treat 
Exposed [ITT-E] population)

Incidence and severity of select AEs and 
laboratory abnormalities over time including 
Week 48

Proportion of participants who discontinue 
treatment due to AEs over time including 
Week 48

Absolute values and changes in select 
laboratory parameters over time including 
Week 48

Incidence of observed genotypic and 
phenotypic resistance to current 
antiretroviral regimen and to CAB or RPV 
for participants meeting confirmed virologic 
failure

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Objectives
Endpoints
To characterize CAB and RPV concentrations 
and population pharmacokinetics and identify 
important determinants of variability.

Plasma PK parameters for CAB LA and 
RPV LA (when evaluable, Ctrough,
concentrations post dose [~Cmax], and 
area under the curve [AUC])

Demographic parameters including, but not 
limited to, age, sex, race, body weight, body 
mass index, and relevant laboratory 
parameters will be evaluated as potential 
predictors of inter- and intra-participant 
variability for pharmacokinetic parameters
To evaluate the antiviral and immunologic 
effects, safety, tolerability, and viral resistance 
of CAB LA + RPV LA for participants during the 
Extension Phase

For participants randomized to CAB 
LA+ RPV LA at Day 1

For participants electing to transition to 
CAB LA + RPV LA in the Extension 
Phase

Proportion of participants with plasma HIV-1 
RNA <50 c/mL over time including week 96 
(Observed Case).

Proportion of participants with confirmed 
virologic failure (two consecutive plasma 
HIV-1 RNA levels 200 c/mL after prior 
suppression to <200 c/mL) through Week 
96

Absolute values and change from Baseline 
in plasma HIV-1 RNA over time including
Week 96

Absolute values and changes from Baseline 
in CD4+ cell counts over time including 
Week 96

Incidence of disease progression (HIV-
associated conditions, acquired 
immunodeficiency syndrome [AIDS] and 
death)

Incidence and severity of AEs and 
laboratory abnormalities over time including 
Week 96

Proportion of participants who discontinue 
treatment due to AEs over time including 
Week 96

Absolute values and changes in laboratory 

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Objectives
Endpoints
parameters over time including Week 96

Incidence of treatment emergent genotypic 
and phenotypic resistance to CAB, RPV, 
and other on study ART at Week 96
To assess the acceptance of pain and injection 
site reactions following injections 

Change from Week 5 in Dimension scores 
(“Bother of ISRs”, “Leg movement”, “Sleep”, 
and “Injection Acceptance”) and individual 
item scores assessing pain during injection, 
anxiety before and after injection, 
willingness to be injected in the future and 
overall satisfaction with mode of 
administration over time using the 
Perception of iNjection questionnaire (PIN) 

Proportion of participants  considering pain 
and local reactions following injection to be 
extremely or very acceptable based on the 
acceptability score over time using the 
Perception of iNjection questionnaire (PIN)
To assess degree of health-related quality of life 
(HRQoL) 

Change from Baseline in HR QoL using the 
HIV/AIDS-targeted quality of life 
questionnaire (HAT QoL) short form at 
Week 24, Week 48, Week 96 (or 
Withdrawal).
To assess the health status 

Change from Baseline in health status at 
Week 24, Week 48, and Week 96 (or 
Withdrawal) using the 12-item Short Form 
Survey (SF-12). .
To assess treatment satisfaction of CAB LA + 
RPV LA compared to continuation of current 
ART

Change from baseline in total “treatment 
satisfaction” score, and individual items 
scores of the HIVTSQs at Weeks 4b, 24, 
44, 96 (or Withdrawal)

Change in treatment satisfaction over time 
using the HIVTSQc at Week 48 (or 
Withdrawal)
To assess treatment acceptance 

Change from Baseline in treatment 
acceptance at Week 8, Week 24, Week 48, 
Week 96 (or Withdrawal) using the “General 
acceptance” dimension of the Chronic 
Treatment Acceptance (ACCEPT) 

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Objectives
Endpoints
questionnaire
To assess tolerability of injections 

Change from Week 4b in tolerability of 
injection at Week 5, Week 40, Week 41, 
and Week 96 using the Numeric Rating 
Scale (NRS) within the CAB + RPV LA arm.
Exploratory
To explore the effect of patient characteristics 
(e.g., demographic factors, Baseline CD4+) on 
the virologic and immunologic responses to 
CAB LA+ RPV LA compared to continuation of 
current ART

Proportion of participants by patient 
subgroup(s) (e.g., by age, gender, BMI, 
race, HIV-1 subtype, Baseline CD4+) with 
Virologic Failure over time including Week 
48 using the Snapshot algorithm for the ITT-
E population

Proportion of participants by patient 
subgroup(s) (e.g., by age, gender, body 
mass index (BMI), race, HIV-1 subtype, 
Baseline CD4+) with plasma HIV-1 RNA 
<50 c/mL over time including Week 48 
using the Snapshot algorithm for the ITT-E 
population

Change from Baseline in CD4+ cell counts 
by subgroups at Week 48
To explore relationship(s) between plasma 
concentrations of CAB and RPV and 
pharmacodynamic endpoints.

Relationship between plasma PK 
concentrations and virologic, immunologic 
responses, and/or occurrence of adverse 
events [AEs] over time may be explored.
To evaluate renal and bone biomarkers in 
participants treated with CAB LA + RPV LA 
compared to continuation of current ART

Absolute value and change from Baseline in 
renal (in urine and blood), and bone (in 
blood) over time
To assess preference for CAB LA+ RPV LA 
compared to oral ARV using a single 
dichotomous preference question.

For patients randomized to the “CAB LA + 
RPV LA” arm, preference for CAB LA + 
RPV LA compared to oral ARV regimen, at 
Week 48

For patients randomized to the “Current 
ART” arm who switched to the injectable 
treatment, preference for CAB LA + RPV LA 
compared to current ART regimen at Week 
96 (end of extension phase- secondary 

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Objectives
Endpoints
analysis) 
To assess reason for switching using a single 
question. 

The reasons for willingness to switch ART 
at baseline and for patients randomized to 
the “Current ART” arm at Week 52.
4.
STUDY DESIGN
4.1.
Overall Design
201585 (ATLAS) is a Phase III, randomized, open-label, active-controlled, multicenter, 
parallel-group, non-inferiority study designed to assess the antiviral activity and safety of 
a two drug regimen of CAB LA + RPV LA compared with maintenance of current ART.  
Approximately 570 adult HIV-1 infected patients who are on a stable ARV regimen 
containing 2 NRTIs plus an INI, NNRTI, or a PI will be randomized 1:1 to continue 
current ART or be switched to the CAB LA + RPV LA regimen through 52 weeks. The 
study will continue with an Extension Phase up to at least 96 weeks.
Participants will be randomized (1:1) at Day 1 to either continue on current ART or to 
discontinue current ART and begin oral therapy with CAB 30 mg + RPV 25 mg once 
daily to determine individual safety and tolerability, prior to administration of CAB LA + 
RPV LA.  Current ART dosing on Day 1 is recommended to occur after randomization to 
avoid overlap of regimens (in the event that the participant is assigned to the CAB LA + 
RPV LA treatment arm).  However, if the participant takes current ART prior to coming 
into the clinic, randomization and initiation of oral CAB and RPV should continue as 
planned for Day 1. 
For those randomized to receive CAB + RPV, at the Week 4a visit safety assessments 
(including e.g., clinical chemistries) will be performed as per the Time and Events Table 
(Section 7.1).  At visit Week 4b, participants will return to the clinic, take the last dose of 
oral CAB + RPV, and receive the first CAB LA (600 mg) + RPV LA (900 mg) injections 
(within 2 hours of the final oral dose of CAB + RPV).  The first injection visit (Week 4b) 
can be performed once central lab results are available and safety parameters are 
reviewed.  If a retest is required based on Week 4a labs, the retest should be performed as 
soon as possible (and preferably no later than 7 days following Week 4a).  Participants 
will remain on oral CAB 30 mg + RPV 25 mg until the Week 4b injection visit, and until 
any required Visit 4a retest results are available for review.  The visit schedule following 
the oral lead-in phase will be based on timing of the first injection visit at Week 4b such 
that the Week 5 visit should be performed approximately 7 days after the Week 4b visit. 
Participants who are randomized to continue current ART and successfully complete 
Week 48 (without meeting study defined withdrawal criteria and remain virologically 
suppressed:  HIV-1 RNA <50 c/mL) will be given the option at Week 52 to switch to the 
LA arm in the Extension Phase or be withdrawn from the study.

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Randomization will be stratified by baseline third agent class (PI, INI, or NNRTI), and 
gender at birth.  The primary endpoint for the study is the proportion of participants who 
meet the Snapshot virologic failure criteria at Week 48. The proportion of participants 
with plasma HIV-1 RNA <50 c/mL at Week 48 using the FDA Snapshot algorithm 
(Missing, Switch or Discontinuation = Failure, Intent-to-Treat Exposed [ITT-E] 
population) is a key secondary endpoint.
The sample size of 285 per arm is such that the study has approximately 97% power to 
demonstrate non-inferiority in the proportion of participants with snasphot virologic 
failure at Week 48 using a 6% margin, assuming a true 3% failure rate for CAB LA + 
RPV LA and a 2% failure rate for the current ART control arm and using a 2.5% one-
sided alpha level.  This sample size is primarily chosen so that the pooled analysis of data 
from this study and study 201584 (combined sample size of 570 per arm) will have 90% 
power to show non-inferiority for the proportion of participants with Snapshot virologic 
failure at Week 48 using a 4% non-inferiority margin, under the assumptions described 
above.The randomized portion of the study will continue for 52 weeks with an Extension 
Phase up to at least 96 weeks
An Independent Data Monitoring Committee (IDMC) will evaluate interim efficacy, 
tolerability, safety and PK of CAB LA + RPV LA at predefined times during the study.  
An interim futility analysis will be performed for the IDMC with the intent of having 
approximately 50% of participants reaching Week 24 with the intent to complete this 
analysis prior to any participants transitioning to the Extension Phase at Week 52.  In 
addition, an ad hoc IDMC review of safety and efficacy data would also be triggered if 
the number of virologic failures exceeds pre-specified thresholds as per the IDMC 
charter.  In addition, the IDMC may also monitor the incidence of participants meeting 
PDVF criteria through Week 48 to ensure that participants are not being sub-optimally 
treated in the CAB LA + RPV LA arm.  Additional details are provided in Section 
9.3.2.4, and in the IDMC charter, which is available upon request.
No dose reductions, modifications, or changes in the frequency of any components of 
each regimen will be allowed during this study, except those allowed and defined in the 
protocol.  Protocol waivers or exemptions are not allowed.  Therefore, adherence to the 
study design requirements, including those specified in the Time and Events Table 
(Section 7.1), are essential and required for study conduct.  If deviations are required for 
the management of immediate safety concerns, these should be communicated promptly 
to the study medical monitor.

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Figure 1
201585 (ATLAS) Study Schematic
PI, NNRTI or 
INI Based 
Regimen 
with 2 NRTI 
Backbone#
Day 1
Wk 96
Randomization 
1:1
N= 570
CAB LA + RPV LA¥ 
Wk 48
1o
Endpoint
Wk 4b
Oral CAB
+ RPV
2o
Endpoint
Oral CAB
+ RPV
Wk 52
Extension Phase¥
Screening Phase
Maintenance Phase
†Extension Phase
Wk 4a
Wk 56a
Wk 56b
PI, NNRTI or INI 
Current ART
Q4 Weeks
Q4 Weeks
N=570, randomized 1:1 to each arm and stratified by baseline 3rd Agent class and gender at birth.
# Must be on uninterrupted current regimen (either the initial or second cART regimen) for at least 6 months prior to 
Screening (See Section 5.1 and Section 5.2). Documented evidence of at least two plasma HIV-1 RNA measurements 
<50 c/mL in the 12 months prior to Screening: one within the 6 to 12 month window, and one within 6 months prior to 
Screening.  No history of virologic failure.  No evidence of viral resistance based on the presence of any resistance-
associated major INI,  or NNRTI mutation (except K103N) from prior genotype assay results. No current or prior history 
of etravirine use.
INI based regimen excludes abacavir/dolutegravir/lamivudine (TRIUMEQ), and INI therapy will be capped at 
approximately 40% of study enrolment for current ART 
†Optional Extension Phase to CAB LA + RPV LA at Wk 52 for participants randomized to current ART
¥Participants who withdraw from IM arm must go into 52 week long term follow up phase
4.2.
Treatment Arms and Duration
4.2.1.
Screening Phase (Up to 35 days)
Informed consent must be obtained prior to any study procedures, including any 
Screening assessment.
Participants will complete a screening period of up to 35 days.  A single repeat of a 
procedure/lab parameter is allowed to determine eligibility (unless otherwise specified).  
In exceptional circumstances only, if a repeat lab is required because a central lab result 
cannot be generated, local labs can be reviewed and approved by the Medical Monitor for 
consideration of participant eligibility.  A repeat central lab will be submitted 
concurrently or at the next planned visit. Participants may be re-screened once which 
requires a new participant number.  Participants who are randomized into the trial and 
subsequently withdrawn from the study, for any reason, may not be re-screened.  
Participants may be randomized as soon as all eligibility requirements have been 
confirmed at the site.  
4.2.2.
Maintenance Phase (Day 1 up to Week 52)
At Day 1, Eligible participants will be randomized 1:1 to either:

Oral CAB 30 mg + RPV 25 mg once daily for four weeks (participants will be 
assessed for safety and tolerability after four weeks).  At Week 4a, participants 

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will have the assessments completed as per the Time and Events Table (Section 
7.1.), including clinical chemistries.  At visit Week 4b, the participant will return 
to the clinic to take the last dose of oral CAB + RPV, and to receive the first CAB 
LA + RPV LA injections (within 2 hours of the final oral dose).  The first 
injection visit with IM CAB LA 600 mg and RPV LA 900 mg (Week 4b) can be 
performed once central lab results are available and safety parameters are 
reviewed.  The second and third IM injections with CAB LA 400 mg and RPV 
LA 600 mg will be performed at Week 8 and Week 12.  There will be a one week 
dosing window for the second and third IM injections such that the second 
injection occurs within the window of Week 7 and Week 8 but no later than Week 
8 and the third injection occurs within the window of Week 11 and Week 12 but 
no later than Week 12.  Subsequent injections with CAB LA 400 mg and RPV LA 
600 mg will occur every 4 weeks thereafter (7 days from the visit schedule 
allowed but not preferred).  In addition, starting after the Week 12 injection, 
efforts should be made to limit time between injection visits 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.
OR

Continue on current ART regimen for 52 weeks.  Participants who successfully 
complete Week 52 (without meeting study defined withdrawal criteria and who 
remain virologically suppressed:  HIV-1 RNA <50 c/mL) will be given the option 
to switch to the LA arm in the Extension Phase or be withdrawn from the study.
If in the opinion of the Investigator, a participant experiences a significant safety event 
while taking oral CAB or RPV, administration of the first injections will be determined 
ONLY in consultation with the Medical Monitor.  Any rash that is possibly related to 
study drug, and is present during the CAB + RPV oral lead-in period, must be discussed 
with the Medical Monitor prior to initiation of CAB LA or RPV LA (See Section 
7.4.4.13).
Randomization will be stratified by baseline third agent class (INI, NNRTI, or PI), and 
gender at birth.
CAB + RPV oral, CAB LA + RPV LA IM, and current ART will be administered in an 
open-label fashion throughout the study.  For participants randomized to the current ART 
arm, provisions will be in place, as needed and after discussion with the study team, to 
assist patients in obtaining their current ART during the Maintenance Phase. 
The primary endpoint analysis of the proportion of participants with snapshot virologic 
failure and the key secondary endpoint analysis of the proportion of participants with 
plasma HIV-1 RNA <50 copies per milliliter (c/mL), both defined according to the FDA 
Snapshot algorithm for the Intent-to-treat exposed (ITT-E) population, will occur at 
Week 48. The study will continue through the Extension Phase, enabling longer-term 
evaluation of CAB+ RPV on measurements of efficacy, safety, and tolerability.
Following the Week 48 primary endpoint visit, participants randomized to current ART 
electing to participate in the Extension Phase will stay on their current ART regimen until 

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Week 52 to ensure availability of results from the Week 48 HIV-1 RNA testing. A single 
repeat of HIV-1 RNA for any participant with a HIV-1 RNA 50 c/mL and < 400 c/mL 
at Week 48 must be performed. The retest should be scheduled as soon as possible (but 
no later than 4 weeks from the Week 48 visit).  As per the snapshot algorithm, if the 
retest HIV-1 RNA is <50 c/mL then the participant will be considered to have met the 
secondary endpoint of virologic responder by FDA’s Snapshot algorithm at Week 48. If 
the retest HIV-1 RNA is 50 c/mL then the participant will be considered to be a 
virologic non-responder at Week 48.
4.2.3.
Extension Phase
4.2.3.1.
Participants Entering from the CAB LA + RPV LA Arm
All participants who successfully complete 52 weeks of CAB LA + RPV LA treatment in 
the Maintenance Phase will continue to have access to both CAB LA and RPV LA in the 
Extension Phase until study treatment is either locally approved and commercially 
available (including through local public/government health sectors), the participant no 
longer derives clinical benefit, the participant meets a protocol-defined reason for 
discontinuation or until development of either CAB LA or RPV LA is terminated.  Visits 
will continue to occur every 4 weeks as per the Time and Events Schedule (Section 7.1) 
4.2.3.2.
Participants Entering from the current ART ARM
Participants randomized to continue current ART will have the option to either continue 
study participation by switching to CAB LA + RPV LA in the Extension Phase, or to 
complete their study participation at Week 52 (no withdrawal visit needed).
Participants who choose to continue on to the Extension Phase will need to be assessed 
for eligibility to begin the CAB LA + RPV LA regimen. Participants will continue on 
their current ART Maintenance regimen while eligibility is being confirmed. All 
participants with an undetectable HIV-1 RNA (<50 c/mL) result from the Week 48 visit 
are eligible to enter the Extension Phase.  A single repeat of HIV-1 RNA for any 
participant with a HIV-1 RNA 50 c/mL and < 400 c/mL at Week 48 must be performed.  
The retest should be scheduled as soon as possible (but no later than 4 weeks from the 
Week 48 visit).  Participants with HIV-1 RNA <50 c/mL upon retest are eligible to enter 
the Extension Phase. Participants with HIV-1 RNA ≥400 c/mL at Week 48 are not 
eligible to enter the Extension Phase, will not be allowed a repeat to determine eligibility, 
and will therefore be withdrawn from the study.

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Eligibility and Participant Management for entry into Extension Phase (Current 
ART ARM)
Result of HIV-1 RNA at Week 48
Action
<50 c/mL
Begin Extension Phase with Oral CAB + 
Oral RPV at Week 52
50 c/mL but <400 c/mL
Perform HIV-1 RNA retest as soon as 
possible (not later than 4 weeks).

Single repeat <50 c/mL
Begin Extension Phase with Oral CAB + 
Oral RPV at Week 52

Single repeat 50 c/mL
Cannot begin Extension Phase and must be 
withdrawn from study; Complete Week 52 
visit (no additional withdrawal visit 
required)
400 c/mL
Cannot begin Extension Phase and must be 
withdrawn from study; Complete Week 52 
visit (no additional withdrawal visit 
required)
Participants with a Week 48 HIV-1 RNA <50 c/mL, will initiate a 4 week lead-in of oral 
CAB 30 mg + oral RPV 25 mg once daily at Week 52. Clinical chemistries will also be 
assessed. At Week 56a, following the 4 week CAB + RPV oral lead-in, participants will 
have additional safety assessments including clinical chemistries as per the Time and 
Events Table (Section 7.1).  In addition, central lab results and safety parameters from the 
Week 56a visit must be available and reviewed before the Week 56b visit.  If a clinical 
chemistry retest is required base on the Week 56a labs, the retest should be performed as 
soon as possible (and preferably no later than 7 days following Week 56a).  Participants 
will remain on oral CAB 30 mg + RPV 25 mg until the Week 56b injection visit, and 
until any required Visit 56a retest results are available for review. 
At visit Week 56b, participants will return to the clinic, take the last dose of oral CAB + 
RPV, and receive the first CAB LA + RPV LA injections (within 2 hours of the final oral 
dose of CAB + RPV). The Week 56b visit can be performed as soon as central lab 
results from the Week 56a visit become available and safety parameters are reviewed.  If 
a retest is required based on Week 56a labs, the retest should be performed as soon as 
possible (and preferably no later than 7 days following Week 56a)  Participants will 
remain on oral CAB 30 mg + RPV 25 mg until the Week 56b injection visit, and until 
any required Visit 56a retest results are available for review.  The visit schedule for the 
Extension Phase following the oral lead-in phase will be based on timing of the first 
injection visit at Week 56b.  The second and third IM injections with CAB LA 400 mg 
and RPV LA 600 mg will be performed at Week 60 and Week 64.  There will be a one 

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week dosing window for the second and third IM injections such that the second injection 
occurs within the window of Week 59 and Week 60 but no later than Week 60 and the 
third injection occurs within the window of Week 63 and Week 64 but no later than 
Week 64.  Subsequent injections with CAB LA 400 mg and RPV LA 600 mg will occur 
every 4 weeks thereafter with a two-week dosing window (7 days from the visit 
schedule allowed but not preferred).  Starting after the Week 64 injection, the interval 
between injection visits should be limited to a maximum of 5 weeks.  Following the 
Week 64 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.
Additionalanalyses including safety and efficacy endpoints will be based on Week 96 
data.  A single repeat of HIV-1 RNA for any participant with a HIV-1 RNA 50 c/mL 
and < 400 c/mL at Week 96 must be performed. The retest should be scheduled as soon 
as possible (but no later than 4 weeks from the Week 96 visit.
Participants will continue study treatment in the Extension Phase until CAB LA and RPV 
LA are either locally approved and commercially available (including through local 
public/government health sectors), the participant no longer derives clinical benefit, the 
participant meets a protocol-defined reason for discontinuation or until development of 
either CAB LA or RPV LA is terminated. Visits will continue to occur every 4 weeks.
See the Time and Events Table (Section 7.1) for more information.
Participants not eligible to enter the Extension Phase will end their study participation 
(Week 52 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 participants that do not qualify for the Extension Phase.
4.2.4.
Long-Term Follow-Up (LTFU) Phase – IM Regimen Only
Any participant 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 
HAART for at least 52 weeks after the last dose of CAB LA and/or RPV LA in order to 
prevent the potential selection of INI- and/or NNRTI-resistant mutants.  
Investigators must discuss the choice of the follow-up HAART regimen with the 
Medical Monitor prior to initiating the new regimen with the participant.  HAART 
therapy should be initiated within 4 weeks of the last injection
The LTFU will begin the day of the last CAB LA and/or RPV LA dose and continue for 
52 weeks, or until CAB LA + RPV LA is locally approved and commercially available .  
These participants will not complete a Withdrawal visit, but will instead move directly 
into the Long-Term Follow-Up Phase as per the Time and Events Schedule. 
Participants will be assessed with clinic visits at months 1, 3, 6, 9 and 12 during the 
Follow-Up Phase.  Female participants of child bearing potential must continue to use 
adequate contraception methods (see Study Procedures Manual [SPM] for list of accepted 
forms of contraception) for at least 52 weeks after the last injection. 

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In order to assure that participants have access to HAART during the Long-Term Follow-
Up Phase, GSK may supply HAART regionally or reimbursement will be provided as 
needed during this phase. As participants approach the end of the Long-Term Follow-Up 
Phase (e.g., Prior to Month 12 visit), investigative sites and/or participants must make 
alternative arrangements for independent access of the participant’s continued HAART 
off / post study.
The Long-Term Follow-Up Phase may be shortened at any time during the study for 
various reasons; e.g., better understanding of risks of development of resistance as CAB 
and RPV exposures decline, regulatory approval and commercial availability, end of 
study timings, etc.
This phase is considered study participation and participants will be followed on study 
during this time.  A withdrawal visit is not required for participants who do not complete 
the Long-Term Follow-Up Phase.  The participants’ last on study visit will be considered 
as their withdrawal visit.
4.2.5.
Dose Modifications
No dose reductions, modifications, or changes in the frequency of any components of 
each regimen will be allowed during the study. Protocol waivers or exemptions are not 
allowed.  Therefore, adherence to the study design requirements is essential and required 
for study conduct.
In exceptional circumstances, and in consultation with the Medical Monitor, Investigators 
may provide oral CAB and/or RPV as a short-term “bridging” strategy for participants 
who have begun CAB LA + RPV LA.  Should a participant need “oral bridging”, sites 
must contact the Medical Monitor for guidance on treatment strategies prior to a missed 
CAB LA + RPV LA dose.  Should a participant not notify the site in advance, the 
Medical Monitor must be contacted for further treatment guidance.  See Section 6.8.1 for 
additional information on oral bridging.
4.3.
207966 (ATLAS-2M) Rollover Option
The 207966 (ATLAS-2M) study is being conducted in approximately 1020 participants 
to establish if human immunodeficiency virus type 1 (HIV-1) infected adults with current 
viral suppression (HIV-1 RNA 50 c/mL) remain suppressed upon administration of a 
two-drug intramuscular (IM) long-acting (LA) regimen of cabotegravir (CAB) and 
rilpivirine (RPV) administered every 8 weeks (Q8W; every 2 months).  The ATLAS-2M 
study is designed to demonstrate the non-inferior antiviral activity of CAB LA 600 mg + 
RPV LA 900 mg administered every 8 weeks compared with CAB LA 400 mg + RPV 
LA 600 mg administered every 4 weeks (Q4W; monthly) over a 48-week treatment 
period.  ATLAS-2M will also provide comparative data on antiviral activity, safety,
tolerability, and patient satisfaction through Week 96.  It is anticipated that the majority 
of ATLAS participants will transition to the ATLAS-2M study
Upon local approval and implementation of the ATLAS-2M trial, investigators will 
approach all potentially eligible ATLAS participants with the optional consent for 
ATLAS-2M participation and potential randomization to the CAB LA + RPV LA Q4W 

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or Q8W regimen. If a participant cannot or chooses not to transition to the ATLAS-2M 
trial, or is otherwise determined to be ineligible for ATLAS-2M, the participant can elect 
to continue participation in ATLAS trial without limitations and according to the 
approved protocol design.  
Eligibility to transition to ATLAS-2M at Week 52 (at the earliest) will be determined
once the final central lab results from ATLAS, following (at minimum) completion of the 
ATLAS Week 48 visit are available and safety parameters have been reviewed.  Separate 
Screening Labs will be utilized to inform eligibility for ATLAS-2M; however, in some 
occasions and upon consultation with the Medical Monitor, individual lab results and 
safety data from the final visit of the ATLAS study can be considered towards informing 
eligibility for the ATLAS-2M study as long as all other screening and eligibility criteria 
are met. 
4.3.1.
201585 (ATLAS) to 207966 (ATLAS-2M) Transition Strategy
Upon the final ATLAS on-study visit (ATLAS Week 52 or later), which overlaps with 
the Day 1 Baseline visit for ATLAS-2M, all procedures and assessments must be 
performed and recorded as per both individual study Time and Events Tables with the 
exception that participants will receive only the scheduled Day 1 ATLAS-2M treatment
(participants will not receive the corresponding ATLAS study treatment).
ATLAS participants on current ART therapy who transition to ATLAS-2M at the 
ATLAS Week 52 visit, will begin a 4 week oral lead-in treatment with CAB 30 mg + 
RPV 25 mg once daily, per the ATLAS-2M Time and Events table.  Participants 
currently receiving CAB LA + RPV LA Q4W at the overlapping visit (including those 
who were originally randomized to the Q4W regimen and those who more recently 
switched to the Q4W regimen within the Extension Phase of ATLAS) will continue CAB 
LA + RPV LA Q4W or initiate CAB LA + RPV LA Q8W treatment as per the ATLAS-
2M randomized treatment schedule. 
Following the baseline Day 1 visit for ATLAS-2M, participants will follow all schedules 
and activities of the ATLAS-2M trial. No withdrawal visit nor long-term follow up phase 
participation for ATLAS is required. An in-clinic Follow-Up visit (which may or may not 
overlap with an ATLAS-2M visit) will be conducted approximately 4 weeks after the last 
dose of ATLAS study medication for participants with ongoing AEs, and serious adverse 
events (SAEs) related & not related to study drug and any laboratory abnormalities that 
are considered to be AEs or clinically significant at the last ATLAS on-study visit.
Transition from the ATLAS CAB LA + RPV LA Q4W Arm:
Participants originally randomized to the CAB LA + RPV LA Q4W arm in ATLAS and 
who are eligible for the ATLAS-2M trial can transition to ATLAS-2M upon completion 
of the ATLAS Week 52 primary endpoint or can continue ATLAS participation in the 
Extension Phase, until Study ATLAS-2M has been locally approved/implemented and 
eligibility for the ATLAS-2M trial has been confirmed.
Transition from the ATLAS current ART Arm:

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Participants originally randomized to the current ART Arm in ATLAS will have the 
following options to transition to ALTAS-2M:
At Week 52 Visit

Transition directly from current ART therapy in ATLAS at Week 52 to 
randomization at Day 1 in ATLAS-2M
After Week 52 Visit

Transition from current ART therapy to oral CAB + Oral RPV lead-in treatment 
followed by CAB LA + RPV LA Q4W within the ATLAS Extension Phase and 
transition to ATLAS-2M at a subsequent visit.  This option may be employed in 
the event that the ATLAS-2M study is not approved/implemented locally by the 
time a participant reaches the Week 52 visit (Extension Phase) of ATLAS or a 
decision to transition to ATLAS-2M is made following the transition to the 
Extension Phase.
Additional details of the ATLAS-2M study design, eligibility requirements, and transition 
guidance can be referenced within the current version of the ATLAS-2M protocol. 
4.4.
Independent Data Monitoring Committee
An Independent Data Monitoring Committee (IDMC) will evaluate the efficacy, 
tolerability, safety, and PK of the treatment regimens.  An interim analysis will be 
performed for the IDMC to evaluate the efficacy of CAB LA + RPV LA prior to the final 
analysis.  Full details of the methods, timing, decision criteria and operating 
characteristics will be pre-specified in the IDMC Charter.
An interim futility analysis will be performed with the intent of having approximately 
50% of participants reaching Week 24 and providing sufficient lead time to allow the 
IDMC to review the data prior to any participants reaching the Week 48 visit.  A futility 
rule based on Bayesian posterior predictive probability approach will be applied to assess 
the probability that CAB LA + RPV LA injectable regimen demonstrate non-inferiority 
to the continued current ART arm given the partial data set.  The sponsor will remain 
blinded to this analysis.
In addition, the IDMC may also monitor the incidence of participants meeting CVF 
criteria through Week 48 to ensure that participants are not being sub-optimally treated in 
the CAB + RPV arm.
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.
4.5.
Type and Number of Participants
The target population to be enrolled is virologically suppressed participants with HIV-1 
infection on stable antiretroviral therapy (ART).

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Assuming 30% screen failure rate, approximately 815 HIV-1-infected adult participants 
will be screened to achieve 570 randomized participants for a total of 285 participants per 
treatment group. Participants will be enrolled from multiple countries which may include 
Argentina, Australia, Canada, France, Germany, Italy, Mexico, Russia, South Africa, 
South Korea, Spain, Sweden, and the United States. 
Randomization will be stratified by baseline third agent class (PI, INI, or NNRTI) and 
gender at birth.  201585 (ATLAS) will exclude enrolment of participants treated with 
abacavir/dolutegravir/lamivudine (TRIUMEQ) and will aim to limit enrolment of 
participants on an INI to approximately 40%.  TRIUMEQ comparator data for the CAB 
LA + RPV LA program will be generated from study 201584 (FLAIR) and will be 
included within a planned pooled analysis with 201585 (ATLAS) results.  A goal of this 
study is to enrol populations who are underrepresented in clinical studies including 
approximately 25% women.  To provide sufficient data to determine whether either 
gender is correlated with treatment response, sites are expected to take into account 
gender in their screening strategies. Enrolment may be allowed to continue at select sites 
in order to reach targets in these key study populations.
4.6.
Design Justification
The design of this study (1:1 randomized, open-label, active-controlled, multicenter, 
parallel group, non-inferiority study) is well established for confirming the non inferiority 
of an investigational agent compared with an active comparator and is generally accepted 
by regulatory authorities as rigorous proof of antiviral activity. The primary endpoint, 
proportion of participants defined as virologic failures by the FDA Snapshot algorithm is 
recommended in the FDA’s 2015 guidance document (FDA, 2015) for assessing efficacy 
in Switch Trials.  The key secondary endpoint, proportion with plasma HIV-1 RNA <50 
c/mL at Week 48, is also a well-established surrogate endpoint for prognosis of HIV-1 
infection and disease progression. The Extension Phase will allow for a collection of both 
additional data for participants switching from current ART to CAB LA + RPV LA, as 
well as longer term efficacy, safety and tolerability data from participants randomized to 
CAB LA + RPV LA during the Maintenance Phase.
Various approaches to simplify a patient's antiretroviral therapy (ART) regimen, after 
achieving viral 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 
participants studied who have effectively maintained viral suppression. 
The 200056 (LATTE-2) (GlaxoSmithKline Document Number 2013N168152_05) 
clinical trial evaluated a different simplification approach and served as proof of concept 
for 201585.  In 200056, HIV-1 RNA suppression was induced with a three drug 
antiretroviral regimen consisting of CAB + ABC/3TC FDC, and then participants 
switched to a two-drug two-class regimen consisting of CAB LA + RPV LA for the 
maintenance of HIV-1 RNA suppression.  Results demonstrate that through 32 weeks on 

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two-drug maintenance therapy, 95% (Q8W) and 94% (Q4W) of participants on injectable 
dosing were virologic successes by snapshot, compared to 91% of participants continuing 
three drug oral CAB + NRTIs, meeting pre-specified criteria for comparability between 
the dosing arms. By Week 48, Q4W and Q8W arms continued to demonstrate similar 
efficacy (see Section 2  “Introduction” for further details).  On the basis of this 200056 
data, Q4W dosing was selected to progress into Phase 3 for further clinical development.
Several studies recently conducted have demonstrated the value/feasibility of a switch 
study design, an approach that has been shown to generate valuable data supporting ARV 
combinations that allow dosing flexibility, reduced toxicity and/or drug interactions or a 
reduction in pill burden.  An injectable ART regimen may also contribute to increased 
medication adherence and reduced HIV transmission.  A potential disadvantage of a 
switch study design is that effective, well-tolerated ART is discontinued at the time of 
switching to the simplified regimen [Carr, 2012].
The open-label design best suits the objectives of this study.  A double-dummy design 
could not be undertaken given the diversity of the comparator regimens, and the logistical 
challenges of providing blinding for each regimen, along with the marked increase in pill 
burden that would result from this blinding.  This marked increase in pill burden could 
both substantially hinder compliance, and discourage participant enrolment.  Therefore, 
the value of blinding the CAB LA + RPV LA injectable regimen would be limited, 
relative to the burden of participants in the current ART arm receiving Q4 weekly IM 
injections for the duration of the study.  Participants receiving placebo injections who 
believe that they are receiving LA injections might become less compliant with oral 
medication and increase risk taking behaviours.  A reduction in medication adherence in 
turn could lead to risk of regimen failure and potential virologic resistance impacting 
future treatment options. Elevated risk taking could increase opportunities for virus 
transmission to uninfected partners.  The additional risk of inadvertent non-adherence to 
oral ART outweighs any benefits that may be gained through a blinded design. 
Importantly, a key objective for the planned Phase 3 studies is to understand the 
acceptability and patient reported preferences to this novel injectable regimen, relative to 
daily oral standard of care (SOC) ART.  An unblinded study design supports collection of 
participant preference data in a way that would not be possible if a double-blind, double-
dummy design were implemented.
Due to the complexities, limitations and risks of blinding each switch study, both Phase 3 
switch studies (201585-ATLAS and 201584-FLAIR) are planned as open label studies.  
4.7.
Dose Justification
4.7.1.
Oral Lead-In Phase
During the oral lead-in phase of this study, oral formulations of CAB and RPV will be 
co-administered to confirm tolerability in each participant prior to possible IM dosing 
with CAB LA and RPV LA.  Data from study LAI116181 [GlaxoSmithKline Document 
Number 2011N130484_00] have demonstrated that there is no clinically relevant drug-
drug interaction following repeat oral administration of CAB with RPV.  The 
combination of oral RPV (25 mg once daily) and CAB (10, 30 or 60 mg once daily) has 

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been administered to HIV-infected participants in both Study LAI116482 LATTE and 
Study 200056 LATTE-2 (oral lead-in).  In the present study, the approved recommended 
dose of RPV 25 mg once daily will be used in combination with CAB 30 mg once daily.  
The oral dose of CAB was selected based on observed safety and efficacy from the Phase 
2b study 200056 LATTE study.  
CAB has demonstrated good short-term safety/tolerability and antiviral activity as 
monotherapy following oral administration of 5 mg and 30 mg once daily.  LAI116482 
(LATTE) is an ongoing Phase IIb, dose-ranging study (randomized 1:1:1: to CAB 10 mg, 
30 mg, or 60 mg) evaluating the long-term efficacy and safety of a two-drug, two-class, 
once daily combination of CAB + RPV in HIV-infected, treatment-naïve adult 
participants.  Following a 24-week phase of induction of virologic suppression using 
CAB + 2 NRTIs, the regimen was simplified to oral CAB + RPV once daily for an 
additional 72-weeks (total comparative study duration of 96 weeks).  The results of this 
study also informed the Phase IIb study 200056 (LATTE-2) with intramuscular CAB LA 
and RPV LA.  
Comparable efficacy, safety and tolerability were observed across all three CAB doses at 
the early dose selection and confirmation visits at Week 16 and 24 in LATTE.  
Additionally, the proportion of participants who achieved the primary endpoint of HIV-1 
RNA <50 c/mL (Missing, Switch, Discontinuation=Failure [MSDF] algorithm) at Week 
48 (24 weeks on Maintenance) remained consistently high across the CAB dose arms 
(≥80%) with a low rate of confirmed virologic failure (Table 1).   Across all dose arms, 
CAB achieved similar efficacy at Week 24 of Induction when co-administered with 2 
NRTIs and at Week 96 when co-administered with RPV 25 mg once daily (72 weeks on 
Maintenance).   Rates of virologic suppression through Week 96 (Maintenance) on the 
two drug regimen remained similar to that attained through Week 24 (Induction) on 
three-drug ART.  
Table 1
Proportion (95% CI) of Participants with Plasma HIV-1 RNA <50 c/mL 
at Key Visits - Snapshot (MSDF) Analysis (ITT-E Population) in 
LATTE
Visit
CAB
10 mg N=60
CAB
30 mg N=60
CAB
60 mg N=61
CAB
Subtotal 
N=181
EFV
600 mg
N=47
Week 16
n (%)
54 (90)
50 (83)
53 (87)
157 (87)
46 (74)
95%CI
Proportion
(82, 98)
(74, 93)
(78, 95)
(82, 92)
(63, 85)
Week 24
n (%)
52 (87)
51 (85)
53 (87)
156 (86)
46 (74)
95%CI
Proportion
(78, 95)
(76, 94)
(78, 95)
(81, 91)
(63, 85)
Week 48
n (%)
48 (80)
48 (80)
53 (87)
149 (82)
44 (71)
95%CI 
Proportion
(70, 90)
(70, 90)
(78, 95)
(77, 88)
(60, 82)
CAB was administered with 2 NRTIs during the 24 week induction Phase of LATTE.
95% CIs are normal approximation confidence intervals.

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CAB was well tolerated across all doses studied and none of the doses met pre-defined 
safety stopping criteria.  A good safety and tolerability profile with a low discontinuation 
rate due to AEs was observed in all three dose arms with no significant dose-dependent 
trends in safety parameters.  
Although CAB 30 mg was already selected based on short-term efficacy and safety 
through Week 24, the observed durability of viral suppression through 96 weeks, across 
all doses, provides further support for selection of the CAB 30 mg dose for Phase 3.  In 
addition, the 30 mg dose achieves trough CAB plasma concentrations that are greater 
than mean CAB plasma concentrations observed following CAB LA dosing which allows 
an adequate assessment of safety and tolerability prior to transitioning to the long-acting, 
Maintenance Phase of the study.  
CAB has low risk of causing or being a victim of drug-drug interactions, and therefore, 
the selected 30 mg dose can be safely used with most common concomitant medications 
without dose adjustment.  CAB exposures are not impacted by the presence of food; 
however, given that it will be co-administered with RPV which requires food for optimal 
absorption, the recommended intake of oral CAB in the Phase 3 studies is with food at 
the same time as RPV.  
Overall, the efficacy and safety data from the LATTE study, CAB LA dose simulations 
detailed in Section 4.7.2, and limited drug-drug interaction potential, support selection of 
the CAB 30 mg dose for once daily administration with the recommended approved dose 
of RPV 25 mg once daily during the oral lead-in phase of this study.  
4.7.2.
Long Acting Injectable for Maintenance Phase
During the Maintenance and Extension Phases of this study, CAB LA and RPV LA will 
be co-administered as two separate IM injections at each dosing visit. A CAB LA and 
RPV LA 4-weekly dosing regimen has been selected for evaluation in Phase 3.  
The safety and efficacy of a 2-drug regimen with CAB and RPV for maintenance of 
virologic suppression was established in LATTE, as detailed in Section 4.7.1, and 
informed the Phase 2b study (LATTE-2) with CAB LA and RPV LA.  Study 200056 
(LATTE-2) is an ongoing, Phase 2b dose-ranging study evaluating the long-term efficacy 
and safety of a two-drug, two-class combination of CAB LA + RPV LA given every 4 
weeks (Q4W) or every 8 weeks (Q8W), as compared to an oral three-drug regimen, for 
maintenance of virologic suppression in HIV-infected, treatment-naive adults.  The first 
phase of the LATTE-2 study was a 20 week Induction Phase (16 weeks of oral CAB + 2 
NRTIs, 4 weeks of CAB + 2 NRTIs + oral RPV).  Participants who were eligible to 
continue into the Maintenance Phase were then randomized (2:2:1) to receive IM 
injections of CAB LA every 4 weeks (800 mg Day 1 then 400 mg Q4W) or every 8 
weeks (800 mg Day 1, 600 mg Week 4, 600 mg Week 8, then 600 mg Q8W) in 
combination with IM RPV LA every 4 weeks (600 mg Day 1 then 600 mg Q4W) or 
every 8 weeks (900 mg Day 1, 900 mg Week 8, then 900 mg Q8W), respectively, or to 
continue on their triple ART regimen.

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The Q4W dosing strategy was selected for further investigation in Phase 3 based on the 
efficacy, safety and tolerability at Week48, and compared to oral.  Thus, the results from 
LATTE-2 provide the basis for the LA dosing strategy in the present study.   
The proportion of participants who achieved the primary endpoint of HIV-1 RNA <50 
c/mL (Missing, Switch, Discontinuation=Failure [MSDF] algorithm) by Week 32 was 
consistently high across both Q4W and Q8W dosing strategies (≥94%) with one 
participant, randomized to the Q8W regimen and one participant in the oral treatment arm 
with protocol-defined virologic failure during LA therapy.  At Week 32, snapshot failure 
rate was 4% (n=5) for the Q8W Arm and <1% (n=1) for the Q4W Arm.  Although the 
snapshot success rate at Week 48 was similar between treatment arms, the rate of
snapshot failures at Week 48 increased to 7% (n=8) for the Q8W Arm but remained at 
<1% (n=1) for the Q4W Arm (Table 2).   Refer to Section 2.2 for additional information 
on LATTE-2 data.

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Table 2
Proportion (95% CI) of Participants with Plasma HIV-1 RNA <50 c/mL 
at Week 48 - Snapshot (MSDF) Analysis (ITT-E Population) in LATTE-
2
Outcome
Q8W IM
N=115
n (%)
Q4W IM
N=115
n (%)
Q8W+Q4W
N=230
n (%)
CAB 30 mg
N=56
n (%)
Virologic Success, n (%)
106 (92)
105 (91)
211 (92)
50 (89)
Virologic Failure, n (%)
8 (7)
1 (<1)
9 (4)
1 (2)
Data in window not below threshold
6 (5)
1 (<1)
7 (3)
0
Discontinued for lack of efficacy
1 (<1)
0
1 (<1)
1 (2)
Discontinued for other reason while not below 
threshold
1 (<1)
0
1 (<1)
0
No Virologic Data
1 (<1)
9 (8)
10 (4)
5 (9)
Discontinued due to AE or Death
0
6 (5)
6 (3)
2 (4)
Discontinued for Other Reasons
1 (<1)
3 (3)
4 (2)
3 (5)
CAB LA and RPV LA were both well tolerated resulting in a low discontinuation rate 
due to AEs, including injection site reaction (ISR) related AEs, with no significant trends 
in safety parameters in either the Q8W or Q4W dosing regimens.
Due to the increased Snapshot failure rate at Week 48 for the Q8W Arm, a Q4W dosing 
strategy was selected for further evaluation in Phase 3.  To allow some flexibility, with 
the exception of Week 8 and Week 12, a one-week window (on each side) around the 4-
weekly dosing regimen can be allowed following Week 12 (third injection), without 
anticipated impact on the safety or efficacy of the regimen.  For Week 8 and Week 12, 
there is only a minus one week window such that injections should be administered no 
later than Week 8 and Week 12.  
For CAB LA, steady-state mean CAB pre-dose concentrations following Q4W dosing 
remain between the oral CAB 10 mg and 30 mg once daily mean trough concentrations, 
which were both doses found to be safe and efficacious in the LATTE study.  For RPV 
LA, steady-state mean RPV pre-dose concentrations following Q4W dosing are 
comparable with the range of exposures following oral RPV 25 mg once daily observed 
to be safe and efficacious in pivotal Phase 3 studies.  Maintenance Phase PK data in 
LATTE 2 are summarized for both regimens of CAB LA (Table 3, Figure 2) and RPV 
LA (Table 4, Figure 3).

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Table 3
Summary of Observed PK Parameters following Repeat Dose 
Administration of Cabotegravir LA to HIV-infected Participants 
(LATTE-2)
Cohort
Plasma CAB PK Parametera
AUC(0-)b
(g.h/mL)
Cmaxc
(g/mL)
Individual 
Average C0d
(g/mL)
tmaxe
(d)
Week 24
Week 40
Week 24
Week 40
Week 24
Week 40
Week 24
Week 40
Q4W
(n=115)
1858
(1719, 2007)
[37]
2017 
(1847, 2203)
[41]
3.50 
(3.2, 3.8)
[39]
3.50  
(3.3, 3.8)
[37]
2.35
(2.2, 2.5)
[32]
2.56  
(2.4, 2.7)
[32]
6.9
(0 – 29)
6.9 
(0 – 28)
Q8W
(n=115)
3037
  (2786, 3310)
[42]
3027 
(2762, 3322)
[47]
3.55
(3.2, 3.9)
[56]
3.33 
(3.1, 3.6)
[47]
1.43
(1.3, 1.6)
[54]
1.49 
(1.4, 1.6)
[42]
6.9 
(0 – 59)
7.0 
(0 –  57)
Oral)f
(n=50)
------
------
------
------
4.51
(4.1, 5.0)
[37]
4.54 
(4.1, 5.0)
[38]
------
------
a.
Geometric mean (95% CI) [CVb%]
b.
AUC(0-) = AUC(Week 24 to Week 28) for Q4W regimen (n=84), and AUC(Week 24 to Week 32) for Q8W 
regimen (n=86) or AUC(Week40 to Week 44) for Q4W  (n=80) and AUC(Week40 to Week 48) for Q8W 
regimen (n=93)
c.
Cmax:  Q4W:   between Week 24 and Week 28 (n=97)  or Week 40 and  Week 44 (n=95);  Q8W:  between 
Week 24 to Week 32 (n=98) or Week 40 and Week 48 (n=104)
d.
Individual Average C0 W24 observed using troughs at Week 20, Week 24, Week 28 and Week 32 for the 
Q4W arm (n=108) and at Week 24, and Week 32 for Q8W arm (n=100) and Individual Average C0 W40 
using troughs at W40, 44, and 48 for Q4W (n=98) and W16, 24, 32, 40 and 48 for Q8W (n=112)
e.
Tmax presented as median (range) in days, (Week 24-32:  n=97 Q4W arm, n=98, Q8W arm; Week 40- 48:  
n=95 Q4W, n=104 Q8W)
f.
Oral comparator arm combined troughs at Day 1, predose and at Week 32 Week 48.

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Figure 2
Mean (SD) Observed Concentration-Time Data following CAB LA 
Q8W and Q4W and C(following 30mg Oral Once Dailya) through 
Week 48 (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)
a)
Oral CAB 30 mg once daily administered for four weeks prior to first injection.

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Table 4
Summary of Observed RPV PK Parameters following Repeat Dose 
Administration of Rilpivirine LA to HIV-infected Participants (LATTE-
2)
Cohort
Plasma RPV PK Parametera
AUC(0-)b
(ng.h/mL)
Cmaxc
(ng/mL)
Individual Average 
C0d
(ng/mL)
tmaxe
(d)
Week 24
Week 40
Week 24
Week 40
Week 24
Week 40
Week 
24
Week 
40
Q4W 
(n=115)
61309 
(56724, 66264)
[37]
71106
(65354,  77366)
[39]
103 
(94, 114)
[49]
127
(118, 136)
[36]
77.2 
(72, 83)
[35]
92.1 
(87, 98)
[32]
6.99
(0-29)
6 0.
(0-28)
Q8W 
(n=115)
96196 
(87286, 
106015)
[48]
116160 
(108189,  124719)
[35]
104
(95, 114)
[47]
121
(111, 
131)[42]
49.3 
(46, 53)
[41]
63.2  
(59,  68)
[35]
7.00
(0-57)
6 0.
(0-59)
a.
Geometric mean (95% CI) [Cvb%]
b.
AUC(0-) = AUC(Week 24-Week 28) for Q4W regimen (n=84), and AUC(Week 24-Week 32) for Q8W 
regimen (n=86) or AUC(Week40 to Week 44) for Q4W  (n=80) and AUC(Week40 to Week 48) for Q8W 
regimen (n=92) via non-compartmental PK analysis
c.
Cmax:  Q4W:   between Week 24 and Week 28 (n=96)  or Week 40 and  Week 44 (n=94);  Q8W:  between 
Week 24 to Week 32 (n=97) or Week 40 and Week 48 (n=104)
d.
Individual Average C0 W24 observed using troughs at  Week 24, Week 28 and Week 32 for the Q4W arm 
(n=104) and at Week 24, and Week 32 for Q8W arm (n=101); Individual Average C0 W40 using troughs at W 
36, 40, 44, and 48 for Q4W (n=102) and W40 and 48 for Q8W (n=100)
e.
Tmax presented as median (range), (Week 24-32: :n=96 Q4W arm, n=97 Q8W arm; Week 40- 48:  n=94 
Q4W, n=104 Q8W)

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Figure 3
Mean (SD) Observed Concentration-Time Data following RPV LA 
Q8W and Q4W through Week 48 and Day 1 C(following RPV 25mg 
Oral Once Dailya)  (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)
a)
Oral RPV 25 mg once daily administered for four weeks prior to first injection.
The Q4W dosing schedule for both CAB LA and RPV LA has been optimized for the 
present study.  In LATTE-2, the Q4W dosing regimen for CAB LA included a 1st dose of 
800 mg (two 2mL injections) at Day 1, followed by 400 mg IM Q4W starting at Week 4.  
For RPV LA in LATTE-2, the Q4W treatment arm was 600mg IM Q4W from Day 1.  
This specific schedule from the LATTE-2 Q4W dosing regimens for both compounds 
was modified for Phase 3 to align dosing for both compounds and minimize the number 
of injections needed.  Both observed and model predicted CAB concentrations indicated 
that the loading dose strategy could be optimized while maintaining plasma 
concentrations during the early phase at levels associated with good efficacy and safety; 
i.e. by lowering the first CAB LA loading dose from 800 mg to 600 mg.  This change 
reduces the number of injections to a single 3-mL injection for the first CAB LA 
injection (Week 4b in this protocol).  For RPV LA, modeling and simulation indicates 
that a 900 mg IM loading dose (one 3 mL injection) on Day 1 rather than a 600mg IM 
first dose brings RPV plasma concentrations closer to steady-state values during the early 
phase.  The dosing schedule in the protocol includes a 4 week oral lead-in beginning at 
Day 1.  Therefore, the timing in the Time and Events Table translates to the following:  
Day 1, Week 4, and Q8W thereafter = Study Week 4b, and Q4W thereafter, respectively. 

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In summary, a modified Q4W dosing regimen that aligns the dosing of CAB LA + RPV 
LA to one injection of each compound at each visit was selected for Phase 3.  The first 
injections of CAB LA and RPV LA will be administered as 3mL each, at doses of 600 
mg and 900 mg, respectively.  Subsequent injections of CAB LA and RPV LA will be 
2mL each, at doses of 400 mg and 600 mg, respectively (see also Section 4.7.3). 
4.7.3.
Modeling and Dose Simulations for CAB LA and RPV LA
Modeling and simulation was used to provide confidence in the selected regimen, inform 
the injection loading dose strategy, flexibility around dosing windows and the use of the 
oral bridging strategy.  
4.7.3.1.
CAB LA
For CAB LA, the model included data from 416 participants who received CAB LA IM 
as single or repeat administration, with approximately 50% of data obtained from  
200056 (LATTE-2), ~20% from study 201120 (CAB LA pre-exposure prophylaxis 
[PrEP] study, GlaxoSmithKline Document Number 2015N229664_00) and ~30% from 
Phase 1 studies).  The simulation of the predicted median (90% prediction interval [PI]) 
CAB concentration-time profile based on the population PK model is shown in Figure 4.  
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 the - Protein adjusted 90% inhibitory concentration (PA-IC90), 
and 88% are predicted to achieve trough concentrations above the geometric mean trough 
following the 10mg oral dose in LATTE of 1.35g/mL (8-fold PA-IC90).  

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Figure 4
Simulated* Median (90% Prediction Interval [PI]) CAB Plasma 
Concentrations versus Time for the CAB LA Q4W Regimen (600 mg 
IM Day 1, then 400mg IM Q4W)^
Medium dashed line at 1.35g/mL corresponds to the geometric mean Ctrough following oral CAB 10mg 
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.
*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 4b 
study visit); Week 4 = second injections (Week 8 study visit)
At steady state, a one week delay in dosing of the Q4W regimen results in an 
approximately 15% reduction in median C.  With this delay, 95% are predicted to 
remain above 4x PA-IC90, and 79% are predicted to remain above the 10mg oral target 
(Figure 5).  Simulations including delays greater than one week have been explored (not 
shown), with <70% of subjects remaining above the 10mg oral target. Therefore, a 1-
week delay is the maximum allowed per the protocol.  

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Figure 5
Impact of a 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 CAB LA Q4W regimen (600mg 
IM Day 1, then 400mg IM Q4W thereafter)^
Medium dashed line at 1.35g/mL corresponds to the geometric mean Cfollowing oral CAB 10mg 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.
*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 4b 
study visit); Week 4 = second injections (Week 8 study visit)
4.7.3.2.
RPV LA
The 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 6).  With this regimen, >99% of participants remain above the 
5th percentile of steady state trough values following oral RPV 25mg (corresponding to 
2x the PA-IC90).  With a loading dose of 900 mg RPV LA on Day 1, the anticipated 

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median RPV Cat Week 4 is 42 ng/mL, with >98% of participants above the RPV PA-
IC90.
Figure 6
Simulated* Median (90% PI) RPV Plasma Concentrations versus 
Time Profile for the RPV LA Q4W regimen (900 mg IM Day 1, then 
600mg IM Q4Wa 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 4b study visit); Week 4 = second injections (Week 8 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).  Dotted lines 
correspond to 5th and 95th percentile of oral Cfollowing oral RPV 25 mg once daily; 5th percentile (26.5 ng/mL) 
corresponds to 2x the PA-IC90 for RPV (2x 12 ng/mL)
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 25mg (Figure 7).  
This supports allowance of some flexibility in the dosing regimen.

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Figure 7
Impact of 1-week Delay in Dosing at Steady State (Week 40 delayed 
to Week 41) on Simulated* Median (90% PI) RPV Plasma 
Concentrations versus Time for 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 4b study visit); 
Week 4 = second injections (Week 8 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)

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4.8.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with oral 
and CAB LA or RPV LA can be found in the Investigator’s Brochures (GlaxoSmithKline 
Document Number RH2009/00003/06, 2015; RPV IB, 2017).
Oral RPV is an approved medicinal product and detailed information on its benefit/risk 
profile together with any risk mitigation measures are described in product labeling 
(Edurant®, 2015).  Current ART administered in this protocol have 2 NRTIs plus INI, 
NNRTI or PI as the third agent. Current ART are established antiretroviral treatments that 
have been in clinical use for several years and have well established benefit/risk profiles 
described in detail in their respective product labels.  
The following section outlines the risk assessment and mitigation strategy for this 
protocol:  
4.8.1.
Risk Assessment
Oral CAB and CAB LA (GSK1265744/GSK1265744 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.

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Potential Risk of 
Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
Drug Induced Liver 
Injury (DILIs)
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 Alanine 
aminotransferase (ALT) elevation).  
In some of these participants’ 
transient transaminitis were 
explained by acute hepatitis C 
infection whilst a small number of 
others did not have alternative 
explanations, suggesting a mild 
form of Drug induced liver injury 
(DILI) 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 IM or Placebo IM 
administration.  

Exclusion criteria as described in 
Section 5.2 will prohibit 
participants with significant liver 
impairment based on screening 
liver chemistry including 
transaminases (ALT and Aspartate 
aminotransferase [AST]) as well 
on prior medical history. 
Participants with a history of 
chronic liver disease with ongoing 
inflammation and/or fibrosis will 
have additional confirmatory 
assessments to confirm suitability 
for entry into the study. 

A 4-week oral lead- in Phase is 
being implemented in this study, 
where all participants will receive 
oral CAB prior to the 
administration of IM CAB to 
determine individual safety and 
tolerability 

Liver transaminases (ALT and 
AST) 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 5.5.1.1 of this protocol. 
Participants will be withdrawn 
from CAB treatment where no 
compelling alternative cause is 
identified and DILI is suspected.

Participants who develop ALT ≥3 
times the upper limit of normal 
(ULN) while on study must 
consult with Medical Monitor 
prior to initiation or continuation 
of CAB LA + RPV LA.  
Injection Site 
Reactions (ISRs)
Clinical, experience to date has 
demonstrated ISRs occur in the 
majority of exposed participants 
treated with CAB LA but are 
generally mild (Grade 1) or 
moderate (Grade 2) and include 
events of pain, tenderness, 
erythema, or nodule formation of 
several days duration (median 
duration for individual events <1 
week). ISRs may occur more than 
once in an individual participant 

Administration advice will be 
given to minimize risk of poor 
administration technique giving 
rise to injection site reactions. 
Advice on care, monitoring, 
natural course, and treatment of 
ISRs is given in study 
documentation 

Advice will be given to 
participants on care of injection 
site on day/days immediately post 

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Potential Risk of 
Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
receiving multiple injections. 
Although some Grade 3 ISRs were
reported, overall ISRs have been 
well tolerated and have not to date 
been associated with an excess of 
participants’ withdrawal.
None of the ISRs reported to date 
was serious and no clinically 
significant complications were 
reported
administration, use of analgesia, 
compresses where appropriate.

Participants will be closely 
monitored for ISRs particularly 
for signs of pain, tenderness, 
infections, erythema, swelling, 
induration, or nodules 
(granulomas or cysts) throughout 
the study. 

Complications of ISRs such as 
infections (abscess, cellulitis) and 
collections of  fluid requiring 
drainage will be monitored 

Significant ISRs may be 
photographed and referred to a 
dermatologist for specialist
advice.
Hypersensitivity 
Reactions (HSR)
Hypersensitivity reactions have 
been reported as uncommon 
occurrences with integrase 
inhibitors, including the closely 
related compound dolutegravir, and 
were characterized by rash, 
constitutional findings, and 
sometimes, organ dysfunction, 
including liver injury. 
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 
IM CAB. The long exposures 
anticipated after IM CAB injection 
may complicate the management of 
a drug hypersensitivity reaction, 
were it to occur.

The risk of developing a 
hypersensitivity reaction post 
administration of IM CAB will be 
minimized by the use of a 4-week 
oral lead-in of oral CAB to 
determine individual safety and 
tolerability prior to the 
introduction of IM CAB. 

Clinical assessments, laboratory 
tests (including liver 
transaminases) and vital signs will 
be performed throughout this 
study (refer to Time & Events 
Table, Section 7.1). Results from 
these assessments may aid early 
detection of HSR. 

Oral CAB will be withdrawn 
immediately for cases with 
suspected HSR during the oral 
CAB lead-in phase and would not 
proceed to the injection phase. 
Participants in the injection phase 
would not receive further 
injections.  During oral and IM 
CAB treatment, any HSR 
reactions that occur would be 
managed supportively.
Development of 
Resistance following 
Residual concentrations of CAB 
would remain in the systemic 

Alternative oral HAART 
regimens will be prescribed within 

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Potential Risk of 
Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
discontinuation of 
CAB LA
circulation of participants who 
stopped CAB LA treatment for 
prolonged periods (more than 1 
year, in some subjects, 
GlaxoSmithKline Document 
Number 2016N269422_00) 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. 
4 weeks after participants stop 
CAB LA.  This would be 
anticipated to result in rapid 
resuppression of HIV-1 RNA thus 
minimizing the risk of emergent 
resistance

The participants in this study who 
discontinue IM CAB for any 
reason will be monitored for a 
minimum of 52 weeks from the 
time of the last IM CAB injection.
Drug-Drug 
Interactions (DDIs)
For a complete listing of permitted 
and prohibited concurrent 
medications for CAB and CAB 
LA, refer to Section 6.13
CAB and CAB LA should not be 
co-administered with the following 
medicinal products, as significant 
decreases in CAB plasma 
concentrations may occur (due to 
UGT enzyme induction), which 
may result in loss of therapeutic 
effect of CAB.
-
the anticonvulsants 
carbamazepine, 
oxcarbazepine, phenobarbital, 
phenytoin
-
the antimycobacterials 
rifampicin, rifapentine, 
rifabutin
-
St John’s wort (Hypericum 
perforatum).
Chronic use of oral glucocorticoids 
must be avoided; however, short 
treatment courses (for example, 21 
days or less) and topical, inhaled or 
intranasal use of glucocorticoids 
will be allowed.
Oral CAB administration only:  
Antacid products containing 
divalent cations (e.g., aluminium, 
calcium and magnesium) must be 
taken at least 2 hours before or at 

All participants will be informed 
of prohibited medications 
throughout the study and updates 
provided as needed via the 
informed consent.

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Potential Risk of 
Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
least 4 hours after CAB
Participants discontinuing a LA 
regimen may be at risk for 
developing DDIs many weeks after 
discontinuing injectable therapy.  
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 LA are 
currently unknown.  HIV-1 viral 
suppression may not be effective 
following accidental 
maladministration.
CAB

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 post 
dose  electrocardiogram (ECG) , 
vital signs, or any other supportive 
testing may be obtained at the 
discretion of the investigator, and 
the medical monitor will be 
notified.  

Laboratory samples for safety 
parameters and HIV-1 RNA will 
be closely monitored in all 
participants.  Additionally, 2 hour 
post dose PK samples will be 
obtained at a few early timepoints 
for determination of CAB 
concentration and possible 
pharmacokinetic correlation with 
safety parameters such as ECG 
changes and virologic response.  
Additionally, an unscheduled PK 
sample may be drawn 
approximately 2 hours post dosing 
for future evaluation of CAB 
concentrations.
ORAL RPV
For safety and risk mitigation for oral RPV refer to the RPV local prescribing information 
[Edurant ® Product Information, 2015].  
RPV LA 
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

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Potential Risk of 
Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
Injection Site 
Reactions
Clinical, experience to date has 
demonstrated ISRs occur in the 
majority of exposed participants 
treated with RPV LA but are 
generally mild (Grade 1) or 
moderate (Grade 2) and include 
events of pain, tenderness, 
erythema, or nodule formation of 
several days duration (median 
duration for individual events <1 
week). ISRs may occur more than 
once in an individual participant 
receiving multiple injections. 
Although some Grade 3 ISRs were 
reported, overall ISRs have been 
well tolerated and have not to date 
been associated with an excess of 
participants’ withdrawal due to 
ISRs.
None of the ISRs was serious and 
no clinical significant 
complications were reported

Administration advice to 
minimize risk of poor 
administration technique giving 
rise to injection site reactions. 
Advice on care, monitoring, 
natural course, and treatment of 
ISRs given in study 
documentation 

Advice to participants on care of 
injection site on day/days
immediately post administration, 
use of analgesia, compresses 
where appropriate.

Participants will be closely 
monitored for ISRs particularly 
for signs of pain, tenderness, 
infections, erythema, swelling, 
induration, or nodules 
(granulomas or cysts) throughout 
the study. 

Complications of ISRs such as 
infections (abscess, cellulitis) and 
collections of  fluid requiring 
drainage will be monitored 

Significant ISRs may be 
photographed and referred to a 
dermatologist for specialist 
advice.
Rash
Some observations of rash with 
oral RPV have been reported in 
clinical studies executed to date 
(the majority are Grade 1 or 2). 
Severe skin and hypersensitivity 
reactions have been reported 
during the postmarketing 
experience, including cases of 
Drug Reaction with Eosinophilia 
and Systemic Symptoms (DRESS), 
with oral RPV containing 
regimens. While some skin 
reactions were accompanied by 
constitutional symptoms such as 
fever, other skin reactions were 
associated with organ dysfunctions, 
including elevations in hepatic 
serum biochemistries.

In this study, RPV LA 
administration will be preceded by 
an oral RPV lead in to evaluate 
safety and tolerability in 
individual participants.

Participants with a grade 1 or 2 
rash will be allowed to continue 
treatment or to be rechallenged, 
depending on the clinical 
judgment of the investigator.

All participants experiencing a 
grade 3 or 4 rash should 
discontinue their ARV medication 
(study medication and background 
regimen) and be withdrawn from 
the study.

All rash events should be assessed 

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Potential Risk of 
Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
with special attention to systemic 
symptoms, laboratory 
abnormalities, or mucosal 
involvement. Close clinical 
follow-up, including follow-up of 
laboratory abnormalities, and 
appropriate medical intervention, 
including referral to dermatologist 
as appropriate, should be 
instituted for these events; daily 
follow-up is recommended for 5 
days from the onset of the event to 
monitor for progression of the 
event.  See Section 7.4.4.13 for 
additional guidance on 
management of rash events.
Development of 
Resistance
Residual concentrations of RPV 
LA can remain in the systemic 
circulation of participants who 
stopped treatment (e.g., for 
tolerability issues or treatment 
failure) for prolonged periods 
(months to more than a year, in 
some subjects, McGowan, 2016).
Participants discontinuing a LA 
regimen may be at risk for 
developing resistance to RPV 
many weeks after discontinuing 
injectable therapy.

Alternative oral HAART 
regimens will be prescribed within 
4 weeks after participants stop 
RPV LA.  This would be 
anticipated to result in rapid 
resuppression of HIV-1 RNA thus 
minimizing the risk of emergent 
resistance

The Sponsor will continue to 
monitor participants 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)
For a complete listing of permitted 
and prohibited concurrent 
medications for RPV and RPV LA, 
refer to Section 6.13
RPV LA should not be co-
administered with the following 
medicinal products, as significant 
decreases in RPV plasma 
concentrations may occur (due to 
CYP3A enzyme induction), which 
may result in loss of therapeutic 
effect of RPV LA.
-
the anticonvulsants 
carbamazepine, 
oxcarbazepine, phenobarbital, 
phenytoin
-
the antimycobacterials 

All participants will be informed 
of prohibited medications 
throughout the study and updates 
provided as needed via informed 
consent.

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Potential Risk of 
Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
rifampicin, rifapentine, 
rifabutin
-
the glucocorticoid systemic 
dexamethasone, except as a 
single dose treatment
-
St John’s wort (Hypericum 
perforatum).
Of note, evidence to date indicates 
that clinically relevant DDIs with 
RPV LA and other antiretrovirals 
are unlikely to occur. 
Oral RPV 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 RPV.
-
H2-antagonists must be taken 
at least 12 hours before or at 
least 4 hours after taking RPV.
-
RPV should not be co-
administered with proton 
pump inhibitors, such as 
esomeprazole, lansoprazole, 
omeprazole, pantoprazole, 
rabeprazole;

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Potential Risk of 
Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
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.  This could 
be due to administrator error, 
improper injection technique and / 
or improper needle length used 
based on body type.  
Accidental intravenous 
administration may result in 
overdose shortly after injection. In 
general, no cases of overdosage 
with RPV have been described to 
date.  In addition, HIV-1 viral 
suppression may not be effective 
following accidental 
maladministration.

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),  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 
participants.  Additionally, 2 hour 
post dose PK samples will be 
obtained at a few early timepoints 
for determination of 
RPVconcentration and possible 
pharmacokinetic correlation with 
safety parameters such as ECG 
changes and virologic response. 
Additionally, an unscheduled PK 
sample may be drawn 
approximately 2 hours post dosing 
for future evaluation of CAB and 
RPV concentrations.
Study Procedures
Risks of ECG pad 
removal
Participants will be required to 
have ECG tracings recorded 
periodically throughout the study

Some discomfort and rash may 
occur where the ECG pads are 
removed.
Other 
Risk of Treatment 
Failure
This study employs a novel 
maintenance approach to the 
treatment of HIV-1 infection. 
Following viral suppression, 
participants will be transitioned off 
of a 3 drug ART regimen to a 2 
drug LA ART regimen that 
remains experimental.  Although 
both IM CAB and RPV have 
demonstrated antiviral activity in 
large clinical studies and the two 
drug combination has demonstrated 
antiviral activity in study 
Viral loads 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.  
HIV-1 RNA viral loads will be closely 

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Potential Risk of 
Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
LAI116482, the risk of virologic 
failure in study 200056 is 
unknown.  
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.  
Due to administration error, it is 
possible that a participant 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.  
monitored throughout the injection period 
of the study. 
4.8.1.1.
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 Brochures (GSK Document number 
RH2009/00003/06 [CAB IB], RPV IB, 2017).  
Adverse Events of Special Interest:
Seizure
Three cases of seizures have occurred in the cabotegravir programme cumulatively 
through 15 May 2016. Two of the cases occurred in HIV uninfected subjects with a prior 
history of seizure and one case involved a subject in study 200056 with circumstantial 
and anecdotal evidence of illicit drug use. Overall, there is not convincing evidence that 
cabotegravir 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 are considered as AEs of special 
interest for close monitoring in future studies. Subjects with recent history of, or recent 
treatment for, seizure will be excluded from study participation.

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4.8.2.
Benefit Assessment
The antiviral activity against HIV-1 of CAB has been well established through Phase 2a 
and Phase 2b studies. RPV is an established antiviral agent against HIV-1 in treatment 
naive patients, with long term durability (>96 weeks in Phase 3 and >240 weeks in Phase 
IIb).
Participants receiving CAB LA + RPV LA are anticipated to benefit from maintenance of 
virological suppression using LA agents. Participants randomized to an arm containing 
CAB LA+ RPV LA will have Q4 weekly dosing without the need to take concomitant 
daily oral therapy.  Adherence in these participants is expected to be improved and will 
be directly observed during IM injections. 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 IM agents, has been demonstrated through Week 48 
of the ongoing 200056 study. The reduction in ART, and the discontinuation of NRTIs, 
may offer long term safety and tolerability benefits in these participants.
4.8.3.
Overall Benefit:Risk Conclusion
Taking into account the measures taken to minimize risk to participants participating in 
this study, the potential risks identified in association with CAB LA and RPV LA and the 
study as a whole are justified by the anticipated benefits that may be afforded to 
treatment-experienced patients with HIV-1 infection.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the investigational regimen or other study treatment 
that may impact participant eligibility is provided in the current Investigator’s Brochures 
(IB) for CAB (GlaxoSmithKline Document Number RH2009/00003/06, 2016) and 
RPV(RPV IB, 2017) and RPV product label.
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
participant safety. Therefore, adherence to the criteria as specified in the protocol is 
essential.
5.1.
Inclusion Criteria
A participant will be eligible for inclusion in this study only if all of the following criteria 
apply:

Be able to understand and comply with protocol requirements, instructions, and 
restrictions;

Understand the long term commitment to the study and be likely to complete the 
study as planned;

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
Be considered appropriate candidates for participation in an investigative clinical trial 
with oral and intramuscularly injectable medications (e.g., no active substance use 
disorder, acute major organ disease, or planned long-term work assignments out of 
the country, etc.).  
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 participants, taking into consideration any local treatment 
practices or guidelines and good clinical practice (GCP).  All participants must be 
considered appropriate candidates for 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.  In exceptional circumstances only, if a repeat lab is required because 
a central lab result cannot be generated, local labs can be reviewed and approved by the 
Medical Monitor for consideration of participant eligibility.  A repeat central lab will be 
submitted concurrently or at the next planned visit.
Source documentation to verify entry criteria must be reviewed by the Principal 
Investigator or designee prior to randomization.  Source documents from other medical 
facilities must be located/received during the 14 day screening phase (or up to 35 days) 
and under no circumstances may the participant be randomized in the absence of source 
documentation. 
Participants eligible for enrolment in the study must meet all of the following criteria:
AGE
1. Aged 18 years or older (or ≥19 where required by local regulatory agencies), at 
the time of signing the informed consent.
TYPE OF PARTICIPANT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Must be on uninterrupted current regimen (either the initial or second ARV 
regimen) for at least 6 months prior to Screening. Any prior switch, defined as a 
change of a single drug or multiple drugs simultaneously, must have occurred due 
to tolerability/safety, access to medications, or convenience/simplification, and 
must NOT have been done for treatment failure (HIV-1 RNA ≥400 c/mL). 
Acceptable stable (initial or second) ARV regimens prior to Screening include 2 
NRTIs plus: 

INI with the exception of ABC/DTG/3TC (either the initial or second 
cART regimen) 

NNRTI (either the initial or second cART regimen)

Boosted PI (or atazanavir [ATV] unboosted) (must be either the initial 
cART regimen or one historical within class switch is permitted due to 
safety/tolerability)
The addition, removal, or switch of a drug(s) that has been used to treat HIV 

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based on antiretroviral properties of the drug constitutes a change in ART with the 
following limited exceptions: 

Historical changes in formulations of ART drugs or booster drugs will not
constitute a change in ART regimen if the data support similar exposures 
and efficacy, and the change must have been at least 3 months prior to 
Screening.

Historical perinatal use of an NRTI when given in addition to an ongoing 
HAART will not be considered a change in ART regimen.

A change in dosing scheme of the same drug from twice daily to once 
daily will not be considered a change in ART regimen if data support 
similar exposures and efficacy.  
3. Documented evidence of at least two plasma HIV-1 RNA measurements <50 
c/mL in the 12 months prior to Screening: one within the 6 to 12 month window, 
and one within 6 months prior to Screening; 
4. Plasma HIV-1 RNA <50 c/mL at Screening; 
SEX
5. A female participant is eligible to participate if she is not pregnant (as confirmed 
by a negative serum human chorionic gonadotrophin (hCG) test at screen and a 
negative urine hCG test at Randomization), not lactating, and at least one of the 
following conditions applies:
a. Non-reproductive potential defined as:

Pre-menopausal females with one of the following:

Documented tubal ligation

Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion

Hysterectomy

Documented Bilateral Oophorectomy

Postmenopausal defined as 12 months of spontaneous amenorrhea [in 
questionable cases a blood sample with simultaneous follicle stimulating 
hormone (FSH) and estradiol levels consistent with menopause (refer to 
laboratory reference ranges for confirmatory levels)]. Females on hormone 
replacement therapy (HRT) and whose menopausal status is in doubt will 
be required to use one of the highly effective contraception methods if 
they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of post-menopausal status prior to 

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study enrolment. 
b. Reproductive potential and agrees to follow one of the options listed in the 
Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of 
Reproductive Potential (FRP) (see Section 12.7.1, Appendix 7) from 30 days prior 
to the first dose of study medication, and until from 30 days prior to the first dose 
of study medication throughout the study, and for at least 30 days after 
discontinuation of all oral study medications and for at least 52 weeks after
discontinuation of CAB LA and RPV LA. 
The investigator is responsible for ensuring that participants understand how to properly 
use these methods of contraception. 
INFORMED CONSENT
Capable of giving signed informed consent as described in Section 10.2, which includes 
compliance with the requirements and restrictions listed in the consent form and in this 
protocol. Eligible participants or their legal guardians (and next of kin when locally 
required), must sign a written Informed Consent Form before any protocol-specified 
assessments are conducted. Enrolment of participants who are unable to provide direct 
informed consent is optional and will be based on local legal/regulatory requirements and 
site feasibility to conduct protocol procedures.
OTHER
Participants enrolled in France must be affiliated to, or a beneficiary of, a social 
security category.  
All participants participating in the study should be counselled on safer sexual practices 
including the use and benefit/risk of effective barrier methods (e.g., male condom) and on 
the risk of HIV transmission to an uninfected partner.
5.2.
Exclusion Criteria
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability, or participant 
safety.  Therefore, adherence to the criteria as specified in the protocol is essential.  A 
participant will not be eligible for inclusion in this study if any of the following criteria 
apply:
Exclusionary Criteria prior to Screening or Day 1
1. Within 6 months prior to Screening and after confirmed suppression to <50 c/mL 
on current ART regimen, any plasma HIV-1 RNA measurement 50 c/mL
2. Within the 6 to 12 month window prior to Screening and after confirmed 
suppression to <50 c/mL, any plasma HIV-1 RNA measurement >200 c/mL, or 
2 or more plasma HIV-1 RNA measurements 50 c/mL
3. Any drug holiday during the window between initiating first HIV ART and 6 

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months prior to Screening, except for brief periods (less than 1 month) where all 
ART was stopped due to tolerability and/or safety concerns
4. Any switch to a second line regimen, defined as change of a single drug or 
multiple drugs simultaneously, due to virologic failure to therapy (defined as a 
confirmed plasma HIV-1 RNA measurement 400 c/mL after initial suppression 
to <50 c/mL while on first line HIV therapy regimen) 
5. Abacavir/dolutegravir/lamivudine, (ABC/DTG/3TC) as current ART regimen
6. A history of use of any regimen consisting of only single NNRTI therapy (even if 
only for peri-partum treatment), or only single or dual NRTI therapy prior to 
starting cART
7. Participants who are currently participating in or anticipate to be selected for any 
other interventional study
Exclusionary medical conditions
8. Women who are pregnant, breastfeeding or plan to become pregnant or breastfeed 
during the study
9.
Any evidence of an active Center for Disease Control and Prevention (CDC) 
Stage 3 disease [CDC, 2014], except cutaneous Kaposi’s sarcoma not requiring 
systemic therapy and historical or current CD4 cell counts less than 200 
cells/mm3
10. Participants with moderate to severe hepatic impairment
11. Any pre-existing physical or mental condition (including substance use disorder) 
which, in the opinion of the Investigator, may interfere with the participant’s 
ability to comply with the dosing schedule and/or protocol evaluations or which 
may compromise the safety of the participant
12. Participants determined by the Investigator to have a high risk of seizures, 
including participants with an unstable or poorly controlled seizure disorder. A 
participant with a prior history of seizure may be considered for enrolment if the 
Investigator believes the risk of seizure recurrence is low.  All cases of prior 
seizure history should be discussed with the Medical Monitor prior to enrolment
13. All participants will be screened for syphilis (rapid plasma reagin [RPR]).  
Participants with untreated syphilis infection, defined as a positive RPR without 
clear documentation of treatment, are excluded. Participants with a serofast RPR 
result (persistence of a reactive nontreponemal syphilis test) despite history of 
adequate therapy and no evidence of re-exposure may enrol after consultation 
with the Medical Monitor. Participants with a positive RPR test who have not 
been treated may be rescreened at least 30 days after completion of antibiotic 
treatment for syphilis
14. Participants who, in the investigator's judgment, pose a significant suicide risk.  
Participant’s recent history of suicidal behavior and/or suicidal ideation should 
be considered when evaluating for suicide risk
15. The participant has a tattoo or other dermatological condition overlying the 

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gluteus region which may interfere with interpretation of injection site reactions
16. Evidence of Hepatitis B virus (HBV) infection based on the results of testing at 
Screening for Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody 
(anti-HBc), Hepatitis B surface antibody (anti-HBs) and HBV DNA as follows:
•Participants positive for HBsAg are excluded;
•Participants negative for anti-HBs but positive for anti-HBc (negative HBsAg 
status) and positive for HBV DNA are excluded
Note: Participants positive for anti-HBc (negative HBsAg status) and positive for 
anti-HBs (past and/or current evidence) are immune to HBV and are not excluded.
17. 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; participants who are anticipated to require HCV 
treatment within 12 months must be excluded.  (HCV treatment on study may be 
permitted post Week 48, following consultation with the medical monitor)
Participants with HCV co-infection will be allowed entry into phase 3 studies if: 
•
Liver enzymes meet entry criteria
•
HCV Disease has undergone appropriate work-up, and is not advanced, 
and will not require treatment prior to the Week 48 visit.  Additional 
information (where available) on participants with HCV co-infection at 
screening should include results from any liver biopsy, Fibroscan, 
ultrasound, or other fibrosis evaluation, history of cirrhosis or other 
decompensated liver disease, prior treatment, and timing/plan for HCV 
treatment.
•
In the event that recent biopsy or imaging data is not available or 
inconclusive, the Fib-4 score will be used to verify eligibility 
•
Fib-4 score > 3.25  is exclusionary 
•
Fib-4 scores 1.45 – 3.25 requires Medical Monitor consultation
Fibrosis 4 Score Formula:
( Age x AST ) / ( Platelets x ( sqr [ ALT ])
18. Unstable liver disease (as defined by any of the following: presence of ascites, 
encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, 
or persistent jaundice or cirrhosis), known biliary abnormalities (with the 
exception of Gilbert's syndrome or asymptomatic gallstones or otherwise stable 
chronic liver disease per investigator assessment)
19. History of liver cirrhosis with or without hepatitis viral co-infection.
20. Ongoing or clinically relevant pancreatitis
21. Clinically significant cardiovascular disease, as defined by history/evidence of 
congestive heart failure, symptomatic arrhythmia, angina/ischemia, coronary 
artery bypass grafting (CABG) surgery or percutaneous transluminal coronary 
angioplasty (PTCA) or any clinically significant cardiac disease
22. Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell 

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carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma, or 
cervical intraepithelial neoplasia; other localized malignancies require 
agreement between the investigator and the Study medical monitor for inclusion 
of the participant prior to randomization
23. Any condition which, in the opinion of the Investigator, may interfere with the 
absorption, distribution, metabolism or excretion of the study drugs or render the 
participant unable to receive study medication
24. 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, participants with a history of sensitivity to heparin or heparin-induced 
thrombocytopenia must not be enrolled
25. Current or anticipated need for chronic anti-coagulation with the exception of 
the use of low dose acetylsalicylic acid (≤325mg)
Exclusionary Laboratory Values or Clinical Assessments at Screening (a single repeat to 
determine eligibility is allowed)
26. Any evidence of primary resistance based on the presence of any major known 
INI or NNRTI resistance-associated mutation, except for K103N, (International 
AIDS Society [IAS]-USA, 2015) by any historical resistance test result.
Note: Prior genotypic resistance testing is not required but if available it must be 
provided to GSK, after screening and before randomization according to 
guidance in the SPM, to provide direct evidence of no pre-existing exclusionary 
resistance mutations. You must wait for the study virologists to confirm the lack 
of exclusionary resistance mutations, which will be provided before the 
screening window closes. Details regarding baseline or prior resistance data 
must be noted in the source documentation
27. Any verified Grade 4 laboratory abnormality. A single repeat test is allowed
during the Screening phase to verify a result 
28. Any acute laboratory abnormality at Screening, which, in the opinion of the 
investigator, would preclude the participant’s participation in the study of an 
investigational compound
29. Participant has estimated creatine clearance <50mL/min per 1.73m2 via CKD-
EPI Method
30. Alanine aminotransferase (ALT) 3 × ULN
Concomitant Medications
31. Exposure to an experimental drug or experimental vaccine within either 30 days, 
5 half-lives of the test agent, or twice the duration of the biological effect of the 
test agent, whichever is longer, prior to Day 1 of this study;
32. Treatment with any of the following agents within 28 days of Screening:

radiation therapy; 

cytotoxic chemotherapeutic agents; 

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
tuberculosis therapy with the exception of isoniazid (isonicotinylhydrazid, 
INH);

anti-coagulation agents;

Immunomodulators that alter immune responses such as chronic systemic 
corticosteroids, interleukins, or interferons. Note: Participants using short-
term (e.g. ≤21 days) systemic corticosteroid treatment; topical, inhaled and 
intranasal corticosteroids are eligible for enrolment. 
33. Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of 
Screening
34. Treatment with any agent, except recognized ART as allowed above, with 
documented activity against HIV-1 within 28 days of study Day 1
35. Use of medications which are associated with Torsade de Pointes. (See SPM for 
a list of relevant medications)
36. Current or prior history of etravirine (ETR) use
37. Current use of tipranavir/ritonavir or fosamprenavir/ritonavir
38. Participants receiving any prohibited medication listed in Section 6.13.2 and 
who are unwilling or unable to switch to an alternate medication. Note: Any 
prohibited medications listed in Section 6.13.2 that decrease CAB or RPV 
concentrations should be discontinued for a minimum of four weeks or a 
minimum of three half-lives (whichever is longer) prior to the first dose and any 
other prohibited medications should be discontinued for a minimum of two 
weeks or a minimum of three half-lives (whichever is longer) prior to the first 
dose (see Section 6.13.2 for details of prohibited medications)
5.3.
Additional Eligibility Criteria
To assess any potential impact on participant eligibility with regard to safety, the 
investigator must refer to the 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 
study drugs.
Notwithstanding these minimum inclusion and exclusion criteria, investigators must 
also follow country specific guidelines where they exist when making decisions about 
participants who are eligible for study participation.
5.4.
Screening/Baseline/Run-in Failures
Screen failures are defined as participants who consent to participate in the clinical trial 
but are never subsequently randomized. In order to ensure transparent reporting of screen 
failure participants, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and Serious Adverse Events (see Section 7.4.3.2).

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A single repeat of a procedure / lab parameter is allowed to determine eligibility (unless 
otherwise specified).
Participants are allowed to re-screen for this study one time.  This will require a new 
participant number.
5.5.
Withdrawal/Stopping Criteria
Participants permanently discontinuing study treatments prior to the Week 52 visit are 
considered to be withdrawn from the study treatments.  Participants who enter the 
Extension Phase but permanently discontinue participation in the Extension Phase prior 
to commercially available CAB LA + RPV LA are considered to be withdrawn from the 
study treatments but are not considered to be withdrawn from the study because they will 
enter the follow Follow-up Phase. 
A participant may withdraw consent and discontinue participation in this study at any 
time at his/her own request. The investigator may also, at his or her discretion, 
discontinue the participant from participating in this study at any time (e.g., safety, 
behavioural or administrative reasons).  If a participant withdraws from the study, he/she 
may request destruction of any samples taken, and the investigator must document this in 
the site study records. Withdrawn participants will not be replaced.  
All participants who discontinue prematurely from the study, irrespective of arm, will be 
asked for additional information to establish the reason for withdrawal.
Participants are not obligated to state the reason for withdrawal.  However, the reasons 
for withdrawal, or failure to provide a reason, must be documented by the Investigator on 
the Completion/Withdrawal section of the electronic case report form (eCRF). Every 
effort should be made by the Investigator to follow-up participants who withdraw from 
the study. 
Participants may have a temporary interruption to their study treatment for management 
of toxicities.
Participants may be prematurely discontinued from the study for any of the 
following reasons:

Adverse event / Serious adverse event

Protocol deviation

Intolerability of injections

Participant lost to follow-up

Participant or Investigator non-compliance;

Termination of the study by the Sponsor

At the request of the participant, Investigator, GSK or ViiV Healthcare;

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
The participant requires concurrent prohibited medications during the course of 
the study. The participant may remain in the study if in the opinion of the 
Investigator and the medical monitor; such medication will not interfere with the 
conduct or interpretation of the study or compromise the safety of the participant.
Participants must be discontinued from the study for any of the following reasons:

Participants who are not eligible to continue into the Maintenance Phase.

Participants who are not eligible, or do not wish to continue on to the Extension 
Phase.

Virologic withdrawal criteria as specified in Section 5.5.4 are met;

For participants in the current ART arm during the Maintenance Phase, plasma 
HIV-1 RNA 50 c/mL at Week 48 with a confirmatory retest;

Participant requires substitution or dose modification of current ART; 

Participant requires substitution or dose reduction of CAB LA or RPV LA (oral 
bridging supply and potential for a second loading dose may be permissable 
following discussion with the Medical Monitor).

Liver toxicity where stopping criteria are met and no compelling alternate cause is 
identified (see Section 5.5.1);

Renal toxicity are met and no compelling alternate cause is identified;

QT interval (QTc) interval > 550 msec from three or more tracings separated by at 
least 5 minutes and considered causally related to IP.  

Grade 4 clinical AE considered causally related to study drug; 

Participant has a Grade 3 or higher rash or Grade 2 rash with evidence of systemic 
involvement and no compelling alternative cause is identified

Pregnancy (intrauterine), regardless of termination status of pregnancy. 

Participant withdrew consent
Efficacy data for participants 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 
participants who complete the study.
Safety data for all participants who receive any amount of study drug, including 
participants who withdraw from the study, will be included in evaluations of safety.
If a participant is prematurely or permanently withdrawn from the study, the procedures 
described in the Time and Events Table for the in-clinic Withdrawal visit are to be 
performed.  An in-clinic Follow-Up visit will be conducted 4 weeks after the last dose of 
study medication for participants with ongoing AEs, and serious adverse events (SAEs) 

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related & not related to study drug and also any laboratory abnormalities that are 
considered to be AEs or potentially harmful to the participant, at the last on-study visit. 
All data from the Withdrawal visit will be recorded, as they comprise an essential 
evaluation that should be done prior to discharging any participant from the study.
The following actions must be taken in relation to a participant who fails to attend the 
clinic for a required study visit:

The site must attempt to contact the participant and re-schedule the missed visit as 
soon as possible. 

The site must counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study. 

In cases where the participant is deemed ‘lost to follow up’, the investigator or 
designee must make every effort to regain contact with the participant (where 
possible, 3 telephone calls and if necessary a certified letter to the participant’s 
last known mailing address or local equivalent methods). These contact attempts 
should be documented in the participant’s medical record. 

Should the participant continue to be unreachable, only then will he/she be 
considered to have withdrawn from the study with a primary reason of “Lost to 
Follow-up”. 
A participant may withdraw from study treatment at any time at his/her own request, or 
may be withdrawn at any time at the discretion of the investigator for safety, behavioural 
or administrative reasons. If a participant withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records. 
5.5.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
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, sites should evaluate the presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver 
injury.  If testing is unavailable and a participant meets the criterion of total 
bilirubin 2xULN, then the event meets liver stopping criteria.

ALT 8xULN.

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
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.
See Section 5.5.1.1 for Participant Management and Follow-Up.
5.5.1.1.
Liver Chemistry Stopping Criteria, Participant Management and Follow-
Up
Participants 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 criteria is met, do the following:

Immediately hold IP.  If on LA therapy, do not administer another injection 
until approval is received from the ViiV Safety and Labelling Committee.

Report the event to the Medical Monitor within 24 hours of learning its 
occurrence (Section 7.4.3.4).

Complete the liver event eCRF and SAE eCRF, where applicable, (see Section 
7.4.3.4)

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 
participant until liver chemistries resolve, stabilize, or return to Baseline values as
described below.

Make every reasonable attempt to have participants 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 participants 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 immunoglobulin M (IgM) antibody;
o
Hepatitis B surface antigen (HBsAg) and Hepatitis B Core Antibody (IgM);

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o
Hepatitis C RNA;
o
Hepatitis E IgM antibody;
o
Cytomegalovirus IgM antibody;
o
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 participant’s 
best approximation.  If the date/time of the last dose cannot be approximated OR 
a PK sample cannot be collected in the time period indicated above, do not 
obtain a PK sample.  Instructions for sample handling and shipping are in the 
SPM.

Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH);

Fractionated 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, and quantitative total immunoglobulin G (IgG or 
gamma globulins);

Liver imaging (ultrasound, magnetic resonance, or computerized tomography) 
and/or liver biopsy to evaluate liver disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.

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.
5.5.1.2.
Liver Event Adjudication Committee
A liver safety panel will be used to evaluate all participants who meet liver stopping 
criteria.  Uniform sets of data and standards for adjudication will be applied across cases 
to inform outcomes.  Full details of the analysis, timing, and the decision criteria will be 
pre-specified in an Adjudication Committee Charter. 

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5.5.1.3.
Liver Chemistry Stopping Criteria – Restart/Rechallenge
Participants 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 12.3, Appendix 3) must 
be followed.
5.5.1.3.1.
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 participant 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 participant 
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 participant 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.

Participants 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.  If protocol defined stopping criteria for liver chemistry 
elevations are met, study drug must be stopped.
5.5.1.3.2.
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/redosing of drug is approved by the VSLC in writing, the participant 
must be provided with a clear description of the possible benefits and risks of 
drug administration, including the possibility of recurrent, more severe liver 
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
The participant 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.
Participants 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 12.3, Appendix 3 for full guidance.
5.5.2.
QTc Stopping Criteria
A participant who has a QTc interval >550 msec considered causally related to IP will be 
withdrawn from the study. The QTc should be based on averaged QTc values of 
triplicate electrocardiograms obtained over a brief (e.g., 5 to 10 minute) recording 
period.
If an alternative cause of the QT prolongation is determined (e.g., participant receiving 
drug known to cause prolonged QT or TdP), the IP may be restarted (or continued) after 
consultation and agreement with the Medical Monitor. 
The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study. This formula may not be 
changed or substituted once the participant has been enrolled.
For example, if a participant is eligible for the protocol based on QTcB, then QTcB must 
be used for discontinuation of this individual participant as well.
Once the QT correction formula has been chosen for a participant’s eligibility, the same 
formula must continue to be used for that participant for all QTc data being collected for 
data analysis. Safety ECGs and other non-protocol specified ECGs are an exception.
5.5.3.
Virologic Failure
Only plasma HIV-1 RNA values determined by the central laboratory will be used to 
assess virologic failure. 
5.5.4.
Definition of Confirmed Virologic Failure
For the purposes of clinical management in this study, CVF is defined as: 
Rebound as indicated by two consecutive plasma HIV-1 RNA levels 200 c/mL after 
prior suppression to <200 c/mL.
5.5.5.
Managing Virologic Failure
Following study entry, no changes, or intensification of ART will be permitted prior to 
protocol-defined virologic failure, outside of the planned protocol regimens.  Only 

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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 study 
Day 1.  The definition of confirmed virologic failure does not apply to participants in the 
Long-Term Follow-Up Phase.  These participants will be followed for the emergence of 
viral resistance. 
Inadequate adherence is a common cause for virologic failure, and should be explored as 
a first step in the management of study participants (e.g., at the first indication of 
inadequate virologic response or rebound). Upon notification that a participant’s HIV-1 
RNA plasma level qualifies him/her as a suspected virologic failure, the Investigator 
should query the participant regarding intercurrent illness, recent immunization, or 
interruption of therapy.
5.5.5.1.
HIV-1 RNA Blips
HIV-1 RNA “blips” are not usually associated with subsequent virologic failure [DHHS, 
2015].  Although the implications of persistent HIV-1 RNA levels between the lower 
level of detection and <200 c/mL are unclear, the risk of emerging resistance is believed 
to be relatively low.  
Participants with transient increases in HIV-1 RNA (‘blips’ HIV-1 RNA <200 c/mL) are 
not considered suspected virologic failures and do not require a change in therapy.  
Participants who have a HIV-1 RNA ≥50 c/mL and < 200 c/mL at certain analysis 
timepoints (Week 48, Week 96) must return to the clinic as soon as possible (but no later 
than 4 weeks after the date of the Week 48 or Week 96 visit) for a repeat HIV-1 RNA test 
such that the result falls within the same analysis window.
In order to better characterize HIV-1 RNA ‘blips,’ if there is a known reason / 
explanation for the blip (e.g., immunization, allergies, etc), the study team should be 
notified of the reason and case context.
If the Investigator has concerns regarding persistent low level viremia (HIV-1 RNA ≥50 
c/mL and <200 c/mL), the Medical Monitor should be contacted to discuss participant 
management.  Following discussion with the Medical Monitor, additional viral load 
testing may be performed between visits to determine the appropriate participant 
disposition for the next scheduled visit
5.5.5.2.
Suspected Virologic Failure
Upon notification that a participant’s HIV-1 RNA plasma level meets the definition 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:

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
Confirmatory testing should be scheduled within 2 to 4 weeks 
following resolution of any intercurrent illness, during which time the 
participant should receive full dose of all IP.

Confirmatory testing should be scheduled at least 4 weeks following 
any immunization, during which time the participant 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 participant 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 participants on 
CAB LA + RPV LA treatment.  The study team should be contacted to discuss any 
treatment interruptions for participants meeting the definition of virologic failure.
In addition, the Investigator should query the participant regarding intercurrent illness, 
recent immunization, or interruption of therapy.
Sites should contact the Medical Monitor to discuss individual participants, 
whenever necessary.
5.5.5.3.
Confirmed Virologic Failure
Participants who confirm virologic failure must be discontinued from the study.  
However, participants 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 Phase (see Section 4.2.4).
A plasma sample from the suspected virologic failure visit as well as Day 1 (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 future analyses, e.g., for 
genotypic and phenotypic analyses of participants who experience virologic failure. See 
Section 7.8 for additional details for viral genotyping and phenotyping.
For all participants who meet CVF, baseline and suspected virologic failure plasma 
samples with HIV-1 RNA level 200 c/mL will be analyzed in an attempt to obtain 
genotype/phenotype data on as many samples as possible. Plasma samples for storage 
will also be obtained at unscheduled visits including confirmation of CVF. Participants 
may continue to receive study drug at the discretion of the investigator until results of 
resistance testing are available at which time the participant must be discontinued from 
the study. Even if genotype/phenotype data cannot be generated, participant must also be 
discontinued from the study.

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If a participant is prematurely discontinued from the study, the investigator must make 
every effort to perform the Withdrawal Visit evaluations outlined in the Time and Events 
Section 7.1. These data will be recorded as they comprise essential evaluations needed to 
be done before discharging any participant from the study.
5.6.
Participant and Study Completion
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the participant’s medical condition. 
Study Completion
Participants are considered to have completed the study if they remain on therapy (i.e., 
have not permanently discontinued IP) and satisfy one of the following:

Randomly assigned to either treatment group, completed the randomized 
Maintenance Phase including the Week 52 visit, and did not enter the Extension 
Phase;

Randomly assigned to either treatment group, completed the randomized 
Maintenance Phase including the Week 52 visit, and entered and completed the 
Extension Phase (defined as remaining on study until commercial supplies of 
CAB LA + RPV LA become locally available or development of CAB LA + RPV 
LA is terminated or participant rolls over into ATLAS 2M).
Participants who withdraw from CAB LA + RPV LA and go into the Long-Term Follow-
Up Phase will be considered to have prematurely withdrawn from the study, even if they 
complete the 52 week follow-up phase.
In addition to the 52 week Follow-Up phase required for participants randomized to CAB 
LA + RPV LA, an in-clinic Follow-Up visit will be conducted approximately 4 weeks 
after the last dose of study medication for participants randomized to current ART with 
ongoing AEs, and serious adverse events (SAEs) and also any laboratory abnormalities 
that are considered to be AEs or potentially harmful to the participant, at the last on-study 
visit.  Assessments at the Follow-up visit should reflect any ongoing complaints (e.g., 
blood draws to follow a laboratory abnormality).  Follow-Up visits are not required for 
successful completion of the study.
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination
of products received by the participant as per the protocol design.  Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.

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Investigational product (IP) in this protocol refers to the investigational study drugs Oral 
Cabotegravir, Cabotegravir LA, Oral Rilpivirine and Rilpivirine LA.  These will be 
supplied by GlaxoSmithKline/ViiV Healthcare and Janssen Pharmaceuticals, 
respectively. 
Participants randomly assigned to remain on their current ART will not have drug 
provided as clinical trial material.  Current ART will be recorded on the Concomitant 
Antiretroviral Therapy (ConART) eCRF page. 
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 must be stored in a secure area under the appropriate physical 
conditions for the product.  Access to and administration of the investigational product 
will be limited to the investigator and authorised site staff.  Investigational product and 
background NRTIs must be dispensed or administered only to participants enrolled in the 
study and in accordance with the protocol. For further details on IP storage, access, and 
administration refer to SPM. 
6.1.1.
Formulations of CAB + RPV
6.1.1.1.
Cabotegravir Tablets (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 
induction seal. CAB tablets will be packaged in bottles of 30 tablets. Participants 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 [86°F] 
and protected from moisture.
CAB Tablet is composed of cabotegravir sodium, lactose monohydrate, microcrystalline 
cellulose, hypromellose, sodium starch glycolate, magnesium stearate, and white film-
coating.  The white film-coating contains hypromellose, titanium dioxide and 
polyethylene glycol.
6.1.1.2.
Rilpivirine Tablets (RPV)
RPV [Edurant® Product Information, 2015] is provided by Janssen Research & 
Development, LLC, a division of Janssen Pharmaceuticals, as 25 mg tablets that are off-
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side with “25”.  RPV is manufactured by Janssen -Cilag S.p.A, Latina, Italy.  RPV will 
be provided as a globally marketed product which includes approvals in the US and the 
European Union.  RPV will be overlabeled and packaged in bottles of 30 tablets.  RPV 
tablets should be stored at 25°C (excursions permitted to 15°-30°C [59°-86°F]) and 
protected from light.
Each tablet contains 27.5 mg of rilpivirine hydrochloride, which is equivalent to 25 mg of 
RPV. Each tablet also contains the inactive ingredients croscarmellose sodium, lactose 
monohydrate, magnesium stearate, polysorbate 20, povidone K30 and silicified 
microcrystalline cellulose. The tablet coating contains hypromellose 2910 6 mPa.s, 
lactose monohydrate, PEG 3000, titanium dioxide and triacetin.
6.1.1.3.
Cabotegravir Injectable Suspension (CAB LA)
CAB LA (GSK1265744 LA) is manufactured by GlaxoSmithKline and is a sterile white 
to slightly pink suspension containing 200 mg/mL of GSK1265744 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-
dose 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.
6.1.1.4.
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, LLC, a division 
of Janssen Pharmaceuticals, as a sterile white suspension containing 300 mg/mL of RPV 
as the free base. The route of administration is by intramuscular (IM) injection. RPV LA 
is packaged in a single use 4 mL USP Type I glass vial with a 13 mm grey stopper and 
aluminum seal. Each vial contains a nominal fill of 2.0 mL, and does not require dilution 
prior to administration. RPV LA injectable suspension should be kept in the outer 
package and stored at 2-8°C (do not freeze). RPV should also be protected from light.
RPV LA is composed of RPV free base, poloxamer 338, sodium dihydrogen phosphate 
monohydrate, citric acid monohydrate, glucose monohydrate, sodium hydroxide, water 
for injection.
6.2.
Treatment Assignment
Informed consent must be obtained prior to any study procedures, including Screening 
visit activities. Participants will be assigned to study treatment in accordance with the 
randomization schedule. The randomization schedule, including stratification, will be 
generated using the GSK validated randomization software RANDALL NG. The 
randomization schedule is comprised of a series of blocks, with equal treatment 
allocation within each block, which are shared across centres via central randomization. 

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Given the open-label study design, central randomization was used to eliminate selection 
bias due to foreknowledge of randomized treatment. With central randomization, 
knowledge at a site of the randomized treatment group for previous subjects does not 
predict which treatment group will be assigned to the next randomized subject. 
Randomization and study treatment assignment will be facilitated by the interactive 
response technology (IRT) through the central Randomization and Medication Ordering 
System Next Generation (RAMOS NG). 
Following confirmation of fulfilment of study entry criteria, study site personnel will be 
required to register participants using RAMOS NG for assignment of a unique identifier 
(designating the participant’s randomization code and treatment sequence assignment) for 
each participant participating in the study.  A unique treatment number will be assigned 
for each participant participating in the study. Participants will be randomized in a 1:1 
ratio to CAB + RPV or to remain on their current ART through Week 52, in accordance 
with the computer generated randomization schedule. 
Participants who successfully complete 52 weeks of treatment and have a viral load <50 
c/ml at Week 48 (or upon retest by Week 52) will be given the opportunity to enter the 
extension phase in which they will receive CAB LA + RPV LA.  In addition, RAMOS 
NG will facilitate the initial supply and subsequent resupply of IP to study sites.
6.3.
Dosage and Administration
Participants will be randomly assigned to receive treatment with Oral CAB 30 mg + RPV 
25 mg once daily for 4 to 5 weeks during the Oral Phase, followed by CAB LA 600mg + 
RPV LA 900mg IM at Week 4b, CAB LA 400mg + RPV LA 600 mg IM at Week 8 and 
Q4 weekly thereafter, or to remain on their current ART.  Regardless of treatment arm 
assignment, the investigator should instruct all participants on the importance of 
treatment adherence.  This study has an open-label design.  Dosing is outlined in Table 5
below.

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Table 5
Dosage and Administration
Maintenance Phase (Day 1 to Week 52) 
CAB LA + RPV LA Arm
Oral Lead-In
Day 1 to Week 4b
(2 tablets once daily)
Take 1 tablet CAB 30 mg once daily.
Take 1 tablet RPV 25 mg once daily.
Should be taken together once daily at approximately the same 
time each day, with a meal.
First Injections (Loading Dose) – Week 4b^
Week 4b
(two 3mL injections once)
Receive last dose of oral CAB + RPV regimen
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 
Maintenance Injections – every 4 Weeks (Q4W) following Week 4b
Week 8 to Week 52
(two 2mL 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
Current ART Arm*
Day 1 to Week 52
(Tablets once daily)
Take 2 NRTIs + INI or 2 NRTIs + NNRTI or 2 NRTIs + PI 
according to approved labeling.
*Take Day 1 dose after randomization
Extension Phase (Week 52 through End of Study) 
CAB LA + RPV LA Arm – continue IM dosing every 4 Weeks+
Current ART Arm (Transition to CAB LA + RPV LA)
Oral Lead-In
Week 52 to Week 56b
(2 tablets once daily)
Take 1 tablet CAB 30 mg once daily.
Take 1 tablet RPV 25 mg once daily.
Should be taken together once daily at approximately the same 
time each day, with a meal.

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First Injections (Loading Dose) – Week 56b^
Week 56b
(two 3mL injections once)
Receive last dose of oral CAB + RPV regimen
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 
Maintenance Injections – every 4 Weeks (Q4W) following Week 56b
Week 60 forward
(two 2 mL 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
+Until locally approved and commercially available, the participant no longer derives clinical benefit, the participant 
meets a protocol-defined reason for discontinuation or until development of CAB LA or RPV LA is terminated
*Participants randomized to current ART will be given an option to switch to CAB LA + RPV LA (or be discontinued 
from the study) at Week 52.  If the participant decides not to continue participation in the study, any arrangements for 
off-study ART should be made in advance of this Week 52 visit.
^See Section 6.6.1 for Dosing Considerations for CAB LA + RPV LA
The CAB + RPV oral regimen should be administered together once daily at 
approximately the same time each day with a meal.  
6.4.
Blinding
This will be an open-label study and therefore no blinding is required. No summaries of 
the study data according to actual randomized treatment groups will be available to 
sponsor staff prior to the planned Week 48 primary analysis. 
6.5.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.6.
Preparation/Handling/Storage/Accountability
In accordance with local regulatory requirements, the investigator, institution, or the head 
of the medical institution (where applicable) is responsible for study treatment 
accountability, reconciliation, and record maintenance (i.e. receipt, reconciliation and 
final disposition records).  The amount of IP dispensed and/or administered to study 
participants, the amount returned by study participants, and the amount received from and 
returned to GSK must be documented.
Only participants enrolled in the study may receive study treatment and only authorized 
site staff may supply or administer study treatment.  All study treatments must be stored 
in a secure environmentally controlled and monitored (manual or automated) area in 
accordance with the labelled storage conditions with access limited to the investigator 
and authorized site staff.

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IP accountability will be evaluated using pill counts of unused IP for patients receiving 
oral treatment (oral CAB, oral RPV).  This assessment will be conducted, when the 
participant completes oral CAB and RPV lead-in treatment in the Maintenance or 
Extension Phase, or any withdrawal that occurs during an oral treatment phase.
IP accountability for participants receiving CAB LA + RPV LA will be performed at the 
‘vial’ level (e.g., correct number of vials were used for each injection).  There may be a 
small amount of solution remaining in the vial which does not require quantification.  
Used vials may be discarded at the site once accountability is complete.
Product accountability records must be maintained throughout the course of the study.

Under normal conditions of handling and administration, IP 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.  In the case of unintentional 
occupational exposure notify the monitor, Medical Monitor and/or GSK study 
contact.

A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK.

Further guidance and information for final disposition of unused study treatment are 
provided in the SRM. 
6.6.1.
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.  Since RPV LA requires refrigeration, sites should allow the 
vial to come to approximately room temperature prior to injecting. The vials should be 
gently inverted 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.  
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 participant 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 needle of appropriate gauge and length (recommended 1.5” 23 gauge needle for 
CAB LA and a 1.5” 23 gauge needle for RPV LA in most participants).  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 and/or needles with different gauge (CAB LA: 21 to 
25 gauge; RPV LA: 21 to 23 gauge) are permitted if needed to accommodate individual 
body types.  Longer needle lengths may be required for participants with higher body 
mass indexes (BMIs, example > 30), to ensure that injections are administered 
intramuscularly as opposed to subcutaneously.  BMI, needle gauge and length used will 

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be collected in the eCRF. Additional details of the injection device used by sites for IM 
administration including, but not limited to functional performance, may also be collected 
within the eCRF.
At the Week 4b visit, participants should be dosed with the IM regimen within 2 hours of 
taking the last oral regimen dose where possible. The same should apply to participants 
switching from the oral regimen to an IM regimen at Week 56b.
Should IM maladministration be suspected at any time (e.g., suspected under or overdose 
or inadvertent IV dosing), the investigator may consider requesting the participant stay 
onsite for approximately 2-3 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 plasma concentrations.
Additional dosing instructions and considerations can be found in the SPM
6.7.
Compliance with Study Treatment Administration
When participants are dosed at the site, they will receive study treatment directly from 
the investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the participant’s eCRF.  The dose of study 
treatment and study participant identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study treatment. 
When participants self-administer oral study treatments at home, compliance with CAB + 
RPV dosing will be assessed through querying the participant during the site visits and 
documented in the source documents and CRF.  IP accountability will be evaluated using 
pill counts of unused IP (CAB and RPV tablets).  This assessment will be conducted each 
time the participant receives a new (refill) supply of oral study medication, completes the 
oral lead-in or any oral bridging phase.  A record of the number of CAB and RPV tablets 
dispensed to and taken by each participant must be maintained and reconciled with study 
treatment and compliance records.  Treatment start and stop dates will also be recorded in 
the eCRF. 
Due to the long acting nature of the CAB LA and RPV LA it will be imperative that the 
participant is compliant with dosing instructions.  As part of the screening and participant 
selection process, it is imperative that Investigators discuss with potential participants the 
long-term commitments for the trial, and the importance of adhering to treatment 
regimens.  Sites are to have plans in place for adherence counselling for both treatment 
arms of the study for the duration of the study including the Long-Term Follow-Up 
Phase.  In addition, Investigators must have plans in place to perform visit reminders, 
utilizing patient trackers provided by the study team as needed, and to verify the 
participant’s contact information at each visit.  Investigators should contact patients 
directly in the event that a participant misses any scheduled visit. 

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6.8.
Protocol Permitted Substitutions
6.8.1.
Oral Bridging
In exceptional circumstances, to address pre-planned missed CAB LA + RPV LA dosing 
visits, in consultation with the medical monitor, Investigators may  provide daily oral 
CAB 30 mg and RPV 25mg as a short-term “bridging” strategy for participants who have 
begun CAB LA + RPV LA.  In certain circumstances (e.g., prior to steady state dosing 
and following a >4 week oral bridge) repeating the loading doses of CAB IM and RPV 
IM may be required.  Should a participant require “oral bridging”, sites must contact the 
medical monitor for guidance with treatment and dosing strategies prior to a missed CAB 
LA + RPV LA dose.
6.9.
Interruption of Study Treatment and Visit/Dosing Windows
IP or current ART 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 participant’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.
6.9.1.
IM Dosing
Participants receiving CAB LA and/or RPV LA are anticipated to be at risk for 
development of virologic resistance if ART is interrupted.  The time period during which 
participants 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 LA drugs may be measurable for more than one year 
following IM injections. Any interruption in IM dosing should be discussed with the 
Medical Monitor.  Investigators should ensure that the participant initiates alternative 
highly active ART to minimize the risk of developing resistance as concentrations of 
CAB and RPV decline over time.
IM dosing is expected to occur during the week in which the participant’s projected visit 
falls (as according to the date of the first injection).  The first injections are administered 
at Week 4b (can be performed as soon as lab results from Week 4a become available), 
and the second injections are given at Week 8.  The dosing window for the second 
injections allows administration between Week 7 and Week 8, but not later than Week 8. 
The dosing window for the third injections allows administration between Week 11 and 

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Week 12 but not later than Week 12.   For subsequent injection visits, an additional 
(+ or -) 7 day window, from the projected visit date, is allowable for IM dosing but also 
not preferred.  In addition, starting after the Week 12 injection, efforts should be made to 
limit time between injection visits 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.  For the duration of the study, the injection visit schedule should be maintained 
according to the first IM injections given at Week 4b.
For participants transitioning from current ART to IM dosing, the first injections are 
administered at Week 56b (can be performed as soon as lab results from the 56a visit 
become available), and the second injections are given at Week 60.  The dosing window 
for the second injections allows administration between Week 59 and Week 60, but not 
later than Week 60.  The dosing window for the third injections allow administration 
between Week 63 and Week 64, but not later than Week 64.  For subsequent visits, a (+ 
or -) 7 day window, from the projected visit date, is allowable for IM dosing but also not 
preferred.  
At the one-week post dose visits (Week 5 and Week 41), there is no defined visit 
window, rather visits should occur approximately one 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 and/or RPV may be an option 
based on individual participant circumstance as described in Section 6.8.

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.
6.9.2.
Oral Dosing
Visits for participants 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 participants in Long Term Follow Up are expected to occur as projected 
according to the last injection.  

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6.10.
Discontinuation of Study Treatment
Participants unable to manage drug toxicity or tolerate investigational product (IP, either 
formulations of CAB or RPV) must have IP discontinued.  Any participant 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 Phase for 52 weeks of follow up 
(see Section 4.2.4).
6.11.
Treatment of Study Treatment Overdose
For participants receiving Oral CAB, any tablet intake exceeding a total daily dose of 30 
mg will be considered an overdose.  For participants receiving oral RPV, any dose 
exceeding a total daily dose of 25 mg 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, specifically overdose or inadvertent IV dosing, be 
suspected at any time, the participant will stay onsite for approximately 2-3 hours post 
dose for safety monitoring and an ECG will be performed at 2 hours post dose.  The 
Medical Monitor will be notified in the event of a suspected maladministration. 
In the event of suspected maladministration, additional PK samples will be drawn at 2 
hours post dosing for evaluation of CAB and RPV concentrations.
For the purposes of this study, an overdose is not an AE (refer to Section 12.6.1 ) 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 12.6.2).
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 ViiV Healthcare 
is unable to recommend specific treatment.
In the event of an overdose the investigator or treating physician should:
1. Contact the Medical Monitor immediately
2. Closely monitor the participant for adverse events (AEs)/serious adverse events 
(SAEs) and laboratory abnormalities until the IP can no longer be detected 
systemically (at least 5 days for oral CAB and oral RPV, and 52 weeks for CAB LA 
and RPV LA
3. Obtain a plasma sample for pharmacokinetic (PK) analysis if possible within 2 days 
from the date of the last dose of study treatment if requested by the Medical Monitor 
(determined on a case-by-case basis).
4. Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.

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Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.
6.12.
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 participant’s medical condition, whether or not GSK is providing 
specific post-study treatment.  Participants who have successfully completed 96 weeks of 
treatment will continue to have access to both CAB LA and RPV LA in the Extension 
Phase until study treatment is either locally approved and commercially available, the 
participant no longer derives clinical benefit, the participant meets a protocol-defined 
reason for discontinuation or until development of either CAB LA or RPV LA is 
terminated.
6.13.
Concomitant Medications and Non-Drug Therapies
Participants 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.  Concomitant 
medications (prescription and non-prescription) will be permitted during the course of the 
study at the investigator’s discretion (except for prohibited medications described in 
Section 6.13.2) and should be administered only as medically necessary during the study.  
All concomitant medication, blood products, and vaccines taken during the study will be 
recorded in the eCRF.  The minimum requirement is that the drug name, route, and the 
dates of administration are to be recorded.
6.13.1.
Permitted Medications and Non-Drug Therapies
Chemoprophylaxis for HIV-associated conditions is encouraged, if appropriate, at the 
discretion of the participant 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 (should be spaced 2 cm or more away from site of 
IP injection).
Antacid and H2 Antagonist Use:
While both oral CAB and RPV have dosing requirements with antacid products 
containing divalent cations, only oral RPV has requirements for dosing with H2 

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antagonists.  Since co-administration of oral CAB and RPV is required in this study, the 
most restrictive dosing requirements must be taken into consideration.
CAB 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.
Concurrent administration of multivitamins is acceptable.
RPV 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 RPV. H2-Receptor antagonists (e.g. cimetidine, famotidine, nizatidine, 
ranitidine) may cause significant decreases in RPV plasma concentrations.  H2-receptor 
antagonists should only be administered at least 12 hours before or at least 4 hours after 
RPV.  RPV should not be co-administered with proton pump inhibitors, such as 
esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole.
RPV:  Administration of clarithromycin, erythromycin and telithromycin is not 
recommended with RPV due to possible increase in plasma concentration of RPV due to 
CYP3A enzyme inhibition.  Where possible, alternatives such as azithromycin should be 
considered.  Please refer to the local rilpivirine prescribing information for guidance 
regarding other drugs that are prohibited, should be used with caution, require dose 
adjustment, or increased clinical monitoring if taken with rilpivirine.
Drugs that cause Torsade des Pointes (TdP) should be used with caution when on 
rilpivirine (see SPM for list of drugs associated with TdP).
6.13.2.
Prohibited Medications and Non-Drug Therapies
The following concomitant medications or therapies are not permitted at any time during 
the study:

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 #32, Section 5.2). 

Systemically administered immunomodulators (such as interleukin and 
interferon agents) are prohibited (a list of examples is provided in the SPM).  
This includes topical agents with substantial systemic exposure and systemic 
effects.  Use of topical imiquimod is permitted.  

Acetaminophen (paracetamol) cannot be used in patients with acute viral 
hepatitis (James, 2009).

Chronic use of systemic (oral or parenteral) glucocortioids must be avoided due 
to their immunosuppressive effect and potential decreases in RPV plasma 
concentrations; however, short treatment courses with oral prednisone/ 
prednisolone/methylprednisolone (e.g. adjunctive treatment of Pneumocystis 
pneumonia with ≤ 21 days of tapering prednisone) are allowed. A single dose of 

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systemic dexamethasone is permitted (more than a single dose in a treatment 
course may cause significant decrease in RPV plasma concentration and is 
prohibited). Topical, inhaled or intranasal use of glucocortioids will be allowed.  

Hepatitis C infection therapy is prohibited during the Maintenance Phase before 
the Week 48 primary endpoint, and interferon-based HCV therapy or use of any 
drugs that have a potential for adverse drug:drug interactions with study 
treatment is prohibited throughout the entire study. 
For information on concurrent therapies and interactions suspected to be relevant to other 
antiretroviral therapy in the regimen, please consult the local prescribing information.
6.13.2.1.
Concurrent with CAB and/or RPV
For participants 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 (Hypericum perforatum)
Concurrent with RPV
In addition, participants 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, for both Oral RPV and RPV 
LA)
If the participant cannot discontinue use or change to an allowable alternative while 
receiving treatment with RPV, the participant should not be randomized into the study.
6.13.2.2.
Concurrent with either CAB LA or RPV LA
In addition, for participants receiving CAB LA and RPV LA, use of anticoagulation 
agents for greater than 14 days is prohibited, with the exception of the use of 
anticoagulation for DVT prophylaxis (e.g., postoperative DVT prophylaxis) or the use of 
low dose acetylsalicylic acid (≤325mg). Systemic anticoagulation (including prophylaxis 
doses) on the day of an IM injection should be avoided.

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Note: Any prohibited medications that decrease cabotegravir or rilpivirine concentrations 
should be discontinued for a minimum of four weeks or a minimum of three half-lives 
(whichever is longer) prior to the first dose and any other prohibited medications should 
be discontinued for a minimum of two weeks or a minimum of three half-lives 
(whichever is longer) prior to the first dose.
6.13.2.3.
Prohibited Medications for Participants Receiving Current Regimen
For participants randomly assigned to remain on their current ART, refer to local 
prescribing information for details regarding concurrent therapies.
7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table (Section 7.1).
The following points must be noted: 

If assessments are scheduled for the same nominal time, THEN the assessments 
should occur in the following order:
1. 12-lead ECG
2. vital signs
3. blood draws  
Note: The timing of the assessments should allow the blood draw to occur at the 
exact nominal time.

The timing and number of planned study assessments, including safety, 
pharmacokinetic, pharmacodynamic/biomarker assessments may be altered 
during the course of the study based on newly available data (e.g., to obtain data 
closer to the time of peak plasma concentrations) to ensure appropriate 
monitoring. 

The IRB/IEC will be informed of any safety issues that require alteration of the 
safety monitoring scheme or amendment of the Informed Consent Form. 

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7.1.
Time and Events Table
Note:  While some assessments included in the Time and Events Table are conducted less frequently following the secondary endpoint 
(Week 96), IM injections for participants randomized to CAB LA + RPV LA (and for participants who switch to CAB LA + RPV LA 
during the Extension Phase) will continue to be administered Q4W.  Beginning after Week 96, the schedule of assessments for all 
participants will be modified to collect clinical chemistries,  HIV-1 RNA, and CD4+ cell count every 12 weeks. 
From Week 60 forward, all participants (from both originally randomized treatment arms), will have the same schedule of events (same 
visits, same assessments, same time frame).
Procedure
Screening Visita
Maintenance Phase
Extension Phase
Withdrawal
Follow-up Phase
Baseline, Day 1
Week
4A
4Bb
5b
8, 12,16,20
24
28, 32, 36,40
41b
44
48
52
56A
56Bb
60
64, 72, ,80, 88
68, 76, 84, 92
96
Every 
4 
Weeks 
After 
Week 
96
Every 12
Weeks
After 
Week 96
Clinical and Other Assessments
Written informed 
consent
X
Eligibility 
Verification 
(Inclusion/Exclusion 
Criteria)
X
Xc
Xc
Randomization
X
Demography
X

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Procedure
Screening Visita
Maintenance Phase
Extension Phase
Withdrawal
Follow-up Phase
Baseline, Day 1
Week
4A
4Bb
5b
8, 12,16,20
24
28, 32, 36,40
41b
44
48
52
56A
56Bb
60
64, 72, ,80, 88
68, 76, 84, 92
96
Every 
4 
Weeks 
After 
Week 
96
Every 12
Weeks
After 
Week 96
Medical Historyd
X
Medication History/ 
Prior ART history
X
Symptom Directed 
Physical Exam and 
Medical 
Assessmente
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight, Height and 
BMIf
X
X
X
X
X
Cardiovascular risk 
assessment
X
X
Vital Signs (BP, 
HR,Temperature)g
X
X
X
X
X
X
12-lead ECG h
X
X
pre-
dose 
x3
X
X
X
X
X

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Procedure
Screening Visita
Maintenance Phase
Extension Phase
Withdrawal
Follow-up Phase
Baseline, Day 1
Week
4A
4Bb
5b
8, 12,16,20
24
28, 32, 36,40
41b
44
48
52
56A
56Bb
60
64, 72, ,80, 88
68, 76, 84, 92
96
Every 
4 
Weeks 
After 
Week 
96
Every 12
Weeks
After 
Week 96
CDC HIV-1 
classification
X
X
HIV Associated 
Conditions
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AEs, SAEs, 
Concomitant 
Medications
Xi
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ISR Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 
Columbia Suicide 
Severity Rating 
Scale (eC-SSRS) j
X
X
X
X
X
X
X
X
X
W
72
W
84
X
X
Clinical chemistry 
and Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Rapid Plasma 
Reagin (RPR)
X
X
Pregnancy Testingk
SR
UR
SR
UR
SR
SR
SR
SR
SR
SR
SR
UR
SR
SR
SR
SR
SR
SR
SR
SR

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Procedure
Screening Visita
Maintenance Phase
Extension Phase
Withdrawal
Follow-up Phase
Baseline, Day 1
Week
4A
4Bb
5b
8, 12,16,20
24
28, 32, 36,40
41b
44
48
52
56A
56Bb
60
64, 72, ,80, 88
68, 76, 84, 92
96
Every 
4 
Weeks 
After 
Week 
96
Every 12
Weeks
After 
Week 96
HIV-1 RNA and 
sample for storagel
(S)=Storage only
X
X
X
X
X
X
X
X
S
X
X
X
X
X
X
X
CD4+ cell count
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CD8+ cell count
X
X
X
X
X
X
X
Urinalysism
X
X
X
X
X
X
X
Fasting Lab 
Assessments:  
Glucose, 
Cholesterol (Total, 
HDL and LDL) and 
Triglyceridesn
X
X
X
Xo

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Procedure
Screening Visita
Maintenance Phase
Extension Phase
Withdrawal
Follow-up Phase
Baseline, Day 1
Week
4A
4Bb
5b
8, 12,16,20
24
28, 32, 36,40
41b
44
48
52
56A
56Bb
60
64, 72, ,80, 88
68, 76, 84, 92
96
Every 
4 
Weeks 
After 
Week 
96
Every 12
Weeks
After 
Week 96
Hepatitis B 
(HBsAg), Anti-HBc, 
and Anti-HBsAG, 
Hepatitis C 
(anti-HCV Ab)
X
HLA-B*5701
X
PT/PTT/INR 
X
X
Renal, bone, 
marker analytes 
(blood/urine)p
X
X
X
X
PBMCsq
X
X
X
Genetics sampler
X

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Procedure
Screening Visita
Maintenance Phase
Extension Phase
Withdrawal
Follow-up Phase
Baseline, Day 1
Week
4A
4Bb
5b
8, 12,16,20
24
28, 32, 36,40
41b
44
48
52
56A
56Bb
60
64, 72, ,80, 88
68, 76, 84, 92
96
Every 
4 
Weeks 
After 
Week 
96
Every 12
Weeks
After 
Week 96
Pharmacokinetics – CAB + RPV only
PK samplings
(S)=Storage only
X
X
X
X
X
X
X
X
X
X
X
S
X
X
S
Investigational Products
Oral CAB and Oral 
RPV Dispensationt
X
X
X
X
IP accountability 
(Pill Counts)
X
X
X
X
IM treatment 
administrationu
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

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Procedure
Screening Visita
Maintenance Phase
Extension Phase
Withdrawal
Follow-up Phase
Baseline, Day 1
Week
4A
4Bb
5b
8, 12,16,20
24
28, 32, 36,40
41b
44
48
52
56A
56Bb
60
64, 72, ,80, 88
68, 76, 84, 92
96
Every 
4 
Weeks 
After 
Week 
96
Every 12
Weeks
After 
Week 96
Patient Reported OutcomesV
HAT-QoL (short-
form)
X
X
X
X
X
SF-12
X
X
X
X
X
HIV TSQs
X
X
X
X
X
X
HIV TSQcw
X
X
ACCEPT
X
X 
Wk8
only
X
X
X
X
Reason for Switchx
X
X
Preferencey
X
X
NRSz
X
X
X 
Wk40 
only
X
X
PIN
X
X
X
X
X

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Procedure
Screening Visita
Maintenance Phase
Extension Phase
Withdrawal
Follow-up Phase
Baseline, Day 1
Week
4A
4Bb
5b
8, 12,16,20
24
28, 32, 36,40
41b
44
48
52
56A
56Bb
60
64, 72, ,80, 88
68, 76, 84, 92
96
Every 
4 
Weeks 
After 
Week 
96
Every 12
Weeks
After 
Week 96
Follow Up Visit:  Conduct approximately 4 weeks after the last dose of IP.  Required only if the participant has ongoing AEs or lab abnormalities at the last on-study visit.  This visit may 
be conducted by telephone.
a.
Complete all Screening assessments within 35 days.  Participants may begin the Maintenance Phase as soon as all Screening assessments are complete.  Participants may be 
rescreened once and will be assigned a new participant number.  HLA-B*5701 result is not required to inform eligibility status.
b.
Visits at Weeks 4b, 5, 41, and 56b are only for participants randomized to CAB LA + RPV LA or transitioning from current ART to CAB LA + RPV LA during the Maintenance or 
Extension Phase, respectively.
c.
Confirmation of eligibility to enter the Maintenance Phase (Section 5), and eligibility to enter the Extension Phase (Section 4.2.3).
d.
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, bone, and 
neurologic disorders.
e.
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 participants management and/or care of participant.  
f.
Height collected at Baseline only.
g.
Measure vital signs after about 5 minutes of rest in a semi-supine position.
h.
A 12-lead ECG will be performed after resting in a semi-supine position for at least 5 minutes.  ECGs will be performed pre-dose.  ECG will be performed in triplicate at Baseline 
(Day 1).  In addition to a pre-dose ECG, a 2 hour post-dose ECG will be performed at Weeks 4B and Week 48 for subjects randomized to CAB LA + RPV LA only.
i.
Only SAEs related to study participation or to a concomitantly administered ViiV/GSK product will be collected between obtaining informed consent and administration of study 
drug at Day 1.
j.
On Day 1, the eC-SSRS is to be administered prior to randomization.  The eC-SSRS will be administered at each Q4W injection visit through the Week 48 primary endpoint, 
followed by Q12W thereafter through Week 96 (Week 60, 72, 84, 96).  The eC-SSRS will preferably be completed at the beginning of the visit following administration of other 
PROs required prior to injections.
k.
Women of childbearing potential only.  SR=serum, UR=urine.  Pregnancy events will be captured starting at Day 1 following exposure to study drug.  Serum pregnancy test can 
substitute for urine pregnancy test if locally required but must be appropriately timed to confirm pregnancy status prior to randomization and first IM administration.
l.
HIV-1 RNA will not be collected for analysis at Week 52 and Week 100 (Week 48 or Week 96 retest will be captured as unscheduled visit).  Plasma for storage will be collected at 
Week 52 and Week 100.  Plasma for storage samples will be used for possible future analyses

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m.
A morning specimen is preferred.  To assess biomarkers: urine albumin/creatinine ratio; urine protein/creatinine ratio; and urine phosphate.
n.
An overnight fast is preferred; however, a minimum of a 6-hour fast is acceptable.
o.
Only collect if the Withdrawal visit occurs at Week 48, or 96.
p.
Blood sample for renal and bone biomarker assessments: Renal: Cystatin C; Retinol Binding Protein (RBP);.Bone: bone specific alkaline phosphatase, procollagen type 1-N-
propeptide, type 1 collagen cross-linked C-telopeptide, osteocalcin, 25 hydroxy-Vitamin D
q.
Whole blood/PBMC collection samples may be used for virologic analyses as described in Section 7.8.  PBMCs will be collected at Day 1, Week 96, and Withdrawal if prior to 
Week 96.
r.
Informed consent for genetic research must be obtained before sample collection
s.
One blood sample for CAB and RPV each to be collected at each PK timepoint.  PK samples are to be collected pre-dose during visits requiring IM administration.  2 hour post 
dose samples also taken at Weeks 4b, 48, 56b, and 96.  Pre-dose samples at Weeks 56b, 60, and 2 hour post-dose sample at Week 56b are only for subjects transitioning from 
Current Art arm to CAB LA + RPV LA.  Pre-dose samples are to be collected after review of PK diary at Week 4b and 56b and prior to the final oral dose of CAB + RPV. 
Additionally PK samples will be taken during the 1 week post-dose Week 5 and 41 visits.  PK window allowed for sample collection; includes 3 to 10 days for 1 wk post dose 
sample (Visits 5 and 41); one hour for 2 hour post dose sample (Weeks 4b, 48, 56b, and 96).  See Section 7.5.1 for details of PK sampling schedule.
t.
Only for Participants entering CAB + RPV Oral Treatment 
u.
Participants switching to CAB LA + RPV LA will take final dose of oral lead-in regimen in the clinic at The Week 4b visit or Week 56b and begin injections.  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.  The first injection can be performed as soon 
as central lab results become available and safety parameters are reviewed.  
v.
With the exception of the NRS questionnaire, all Patient Report Questionnaires/Surveys are recommended to be administered via validated electronic site pad or paper instrument 
at the beginning of the visit before any other assessments are conducted and prior to administration of the eC-CSSRS. NRS is to be given post injection.  Conduct 
questionnaires/surveys at Withdrawal if occurring prior to Week 96.
w.
HIV TSQ (c) to be administered at Week 48 to LA injection arm only 
x.
“Reason for switch” will be administered prior to randomization at Day 1.  At Week 52, “Reason for Switch” will be given only to participants randomized to the “Current ART” arm.
y.
Preference” question to be administered at Week 48 to patients randomized to CAB LA + RPV LA arm, and at Week 96 to patients randomized to the “current ART arm” who 
switched to CAB LA + RPV LA at the end of maintenance phase.
z.
NRS will be administered on injection visits approximately 30-60 minutes following injections.  Participant should record the maximum level of pain experienced with the most 
recent injections.
Note: BP – Blood pressure, HR – Heart Rate, HDL – High Density Lipoprotein, LDL – Low Density Lipoprotein, PT Prothrombin Time, PTT Partial Thromboplastin 
Time, INR International normalized ratio

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7.2.
Screening and Critical Baseline Assessments
Written informed consent must be obtained from each potentially eligible participant 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 
(IRB)/Independent Ethics Committee (IEC). After signing an informed consent, 
participants will complete Screening assessments to determine participant eligibility. 
Each participant being screened for study enrolment evaluation will be assigned a 
participant number at the Screening visit. This number will be given sequentially in 
chronological order of participant presentation according to a numeric roster provided by 
GSK.
7.2.1.
Screening Assessments
Eligibility criteria must be carefully assessed at the Screening visit. Physical 
examinations should be conducted as part of normal routine clinical care but will not be 
collected systematically in the eCRF. Background information to be collected at 
Screening includes demography and prior ART history.
Eligible participants may be randomly assigned immediately as soon as all Screening 
assessments are complete and the results are available and documented. All participants 
will complete the screening period of approximately 14 days prior to Baseline (Day 1) 
during which all clinical and laboratory assessments of eligibility must be performed and 
reviewed. The Screening period may be extended to 35 days to accommodate availability 
of all Screening assessment results, completion of source document verification to satisfy 
the Inclusion and Exclusion Criteria, and scheduling. All Screening results must be 
available prior to randomization. 
All information about the participant’s current regimen must be available for 
review by the Principal Investigator or designee prior to randomization.  Source 
documents from other medical facilities must be located/received during the 14 day 
(up to 35 days) screening period and under no circumstances may the participant be 
randomized in the absence of source documentation even if there are delays in 
receipt of this information.
Any available prior genotypic resistance testing must be provided to GSK, after screening 
and before randomization according to guidance in the SPM, to provide direct evidence 
of no pre-existing exclusionary resistance mutations. The lack of exclusionary resistance 
mutations must be confirmed by the study virologist, which will be provided before the 
screening window closes. Details on use of RAMOS for tracking historic resistance 
report availability and submission to ViiV Healthcare Virology for evaluation are 
described in the SPM. Details regarding baseline or prior resistance data must be noted in 
the source documentation.
Participants infected with HBV will not be enrolled in the study.  Evidence of HBV 
infection is based on the results of testing at Screening for hepatitis B surface antigen 
(HBsAg), hepatitis B core antibody (anti-HBc), hepatitis B surface antibody (anti-HBs), 
and HBV DNA.  HBV DNA will only be performed for participants with positive anti-
HBc and negative HBsAg and negative anti-HBs (past and/or current evidence). 

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Participants 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.
All participants will be screened for syphilis (rapid plasma reagin [RPR]) at Screening.  
Participants with untreated syphilis infection, defined as a positive RPR without clear 
documentation of treatment, are excluded.  Participants with a serofast RPR result despite 
history of adequate therapy and no evidence of re-exposure may enrol after consultation 
with the Medical Monitor. Participants with a positive RPR test who have not been 
treated may be rescreened at least 30 days after completion of antibiotic treatment for 
syphilis.
The eCSSRS (see Section 7.4.5) assessed at the Screening visit will assess the 
participant’s lifetime risk (any suicidal ideation, behavior, etc occurring over the 
participant’s lifetime).  A positive alert (indicating some risk) is not necessarily 
exclusionary, rather a means to assess overall risk.
Participants who meet all entry criteria are randomized and assigned a randomization 
number. A single repeat of a procedure/lab parameter is allowed to determine eligibility 
(unless otherwise specified).  Participants not meeting all inclusion and exclusion criteria 
at initial screen may be rescreened and receive a new participant number one time unless 
they were excluded for reason of having exclusionary historic genotypic resistance.  
Participants who are randomized into the trial and subsequently withdrawn from the 
study for any reason may not be rescreened.
7.2.2.
Baseline Assessments
At Day 1 and prior to randomization, any changes to the eligibility parameters must be 
assessed and any results required prior to randomization (e.g., Day 1 urine pregnancy test 
for women of childbearing potential) must be available and reviewed. The following 
demographic parameters will be captured: year of birth, sex, race and ethnicity. 
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5. 
HIV-1 genotypic resistance testing and plasma HIV-1 RNA measurement results from 
Screening must be available prior to the Baseline visit.
Baseline information to be collected at Day 1 includes general medical history and 
current medical conditions. Laboratory and health outcomes assessments will also be 
assessed.  Questionnaire/surveys are recommended to be administered at the beginning of 
the visit before any other assessments are conducted, in the order specified.  For 
participants who agree to the optional assessment, a whole blood sample for genetic 
research should be collected at Day 1.

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In addition to a full routine medical history at Baseline, more detailed information will be 
collected for some disease processes such as:

Cardiovascular medical history/risk factors (as detailed in the eCRF) will be 
assessed at Baseline and assessments will include height, weight, blood pressure, 
smoking status and history, pertinent medical conditions (e.g., hypertension, 
diabetes mellitus), and family history of premature cardiovascular disease.  In 
addition, medical history/risk factors for renal disease such as nephropathy, renal 
failure, and nephrolithiasis will be assessed.

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
Procedures conducted as part of the participant’s routine clinical management [e.g., 
laboratory assessments] and obtained prior to signing of informed consent may be 
utilized for Screening or baseline purposes provided the procedure meets the protocol-
defined criteria and has been performed in the timeframe of the study.
7.3.
Efficacy
7.3.1.
Plasma HIV-1 RNA
Plasma for quantitative HIV-1 RNA will be collected according to the Time and Events 
schedule (Section 7.1).  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.
7.3.2.
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 7.1) and Laboratory Assessments 
(Section 7.4.2).

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7.3.3.
HIV Associated Conditions
HIV-associated conditions will be recorded as per Time and Events schedule (Section 
7.1).  HIV-associated conditions will be assessed according to the 2014 CDC Revised 
Classification System for HIV Infection (see Section 12.4).  
7.4.
Safety
7.4.1.
Clinical Evaluations
The following clinical evaluations will be performed according to the Time and Events 
schedule:

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 
7.4.3.1.

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 Day 1 
(Baseline) only.

Vital signs will include systolic and diastolic blood pressure and heart rate 
collected after resting for about 5 minutes.  Temperature will also be collected.

Past medical history, family history, social history, medication history.  Targeted 
history on cardiovascular risk (smoking history, family and personal history).

HIV-associated conditions will be recorded.

Electrocardiogram:  A 12-lead ECG will be performed in a semi-supine position 
after 5 minutes of rest.  On Day 1 (Baseline) of the Maintenance Phase, 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 participant for the 
site.  Regardless, each ECG should be reviewed by a qualified ECG reader.  The 
qualified ECG reader will make the non-calculated ECG interpretations.  The 
same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study. This formula may 
not be changed or substituted once the participant has been enrolled.

Regular monitoring of hematology, blood chemistry, urinalysis and fasting 
glucose and lipids (parameters to be tested listed below).  

Periodic assessment of glucose, insulin, and bone, cardiovascular, and renal 
markers;

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
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).  If serum testing is required locally, the 
results should be available prior to the visit where urine testing is indicated per the 
Time and Events Schedule (Section 7.1).

Evaluation and documentation of all concomitant medications and blood products. 

Injection Site Reactions (ISRs) will be assessed clinically during the Maintenance 
and Extension Phases for the following:
Pain, tenderness, pruritis, warmth, bruising, discoloration, infections, rash, 
erythema, swelling, induration, and nodules (granulomas or cysts).  

A clinical assessment (using Division of Acquired Immunodeficiency Syndrome 
[DAIDS] grading scale) 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, will be 
documented in the ISR AE eCRF.  

Columbia Suicide Severity Rating Scale (eC-SSRS) will be assessed as per the 
Time and Events Schedule (see Section 7.1 and Suicidal Risk Monitoring Section 
7.4.5).
Any appropriately qualified site personnel (e.g., Investigator, sub-Investigator, or study 
coordinator/nurse) can perform assessments.
7.4.2.
Laboratory Assessments
All protocol required laboratory assessments, as defined in the Time and Events Schedule 
(see Section 7.1), 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 participant 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.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the eCRF.  Local laboratory services may 
be used to verify pending laboratory parameters only after consultation and agreement 
with the study team.
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 12.2 “Division of AIDS Table for Grading the Severity of Adult and 
Pediatric Adverse Events”).

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For fasting laboratory assessments, an overnight fast is preferred; however, a minimum of 
a 6 hour fast is acceptable.
Table 6 includes lab parameters to be assessed as per the Time and Events Schedule (see 
Section 7.1):
Table 6
Safety Laboratory Assessments
Hematology
Platelet count 
Automated WBC differential:
RBC count
Neutrophils
WBC count (absolute) 
Lymphocytes
Hemoglobin
Monocytes
Hematocrit
Eosinophils
MCV
Basophils
Clinical Chemistry
BUN
Potassium
AST 
Total bilirubina
Creatinine
Chloride
ALT 
Albumin 
Glucosec
Total CO2
Alkaline phosphatase
Creatine phosphokinase
Sodium
Lipase
Phosphate
Creatinine clearanceb
Fasting Lipid Paneld
Total cholesterol
HDL cholesterol
LDL cholesterol
Triglycerides
Other Tests
Plasma HIV-1 RNAe
CD4+ and CD8+ cell counts [CD4/CD8 ratio]f
Peripheral Blood Mononuclear Cells (PBMCs):  Day 1, Week 96, Withdrawal only
Hepatitis B (HBsAg), anti-HBc, anti-HBsAg, and hepatitis C antibody (Screening)g
Rapid Plasma Reagin (RPR) (Screening and Baseline)
HLA-B*5701 (Screening only)
Prothrombin Time (PT)/International Normalized Ratio (INR)/ Partial Thromboplastin Time (PTT)
Pregnancy test for women of childbearing potentialh
Urinalysis, urine albumin/creatinine ratio, and urine protein/creatinine ratio, urine phosphate
Genetics Sample 
Renal biomarkers including Cystatin-C (blood), Retinol Binding Protein (RBP, blood/urine)i
Bone biomarkers including: Bone-specific alkaline phosphatase, procollagen type 1 N-propeptide, type 1 collagen 
cross-linked C-telopeptide, osteocalcin, 25 hydroxy-Vitamin Di
Follicle stimulating hormone (FSH) and estradiol (only for instances when postmenopausal status is questionable)
MCV = mean corpuscular volume, RBC = red blood cells, WBC = white blood cells, BUN = Blood urea nitrogen, 
AST=aspartate aminotransferase, ALT = alanine aminotransferase, CO2 = carbon dioxide, HDL = high density 
lipoprotein, LDL = low density lipoprotein, HBsAg= hepatitis B virus surface antigen, PT/INR = prothrombin 
time/international normalized ratio.
a)
Direct bilirubin will be reflexively performed for all total bilirubin values >1.5 × ULN.
b)
Glomerular filtration rate (GFR) will be estimated by the central laboratory using the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) [Levey, 2009].
c)
For fasting glucose assessments, an overnight fast is preferred; however, a minimum of a 6-hour fast is 
acceptable for participants with afternoon appointments.
d)
For fasting lipids assessments, an overnight fast is preferred; however, a minimum of a 6-hour fast is acceptable 
for participants with afternoon appointments.
e)
For participants meeting virologic withdrawal criteria, plasma samples will be analyzed in attempt to obtain 
genotype/phenotype data.
f)
CD8+ cells will only be reported at Baseline, Day 1, Weeks 4b, 24, 48, and 96.
g)
HBV DNA will only be performed for participants with a positive anti-HBc and negative HBsAg and negative anti-

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HBs (past and/or current evidence).
h)
Urine pregnancy test/ serum pregnancy test will be performed according to the Time and Events Table (Section 
7.1). 
i)
Since the intention is to utilize these biomarker data for research purposes, the sponsor will not be reporting the 
results of these assessments to the investigator, except for 25 hydroxy-vitamin D.
7.4.3.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
7.4.3.1.
Time period and Frequency for collecting AE and SAE information

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded from the time a participant consents to participate in the 
study up to and including any follow-up contact. 

AEs will be collected from the start of Study Treatment until the follow-up 
contact (see Section 7.4.3.1), at the timepoints specified in the Time and Events 
Table (Section 7.1).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the eCRF.

The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided 
in   Section 12.6, Appendix 6

Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the investigator learns of any SAE, including a death, at 
any time after a participant has been discharged from the study, and he/she 
considers the event reasonably related to the study treatment or study 
participation, the investigator must promptly notify GSK.

During the Extension Phase, AEs leading to Withdrawal and all SAEs will be 
recorded.
7.4.3.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the participant is the preferred method to inquire 
about AE occurrence.  Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?”

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7.4.3.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts.  All SAEs, and non-serious AEs of special 
interest (as defined in Section 7.4.4) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the participant is lost to follow-
up (as defined in Section 5.5). Further information on follow-up procedures is given in 
Section 12.6, Appendix 6).
7.4.3.4.
Prompt Reporting of Serious Adverse Events and Other Events
SAEs, pregnancies, and liver function abnormalities meeting pre-defined criteria will be 
reported promptly by the investigator to the medical monitor as described in Table 7 once 
the investigator determines that the event meets the protocol definition for that event.  
Any seizure or suspected seizure should be reported in an expedited manner, as noted in 
Table 7.
Criteria for liver chemistry stopping and follow-up criteria are in Section 5.5.1.

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Table 7
Reporting of Serious Adverse Events and Other Events
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 or 
death event
Initial and 
follow-up 
reports to be 
completed when 
the 
cardiovascular 
event or death 
is reporteda
“CV events” and/or 
“death” data 
collection tool(s) if 
applicable
Initial and follow-up 
reports to be 
completed when 
the cardiovascular 
event or death is 
reporteda
Updated “CV events” 
and/or “death” data 
collection tool(s) if 
applicable
Pregnancy
24 hours
“Pregnancy 
Notification Form”
Within 24 hours of 
investigator 
awareness of 
pregnancy outcome
“Pregnancy Follow-
up Form” and SAE if 
required
Seizure or suspected 
seizure
24 hours
eCRF
24 hours
eCRF
Suspected ABC HSR in 
participants 
randomized to the 
current ART arm or 
receiving Oral SOC 
during the Long-Term 
Follow-Up Phase b
1 week
ABC HSR eCRF
1 week
Updated ABC HSR 
eCRF
ALT3×ULN and
bilirubin2×ULN (>35% 
direct) (or ALT3×ULN)
24 hoursc
“SAE” data 
collection tool. 
“Liver Event eCRF” 
and “Liver Imaging” 
and/or “Liver 
Biopsy” eCRFs, if 
applicabled
24 hours
Updated “SAE” data 
collection tool/“Liver 
Event” documentsd

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Initial Reports
Follow-up Information on a Previous 
Report
Type of Event
Time Frame
Documents
Time Frame
Documents
ALT≥5×ULN that 
persists ≥2 weeks 
24 hoursc
Liver Event eCRFd
24 hours 
Updated Liver Event 
eCRFd
ALT ≥8×ULN 
24 hoursc
Liver Event eCRFd
24 hours 
Updated Liver Event 
eCRFd
ALT ≥3×ULN  (if 
baseline ALT is <ULN) 
or ALT ≥3 fold increase 
from baseline value 
with appearance or 
worsening of symptoms 
of hepatitis or 
hypersensitivity
24 hoursc
Liver Event eCRFd
24 hours 
Updated Liver Event 
eCRFd
a.
Additional details and time frames for reporting supplementary information for cardiovascular and death events 
are provided in Section 7.4.3.7 and Section 7.4.3.8, respectively.
b.
ABC HSR eCRF only required if event meets one of the ICH E2A definitions of seriousness.
c.
GSK must be contacted at onset of liver chemistry elevations to discuss participant safety.
d.
Liver event documents (i.e., “Liver Event eCRF” and updates, “Liver Imaging eCRF” and/or “Liver Biopsy eCRF”, 
as applicable) should be completed as soon as possible.
The method of recording, evaluating, and follow-up of AEs and SAEs plus procedures 
for completing and transmitting SAE reports to the medical monitor are provided in the 
SPM.  Procedures for post study AEs/SAEs are provided in the SPM.  Primary and 
secondary Medical Monitor/SAE contact information is provided on the Medical 
Monitor/Sponsor Information Page of the current protocol.
7.4.3.5.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
Disease related events (DREs) or outcomes listed in the CDC Classification System for 
HIV-1 Infections (Appendix 4) can be serious/life threatening and will be recorded on the 
HIV-Associated Conditions eCRF page if they occur. However, these individual events 
or outcomes, as well as any sign, symptom, diagnosis, illness, and/or clinical laboratory 
abnormality that can be linked to any of these events or outcomes are not reported to 
GSK as AEs and SAEs even though such event or outcome may meet the definition of an 
AE or SAE. However, if either of the following conditions applies, then the event must 
be recorded and reported as an SAE (instead of a DRE):

The investigator determines that the event or outcome qualifies as an SAE 
under part ‘other situations’ of the SAE definition (see Section 12.6.2), or

The event is, in the investigator’s opinion, of greater intensity, frequency, 
or duration than expected for the individual participant, or

The investigator considers that there is a reasonable possibility that the 
event was related to treatment with the investigational product, or

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
Death occurring for any reason during a study, including death due to a 
disease-related event, will always be reported promptly.

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 any 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 7.4.3.4) to GSK.
7.4.3.6.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs related to study treatment (even 
for non- interventional post-marketing studies) is essential so that legal obligations and 
ethical responsibilities towards the safety of participants and the safety of a product under 
clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee
(IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.4.3.7.
Cardiovascular and Death Events
Investigators will be required to fill out the specific CV event page of the eCRF 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

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Deep venous thrombosis/pulmonary embolism
Revascularisation
For any cardiovascular events detailed above, whether or not they are considered SAEs, 
and all deaths, specific Cardiovascular (CV) and Death sections of the eCRF will be 
required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the eCRF within one week of receipt of a CV Event data query prompting its completion. 
7.4.3.8.
Death Events
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
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.
Adverse events that occur during the trial should be evaluated by the investigator and 
graded according to the Division of Acquired Immunodeficiency Syndrome (DAIDS) 
toxicity scales (see Appendix 2). Additional information regarding detecting, 
documenting and reporting AEs and SAEs are available in Section 7.4.3.2. and Section 
12.6.
7.4.3.9.
Treatment Interruption Due to an Adverse Event
IP may be interrupted at the discretion of the investigator and according to the severity of 
the AE. If one or more ART medication is held due to toxicity or AEs, all ART 
medications should be held to reduce the risk of development of resistance taking into 
account the length of the planned interruptions and the PK half-life of each ART of the 
regimen, in order to minimize the risk of development of resistance.
No toxicity-related dose reductions of IP will be allowed.  IP 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).  Any interruption in 
therapy during the Maintenance Phase, 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 6.9).  IM dosing is 
expected to occur during the week in which the participant’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 

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outside of this guidance MUST be discussed with the Medical Monitor prior to 
reinitiating IM IP (see Section 6.9.1).
Guidance is provided below on general participant management and IP interruptions 
based on the severity of the AE.  Information regarding permitted substitutions \ is 
provided in Section 6.8.  All changes in the IP regimen must be accurately recorded in the 
participant’s eCRF.
Note: For participants receiving an ABC-containing product as part of the background 
regimen, in the event of a discontinuation of ABC for any reason, reinitiation of this drug 
should be undertaken with caution. The investigator should obtain a complete history of 
the events surrounding the discontinuation of the ABC-containing product, evaluate for 
the possibility of a clinically suspected HSR, and initiate participant management as 
outlined in the Local Country Prescribing Information, regardless of a participant’s HLA-
B*5701 status. Screening for the presence of HLA-B*5701 is recommended prior to 
reinitiating treatment with ABC-containing products in participants of unknown HLA-
B*5701 status who have previously tolerated ABC but is not required to confirm study 
eligibility.
7.4.3.10.
Grade 1 or Grade 2 Toxicity/Adverse Event
Participants who develop a Grade 1 or Grade 2 AE or toxicity may continue study drug at 
the discretion of the investigator.  Participants who choose to withdraw from the study 
due to a Grade 1 or 2 AE should have study withdrawal and follow-up evaluations 
completed.
Participants who develop ALT ≥3 times ULN while on study must consult with 
Medical Monitor prior to initiation or continuation of CAB LA + RPV LA
7.4.3.11.
Grade 3 Toxicity/Adverse Event
Participants 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 the Medical 
Monitor.

Participants 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 participant, the IP 
should be permanently discontinued and the participant withdrawn from study. 

Participants experiencing Grade 3 AEs requiring permanent discontinuation of 
IP should be followed weekly until resolution of the AE and to have withdrawal 
study evaluations completed.  A follow-up visit should be performed 4 weeks 
after the last dose of IP.  Any participant receiving at least one dose of CAB LA 

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and /or RPV LA who discontinue IP / Withdraw will initiate treatment with 
HAART and enter the Long-Term Follow-Up Phase for 52 weeks of follow up. 

Participants with Grade 3 asymptomatic laboratory abnormalities should be 
investigated for all potential non-drug related causes, and, following discussion 
with the Medical Monitor, may continue IP if the Investigator has compelling 
evidence that the toxicity is not related to IP, with the exception of liver 
chemistry stopping criteria (See Section 7.4.4.1).  Isolated Grade 3 lipid 
abnormalities do not require withdrawal of IP.
7.4.3.12.
Grade 4 Toxicity/Adverse Event

Participants 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, the Medical Monitor.  Participants should be rechecked each week 
until the AE returns to Grade 2.

Participants 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 
participant 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 Phase for 52 weeks of follow up. 

Participants with Grade 4 asymptomatic laboratory abnormalities should be 
investigated for all potential non-drug related causes, and, following discussion 
with the Medical Monitor, 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 7.4.4.1).  An in-clinic follow-up 
visit will be performed approximately 4 weeks after the last dose of study 
medication if AEs, SAEs, or laboratory abnormalities considered potentially 
harmful to the participant are ongoing at the last on-study visit.  Isolated Grade 4 
lipid abnormalities do not require withdrawal of IP.
7.4.4.
Specific Toxicities/Adverse Event Management’
General guidelines for the management of specific toxicities that are considered to be 
associated with treatment of HIV patients. 
Participants who permanently discontinue study drug for reasons of toxicity should be 
followed weekly until resolution of the AE and encouraged to complete the withdrawal 
and Follow-up study evaluations as noted in Section 7.4.3.3.
7.4.4.1.
Liver Chemistry Stopping and Follow-up Criteria
Liver chemistry threshold stopping criteria have been designed to assure participant 
safety and to evaluate liver event etiology during administration of study drug and the 
follow-up phase. All Phase 3 participants who meet liver stopping criteria will be 
adjudicated by the ViiV Safety and Labelling Committee (VSLC) – resulting in a case 

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summary, adjudication, and management plan. The VSLC contains an external expert 
hepatologist, familiar with both DILI and cabotegravir, who will participate in this 
review. This committee meets on a 3-weekly basis, and can be convened on an ad hoc 
basis as needed.
7.4.4.2.
Diarrhea
Participants with Grade 1 or 2 diarrhea may continue study treatment without 
interruption.  Participants 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 the Medical Monitor.
For participants 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 the Medical Monitor.  If Grade 3 
diarrhea recurs within 28 days upon the resumption of IP, the IP should be permanently 
discontinued and the participant withdrawn from the study.  Any participant 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 Phase 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.
7.4.4.3.
Hypertriglyceridemia/ Hypercholesterolemia
Samples for lipid measurements must be obtained in a fasted state according to the Time 
and Events table (Section 7.1).  Participants who experience asymptomatic triglyceride or 
cholesterol elevations may continue to receive IP.  Clinical management of participants 
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.
7.4.4.4.
Seizures
Three cases of seizures have occurred in the CAB program cumulatively through 01 
October 2015.  

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ViiV Healthcare has reviewed these cases in detail and does not believe they constitute a 
reasonable likelihood of causation associated with CAB.  This assessment is supported by 
the lack of preclinical signal, class effect or known CNS mechanism, the relatively low 
frequency of seizures relative to expected rates in both healthy and HIV positive 
participants and clinical confounders in each case.  The Sponsor considers the risk of 
developing seizures on the study as being no higher than that of the rest of the HIV-1 
infected population.  
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, 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 seizure page.
7.4.4.5.
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 participant 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 
participant withdrawn from the study.  Any participant 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 Phase for 52 weeks of follow-up.
7.4.4.6.
Lipase Elevations and Pancreatitis
Participants with asymptomatic Grade 1 or 2 elevations in lipase may be followed closely 
for the development of symptoms.
Participants 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.  
Participants 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.
Participants 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, 

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participants 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 participant should discontinue IP and be withdrawn from 
study.
Any participant 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 
Phase for 52 weeks of follow up.
Drug Restart Following Transient Resolving Liver Events Not Related to Study Drug
Approval by 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 × baseline and ALT 
<3 × ULN). Ethics Committee or IRB approval of drug restart must be obtained, as 
required.
If restart of drug is approved by VSLC in writing, the participant 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 participant 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 VSLC. 
Participants approved by VSLC for restarting study drug 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.
Refer to Section 12.3, Appendix 3: Liver Safety – Study Treatment Restart Guidelines for 
further details.
7.4.4.7.
Decline in Renal Function
Participants who experience an increase in serum creatinine from Baseline of 45 
micromoles/liter (Mol/L) (or 0.5 milligrams/deciliter [mg/dL]) should return for a 
confirmatory assessment within 2 to 4 weeks.  A urinalysis and urine albumin/creatinine 
and urine total protein/albumin ratios should also be done at this confirmatory visit.  If 
the creatinine increase is confirmed, the investigator should contact the study medical 
monitor to discuss additional follow-up and medical management.
Participants who have a decline in the estimated GFR (using the CKD-EPI method) of 
>50% from Baseline must return for a confirmatory assessment as soon as possible 

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[Levey, 2009]. A urinalysis and urine albumin/creatinine and urine protein/creatinine 
ratios should also be done at this confirmatory visit. If the estimated GFR has declined by 
>50% (confirmed), then study drug should be withheld and the investigator should 
contact the study medical monitor to discuss the rationale for restarting study drugs (if 
appropriate).  Consideration for confounding factors (e.g., background therapy, other 
medications, dehydration, concurrent conditions) should be taken into account, and a 
nephrology consult may be obtained.  
7.4.4.7.1.
Proximal Renal Tubule Dysfunctions
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).
Participants meeting criteria for PRTD must return for a confirmatory assessment within 
2 weeks of diagnosis. A urinalysis should also be performed at the time of the 
confirmatory assessment.  If PRTD is confirmed participants should have study drug 
withheld and the investigator should contact the Study medical monitor to discuss the 
rationale for restarting study drugs (if appropriate).  If a participant in the current ART 
arm is also receiving TDF, then a dose adjustment may be considered if restarting study 
drug unless participants met renal toxicity stopping criteria (see Section 7.4.4.7).  
Consideration for confounding factors (e.g., NRTI backbone, other medications, 
dehydration, concurrent conditions) should be taken into account, and a nephrology 
consult may be obtained.  If study drug is reinitiated, it should have been withheld for no 
more than 4 weeks.
7.4.4.8.
Proteinuria
Participants 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 2-4 weeks. If confirmed, then consideration should be given to 
additional evaluation after consultation with the study medical monitor. Additional 
evaluation may include a 24-hour urine protein and creatinine measurement and 
nephrology referral.
Participants 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 μmol/L (or 0.5 mg/dL) should have confirmation of both results within 2 weeks. If 

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confirmed, the study medical monitor should be contacted immediately. Agreement on 
further management should be agreed between the investigator and medical monitor. 
7.4.4.9.
QTc Prolongation
Participants with an average QTc interval > 550 msec 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 participant should be discontinued 
from the study.  If an alternative cause of the QT prolongation is determined (e.g., 
participant receiving drug known to cause prolonged QT or TdP), then IP may be 
restarted after consultation with, and agreement by, the Medical Monitor. 
7.4.4.10.
Injection Site Reactions (ISRs)
Injection site reactions will be managed through investigator assessment throughout the 
study.  All ISRs that are either serious, Grade 3 or higher, or persisting beyond 2 weeks 
must be discussed with the Medical Monitor to determine etiology and assess appropriate 
continued study participation.  
Digital photographs may be documented where possible on all participants who have an 
injection site reaction, with observable findings, that is either serious or Grade 3 or 
higher, or that persists beyond 2 weeks.  Dermatology will be consulted on all 
participants 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 participant’s ability to 
perform activities of daily living.  The required intervention should be documented on the 
appropriate eCRF page.
7.4.4.11.
Allergic reaction
Participants may continue study drug for Grade 1 or 2 allergic reactions at the discretion 
of the Investigator.  The participant 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. 
Participants with Grade ≥3 allergic reactions that are considered to be possibly or 
probably related to the study drug should permanently discontinue the CAB LA + RPV 
LA regimen and the participant should be withdrawn from the study.  Participants should 
be treated as clinically appropriate and followed until resolution of the AE.

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Participants in the current ART arm who are receiving ABC as part of their NRTI 
background regimen should be evaluated for the possibility of a clinically suspected ABC 
hypersensitivity reaction (HSR) and managed appropriately as outlined in the local 
prescribing information for ABC.
7.4.4.12.
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 
participants 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 participants who were HLA-B*5701 negative and who 
received ABC developed a clinically suspected ABC HSR, respectively.
In any participant 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, TRIZIVIR, or TRIUMEQ) if a HSR cannot be ruled out on 
clinical grounds, due to the potential for a severe or even fatal reaction.
7.4.4.12.1. Essential Patient Information
With reference to Local Country Prescribing Information and the ‘Participant Information 
and Consent Form’, Investigators must ensure that participants are fully informed 
regarding the following information on the hypersensitivity reaction prior to commencing 
ABC therapy:

Participants 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.

Participants must also be informed that HLA-B*5701 negative individuals can 
also experience abacavir hypersensitivity reaction.  Therefore, ANY participant 
who develops signs or symptoms consistent with a possible hypersensitivity 
reaction to abacavir MUST CONTACT their doctor IMMEDIATELY.

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
Participants who are hypersensitive to abacavir should be reminded that they must 
never take any abacavir containing medicinal products (e.g., ZIAGEN, 
EPZICOM, KIVEXA, TRIZIVIR, or TRIUMEQ) again, regardless of their HLA-
B*5701 status.

In order to avoid restarting abacavir, participants who have experienced a 
hypersensitivity reaction should be asked to return any remaining EPZICOM / 
KIVEXA tablets to the Investigator or site staff.

Participants, 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 participant 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. 
7.4.4.12.2. 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 12.6.2
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.
7.4.4.13.
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. 
Participants should be instructed to contact the Investigator as soon as possible if they 
develop a rash on study.
Participants 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 
participant should not be re-challenged with any ABC-containing medicinal product (i.e., 
ZIAGEN, TRIZIVIR, EPZICOM, or KIVEXA).

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As many products other than abacavir also cause rash and/or serious skin reactions, all 
other medicinal products that the participant is receiving should also be reviewed and 
discontinued as appropriate.
The following guidance is provided for clinical management of participants who 
experience rash alone in the absence of accompanying diagnosis of ABC HSR, systemic 
or allergic symptoms or signs of mucosal or target lesions.
CAB is an analogue of DTG and mild to moderate rash is an expected adverse reaction 
for DTG-containing ART.  Episodes generally occur within the first ten weeks of 
treatment, rarely require interruptions or discontinuations of therapy and tend to resolve 
within two to three weeks.  No instances of serious skin reaction, including 
Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and erythema 
multiforme, have been reported for DTG in clinical trials.  For further characterization of 
HSR and rash observed with DTG-containing ART, please see the current version of the 
IB [GlaxoSmithKline Document Number RM2007/00683/09].
Rash is an adverse drug reaction (ADR) for RPV.  In clinical trials, most rashes emerged 
during the first 4 weeks of treatment, were transient, and usually mild (Grade 1) to 
moderate (Grade 2).  There were no Grade 4 rashes and none were serious.  Treatment-
related Grade 3 rash was reported in 0.1% of participants in the RPV group.  Treatment-
related rash led to permanent discontinuation in 0.1% of participants in the RPV group.  
No cases of erythema multiforme, SJS or TEN have been reported during clinical 
development of RPV.
Participants with an isolated Grade 1 rash may continue study drug at the Investigator’s 
discretion.  The participant should be advised to contact the Investigator immediately if 
there is any worsening of the rash, if any systemic signs or symptoms appear, or if 
mucosal involvement develops.
Participants may continue study drug for an isolated Grade 2 rash.  However, study drug 
(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 participant 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.
Participants should permanently discontinue study drug [and all other concurrent 
medication(s) suspected in the Investigators causality assessment] for an isolated Grade 3 
or 4 rash, except where the etiology of the rash has been definitively diagnosed as NOT 
attributable to study drug (see below), and the participant should be withdrawn from the 
study.  Participants should be treated as clinically appropriate and followed until 
resolution of the AE.  Every effort should be made to collect as much information as 
possible about the evolution of the event and any relationship with potentially related 
medical events (e.g., viral infection) or start of concomitant medication.

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The rash and any associated symptoms should be reported as adverse events and 
appropriate toxicity ratings should be used to grade the events (based on DAIDS toxicity 
gradings – see Section 12.2, Appendix 2).
However, if the etiology of the rash has been definitively diagnosed as being unrelated to 
study drug and due to a specific medical event or a concomitant infection or a 
concomitant non-study medication, routine management should be performed and 
documentation of the diagnosis provided.  In this situation, the study drug should be 
continued. 
Participants in the current ART arm who are receiving ABC as part of their regimen 
should be evaluated for the possibility of a clinically suspected ABC HSR and managed 
appropriately as outlined in the local prescribing information for ABC.
Any rash that is possibly related to study drug, and is present between Day 1 and 
The Week 4b visit, must be discussed with the Medical Monitor prior to initiation of 
CAB LA or RPV LA.
Any participant 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 
Phase for 52 weeks of follow-up.
7.4.5.
Suicidal Risk Monitoring
Participants with HIV infection may occasionally present with symptoms of depression 
and/or suicidal ideation or behavior.  In addition, there have been some reports of 
depression, suicidal ideation and behavior (particularly in participants with a pre-existing 
history of depression or psychiatric illness) in some patients being treated with INIs.  
Additionally, depression and anxiety has been reported in some participants being treated 
with RPV.  Therefore, it is appropriate to monitor and closely observe participants 
prospectively before and during treatment for suicidal ideation and/or behavior, or any 
other unusual changes in behavior.  It is recommended that the Investigator consider 
mental health consultation or referral for participants who experience signs of suicidal 
ideation or behavior.
Participants presenting with new onset/treatment emergent depression should be advised 
to contact the investigator immediately if symptoms of severe acute depression (including 
suicidal ideation/attempts) develop, because medical intervention and discontinuation of 
the study medication may be required.
Assessment of treatment-emergent suicidality will be monitored during this study using 
the electronic version of the Columbia Suicide-Severity Rating Scale (eC-SSRS).  The 
definitions of behavioural suicidal events used in this scale are based on those used in the 
Columbia Suicide History Form [Posner, 2007].  Questions are asked on suicidal 
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 as a patient completed questionnaire specified in the Time and Events Table 

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(Section 7.1).  The eC-SSRS will be conducted electronically by telephone or by 
computer/tablet connected to the internet.
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 participant that experiences a possible 
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 ViiV/GSK 
within one week of the investigator diagnosing a possible suicidality-related adverse 
event.  All sites should have a plan in place for managing possible risks for suicide 
related events.  
7.4.6.
Pregnancy
7.4.6.1.
Pregnancy testing
Women of childbearing potential must have a negative pregnancy test at Screening, 
Baseline (Day 1), and Week 56 for women transitioning into the Extension Phase from 
the current ART arm.(prior to administration of first CAB LA and / or RPV LA 
injection).  Pregnancy testing will also be conducted as per the Time and Events Table 
(Section 7.1) and at anytime during the trial when pregnancy is suspected.
Additionally, the Medical Monitor may request that a urine pregnancy test be performed 
in the event of a treatment interruption greater than 7 days.
7.4.6.2.
Time Period for Collecting Pregnancy Information
Pregnancy information will be collected from Day 1 until the last follow-up assessment.  
This includes the entirety of the Long-Term Follow-Up Phase.
Female participants that have received at least one dose of CAB LA or RPV LA and do 
not enter the Long-Term Follow-Up Phase 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 participant 
becomes pregnant within 52 weeks of the last dose of study drug the participant should 
notify the study site.
7.4.6.3.
Action to be Taken if Pregnancy Occurs
Any individual who becomes pregnant (intrauterine) while participating in this study 
must be withdrawn from the study and must immediately discontinue study drug.  
Participants 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 Phase 
(see Section 4.2.4 above), after discussion with the Medical Monitor.  

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Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form.  To ensure participant safety, if a pregnancy is reported then the 
investigator should inform GSK within 24 hours of learning of the pregnancy and should 
follow the procedures outlined in Appendix 7.
Participants who have received at least one IM injection of CAB LA and RPV LA and 
become pregnant during the study will have additional PK samples collections to monitor 
CAB LA and RPV LA exposure throughout the pregnancy and at the time of delivery.  
Additionally, there will be an optional umbilical cord blood collection at time of delivery 
and/or breast milk after delivery, requiring additional parental informed consent.  Cord 
blood and breast milk samples would be used to better understand the level of PK 
exposure to the neonate, if any.
The pregnancy must be followed up to determine outcome (including premature 
termination) and status of mother and child(ren).  Pregnancy complications and elective 
terminations for medical reasons must be reported as an AE or SAE.  Spontaneous 
abortions must be reported as SAEs.
Any SAE occurring in association with a pregnancy brought to the investigator’s 
attention after the participant has completed the study and considered by the investigator 
as possibly related to the study treatment, must be promptly reported to ViiV/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 ARV products.  Additional information and a list of participating 
manufacturers/licensees are available from http://apregistry.com/index.htm.
7.4.7.
Physical Exams
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).

A complete physical examination will include, at a minimum, assessment of 
the Cardiovascular, Respiratory, Gastrointestinal, and Neurological systems.  
Height and weight will also be measured and recorded as per the Time and 
Events Table in Section 7.1 above. 

A brief physical examination will include, at a minimum assessments of the 
skin, lungs, cardiovascular system, and abdomen (liver and spleen).

The site of IM injection administration should be assessed at every visit for 
signs of any possible reaction.  See Section 7.4.4.10 for additional information.

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.

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7.4.8.
Vital Signs
Vital signs will be measured in semi-supine position after 5 minutes rest and will include 
temperature, systolic and diastolic blood pressure and pulse rate.  These will be recorded 
as per the Time and Events Table in Section 7.1.
7.4.9.
Electrocardiogram (ECG)
A 12-lead ECG will be performed in a semi-supine position.  On Day 1, (Baseline), 
ECGs should be performed in triplicate prior to first dose.  At Week 4b and Week 48 of 
the Maintenance Phase, a 2 hour post dose ECG will be performed for participants 
randomized to CAB LA + RPV LA.  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 participant.  Regardless, each ECG should be reviewed by a qualified 
ECG reader.  The qualified ECG reader will make the non-calculated ECG 
interpretations.  Refer to the Time and Events Table for collection timepoints (Section 
7.1).  Refer to Section 5.5.2 for [QTc] withdrawal criteria and additional [QTc] readings 
that may be necessary
7.5.
Pharmacokinetics
Plasma samples for determination of CAB and RPV concentration will be collected 
throughout the Maintenance and Extension Phases of the study. Additional samples will 
be collected for storage during the Long-Term Follow-Up Phase (blood and plasma). 
Samples (blood and plasma) for determination of RPV concentrations will be protected 
from light at all times, from sampling collection through analysis.
7.5.1.
PK Sample Collection
Blood samples for evaluation of CAB (2mL each) and RPV (2mL each) plasma PK 
concentrations will be collected from all participants randomized to receive CAB + RPV 
as described in Table 8. 
At Week 4b (and Week 56b for participants transitioning into the Extension Phase from 
the current ART arm), PK samples must be collected within the window of 20-28 hours 
after the last oral dose of CAB + RPV was taken the day prior to the clinic visit. 
Participants will take their final dose of oral CAB + RPV in the clinic at Week 4b (or 
Week 56b) after the pre-dose PK sample. 
Participants will be expected to complete a PK dosing diary card noting the date and time 
of the last three oral doses of IP prior to the scheduled clinic visits at Week 4b (or Week 
56b).  The information from the diary card and the actual date and time of the PK 
samples will be recorded in the eCRF.  Additionally, dosing information on the clinic 
day, including dosing and the actual date and time of the PK samples, must be recorded 

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on the eCRF.  Participants will take their last dose of oral CAB + RPV in the clinic at 
Week 4b (or Week 56b) after the pre-dose PK sample.  
PK concentrations will be summarized and used to evaluate potential exposure-response 
relationships.
The timing of PK samples may be altered and/or PK samples may be obtained at 
additional time points to ensure thorough PK monitoring.  

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Table 8
CAB and RPV Plasma Pharmacokinetic Sample Schedule
Group
Analyte
Sample Times Relative to Dose
All participants 
receiving CAB LA +  
RPV LA IM
CAB
Pre-Dose:  Week 4b, 8, 12, 16, 20, 24, 28, 32, 36, 
40, 44, 48, 52, 96, and Withdrawal.
2 Hours Post Dose:  Week 4b, Week 48 ,Week 96 
1 Week Post Dose:  Week 5 and Week 41
PK samples for storage only:
Pre-dose: Week 64, 72, 80 and 88
Long-term follow-up Period (off-drug; storage 
sample)
Months 1, 3, 6, 9, and 12
RPV
Pre-Dose:  Week 4b, 8, 12, 16, 20, 24, 28, 32, 36, 
40, 44, 48, 52, 96, and Withdrawal.
2 Hours Post Dose:  Week 4b, Week 48, Week 96 (i
1 Week Post Dose:  Week 5 and Week 41
PK samples for storage only:
Pre-dose: Week 64, 72, 80 and 88
Long-term follow-up Period (off-drug; storage 
sample)
Months 1, 3, 6, 9, and 12
Current ART Arm 
Transitioning to 
CAB LA + RPV LA 
IM following Week 
48
CAB
Pre-Dose: Week 56b, Week 60, and Withdrawal
2 Hours Post Dose:  Week 56b 
Long-term follow-up Period (off-drug; storage 
sample)
Months 1, 3, 6, 9, and 12
RPV
Pre-Dose:  Week 56b, Week 60, and Withdrawal
2 Hours Post Dose:  Week 56b
Long-term follow-up Period (off-drug; storage 
sample)
Months 1, 3, 6, 9, and 12
PK visit window and sample collection: Pre-dose visits (from projected visit date): 3 
days (1st injection), minus 7 days (2nd and 3rd injection), and 7days (4th and all 
subsequent injections); Pre-dose sample collection at Week 4b (and Week 56b for 
participants transitioning from the current ART arm): 20 to 28 hours after the last oral 

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dose of CAB and RPV was taken; 2 hours post dose: one hour; one week post dose 
visits: 3 to 10 days post injection.
If a participant 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.
Samples for determination of RPV will be protected from light until analyzed. 
7.5.2.
Rationale of PK Sampling Strategy
Blood sampling for CAB and RPV concentrations will be performed during the 
Maintenance Phase of the study to evaluate PK in HIV infected participants.  The 
proposed PK visits and sampling scheme at each visit presented in Section 7.1 is based on 
consideration of available PK data to support interim and final PK and 
PK/Pharmacodynamic (PD) analysis planned in this study.
7.5.3.
Sample Analysis
7.5.3.1.
CAB Sample Analysis
Plasma CAB analysis will be performed under the control of PTS-DMPK, 
GlaxoSmithKline, the details of which will be included in the Study Reference Manual 
(SRM). Concentrations of CAB will be determined in plasma samples using the 
currently approved bioanalytical methodology. Raw data will be archived at the 
bioanalytical site (detailed in the SRM).
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, GSK protocol.  No human DNA analysis will be performed on these samples.
7.5.3.2.
RPV Sample Analysis
Plasma RPV analysis will be performed under the control of Janssen R&D. 
Concentrations of RPV 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 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 
on these samples.
7.6.
Biomarker(s)
Blood and urine are being collected to perform renal, and bone assessments, as outlined 
in Table 6. Renal biomarkers include Cystatin C (blood), Retinol Binding Protein (RBP, 
blood/urine), urine albumin/creatinine ratio, urine protein/creatinine ratio, urine 

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phosphate and serum creatinine.  Bone biomarkers (blood) include bone-specific alkaline 
phosphatase, procollagen type 1 N-propeptide, type 1 collagen cross-linked C-
telopeptide, osteocalcin, 25 hydroxy-Vitamin D. 
7.7.
Genetics
Information regarding genetic research is included in Appendix 5:  Genetic Research. 
7.8.
Viral Genotyping and Phenotyping
Whole venous blood samples will be obtained from each participant to provide PBMCs 
and plasma for storage samples according to the Time and Events Table (see Section 7.1) 
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), reverse transcriptase (RT), and integrase assays.
7.8.1.
HIV-1 Polymerase Viral Genotyping and Phenotyping
Participants meeting 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 samples collected at the time of meeting suspected virologic failure; 
these results will be reported to the investigator as soon as available to provide guidance 
for election of an alternative regimen.
7.8.2.
HIV-1 Exploratory Analysis
Additional analyses for HIV-1 resistance may, for example, be carried out on peripheral 
blood mononuclear cell (PBMC) samples collected at Baseline and/or on stored blood 
samples from other relevant time points.  These analyses may 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, low level HIV-1 RNA quantitation and 
measurement of viral replicative capacity. HIV-1 PRO and RT genotype and phenotype 
and HIV-1 integrase genotype and phenotype will also be determined on the last on-
treatment isolates from participants who have HIV-1 RNA 200 c/mL regardless of 
confirmatory HIV-1 RNA.
7.9.
Value Evidence and Outcomes 
Health outcomes assessments will be conducted according to the Time and Events Table 
(Section 7.1).  Assessments are recommended to be administered with a electronic site 
pad or paper instrument at the beginning of the visit prior to collection of blood for 
analysis and other scheduled assessments with the exception of the NRS (administered 
post injection). 
The 12-item Short Form Health Survey (SF-12) is a measure that describes the degree of 
general health status and mental health distress [Ware, 1995]. The SF-12 contains 12 

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items and it is derived from the Medical Outcomes Study 36-Item Short Form Health 
Survey. 
The HIV Treatment Satisfaction Questionnaire (HIVTSQ) [Woodcock, 2001 and 
Woodcock, 2006] was developed to evaluate treatments for HIV and patient satisfaction.
The original HIVTSQ included 10 items and underwent two stages of psychometric 
validation (Woodcock, 2001, Woodcock, 2006). Recently, the HIVTSQ was adapted to 
include injectable treatment for HIV following a qualitative study with HIV patients in 
five European countries.  The adaptation of the HIVTSQ included two additional items 
related to the mode of administration (i.e., long acting intramuscular injection). These 
are:

Item 11.  How easy or difficult have you been finding your treatment to be 
recently? 

Item 12.  How satisfied are you with the amount of discomfort or pain involved 
with your present form of treatment? 
Psychometric analyses from three datasets (one from the UK, one from the USA and one 
from the LATTE-2 trial) reveal that the addition of two items in the original version of 
the HIVTSQ is suitable and does not reduce the overall validity of the questionnaire.  The 
current study will be using the HIVTSQs (status version) and the revised HIVTSQc 
(change version) of this recently developed HIVTSQ 12-item questionnaire. The 
HIVTSQ 12-item questionnaire retains the option of calculating the total score as if it 
only had the original 10 items (as the original 10 items are included in the HIV-TSQ12). 
In addition it allows for calculation of an 11-item scale score including the 
“easy/difficult” item (item-11). The “pain/discomfort” item (item-12) will be included in 
the questionnaire as a stand-alone item to evaluate potentially painful injectables. These 
measures will assess change in treatment satisfaction over time (in the same participants) 
and compare current satisfaction with previous treatment satisfaction, from an earlier 
time point.
The Perception of Injection (PIN) questionnaire explores the bother of pain at the 
injection site and ISR, anxiety before and after injection, willingness to receive an HIV 
injectable treatment the following visit and satisfaction with the mode of treatment 
administration of individuals receiving injection and perceptions of individuals associated 
with receiving injections. The PIN questionnaire was derived from the Vaccines' 
Perception of Injection (VAPI) questionnaire (Chevat, 2009), and adapted for HIV-
infected patients who will receive the CAB LA and RPV LA regimen.This measure 
contains 21 items that measure pain at injection site, local site reactions, impact on 
functioning and willingness to pursue injectable treatment outside of a clinical trial. 
Scores range from 1 to 5, and questions are phrased in such a way as to ensure that 1 
always equated with the most favourable perception of vaccination, and 5 the most 
unfavourable.
The ACCEPT questionnaire is a generic medication acceptance measure assessing how 
patients weigh advantages and disadvantages of long-term medications (Marant, 2012). 
ACCEPT may be a predictor of patients' future adherence to and/or persistence with their 

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treatment. While the ACCEPT questionnaire consists of 25 items that capture six 
dimensions, we will use three questions that focus on general acceptance of study 
medication.
The HIV/AIDS Targeted Quality of Life (HAT-QoL) instrument [Holmes, 1998] 
originally contained 42 items, grouped into nine dimensions, assessing overall function 
and well-being. For the purposes of this study, ViiV Healthcare is using a shorter version 
adapted from the original version. This shorter version contains 14 items grouped into the 
three following dimensions: “life satisfaction”, “disclosure worries” and “HIV 
medication”. All items use a ‘‘past 4 weeks’’ timeframe and a Likert response scale from 
1=‘‘all of the time’’ to 5=‘‘none of the time’’
The Numeric Rating Scale (NRS) is a segmented numeric version of the visual analog 
scale (VAS) in which a respondent selects a whole number (0–10 integers) that best 
reflects the intensity of his/her post-injection pain. The NRS is anchored by 0 
representing “No pain” and 10 representing “Extreme pain”.
The “Reason for Switch” question will contain a single item exploring the reasons why 
patients choose to switch study medication. The single item will include six possible 
response options.
The “Preference” questions will contain a single item exploring whether patients prefer 
the CAB LA + RPV LA injectable treatment or the current oral ART or oral ARV 
regimen.
Qualitative interviews may be conducted regarding their experience with study treatment. 
These would be conducted under a separate IRB approved consent. Participation in the 
interviews would be voluntary.
7.9.1.
Value Evidence and Outcomes Endpoints (Secondary)

Change from Week 5 in Dimension scores (e.g., “Bother of ISRs”, “Leg 
movement”, “Sleep”, and “Injection Acceptance”) and individual item scores 
assessing pain during injection, anxiety before and after injection, willingness to 
be injected in the future and overall satisfaction with mode of administration over 
time using the Perception of iNjection questionnaire (PIN). 

Proportion of participants considering pain and local reactions following injection 
to be extremely or very acceptable based on the acceptability score over time 
using the Perception of iNjection questionnaire (PIN).

Change from baseline in total “treatment satisfaction” score, and individual item 
scores of the HIVTSQs at Weeks 4b, 24, 44, 96 (or Withdrawal).

Change in treatment satisfaction over time (using the HIVTSQc) at Week 48 (or 
Withdrawal).

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
Change from Baseline in treatment acceptance (at Weeks 8, 24, 48, 96 (or 
Withdrawal from the study) using the “General acceptance” dimension of the 
Chronic Treatment Acceptance (ACCEPT) questionnaire.

Change from Baseline in health status at Week 24, Week 48, and Week 96 (or 
Withdrawal) using the 12-item Short Form Survey (SF-12).

Change from Baseline in HR QoL (using the HAT-QoL short form) at Weeks 24, 
48, 96 (or Withdrawal from the study).

Change from Week 4b in tolerability of injections (using the NRS) at Weeks 5, 
40, 41, 96.  
7.9.2.
Value Evidence and Outcomes Endpoints (Exploratory)

The “Reason for switch” question will be assessed at baseline and at Week 52 in 
patients randomized to the “Current ART” arm.

The “Preference” question will be assessed at Week 48 ( primary analysis) in 
patients randomized to the “CAB LA and RPV LA” arm to explore patient 
preference between CAB LA + RPV LA injectable regimen and current ART 
regimen.  The question will be assessed at Week 96 ( secondary analysis) in 
patients randomized to “Current ART” arm who decided to switch to CAB LA + 
RPV LA, to explore patient preference between CAB LA + RPV LA injectable 
regimen and “Current ART” regimen.
8.
DATA MANAGEMENT

For this study participant data will be entered into GSK defined 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 Medical 
Dictionary for Regulatory Activities (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.  Participant 
initials will not be collected or transmitted to GSK according to GSK policy.

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9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
The study is designed to demonstrate that the antiviral effect of switching to CAB LA + 
RPV LA (CAB) is non-inferior to continuation of current first line antiretroviral regimen 
(current ART) at Week 48 in HIV-1 infected ART-experienced participants. Non-
inferiority in the proportion of participants with virologic failure at Week 48 (per FDA’s 
snapshot algorithm for assessing HIV-1 RNA 50 copies/mL) can be concluded if the 
upper bound of a two-sided 95% confidence interval for the difference in failure rates 
between the two treatment arms (CAB – current ART) is not more than 6%.
If fla is the failure rate for CAB LA + RPV LA and fc is the failure rate for current ART 
then the hypotheses can be written as follows:
H0: fla – fc 6%  
H1: fla – fc < 6%
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
This study will randomize approximately 285 participants per arm.  Assuming the true 
virologic failure rate is 3% for the CAB LA + RPV LA injectable regimen and 2% for 
current ART arm, a non-inferiority margin of 6%, and a 2.5% one-sided significance 
level, this would provide approximately 97% power to show non-inferiority for the 
proportion of participants with virologic failure (per FDA’s snapshot algorithm for 
assessing HIV-1 RNA 50 copies/mL) at Week 48.  
This sample size of 285 participants per arm will also provide at least 90% power to show 
non-inferiority in the proportion of participants with plasma HIV-1 RNA <50 c/mL (per 
FDA’s snapshot algorithm) at Week 48 over a range of true response rates, on the basis 
of a -10% non-inferiority margin and 2.5% one-sided significance level (see Table 13). 
Assuming true response rates for the CAB LA + RPV LA arm and current ART arm are 
both 87%, the power is at least 94% to show non-inferiority for this key secondary 
endpoint.
In addition, the data from this study, together with data from a separate study, 201584 
(FLAIR), will be combined to assess non-inferiority using a 4% non-inferiority margin.  
The combined sample size from both studies (570 pooled per arm) will provide 90% 
power, under the assumptions described above, to show non-inferiority for the proportion 
of participants with virologic failure (per FDA’s snapshot algorithm for assessing HIV-1 
RNA 50 c/mL) at Week 48.

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9.2.1.1.
Rationale for non-inferiority margin
The selection of the non-inferiority margins in a switch study comparing regimens (rather 
than individual component drugs) is exclusively informed by clinical judgment (and 
practical considerations) since regimen efficacy over placebo will be obvious – if the 
regimen efficacy were no better than placebo virtually all subjects would show virologic 
failure. While this implies that any non-inferiority margin would be justifiable 
statistically, it would not be justifiable clinically to accept more than a 4 to 6 percent 
increase in the rate of virologic failure relative to standard-of-care regimen(s).
The non-inferiority margin of 6% is chosen in consideration of the FDA’s 2015 guidance 
document FDA, 2015 (Human Immunodeficiency Virus-1 Infection: Development of 
ART Drugs for Treatment, November 2015) which is the most current regulatory 
guidance from either the EMA or FDA and includes specific recommendations regarding 
switch studies. It suggests that margins in the neighbourhood of 4% are clinically 
tolerable, with typical observed rates of virological failure ranging from 1 to 3%.
As this study (201585) and study 201584 are not sufficiently powered to rule out 4% 
virologic failure in excess, the 6% margin chosen in each study can be viewed as defining 
criteria for assessing the consistency acceptability of the study-specific results prior to 
integration of the studies in the pooled analysis. Assuming an observed control failure 
rate of 2%, then non-inferiority would be shown in an individual study using a 6% 
margin if the observed CAB LA+RPV LA failure rate was less than 5% (that is, if the 
observed treatment difference was less than 3 percentage points). Accordingly, if the 
individual studies are successful in ruling out a 6% margin, the observed results are 
expected to be similar and reasonable to integrate for the purposes of the primary efficacy 
assessment based on the pooled analysis. In addition, a virologic failure rate in this range 
may be clinically tolerable given the CAB LA + RPV LA regimen may offer important 
advantages over standard 3-drug oral regimens such as better tolerability, as well as 
improved adherence and treatment satisfaction in virologically suppressed subjects. 
Therefore, 6% is considered to be a reasonable non-inferiority margin for the individual 
studies, with a more stringent 4% margin applied for the pooled analysis.
9.2.1.2.
Assumption for Virologic Failure Rate at Week 48 (Primary Endpoint)
9.2.1.2.1.
Control Arm
The control arm will be comprised of participants whose viral load at time of 
randomization is suppressed (<50 c/mL) on INI-, NNRTI- or PI- based regimens.  Based 
on these data, reasonable assumptions for the true failure rates are 2% for the control arm 
and 3% for the CAB + RPV LA injectable regimen.  
Table 9 shows the Snapshot response and failure rates observed in five recent stable 
switch studies.  Table 10 shows the difference in snapshot failure rates between Week 48 
and Week 96 observed in recent treatment naive studies with INI-based regimens.  These 
differences provide an approximate predication of the failure rates that may be seen in 
early switch studies enrolling virologically suppressed participants after 48 weeks of 
initial ART therapy. Taken together, these data suggest that a reasonable assumption for 
the true failure rate for the current ART control arm is 2%.

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Table 9
Snapshot Analysis Outcomes in Recent Stable Switch Studies
Week 48
Study
Treatment Arm
HIV-1 RNA <50 
Virologic Failure 
SPIRITa,b
RPV/FTC/TDF
89%
8/317 (2.5%)
STRATEGY-PIc
QUAD
94%
2/290 (<1%)
PI + FTC/TDF
87%
2/139 (1%)
STRATEGY-NNRTId
QUAD
93%
3/290 (1%)
NNRTI + FTC/TDF
88%
1/143 (<1%)
GS-292-0109e
E/C/F/TAF
97%
10/959 (1%)
TDF-based regimen f
93%
6/477 (1%)
Week 24
STRIIVING
DTG + ABC/3TC STR
85%
1%
Current ART 
88%
1%
a.
Participants in the PI/r +2 NRTIs arm were switched to RPV/FTC/TDF at Week 24 and therefore 
Week 48 response data are not available.
b.
[Palella, 2014]
c.
[Arribas, 2014]
d.
[Pozniak, 2014]
e.
[Martínez, 2010]
f.
E/C/F/TDF or EFC/FTC/TDF or ATV+ FTC/TDF 
Table 10
Snapshot Virologic Failure Rates with INI-based Regimens in 
Treatment Naive Participants
Study
Regimen
Week 48
Week 96
Change
SINGLE
DTG/ABC/3TC
21/414 (5%)
42/414 (10%)
+5%
SPRING-2
DTG + ABC/3TC or TDF/FTC
20/411 (5%)
22 /411 (5%)
+0.5%
FLAMINGO
DTG + ABC/3TC or TDF/FTC
15/242 (6%)
19/242 (8%)
+2%
236-0102
E/C/F/TDF
25/348 (7.2%)
6% 
-1%
236-0103
E/C/F/TDF
19/353 (5.4%)
24/353 (6.8%)
+2%
292-0104/0111
E/C/F/TAF
4%
5%
+1%
E/C/F/TDF
4%
4%
0%
9.2.1.2.2.
CAB LA + RPV LA arm
To inform the failure rate for the CAB LA + RPV LA arm, the Snapshot virologic failure 
rates from the Phase IIb CAB studies are displayed in Table 11 for the Intent-to-Treat 
Exposed population.  Eligible participants included in the ITT-ME population had HIV-1 
RNA <50 c/mL prior to receiving maintenance therapy at Day 1 for LATTE-2 and Week 
24 for LATTE.  
For LATTE, 9% (7%, excluding 1 participant classified as failure due to ART changes 
during the induction period) of participants previously suppressed at Week 20 to Week 
24 were classified as virologic failures at Week 72 (48 weeks of maintenance treatment 
with oral CAB + RPV).  For LATTE-2, 4% of participants randomized to CAB LA + 
RPV LA regimens (pooled) were classified as virologic failures after 48 weeks of 
maintenance treatment.  Furthermore, while the failure rate was <1% at Week 48 for 
Q4W, there was noted variation in the snapshot failure rate over time, ranging between 
0% to 3.5% through Week 48, for Q4W. These results suggests a conservative 
assumption for the true failure rate for the CAB LA + RPV LA Q4W arm of 3%, even 

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though there is no clinical rationale to suggest that the failure rate is truly higher for the 
CAB regimen compared to the control regimen.
Table 11
Snapshot Analysis Outcomes for Phase IIb CAB Studies (Intent-to-
Treat Maintenance Exposed Population)
Week 48
Study
Maintenance Treatment Arm
HIV-1 RNA <50 
Virologic Failure 
LATTE-2 (ITT-ME) a
CAB LA + RPV LA Q8W (N=115)
92%
8/115 (7%)
CAB LA + RPV LA Q4W (N=115)
91%
1/115 (<1%)
Oral CAB + 2NRTIs  (N=56)
89% 
1/56 (2%)
Pooled LA
92%
6/230 (4%)
Week 72 
LATTE (ITT-ME) b
Oral CAB 30mg + RPV (n=53)
83%
9%c
a)
Participants had HIV-1 RNA <50 c/mL at Week -4 and received oral CAB 30mg + 2 NRTIs as initial induction 
period therapy from Week -20 to Day 1.
b)
Participants had HIV-1 RNA <50 c/mL at Week 20 and switched from oral CAB 30mg + 2 NRTIs to Oral CAB 30 
mg + RPV at Week 24.
c)
Includes one participant (2%) that was a virologic success but was classified as failure due to background ART 
change that occurred during the induction period, which is not an applicable failure category for the CAB LA + 
RPV LA regimen
9.2.1.3.
Assumption for Response Rate at Week 48 (Secondary Endpoint)
Given the response rates shown in Table 9 and Table 11, a reasonable assumption for the 
true success response rate (HIV-1 RNA <50 c/mL) for both arms is 87%.
9.2.2.
Sample Size Sensitivity
Figure 8 shows the sensitivity of the power curve for the primary comparison to different 
assumed ‘true’ virologic failure rates with 285 randomized per arm.  Even if the failure 
rates were 3% for CAB LA + RPV LA and 1% for the control arm, the study will still 
have over 92% power to meet its primary objective.  

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Figure 8
Sensitivity of Estimated Power for Snapshot Virologic Failure
Table 12 shows the power with 285 randomized per arm and the sample size required to 
guarantee 90% power, for a range of ‘true’ virologic failure rates.  For instance, even if 
the failure rates were 3% for CAB LA + RPV LA and 1% for the control arm, the study 
will still have over 92% power to meet its primary objective with the planned sample 
size.  However, if the failure rates were 4% for CAB LA + RPV LA and 2% for control, 
an additional ninety-six participants per arm would be required to obtain 90% power for 
the primary treatment comparison. 

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Table 12
Sensitivity of Estimated Power for Snapshot Virologic Failure
Control Arm Virologic 
Failure Rate (%)
CAB LA + RPV LA Arm 
Virologic Failure Rate 
(%)
6% Non-inferiority Margin
Power (%)
with N=285
per arm 
N Required
per arm for
90% Power
1%
1%
>99.9%
73
1%
2%
99.8
124
1%
3%
92.7
257
1%
4%
63.4
564
1.5%
1.5%
>99.9%
98
1.5%
3%
95.2
228
2%
2%
>99.9%
115
2%
2.5%
99.3
153
2%
3%
96.8
205
2%
3.5%
90.8
277
2%
4%
80.0
381
3%
3%
98.7
170
3%
4%
90.1
284
Table 13 show the sensitivity of the estimated sample size and power for the secondary 
endpoint comparison of response rates (HIV-1 RNA <50 c/mL at Week 48) to different 
assumed ‘true’ response rates. 
Table 13
Sensitivity of Estimated Power for Snapshot Virologic Success
Control Arm Virologic 
Success Rate (%)
CAB LA + RPV LA Arm 
Virologic Success Rate 
(%)
-10% Non-inferiority Margin
Power (%)
With N=285 
N Required per arm for
90% Power
85%
85%
91.6
268
86%
85%
86.2
322
86%
86%
93.0
254
86%
87%
97.0
203
87%
85%
78.6
396
87%
86%
88.1
303
87%
87%
94.4
238
87%
88%
97.7
190
88%
87%
90.1
284
88%
88%
95.6
222
88%
89%
98.4
177
89%
89%
96.8
206
9.2.3.
Sample Size Re-estimation or Adjustment
No sample-size re-estimation based on response data is planned for this study.

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9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
9.3.1.1.
Intent-to-Treat Exposed (ITT-E)
The ITT-E population will consist of all randomly assigned participants who receive at 
least one dose of study drug. Participants will be assessed according to their randomized 
treatment, regardless of the treatment they received.  The population used in the primary 
efficacy analysis will be the ITT-E population.
9.3.1.2.
Per-Protocol Population (PP)
The Per-Protocol (PP) Population will consist of all participants in the ITT-E Population 
with the exception of major protocol violators. The PP will be used for sensitivity 
analysis of the primary endpoint.
9.3.1.3.
PK Population
The PK Population will include all participants who receive CAB and / or RPVand 
undergo PK sampling during the study, and provide evaluable CAB and /or
RPV plasma concentration data.  Participants in this population will be included in the 
PK analysis.
9.3.1.4.
Safety Population
The Safety Population will consist of all randomly assigned participants who receive at 
least one dose of study drug. Participants will be assessed according to actual treatment 
received.  Unless otherwise stated, the Safety Population will be used for safety analyses.
9.3.2.
Treatment Comparisons
9.3.2.1.
Primary Comparison of Interest
The primary analysis will be based on the ITT-E population using the Snapshot dataset.  
The primary comparison of will be made at a one-sided 2.5% level of significance. 
Treatment with CAB LA + RPV LA will be declared non-inferior to current ART if the 
upper end of a two-sided 95% confidence interval for the difference between the two 
groups (CAB – current ART) in virologic failure rates at Week 48 lies below 6%.
9.3.2.2.
Other Comparisons of Interest
The analysis described above will also be performed using the PP population and the 
results will be compared for consistency with the results from the ITT-E population.  

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9.3.2.3.
Secondary comparisons
The following key secondary comparison will be tested:

Treatment with CAB LA + RPV LA will be declared non-inferior to current ART if 
the lower end of a two-sided 95% confidence interval for the difference between the 
two groups in response rates at Week 48 lies above -10%.

Superiority of CAB LA + RPV LA compared to continuation of current ART with 
respect to change from baseline HIVTSQs total score at Week 44;

Changes in the PIN acceptance score within the CAB LA + RPV LA arm from Day 4 
to Week 48
9.3.2.4.
Planned Analyses
At least two analyses will be conducted to evaluate primary and secondary objectives of 
the protocol, one after all subjects have completed their visits at Week 48 and one after 
Week 96.  Further data cuts and analyses may be conducted as necessary after Week 96 
in order to support regulatory submissions and publications.  The Week 48 analysis will 
be primary.  No adjustment for multiplicity caused by repeated evaluation of the primary 
endpoint will be made as the Week 96 analyses will be secondary. 
An IDMC will be instituted to ensure external objective medical and/or statistical review 
of efficacy and safety in order to protect the ethical interests and well-being of subjects 
and to protect the scientific validity of this study (201585) and study 201584.  An ad-hoc 
review of data by the IDMC will be triggered whenever the number of confirmed 
virologic failures (Section 5.5.4) in the CAB LA + RPV LA exceeds thresholds pre-
specified in the IDMC charter.  Further, an interim futility analysis will be performed for 
the IDMC to evaluate the efficacy and safety of CAB LA + RPV LA when approximately 
50% of subjects have completed their visit at Week 24; the sponsor will remain blinded 
to this analysis.  Full details of the methods, timing, decision criteria and operating 
characteristics will be pre-specified in the IDMC Charter.
Since the statistical stopping guidelines will not result in early stopping for positive 
efficacy findings, these planned analyses will not inflate the type I error rate for the 
primary treatment comparison at Week 48.
9.4.
Key Elements of Analysis Plan
The study design is open-label.  However, the central GSK team responsible for the 
conduct and analysis of the study will not review any summaries of data grouped by 
treatment prior to database freeze for the primary Week 48 analysis.
This study is conducted in parallel with study 201584 (FLAIR) with the aim to pool data 
generated from the current study with study 201584, in order to evaluate key program 
objectives.

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9.4.1.
Primary Analyses
For the primary efficacy analysis, each participant’s response (e.g., virologic failure) will 
be calculated according to the FDA’s Snapshot algorithm.  The primary analysis at Week 
48 will take place after the last participant has had their Week 48 viral load assessed, 
including a retest if required.  This algorithm treats all participants without HIV RNA 
data at the visit of interest (due to missing data or discontinuation of study drug prior to 
visit window) as non-responders, as well as subjects who switch their concomitant ART 
prior to the visit of interest since no switches are allowed in this protocol.  Otherwise, 
virologic success or failure will be determined by the last available HIV-1 RNA 
assessment while the participant is on-treatment within the window of the visit of interest.  
Full details on the Snapshot algorithm will be contained in the RAP.  
The primary analysis will be based on the ITT-E population using the Snapshot dataset. 
The primary comparison of will be made at a one-sided 2.5% level of significance. 
Treatment with CAB LA + RPV LA will be declared non-inferior to current ART if the 
upper end of a two-sided 95% confidence interval for the difference between the two 
groups (CAB – current ART) in virologic failure rates at Week 48 lies below 6%.
For the primary comparison, adjusted estimates of the difference in the rate of failures 
between the two arms will be presented along with CIs based on a stratified analysis 
using Cochran-Mantel Haenszel (CMH) weights. All CIs will be two-sided and the 
analysis will be stratified according to the baseline third agent class (INI, NNRTI, or PI) 
and gender at birth.  If the adjusted treatment difference is not estimable due to overly 
sparse stratification and/or low number of subjects with virologic failure, then the 
primary comparison will be adjusted for baseline third agent class only; if this also 
encounters numerical issues then the primary comparison will be based on the unadjusted 
analysis.
The CMH estimate of the common difference in rates across strata will be calculated as 
the weighted average of the strata-specific estimates of the difference in response rates 
between the two arms as follows:
•
If nk is the number of CAB treated participants, mk is the number of current ART 
control arm treated participants, and Nk = nk + mk is the total number of 
participants in the kth stratum, then the CMH estimate is given by



k
k
k
cmh
W
d
W
d
ˆ
ˆ
where
k
k
k
k
N
m
n
W 

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are CMH weights and 
k
dˆ
are estimates of the differences in response rates 
between the two treatment arms, fla-fc, for the kth stratum.
using the variance estimator 
)
ˆ
r(
aˆ
v
cmh
d
, given by [Sato, 1989], which is consistent in both 
sparse data and large strata.  The full equation for this variance estimate will be provided 
in the RAP.
The weighted least squares chi-squared statistic [Fleiss, 1981] will be used to test for one-
way homogeneity across the levels of each categorical variable, with each categorical 
variable considered separately. Following Lui and Kelly [Lui, 2000], ½ will be added to 
each cell in any strata for which the stratum-specific rate estimates of either fla or fc are 
zero or one, and tests will be one-sided. Any heterogeneity found to be statistically 
significant will be explored and if necessary results will be reported for each level of the 
categorical variable. Investigation of heterogeneity will be confined to the primary 
endpoint using the Week 48 Snapshot analysis. Tests of homogeneity will be assessed at 
the one-sided 10% level of significance. Full details will be contained in the RAP.
On-treatment data collected from extra visits within a window will be included in the 
derivation of the Snapshot response/failure but summary tables using observed case (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 
changes to the original analysis plan in the protocol will be described in the RAP and/or 
clinical study report (CSR).
The analysis described above will also be performed using the PP population and the 
results will be compared for consistency with the results from the ITT-E population.  
9.4.2.
Secondary Analyses
A key secondary analysis will evaluate the proportion of responders (HIV-1 RNA <50 
c/mL per Snapshot) at Week 48 using a Cochran-Mantel Haenszel test stratified by 
baseline third agent class (INI, NNRTI, or PI) and gender at birth. A non-inferiority 
margin of -10% will be used for this secondary comparison, where if the lower limit of 
the 95% confidence interval (CI) of the difference in responder rate between the two 
study arms is greater than -10%, non-inferiority will be demonstrated. 
Proportion of participants with plasma HIV-1 RNA <200 c/mL and <50 c/mL and 
confirmed virologic failure, respectively, for the ITT-E population over time will be 
summarized using the Snapshot algorithm.  Proportion of participants with confirmed 
virologic failures will also be summarized over time. 
Absolute values and change from Baseline in plasma HIV-1 RNA and CD4+ lymphocyte 
count will be summarized over time. 
The incidence of HIV-1 disease progression (AIDS and death) will be presented.
An efficacy analysis at Week 48 will also be presented by baseline third agent class.

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The OC dataset will be the primary dataset used for analysis of safety endpoints. 
Statistical analysis of selected biomarkers and fasting lipids may be performed overall 
and by baseline third agent class using appropriate methods for missing data. Further 
details will be detailed in the RAP.
The proportion of participants reporting AEs will be tabulated for each treatment group. 
The following summaries of AEs will be provided:

Incidence and severity of all AEs

Incidence and severity of treatment related AEs

Incidence and severity of AEs leading to withdrawal

Incidence of SAEs
The incidence and severity of treatment related AEs, SAEs and AEs leading to 
withdrawal will also be assessed by baseline third agent class.
Changes from baseline in laboratory (including fasting lipids) and vital signs data will be 
summarized by visit and treatment group.  In addition, the number and percentage of 
participants with graded laboratory toxicities (based on DAIDS categories) will be 
summarized by treatment group. The number and percentage of participants with graded 
laboratory toxicities and the change from baseline in fasting lipids will also be assessed 
by baseline third agent class.
Change from baseline in renal, bone and cardiovascular biomarkers will be summarized 
by treatment and visit. 
Further details of safety and exploratory analyses will be included in the RAP.
9.4.3.
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.
Actual sampling and dosing times as recorded in the eCRF will be used for analysis.  
Plasma CAB and RPV concentration data will be listed and summarized by week, day, 
and planned sampling time in both tabular and graphical forms.  A composite predose 
(C0) concentration may be estimated for purposes of PK/PD analysis.  Post hoc estimates 
of PK parameters will be determined by population PK modeling separately (see 
Population PK Analysis below).
9.4.4.
Population PK Analysis:
CAB and RPV population PK models will be constructed separately and individual 
Bayesian PK parameter estimates may be obtained, if the quality of the data permits.  
Data from this study may be merged with previous data to support the model building 

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process.  Sources of variability in pharmacokinetic parameters will be investigated during 
population modeling.  Demographic parameters including, but not limited to age, gender, 
ethnic origin, body size (weight, height, body surface area, body mass index), and 
relevant laboratory parameters will be evaluated as potential predictors of inter- and intra-
participant variability for pharmacokinetic parameters.  Population pharmacokinetic 
modeling will be performed using the non-linear mixed effects software NONMEM 
(ICON; Hanover, MD).  Further details of population pharmacokinetic analyses will be 
described in a separate RAP.  Population PK analyses will be done under separate 
Population-PK Reporting and Analysis Plans, and post hoc PK parameters may be 
determined.
9.4.5.
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; e.g., age, weight, BMI, gender, race, Baseline 
HIV-1 RNA, HIV risk factors, CDC classification, and CD4+ cell count.  
Exploratory analyses will be performed to examine the relationship(s) between plasma 
concentrations of CAB and RPV and pharmacodynamic endpoints.  A population 
pharmacokinetic/pharmacodynamic modeling approach may be further applied to model 
the data using the nonlinear mixed effect modeling software, NONMEM (ICON LLC, 
Hanover, MD).  Details of the PK/PD analyses plans for CAB and / or RPV will be 
provided in separate RAPs.
9.4.6.
Viral Genotyping/Phenotyping Analyses
The incidence of treatment emergent genotypic and phenotypic resistance to NRTIs and 
INIs, PIs, and NNRTIs and in particular to current antiretroviral regimen and to CAB or 
RPV will be summarized by treatment arm for subjects meeting confirmed virologic 
failure criteria (Section 5.5.4). This endpoint will also be assessed by baseline third agent 
class. Details of the analyses to be performed will be specified in the reporting and
analysis plan (RAP).
9.4.7.
Health Outcomes Analyses
Statistical analysis of the key secondary comparisons (Section 7.9.1) for the change from 
baseline in HIVTSQs total score at Week 44 (between treatment group comparison) and 
within treatment group change in PIN acceptance score for subjects randomized to CAB 
LA + RPV LA will be performed using appropriate methods for missing data. 
Further details of the analyses to be performed will be specified in the reporting and
analysis plan (RAP).
9.4.8.
Genetic Analyses
See Appendix 5 for details about the Genetics Analysis Plan.

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9.4.9.
Other Analyses
The proportion of participants with virologic failure ( FDA Snapshot algorithm) and 
HIV-1 RNA <50 c/mL (FDA snapshot algorithm), respectively, over time through 
Week 48 will be analysed by important demographic and baseline characteristic 
subgroups factors (e.g. age, gender, BMI, race, HIV-1 subtype, and Baseline CD4+ cell 
counts).  Changes from baseline in CD4+ lymphocyte count at Week 48 will also be 
summarized by subgroups. Additional details on subgroup analyses will be provide in the 
RAP.  
Longer term antiviral and immunological effect, safety and tolerability of CAB LA + 
RPV LA will be assessed through Week 96 for the CAB LA + RPV LA arm (48 weeks of 
comparative data and 48 weeks of extension data).  Antiviral and immunological effect, 
safety and tolerability of CAB LA + RPV LA will also be evaluated for participants 
switching to CAB LA + RPV LA in the Extension Phase.
Further details of exploratory analyses will be presented in the RAP.
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of participants begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, ViiV/GSK will obtain favorable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with International 
Conference on Harmonisation (ICH) Good Clinical Practice (GCP) and applicable 
country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable participant privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

Investigator reporting requirements (e.g., reporting of AEs/SAEs/protocol 
deviations to IRB/IEC)

ViiV/GSK will provide full details of the above procedures, either verbally, in 
writing, or both.

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
Signed informed consent must be obtained for each participant prior to 
participation in the study (see Inclusion Crietria, Section 5.1; Informed consent).

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, 
written approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the eCRF
will serve as the source document.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of participants are being protected.

Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
10.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and 
the regulatory agencies may conduct a regulatory inspection at any time during or 
after completion of the study. 

In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss 
the conduct of the study, any findings/relevant issues and to implement any 
corrective and/or preventative actions to address any findings/issues identified.

Measures and documentation towards quality assurance that will be completed 
prior to study initiation will also include but not be limited to the study monitoring 

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plan, study risk register, quality assurance plan, protocol deviation management 
plan,  medical monitoring plan, and site feasibility assessments.
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard 
Operating Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this 
study at any time for reasons including, but not limited to, safety or ethical issues 
or severe non-compliance. For multicenter studies, this can occur at one or more 
or at all sites.  

If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable).  When feasible, GSK will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.  

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical 
institution (where applicable) must maintain all site study records (except for 
those required by local regulations to be maintained elsewhere), in a safe and 
secure location.  

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review 
in conjunction with assessment of the facility, supporting systems, and relevant 
site staff.  

Where permitted by local laws/regulations or institutional policy, some or all of 
these records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.  

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, 
including re-generating a hard copy, if required.  Furthermore, the investigator 

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must ensure there is an acceptable back-up of these reproductions and that an 
acceptable quality control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by 
any institutional requirements or local laws or regulations, GSK 
standards/procedures, and/or institutional requirements.  

The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of 
ownership of the records in the event the investigator is no longer associated with 
the site.
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study participants, as 
appropriate.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.
10.8.
Review Committees
10.8.1.
Independent Data Monitoring Committee
An IDMC will be utilized 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 participants 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 
Section 9.3.2.4 and the IDMC the charter, which is available upon request.

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12.
APPENDICES
12.1.
Appendix 1:  Abbreviations and Trademarks
Abbreviations
3TC
Lamivudine, EPIVIR
ABC
Abacavir, ZIAGEN
ABC/3TC
Abacavir/lamivudine, EPZICOM, KIVEXA
ABC/DTG/3TC
Abacavir/dolutegravir/lamivudine, TRIUMEQ
ACCEPT
General acceptance” dimension of the Chronic Treatment 
Acceptance
ADR
Adverse drug reaction
AE
Adverse event
AIDS
Acquired immunodeficiency syndrome
ALT
Alanine aminotransferase
Anti-HBc
Hepatitis B core Antibody
Anti-HBsAg
Antibodies against Hepatitis B surface Antigen
APAP
N-acetyl-para-aminophenol
ARV
Antiretroviral
ART
Antiretroviral therapy
ATV
Atazanavir
AST
Aspartate aminotransferase
AUC
Area under the curve
AUC(0-)
Area under the concentration curve from 0 hours to the time 
of next dosing
BP
Blood Pressure
BUN
Blood Urea Nitrogen
CAB
Cabotegravir
CAB LA
Cabotegravir long-acting
c/mL
Copies/millilitre
cART
Combination antiretroviral therapy
CD4
Cluster of Differentiation 4
CD8
Cluster of Differentiation 8
CDC
Centers for Disease Control and Prevention
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
Cmax
Maximum concentration
CMH
Cochran-Mantel Haenszel
CSR
Clinical Study Report
C-SSRS
Columbia Suicidality Severity Rating Scale
CI
Confidence interval
CONSORT
Consolidated Standards of Reporting Trials
CPK
Creatine phosphokinase
CPMS
Clinical Pharmacology Modelling and Simulation
CSR
Clinical Study Report

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CV
Cardiovascular
CVF
Confirmed Virologic Failure
DAIDS
DILI
Division of Acquired Immunodeficiency Syndrome
Drug induced liver injury
DNA
Deoxyribonucleic acid
DRE
Disease-Related Events
DRV
Darunavir
DTG
Dolutegravir, TIVICAY
ECG
Electrocardiogram
eC-SSRS
Columbia Suicide Severity Rating Scale
eCRF
Electronic case report form
EFV
Efavirenz
eGFR
Estimated glomerular filtration rate
EMA
European Medicines Agency
EQ-5D-5L
European Quality of Life-5 Dimensions-5 Levels
ETR
Etravirine
eGFR
Estimated glomerular filtration rate
EVG
Elvitegravir
FC
Fold Change
FDA
Food and Drug Administration
FDC
Fixed-dose combination
FSFV
First participant first visit
FTC
Emtricitabine
GCP
Good Clinical Practice
GSK
HAART
GlaxoSmithKline
Highly active antiretroviral therapy
HbsAg
Hepatitis B surface Antigen
HAT-QoL
HIV/AIDS-targeted quality of life
HBV
Hepatitis B virus
HCG
human chorionic gonadotrophin
HCV
Hepatitis C virus
HDL
High density lipoprotein
HDPE
High density polyethylene
HIV
HIV TSQ
Human immunodeficiency virus 
HIV treatment satisfaction questionnaire
HLA
Human leukocyte antigen
HSR
Hypersensitivity reaction
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IDMC
Independent data monitoring committee
IEC
IgM
Independent Ethics Committee
Immunoglobulin M
IM
Intramuscular

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INI
Integrase inhibitor
INR
International normalized ratio
IP
Investigational Product
IRB
Institutional Review Board
ITT-E
Intent-to-treat exposed
IUD
Intrauterine device
IRT
Interactive response technology
LA
Long acting
LDL 
Low density lipoprotein
Lp-PLA2
Lipoprotein-associated phospholipase A2
LPV
Lopinavir
MCV
Mean corpuscular volume
MedDRA
Medical dictionary for regulatory activities
Mg
Milligram
Mg/dL
Milligram per deciliter
MSD=F
Missing, switch, or discontinuation equals failure
NNRTI
Non-nucleoside reverse transcriptase inhibitor
NRTI
Nucleoside reverse transcriptase inhibitor
OCT-2
Organic cation transporter
PI
Protease inhibitor
PK
Pharmacokinetic
PP
Per-protocol
PRO
Protease
PRTD
Proximal Renal Tubule Dysfunction
PSRAE
Possible suicidality-related adverse event
QTc
Corrected QT interval 
RAL
Raltegravir
RAP
Reporting and Analysis Plan
RBC
Red blood cell
RBP
Retinol Binding Protein
RNA
Ribonucleic acid
RPR
Rapid plasma regain
RPV
Rilpivirine, Edurant®
RPV LA
Rilpivirine long-acting
RT
Reverse transcriptase
RTV
Ritonavir
SAE
Serious adverse event
SJS
Stevens-Johnson syndrome
SPM
Study Procedures Manual
STR
Single tablet regimen
SVW
Suspected Virologic Withdrawal
TDF
Tenofovir disoproxil fumarate
TEN
Toxic epidermal necrolysis
TMC278
Tibotec Medicinal Compound 278

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TSQ
Treatment Satisfaction Questionnaire
ULN
Upper limit of normal
US
United States
VSLC
ViiV Safety and Labeling Committee
WBC
White blood cell
Trademark Information
Trademarks of ViiV Healthcare
Trademarks not owned by ViiV 
Healthcare
EPIVIR
Edurant
EPZICOM/KIVEXA
Genosure
TIVICAY
Monogram Biosciences
TRIUMEQ
PhenoSense
ZIAGEN

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12.2.
Appendix 2:  Division of AIDS Table for Grading the Severity 
of Adult and Pediatric Adverse Events Version 2.0, 
November 2014
VERSION 2.0, November 2014
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 utilised 
for Adverse Event (AE) reporting.  A grading (severity) scale is provided for each AE 
term.
Estimating Severity Grade for Parameters Not Identified in the Grading Table
The functional table below should be used to grade the severity of an AE that is not 
specifically identified in the grading table. In addition, all deaths related to an AE are to 
be classified as grade 5.
PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE
4
POTENTIALLY 
Clinical adverse
event NOT
identified 
elsewhere in
the
grading table
Mild symptoms
causing no or 
minimal
interference with
usual social &
functional
activities with
intervention not 
indicated
Moderate symptoms
causing greater
than minimal
interference with
usual social &
functional
activities with
intervention 
indicated
Severe symptoms
causing inability
to perform usual
social & 
functional
activities with
intervention or 
hospitalization
indicated
Potentially life-
threatening
symptoms causing
inability to perform
basic self-care functions 
with intervention
indicated to prevent 
permanent impairment, 
persistent disability, or
death
Major Clinical Conditions
Cardiovascular
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GR
AD
E 4
POTENTIALL
Y LIFE-
Arrhythmia
(by ECG or
physical
examination)
Specify type, if
applicable
No symptoms
AND No
intervention 
indicated
No symptoms
AND Non-urgent 
intervention
indicated
Non-life-
threatening 
symptoms AND
Non-urgent
intervention
indicated
Life-threatening 
arrhythmia OR
Urgent 
intervention
indicated
Blood Pressure
Abnormalities1
Hypertension
(with the lowest
reading taken 
after repeat
testing during a
visit)
140 to < 160
mmHg systolic
OR
90 to < 100
mmHg diastolic
≥ 160 to < 
180 mmHg
systolic OR
≥ 100 to < 
110
mmHg
diastolic
≥ 180 mmHg
systolic
OR
≥ 110 mmHg
diastolic
Life-threatening 
consequences in a 
participant not 
previously
diagnosed with
hypertension (e.g., 
malignant

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GR
AD
E 4
POTENTIALL
Y LIFE-
≥ 18 years of
age
hypertension) OR
Hospitalization 
indicated
< 18 years of
age
> 120/80 mmHg
≥ 95th to < 99th
percentile + 5
mmHg adjusted
for age, height,
and gender 
(systolic and/or 
diastolic)
≥ 99
th percentile + 5
mmHg adjusted for
age, height, and 
gender (systolic 
and/or diastolic)
Life-threatening 
consequences in a 
participant not 
previously
diagnosed with
hypertension (e.g., 
malignant
hypertension) OR
Hospitalization 
indicated
Hypotension
No symptoms
Symptoms 
corrected with
oral fluid 
replacement
Symptoms AND IV 
fluids indicated
Shock requiring
use of 
vasopressors or 
mechanical
assistance to 
maintain blood
pressure
Cardiac Ischemia
or
Infarction
Report only one
NA
NA
New symptoms
with ischemia 
(stable angina) OR
New testing
consistent with 
ischemia
Unstable 
angina OR
Acute
myocardial 
infarction
Heart Failure
No symptoms
AND Laboratory
or cardiac 
imaging 
abnormalities
Symptoms with
mild to moderate 
activity or
exertion
Symptoms at rest
or with minimal
activity or exertion
(e.g., hypoxemia) 
OR Intervention
indicated (e.g.,
oxygen)
Life-threatening 
consequences OR
Urgent 
intervention
indicated (e.g.,
vasoactive 
medications,
ventricular assist
device, heart 
transplant)
Hemorrhage
(with significant
acute
blood loss)
NA
Symptoms AND 
No transfusion
indicated
Symptoms
AND
Transfusion of
≤2 units packed
RBCs indicated
Life-threatening 
hypotension OR
Transfusion of > 
2 units packed
RBCs (for 
children, packed
RBCs > 10 cc/kg)
indicated
Prolonged PR 
Interval or AV
Block
PR interval 0.21 to
<
0.25 seconds
PR interval ≥ 0.25
seconds OR Type I
2nd degree AV
block
Type II 2nd degree
AV block OR
Ventricular pause 
≥ 3.0 seconds
Complete AV block

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GR
AD
E 4
POTENTIALL
Y LIFE-
Report only one
> 16 years of age
≤ 16 years of age
1st degree AV block
(PR interval
> normal for age 
and rate)
Type I 2nd degree
AV
Block
Type II 2nd degree
AV block OR
Ventricular pause 
≥ 3.0 seconds
Complete AV block
Prolonged QTc
Interval2
0.45 to 0.47
seconds
> 0.47 to
0.50 
seconds
> 0.50 seconds OR
≥ 0.06 seconds 
above baseline
Life-threatening
consequences (e.g., 
Torsade de 
pointes, other 
associated serious 
ventricular
dysrhythmia)
Thrombosis or
Embolism
Report only one
NA
Symptoms AND
No intervention
indicated
Symptoms AND
Intervention
indicated
Life-threatening
embolic event
(e.g., pulmonary
embolism,
thrombus)
1.
Blood pressure norms for children < 18 years of age can be found in: Expert Panel on Integrated 
Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents. Pediatrics 
2011;128;S213; originally published online November 14, 2011; DOI: 10.1542/peds.2009-2107C. 
2.
As per Bazett’s formula.
Dermatologic
PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE
4
POTENTIALLY 
LIFE-
THREATENING
Alopecia (scalp
only)
Detectable by
study 
participant, 
caregiver, or 
physician AND
Causing no or
minimal
interference with
usual social & 
functional
activities
Obvious on visual 
inspection AND
Causing greater
than minimal
interference with
usual social & 
functional
activities
NA
NA
Bruising
Localized to
one area
Localized to
more than one 
area
Generalized
NA
Cellulitis
NA
Non-parenteral 
treatment
indicated (e.g.,
oral antibiotics, 
antifungals, 
antivirals)
IV treatment
indicated (e.g.,
IV antibiotics, 
antifungals,
antivirals)
Life-threatening 
consequences (e.g., 
sepsis, tissue 
necrosis)

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PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE
4
POTENTIALLY 
LIFE-
THREATENING
Hyperpigmentation Slight or
localized causing
no or minimal
interference with
usual social & 
functional
activities
Marked or 
generalized
causing greater
than minimal 
interference with 
usual social & 
functional
activities
NA
NA
Hypopigmentation
Slight or
localized causing
no or minimal
interference with
usual social & 
functional
activities
Marked or 
generalized
causing greater
than minimal 
interference with 
usual social & 
functional
activities
NA
NA
Petechiae
Localized to
one area
Localized to
more than one 
area
Generalized
NA
Pruritus
3
(without skin
lesions)
Itching causing
no or minimal 
interference with 
usual social & 
functional
activities
Itching causing 
greater than
minimal 
interference with 
usual social & 
functional
activities
Itching
causing 
inability to
perform 
usual social
& functional
activities
NA
Rash
Specify type, if
applicable
Localized rash
Diffuse rash
OR Target
lesions
Diffuse rash
AND Vesicles 
or limited 
number of
bullae or 
superficial
ulcerations of
mucous 
membrane 
limited to one 
site
Extensive or
generalized bullous
lesions OR Ulceration
of mucous membrane 
involving two or more 
distinct mucosal sites 
OR Stevens- Johnson
syndrome OR Toxic 
epidermal necrolysis
3.
For pruritus associated with injections or infusions, see the Site Reactions to Injections and Infusions 
section. 

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Endocrine and Metabolic
PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE
4
POTENTIALLY 
LIFE-
THREATENING
Diabetes Mellitus
Controlled
without 
medication
Controlled with 
medication OR
Modification of 
current
medication 
regimen
Uncontrolled
despite 
treatment 
modification
OR
Hospitalization
for immediate 
glucose 
control
indicated
Life-threatening 
consequences (e.g., 
ketoacidosis, 
hyperosmolar non-
ketotic coma, end
organ failure)
Gynecomastia
Detectable by
study 
participant, 
caregiver, or 
physician AND
Causing no or
minimal
interference with
usual social & 
functional
activities
Obvious on
visual inspection
AND Causing
pain with greater
than minimal 
interference with 
usual social & 
functional
activities
Disfiguring
changes AND
Symptoms 
requiring
intervention or
causing
inability to 
perform usual
social
& functional
activities
NA
Hyperthyroidism
No symptoms
AND Abnormal
laboratory value
Symptoms 
causing greater
than minimal 
interference with 
usual social & 
functional
activities OR
Thyroid 
suppression
therapy indicated
Symptoms 
causing 
inability to
perform usual
social & 
functional
activities OR
Uncontrolled 
despite 
treatment 
modification
Life-threatening 
consequences 
(e.g., thyroid
storm)
Hypothyroidism
No symptoms
AND Abnormal
laboratory value
Symptoms 
causing greater
than minimal 
interference with 
usual social & 
functional
activities OR 
Thyroid 
replacement
therapy indicated
Symptoms 
causing 
inability to
perform usual
social & 
functional
activities OR
Uncontrolled 
despite 
treatment 
modification
Life-threatening 
consequences 
(e.g., myxedema 
coma)
Lipoatrophy
4
Detectable by
study 
participant, 
caregiver, or 
physician AND
Obvious on visual 
inspection AND
Causing greater
than minimal
interference with
Disfiguring
changes
NA

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PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE
4
POTENTIALLY 
LIFE-
THREATENING
Causing no or
minimal
interference with
usual social & 
functional
activities
usual social & 
functional
activities
Lipohypertrophy
5 Detectable by
study 
participant, 
caregiver, or 
physician AND
Causing no or
minimal
interference with
usual social &
functional
activities
Obvious on visual 
inspection AND
Causing greater
than minimal
interference with
usual social & 
functional
activities
Disfiguring
changes
NA
4.
Definition: A disorder characterized by fat loss in the face, extremities, and buttocks.
5.
Definition: A disorder characterized by abnormal fat accumulation on the back of the neck, breasts, 
and abdomen.
Gastrointestinal
PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE
4
POTENTIALLY 
LIFE-
THREATENING
Anorexia
Loss of
appetite 
without
decreased oral
intake
Loss of appetite 
associated with 
decreased oral
intake without
significant weight
loss
Loss of appetite 
associated with 
significant
weight loss
Life-threatening 
consequences OR
Aggressive 
intervention indicated
(e.g., tube feeding,
total parenteral 
nutrition)
Ascites
No symptoms
Symptoms AND
Intervention
indicated (e.g.,
diuretics, 
therapeutic 
paracentesis)
Symptoms 
recur or 
persist despite 
intervention
Life-threatening 
consequences
Bloating or 
Distension
Report only one
Symptoms 
causing no or
minimal 
interference with 
usual social & 
functional
activities
Symptoms 
causing greater
than minimal 
interference with 
usual social & 
functional
activities
Symptoms 
causing 
inability to
perform usual
social & 
functional
activities
NA
Cholecystitis
NA
Symptoms AND
Medical
intervention 
Radiologic, 
endoscopic, or 
operative 
Life-threatening 
consequences 
(e.g., sepsis,

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

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PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE
4
POTENTIALLY 
LIFE-
THREATENING
indicated
hemorrhage, 
sepsis)
Perforation
(colon or rectum)
NA
NA
Intervention 
indicated
Life-threatening 
consequences
Proctitis
Rectal 
discomfort 
with no 
intervention 
indicated
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional 
activities OR 
Medical 
intervention 
indicated
Symptoms 
causing inability 
to perform usual 
social & 
functional 
activities OR 
Operative 
intervention 
indicated
Life-threatening 
consequences (e.g., 
perforation)
Rectal Discharge
Visible 
discharge
Discharge 
requiring the use 
of pads
NA
NA
Vomiting
Transient or 
intermittent 
AND No or 
minimal 
interference 
with oral 
intake
Frequent episodes 
with no or mild 
dehydration
Persistent 
vomiting resulting 
in orthostatic 
hypotension OR 
Aggressive 
rehydration 
indicated (e.g., IV 
fluids)
Life-threatening 
consequences (e.g., 
hypotensive shock)
Musculoskeletal
PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE
4
POTENTIALLY 
LIFE-
THREATENING
Arthralgia
Joint pain
causing no or
minimal 
interference with 
usual social & 
functional
activities
Joint pain causing 
greater than
minimal 
interference with 
usual social & 
functional
activities
Joint pain
causing 
inability to
perform 
usual social
& functional
activities
Disabling joint pain 
causing inability to 
perform basic self-
care functions
Arthritis
Stiffness or joint 
swelling causing
no or minimal 
interference with 
usual social & 
functional
activities
Stiffness or joint 
swelling causing 
greater than
minimal 
interference with 
usual social & 
functional
activities
Stiffness or
joint 
swelling
causing 
inability to
perform 
usual social
& functional
activities
Disabling joint stiffness 
or swelling causing 
inability to perform
basic self-care functions
Myalgia
(generalized)
Muscle pain
causing no or
Muscle pain
causing greater
Muscle pain
causing 
Disabling muscle pain 
causing inability to 

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PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE
4
POTENTIALLY 
LIFE-
THREATENING
minimal 
interference with 
usual social & 
functional
activities
than minimal 
interference with 
usual social & 
functional
activities
inability to
perform usual
social & 
functional
activities
perform basic self-
care functions
Osteonecrosis
NA
No symptoms but 
with radiographic 
findings AND No 
operative 
intervention 
indicated
Bone pain with 
radiographic 
findings OR
Operative 
intervention
indicated
Disabling bone pain
with radiographic 
findings causing
inability to perform
basic self-care functions
Osteopenia
6
≥ 30 years of age BMD t-score
-2.5 to -1
NA
NA
NA
< 30 years of age BMD z-score
-2 to -1
NA
NA
NA
Osteoporosis
6
≥ 30 years of age NA
BMD t-score < -2.5 Pathologic 
fracture (e.g.,
compression 
fracture 
causing loss 
of vertebral
height)
Pathologic fracture 
causing life-
threatening 
consequences
< 30 years of ageNA
BMD z-score < -2
Pathologic 
fracture (e.g.,
compression 
fracture 
causing loss 
of vertebral
height)
Pathologic fracture 
causing life-
threatening 
consequences
6.
BMD t and z scores can be found in: Kanis JA on behalf of the World Health Organization Scientific 
Group (2007). Assessment of osteoporosis at the primary health-care level. Technical Report. World 
Health Organization Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, UK. 
2007: Printed by the University of Sheffield.
Neurologic
PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE
4
POTENTIALLY 
LIFE-
THREATENING
Acute CNS
Ischemia
NA
NA
Transient
ischemic 
attack
Cerebral vascular 
accident (e.g.,
stroke with
neurological deficit)
Altered Mental
Status (for
Dementia, see 
Changes causing
no or minimal 
interference with 
Mild lethargy or 
somnolence 
causing greater
Confusion,
memory 
impairment,
Delirium OR
Obtundation OR
Coma

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PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE
4
POTENTIALLY 
LIFE-
THREATENING
Cognitive,
Behavioral, or 
Attentional
Disturbance 
below)
usual social & 
functional
activities
than minimal 
interference with 
usual social & 
functional
activities
lethargy, or 
somnolence 
causing inability
to perform usual
social & 
functional
activities
Ataxia
Symptoms 
causing no or
minimal
interference with 
usual social & 
functional
activities OR No
symptoms with
ataxia detected 
on examination
Symptoms 
causing greater
than minimal 
interference with 
usual social & 
functional
activities
Symptoms 
causing 
inability to
perform usual
social & 
functional
activities
Disabling symptoms 
causing inability to 
perform basic self-
care functions
Cognitive,
Behavioral, 
or 
Attentional 
Disturbance 
(includes 
dementia and
attention 
deficit
disorder)
Specify type, if
applicable
Disability
causing no or
minimal 
interference with 
usual social & 
functional
activities OR
Specialized 
resources not 
indicated
Disability causing 
greater than
minimal 
interference with 
usual social & 
functional
activities OR
Specialized 
resources on part-
time basis 
indicated
Disability
causing 
inability to
perform usual
social & 
functional
activities OR
Specialized 
resources on a 
full- time basis 
indicated
Disability causing 
inability to perform 
basic self-care
functions OR
Institutionalization 
indicated
Developmental
Delay
< 18
years of
age
Specify type, if
applicable
Mild
developmental 
delay, either
motor or
cognitive, as 
determined by 
comparison with
a developmental 
screening tool 
appropriate for
the setting
Moderate 
developmental
delay, either
motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting
Severe 
developmental 
delay, either
motor or 
cognitive, as 
determined by 
comparison with
a developmental 
screening tool 
appropriate for
the setting
Developmental 
regression, either motor 
or cognitive, as 
determined by 
comparison with a 
developmental
screening tool
appropriate for the 
setting
Headache
Symptoms 
causing no or
minimal 
interference with 
usual social & 
functional
activities
Symptoms 
causing greater
than minimal 
interference with 
usual social & 
functional
activities
Symptoms 
causing 
inability to
perform usual
social & 
functional
activities
Symptoms causing 
inability to perform 
basic self-care
functions OR
Hospitalization 
indicated  OR
Headache with
significant 
impairment of
alertness or other
neurologic 
function

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PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE
4
POTENTIALLY 
LIFE-
THREATENING
Neuromuscular 
Weakness 
(includes 
myopathy and 
neuropathy)
Specify type, if 
applicable
Minimal muscle 
weakness 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities OR No 
symptoms with 
decreased 
strength on 
examination
Muscle weakness 
causing greater 
than minimal 
interference with 
usual social & 
functional 
activities
Muscle 
weakness 
causing 
inability to 
perform usual 
social & 
functional 
activities
Disabling muscle 
weakness causing 
inability to 
perform basic self-
care functions OR  
Respiratory 
muscle weakness 
impairing 
ventilation
Neurosensory 
Alteration 
(includes 
paresthesia and 
painful 
neuropathy)
Specify type, if 
applicable
Minimal 
paresthesia 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities OR No 
symptoms with 
sensory 
alteration on 
examination
Sensory 
alteration or 
paresthesia 
causing greater 
than minimal 
interference with 
usual social & 
functional 
activities
Sensory 
alteration or 
paresthesia 
causing 
inability to 
perform usual 
social & 
functional 
activities
Disabling sensory 
alteration or 
paresthesia 
causing inability to 
perform basic self-
care functions
Seizures
New Onset 
Seizure
≥ 18 years of age
NA
NA
1 to  3 seizures
Prolonged and 
repetitive seizures 
(e.g., status 
epilepticus) OR 
Difficult to control 
(e.g., refractory 
epilepsy)
< 18 years of age 
(includes new or 
pre- existing 
febrile seizures)
Seizure lasting < 
5 minutes with < 
24 hours 
postictal state
Seizure lasting 5 
to < 20 minutes 
with
< 24 hours 
postictal state
Seizure lasting 
≥ 20 minutes 
OR > 24 hours 
postictal state
Prolonged and 
repetitive seizures 
(e.g., status 
epilepticus) OR 
Difficult to control 
(e.g., refractory 
epilepsy)
Pre-existing 
Seizure
NA
Increased 
frequency from 
previous level of 
control without 
change in seizure 
character
Change in 
seizure 
character 
either in 
duration or 
quality (e.g., 
severity or 
focality)
Prolonged and 
repetitive seizures 
(e.g., status 
epilepticus) OR 
Difficult to control 
(e.g., refractory 
epilepsy)
Syncope
Near syncope 
without loss of 
consciousness 
(e.g., pre-
syncope)
Loss of 
consciousness 
with no 
intervention 
indicated
Loss of 
consciousness 
AND 
Hospitalization 
or intervention 
required
NA

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Pregnancy, Puerperium, and Perinatal
PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE
4
POTENTIALLY 
LIFE-
THREATENING
Fetal Death or 
Stillbirth (report
using mother’s 
participant ID)
Report only one
NA
NA
Fetal loss 
occurring at ≥ 
20 weeks 
gestation
NA
Preterm
Delivery
7 
(report using
mother’s 
participant ID)
Delivery at 34 to < 
37 weeks 
gestational age
Delivery at 28 to < 
34 weeks 
gestational age
Delivery at 24
to < 28 weeks 
gestational age
Delivery at < 24
weeks gestational age
Spontaneous 
Abortion or 
Miscarriage
8
(report using
mother’s 
participant ID)
Report only one
Chemical
pregnancy
Uncomplicated 
spontaneous 
abortion or
miscarriage
Complicated 
spontaneous 
abortion or
miscarriage
NA
7.
Definition:  A delivery of a live-born neonate occurring at ≥ 20 to < 37 weeks gestational age.
8.
Definition:  A clinically recognized pregnancy occurring at < 20 weeks gestational age.
Psychiatric
PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE
4
POTENTIALLY 
LIFE-
THREATENING
Insomnia
Mild difficulty 
falling asleep, 
staying asleep,
or waking up
early
Moderate 
difficulty falling
asleep, staying 
asleep, or waking
up early
Severe 
difficulty falling
asleep, staying 
asleep, or
waking up early
NA
Psychiatric 
Disorders 
(includes 
anxiety, 
depression,
mania, and 
psychosis)
Specify disorder
Symptoms with 
intervention not 
indicated OR
Behavior causing
no or minimal 
interference with 
usual social & 
functional
activities
Symptoms with 
intervention
indicated OR
Behavior causing 
greater than
minimal 
interference with 
usual social & 
functional
activities
Symptoms
with 
hospitalization 
indicated OR
Behavior
causing 
inability to
perform usual
social & 
functional
activities
Threatens harm to self
or others OR Acute 
psychosis OR Behavior 
causing inability to 
perform basic self-care 
functions
Suicidal Ideation
or
Attempt
Report only one
Preoccupied with 
thoughts of death 
AND No wish to
kill oneself
Preoccupied with 
thoughts of death 
AND Wish to kill 
oneself with no 
Thoughts of
killing oneself
with partial or 
complete plans 
Suicide attempted

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PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE
4
POTENTIALLY 
LIFE-
THREATENING
specific plan or
intent
but no attempt
to do so OR
Hospitalization 
indicated
Respiratory
PARAMETER
GRADE 1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Acute 
Bronchospasm
Forced
expiratory 
volume in 1
second or peak
flow reduced to 
≥ 70 to < 80%
OR Mild
symptoms with 
intervention not 
indicated
Forced expiratory 
volume in 1
second or peak
flow 50 to < 70%
OR Symptoms 
with intervention 
indicated OR
Symptoms causing 
greater than
minimal 
interference with 
usual social & 
functional
activities
Forced
expiratory 
volume in 1
second or
peak flow
25 to < 50%
OR
Symptoms 
causing
inability to 
perform
usual social 
& 
functional 
activities
Forced expiratory 
volume in 1 second
or peak flow < 25%
OR Life-threatening 
respiratory or 
hemodynamic 
compromise OR
Intubation
Dyspnea or 
Respiratory
Distress
Report only one
Dyspnea on
exertion with no
or minimal 
interference with 
usual social & 
functional
activities OR
Wheezing OR
Minimal increase 
in respiratory rate
for age
Dyspnea on
exertion causing
greater than 
minimal
interference with
usual social & 
functional
activities OR Nasal
flaring OR
Intercostal
retractions OR
Pulse oximetry 90 
to < 95%
Dyspnea at
rest causing
inability to 
perform
usual social 
& functional 
activities OR
Pulse 
oximetry < 
90%
Respiratory failure 
with ventilator support 
indicated (e.g., CPAP, 
BPAP, intubation)
Sensory
PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE
4
POTENTIALLY 
LIFE-
THREATENING
Hearing Loss
≥ 12 years of age NA
Hearing aid
or 
intervention
not indicated
Hearing aid or 
intervention
indicated
Profound bilateral 
hearing loss (> 80 dB 
at 2 kHz and above)
OR Non-serviceable 

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PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE
4
POTENTIALLY 
LIFE-
THREATENING
hearing (i.e., >50 dB
audiogram and <50%
speech discrimination)
< 12 years of
age (based on a
1, 2, 3, 4, 6 and
8 kHz
audiogram)
> 20 dB hearing
loss at ≤ 4 kHz
> 20 dB hearing
loss at > 4 kHz
> 20 dB 
hearing loss at 
≥ 3 kHz in one 
ear with
additional
speech 
language 
related services 
indicated 
(where 
available) OR
Hearing loss 
sufficient to
indicate 
therapeutic 
intervention, 
including
hearing aids
Audiologic indication
for cochlear implant and 
additional speech-
language related
services indicated
(where available)
Tinnitus
Symptoms 
causing no or
minimal 
interference with 
usual social & 
functional
activities with
intervention not 
indicated
Symptoms 
causing greater
than minimal 
interference with 
usual social & 
functional
activities with
intervention 
indicated
Symptoms 
causing 
inability to
perform 
usual social
& functional
activities
NA
Uveitis
No symptoms
AND Detectable 
on examination
Anterior uveitis 
with symptoms 
OR Medical
intervention
indicated
Posterior or
pan- uveitis 
OR Operative 
intervention
indicated
Disabling visual loss 
in affected eye(s)
Vertigo
Vertigo causing
no or minimal 
interference with 
usual social & 
functional
activities
Vertigo causing 
greater than
minimal 
interference with 
usual social & 
functional
activities
Vertigo
causing 
inability to
perform 
usual social
& functional
activities
Disabling vertigo 
causing inability to 
perform basic self-
care functions
Visual Changes
(assessed from
baseline)
Visual changes 
causing no or 
minimal
interference with
usual social & 
functional
activities
Visual changes 
causing greater
than minimal
interference with
usual social & 
functional
activities
Visual
changes 
causing
inability to 
perform usual
social & 
functional
activities
Disabling visual loss 
in affected eye(s)

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Systemic
PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE
4
POTENTIALLY 
LIFE-
THREATENING
Acute Allergic
Reaction
Localized
urticaria 
(wheals) with
no medical
intervention 
indicated
Localized urticaria 
with intervention 
indicated OR Mild 
angioedema with
no intervention 
indicated
Generalized
urticaria OR
Angioedema
with 
intervention
indicated OR
Symptoms of
mild 
bronchospasm
Acute anaphylaxis 
OR Life-threatening 
bronchospasm OR
Laryngeal edema
Chills
Symptoms 
causing no or
minimal 
interference with
usual social & 
functional 
activities
Symptoms 
causing greater
than minimal 
interference with 
usual social & 
functional
activities
Symptoms 
causing 
inability to
perform usual
social & 
functional
activities
NA
Cytokine Release
Syndrome9
Mild signs and 
symptoms AND
Therapy (i.e.,
antibody 
infusion)
interruption not
indicated
Therapy (i.e., 
antibody infusion) 
interruption 
indicated AND
Responds
promptly to
symptomatic 
treatment OR
Prophylactic 
medications 
i di
d f
24
Prolonged
severe signs and
symptoms OR
Recurrence of 
symptoms
following initial
improvement
Life-threatening 
consequences 
(e.g., requiring
pressor or 
ventilator
support)
Fatigue or 
Malaise
Report only one
Symptoms 
causing no or
minimal 
interference with
usual social & 
functional
activities
Symptoms 
causing greater
than minimal 
interference with 
usual social & 
functional
activities
Symptoms 
causing 
inability to
perform usual
social & 
functional
activities
Incapacitating
symptoms of fatigue 
or malaise causing
inability to perform
basic self-care 
functions
Fever (non-
axillary 
temperatures 
only)
38.0 to < 38.6°C 
or 100.4 to <
101.5°F
≥ 38.6 to < 39.3°C 
or ≥ 101.5 to < 
102.7°F
≥ 39.3 to < 
40.0°C or ≥ 102.7
to < 104.0°F
≥ 40.0°C or ≥ 104.0°F
Pain
10 (not
associated with
study agent 
injections and
not specified
elsewhere)
Specify location
Pain causing no
or minimal
interference 
with usual
social & 
functional
activities
Pain causing
greater than
minimal 
interference with 
usual social & 
functional
activities
Pain causing
inability to
perform usual
social & 
functional
activities
Disabling pain causing 
inability to perform
basic self-care
functions OR
Hospitalization
indicated

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PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE
4
POTENTIALLY 
LIFE-
THREATENING
Serum Sickness
11
Mild signs 
and 
symptoms
Moderate signs 
and symptoms
AND Intervention 
indicated (e.g., 
antihistamines)
Severe signs 
and symptoms
AND Higher
level 
intervention
indicated (e.g.,
steroids or IV 
fluids)
Life-threatening 
consequences 
(e.g., requiring
pressor or 
ventilator
support)
Underweight12
> 5 to 19
years of age
NA
WHO BMI z-score 
< -2 to ≤ -3
WHO BMI z-
score
< -3
WHO BMI z-score < -3
with life-threatening 
consequences
2 to 5 years of
age
NA
WHO Weight-
for- height z-
score < -2 to ≤ -3
WHO
Weight-for-
height z-
score < 3
WHO Weight-for-
height z-score < -3
with life- threatening
consequences
< 2 years of age NA
WHO Weight-
for- length z-
score < -2 to ≤ -3
WHO
Weight-for-
length z-
3
WHO Weight-for-
length z-score < -3
with life- threatening
Weight Loss 
(excludes 
postpartum
weight
loss)
NA
5 to < 9% loss in 
body weight
from baseline
≥ 9 to < 20%
loss in body
weight from 
baseline
≥ 20% loss in body
weight from baseline 
OR Aggressive 
intervention indicated
(e.g., tube feeding, total
parenteral nutrition)
9.
Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and/or 
shortness of breath.
10. For pain associated with injections or infusions, see the Site Reactions to Injections and Infusions 
section.
11. Definition: A disorder characterized by fever, arthralgia, myalgia, skin eruptions, lymphadenopathy, 
marked discomfort, and/or dyspnea.
12. WHO reference tables may be accesed by clicking the desired age range or by accessing the following 
URLs: http://www.who.int/growthref/who2007_bmi_for_age/en / for participants > 5 to 19 years of 
age and http://www.who.int/childgrowth/standards/chart_catalogue/en/ for those ≤ 5 years of age.

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Urinary
PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE
4
POTENTIALLY 
LIFE-
THREATENING
Urinary Tract
Obstruction
NA
Signs or symptoms 
of urinary tract 
obstruction
without 
hydronephrosis or 
renal dysfunction
Signs or
symptoms of 
urinary tract 
obstruction
with 
hydronephrosis 
or renal
Obstruction causing
life- threatening 
consequences
Site Reactions to Injections and Infusions
PARAMETER
GRADE 1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE
4
POTENTIALLY 
LIFE-
THREATENING
Injection Site Pain
or
Tenderness
Report only one
Pain or
tenderness 
causing no or 
minimal
limitation of
use of limb
Pain or tenderness 
causing greater
than minimal
limitation of use 
of limb
Pain or
tenderness 
causing
inability to 
perform usual
social & 
functional
activities
Pain or tenderness 
causing inability to 
perform basic self-care 
function OR
Hospitalization
indicated
Injection Site 
Erythema or 
Redness13
Report only one
> 15 years of age
2.5 to < 5 cm in 
diameter OR
6.25 to < 25 cm2
surface area
AND Symptoms 
causing no or
minimal 
interference with 
usual social & 
functional
activities
≥ 5 to < 10 cm in 
diameter OR ≥ 25
to < 100 cm2
surface area OR 
Symptoms 
causing greater
than minimal
interference with
usual social & 
functional
activities
≥ 10 cm in
diameter OR ≥ 
100 cm2
surface area
OR Ulceration 
OR Secondary 
infection OR
Phlebitis OR
Sterile abscess 
OR Drainage 
OR Symptoms 
causing
inability to
perform usual
i l &
Potentially life-
threatening 
consequences (e.g., 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue)

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PARAMETER
GRADE 1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE
4
POTENTIALLY 
LIFE-
THREATENING
≤ 15 years of age
≤ 2.5 cm in
diameter
> 2.5 cm in
diameter with < 
50% surface area 
of the extremity 
segment involved 
(e.g., upper arm
or thigh)
≥ 50% surface 
area of the 
extremity
segment 
involved (e.g.,
upper arm or
thigh) OR
Ulceration OR
Secondary
infection OR
Phlebitis OR
Sterile abscess 
OR Drainage
Potentially life-
threatening 
consequences (e.g., 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue)
Injection Site
Induration or 
Swelling
Report only one
> 15 years 
of age
Same as for 
Injection Site 
Erythema or 
Redness, > 15
years of age
Same as for
Injection Site 
Erythema or 
Redness, > 15
years of age
Same as for
Injection Site 
Erythema or 
Redness, > 15
years of age
Same as for Injection 
Site Erythema or 
Redness, > 15 years 
of age
≤15 years of age
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15
years of age
Same as for
Injection Site 
Erythema or 
Redness, ≤ 15
years of age
Same as for
Injection Site 
Erythema or 
Redness, ≤ 15
years of age
Same as for Injection 
Site Erythema or 
Redness, ≤ 15 years
of age
Injection Site 
Pruritus
Itching localized
to the injection
site that is 
relieved 
spontaneously or
in < 48 hours of 
treatment
Itching beyond
the injection site 
that is not
generalized OR
Itching localized
to the injection
site requiring ≥ 
48 hours
Generalized 
itching 
causing
inability to 
perform usual
social & 
functional
activities
NA
13. Injection Site Erythema or Redness should be evaluated and graded using the greatest single diameter 
or measured surface area.
Laboratory Values
Chemistries
PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE
4
POTENTIALLY 
LIFE-
THREATENING
Acidosis
NA
pH ≥ 7.3 to < LLN
pH < 7.3
without life-
threatening 
consequences
pH < 7.3 with life-
threatening 
consequences

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PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE
4
POTENTIALLY 
LIFE-
THREATENING
Albumin,
Low
(g/dL;
g/L)
3.0 to < LLN
30  to < LLN
≥ 2.0 to < 3.0
≥ 20  to < 30
< 2.0
< 20
NA
Alkaline 
Phosphatase, 
High
1.25 to <
2.5 x ULN
2.5  to < 5.0 x ULN 5.0 to < 10.0 x
ULN
≥ 10.0 x ULN
Alkalosis
NA
pH > ULN to ≤ 7.5
pH > 7.5
without life-
threatening 
consequences
pH > 7.5 with life-
threatening 
consequences
ALT or SGPT,
High
Report only one
1.25 to <
2.5 x ULN
2.5 to < 5.0 x ULN
5.0  to < 10.0 x
ULN
≥ 10.0 x ULN
Amylase 
(Pancreatic) or
Amylase (Total),
High
Report only one
1.1  to < 1.5 x
ULN
1.5  to < 3.0 x ULN 3.0  to < 5.0 x
ULN
≥ 5.0 x ULN
AST or SGOT,
High
Report only one
1.25 to <
2.5 x ULN
2.5  to < 5.0 x ULN 5.0  to < 10.0 x
ULN
≥ 10.0 x ULN
Bicarbonate, Low
(mEq/L; mmol/L)
16.0 to <  LLN
16.0 to <  LLN
11.0 to < 16.0
11.0 to < 16.0
8.0  to < 11.0
8.0  to < 11.0
< 8.0
< 8.0
Bilirubin
Direct
Bilirubin14, 
High
> 28 days of
age
NA
NA
> ULN
> ULN with life-
threatening
consequences (e.g., signs
and symptoms of
liver failure)
≤ 28 days of age ULN to ≤ 1 mg/dL > 1 to ≤ 1.5 mg/dL
> 1.5 to ≤2
mg/dL
> 2 mg/dL
Total
Bilirubin, High
> 28 days 
of age
1.1 to < 1.6 x ULN 1.6 to < 2.6 x ULN
2.6 to < 5.0 x
ULN
≥ 5.0 x ULN
Calcium, High
(mg/dL; mmol/L)
≥ 7 days of age
10.6  to < 11.5
2.65 to < 2.88
11.5 to < 12.5
2.88 to < 3.13
12.5  to < 13.5
3.13 to < 3.38
≥ 13.5
≥ 3.38
< 7 days of age
11.5 to < 12.4
2.88 to < 3.10
12.4 to < 12.9
3.10 to < 3.23
12.9 to < 13.5
3.23 to < 3.38
≥ 13.5
≥ 3.38
Calcium (Ionized), 
High
(mg/dL; mmol/L)
> ULN to < 6.0
> ULN  to < 1.5
6.0 to < 6.4
1.5 to < 1.6
6.4 to < 7.2
1.6 to < 1.8
≥ 7.2
≥ 1.8
Calcium, Low
(mg/dL; mmol/L)

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PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE
4
POTENTIALLY 
LIFE-
THREATENING
≥ 7 days of age
7.8  to < 8.4
1.95  to < 2.10
7.0   to < 7.8
1.75  to < 1.95
6.1  to < 7.0
1.53  to < 1.75
< 6.1
< 1.53
< 7 days of age
6.5  to < 7.5
1.63  to < 1.88
6.0 to < 6.5
1.50  to < 1.63
5.50  to < 6.0
1.38  to < 1.50
< 5.50
< 1.38
Calcium (Ionized),  
Low
(mg/dL; mmol/L)
< LLN  to 4.0
< LLN to 1.0
3.6 to < 4.0
0.9 to < 1.0
3.2 to < 3.6
0.8 to < 0.9
< 3.2
< 0.8
Cardiac Troponin 
I, High
NA
NA
NA
Levels consistent with 
myocardial infarction or 
unstable angina as 
defined by the local 
laboratory
Creatine Kinase, 
High
3 to < 6 x ULN
6 to < 10 x ULN
10 to < 20 x 
ULN
≥ 20 x ULN
Creatinine, High
1.1 to 1.3 x ULN
> 1.3 to 1.8 x ULN 
OR Increase of > 
0.3 mg/dL above 
baseline
> 1.8  to < 3.5 x 
ULN OR 
Increase of 1.5 
to < 2.0 x above
baseline
≥ 3.5 x ULN OR 
Increase of ≥ 2.0 x above 
baseline
Creatinine 
Clearance 15
or eGFR, Low
Report only one
NA
< 90 to 60 ml/min 
or ml/min/1.73 m2
OR 10 to < 30% 
decrease from 
baseline
< 60 to 30 
ml/min or 
ml/min/1.73 m2
OR
≥ 30 to < 50% 
decrease from 
baseline
< 30 ml/min or 
ml/min/1.73 m2
OR
≥ 50% decrease from 
baseline or dialysis 
needed
Glucose
(mg/dL; mmol/L)
Fasting, High
110 to 125
6.11 to < 6.95
> 125 to 250
6.95 to < 13.89
> 250 to 500
13.89 to < 
27.75
> 500
≥ 27.75
Nonfasting, High 116 to 160
6.44 to < 8.89
> 160 to 250
8.89 to < 13.89
> 250 to 500
13.89  to < 
27.75
> 500
≥ 27.75
Glucose, Low
(mg/dL; mmol/L)
≥ 1 month of age
55  to 64
3.05  to 3.55
40  to < 55
2.22  to < 3.05
30  to < 40
1.67 to < 2.22
< 30
< 1.67
< 1 month of age
50 to 54
2.78  to 3.00
40 to < 50
2.22 to < 2.78
30 to < 40
1.67 to < 2.22
< 30
< 1.67
Lactate, High
ULN to  < 2.0
x ULN without 
acidosis
≥ 2.0 x ULN 
without acidosis
Increased 
lactate with pH 
< 7.3 without 
life- threatening
consequences
Increased lactate with pH
< 7.3 with life-
threatening 
consequences

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PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE
4
POTENTIALLY 
LIFE-
THREATENING
Lipase, High
1.1  to < 1.5 x 
ULN
1.5  to < 3.0 x ULN 3.0  to < 5.0 x 
ULN
≥ 5.0 x ULN
Lipid Disorders
(mg/dL; mmol/L)
Cholesterol, 
Fasting, High
≥ 18 years of age
200  to < 240
5.18  to < 6.19
240  to < 300
6.19  to < 7.77
≥  300
≥  7.77
NA
< 18 years of age 170  to < 200
4.40  to < 5.15
200  to < 300
5.15  to < 7.77
≥  300
≥  7.77
NA
LDL, Fasting, 
High
≥ 18 years of age
130  to < 160
3.37  to < 4.12
160 to < 190
4.12  to < 4.90
≥ 190
≥ 4.90
NA
> 2 to < 18 years 
of age
110  to < 130
2.85  to < 3.34
130 to < 190
3.34  to < 4.90
≥ 190
≥ 4.90
NA
Triglycerides, 
Fasting, High
150 to 300
1.71 to 3.42
>300  to 500
>3.42 to 5.7
>500 to < 1,000
>5.7 to 11.4
> 1,000
> 11.4
Magnesium16, Low
(mEq/L; mmol/L)
1.2   to < 1.4
0.60  to < 0.70
0.9  to < 1.2
0.45  to < 0.60
0.6  to < 0.9
0.30  to < 0.45
< 0.6
< 0.30
Phosphate, Low
(mg/dL; mmol/L)
> 14 years of age
2.0 to < LLN
0.81 to < LLN
1.4 to < 2.0
0.65 to < 0.81
1.0 to < 1.4
0.32 to < 0.65
< 1.0
< 0.32
1 to 14 years of 
age
3.0  to < 3.5
0.97  to < 1.13
2.5  to < 3.0
0.81  to < 0.97
1.5  to < 2.5
0.48  to < 0.81
< 1.5
< 0.48
< 1 year of age
3.5  to < 4.5
1.13  to < 1.45
2.5  to < 3.5
0.81  to < 1.13
1.5  to < 2.5
0.48  to < 0.81
< 1.5
< 0.48
Potassium, High
(mEq/L; mmol/L)
5.6  to < 6.0
5.6  to < 6.0
6.0  to < 6.5
6.0  to < 6.5
6.5  to < 7.0
6.5  to < 7.0
≥ 7.0
≥ 7.0
Potassium, Low
(mEq/L; mmol/L)
3.0  to < 3.4
3.0  to < 3.4
2.5  to < 3.0
2.5  to < 3.0
2.0  to < 2.5
2.0  to < 2.5
< 2.0
< 2.0
Sodium, High
(mEq/L; mmol/L)
146  to < 150
146  to < 150
150  to < 154
150  to < 154
154  to < 160
154  to < 160
≥ 160
≥ 160
Sodium, Low
(mEq/L; mmol/L)
130  to < 135
130  to < 135
125  to < 130
125  to < 135
121  to < 125
121  to < 125
≤ 120
≤ 120
Uric Acid, High
(mg/dL; mmol/L)
7.5  to < 10.0
0.45  to < 0.59
10.0  to < 12.0
0.59  to < 0.71
12.0  to < 15.0
0.71  to < 0.89
≥ 15.0
≥ 0.89
14. Direct bilirubin > 1.5 mg/dL in a participant < 28 days of age should be graded as grade 2, if < 10% of 
the total bilirubin.
15. Use the applicable formula (i.e., Cockroft-Gault in mL/min or Schwatrz in mL/min/1.73m2).

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PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE
4
POTENTIALLY 
LIFE-
THREATENING
16. To convert a magnesium value from mg/dL to mmol/L, laboratories should multiply by 0.4114
.
Hematology
PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE
4
POTENTIALLY 
LIFE-
THREATENING
Absolute CD4+
Count, Low
(cell/mm3; cells/L)
> 5 years of age
(not HIV infected)
300 to < 400
300 to < 400
200 to <  300
200 to < 300
100 to < 200
100  to < 200
< 100
< 100
Absolute 
Lymphocyte
Count, Low
(cell/mm3;
cells/L)
> 5 years of
age
(not HIV
infected)
600  to < 650
0.600 x 109 to
< 0.650 x 109
500  to < 600
0.500 x 109 to
< 0.600 x 109
350 to < 500
0.350 x 109 to
< 0.500 x 109
< 350
< 0.350 x 109
Absolute 
Neutrophil
Count (ANC),
Low
(cells/mm3;
cells/L)
800 to 1,000
0.800 x 109 to
1.000 x 109
600 to 799
0.600 x 109 to
0.799 x
109
400 to 599
0.400 x 109 to
0.599 x
109
< 400
< 0.400 x 109
2 to 7 days of age
1,250 to 1,500
1.250 x 109 to
1.500 x 109
1,000 to 1,249
1.000 x 109 to
1.249 x
109
750 to 999
0.750 x 109 to
0.999 x
109
< 750
< 0.750 x 109
≤ 1 day of age
4,000 to 5,000
4.000 x 109 to
5.000 x 109
3,000 to 3,999
3.000 x 109 to
3.999 x
109
1,500 to 2,999
1.500 x 109 to
2.999 x
109
< 1,500
< 1.500 x 109
Fibrinogen,
Decreased
(mg/dL; g/L)
100  to < 200
1.00 to < 2.00
OR
0.75 to < 
1.00 x LLN
75  to < 100
0.75 to < 1.00
OR
≥ 0.50 to < 0.75
x LLN
50  to < 75
0.50 to < 0.75
OR
0.25
to < 
0.50 x
< 50
< 0.50
OR
< 0.25 x LLN
OR Associated
with gross bleeding

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PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE
4
POTENTIALLY 
LIFE-
THREATENING
Hemoglobin17,
Low
(g/dL; mmol/L)18
≥ 13 years of age
(male only)
10.0 to 10.9
6.19 to 6.76
9.0 to < 10.0
5.57 to < 6.19
7.0 to < 9.0
4.34 to < 5.57
< 7.0
< 4.34
≥ 13 years of age
(female only)
9.5 to 10.4
5.88 to 6.48
8.5 to < 9.5
5.25 to < 5.88
6.5 to < 8.5
4.03 to < 5.25
< 6.5
< 4.03
57 days of age to < 
13 years of age
(male and female)
9.5 to 10.4
5.88 to 6.48
8.5 to < 9.5
5.25 to < 5.88
6.5 to < 8.5
4.03 to < 5.25
< 6.5
< 4.03
36 to 56 days of 
age
(
l
d f
l )
8.5 to 9.6
5.26 to 5.99
7.0 to < 8.5
4.32 to < 5.26
6.0 to < 7.0
3.72 to < 4.32
< 6.0
< 3.72
22 to 35 days of 
age
(male and female)
9.5 to 11.0
5.88 to 6.86
8.0 to < 9.5
4.94 to < 5.88
6.7 to < 8.0
4.15 to < 4.94
< 6.7
< 4.15
8 to ≤ 21 days of 
age
(male and female)
11.0 to 13.0
6.81 to 8.10
9.0 to < 11.0
5.57 to < 6.81
8.0 to < 9.0
4.96 to < 5.57
< 8.0
< 4.96
≤ 7 days of age
(male and female)
13.0 to 14.0
8.05 to 8.72
10.0 to < 13.0
6.19 to < 8.05
9.0 to < 10.0
5.59 to < 6.19
< 9.0
< 5.59
INR, High
(not on 
anticoagulation 
1.1  to < 1.5 x 
ULN
1.5  to < 2.0 x ULN 2.0  to < 3.0 x 
ULN
≥  3.0 x ULN
Methemoglobin
(% hemoglobin)
5.0  to < 10.0%
10.0  to < 15.0%
15.0  to < 
20.0%
≥  20.0%
PTT, High
(not on 
anticoagulation 
1.1  to < 1.66 x 
ULN
1.66 to < 2.33 x 
ULN
2.33 to < 3.00 
x ULN
≥  3.00 x ULN
Platelets, Decreased
(cells/mm3; cells/L)
100,000  to
< 124,999
100.000 x 109  to
< 124.999 x 109
50,000  to
< 100,000
50.000 x 109  to
< 100.000 x 109
25,000  to
< 50,000
25.000 x 109  
to
< 50.000 x 
< 25,000
< 25.000 x 109
PT, High
(not on 
anticoagulation
th
)
1.1  to < 1.25 x 
ULN
1.25  to < 1.50 x 
ULN
1.50  to < 3.00
x ULN
≥  3.00 x ULN

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PARAMETER
GRADE
1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE
4
POTENTIALLY 
LIFE-
THREATENING
WBC, Decreased
(cells/mm3; cells/L)
> 7 days of age
2,000 to 2,499
2.000 x 109 to 
2.499 x 109
1,500 to 1,999
1.500 x 109 to 1.999
x
109
1,000 to 1,499
1.000 x 109 to 
1.499 x
109
< 1,000
< 1.000 x 109
≤ 7 days of age
5,500 to 6,999
5.500 x 109 to 
6.999 x 109
4,000 to 5,499
4.000 x 109 to 5.499
x 109
2,500 to 3,999
2.500 x 109 to 
3.999 x
109
< 2,500
< 2.500 x 109
17. Male and female sex are defined as sex at birth.
The conversion factor used to convert g/dL to mmol/L is 0.6206 and is the most commonly used 
conversion factor.  For grading hemoglobin results obtained by an analytic method with a conversion 
factor other than 0.6206, the result must be converted to g/dL using the appropriate conversion factor 
for the particular laboratory.
Urinalysis
PARAMETER
GRADE 1
MILD
GRADE
2
MODERATE
GRADE 3
SEVERE
GRADE
4
POTENTIALLY 
LIFE-
THREATENING
Glycosuria
(random 
collection
tested by 
Trace to 1+ or
≤ 250 mg
2+ or ˃ 250 to
≤ 500 mg
> 2+ or >
500 mg
NA
Hematuria (not to
be reported based
on dipstick 
findings or on
blood believed to
be of
menstrual origin)
6 to < 10 RBCs
per high power
field
≥ 10 RBCs per high
power field
Gross,
with or 
without
clots OR
With RBC
casts OR
Intervention
i di
t d
Life-threatening 
consequences
Proteinuria
(random 
collection
tested by 
dipstick)
1+
2+
3+  or higher NA
Reference
U.S. Department of Health and Human Services, National Institutes of Health, National 
Institute of Allergy and Infectious Diseases, Division of AIDS. Division of AIDS 
(DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 
2.0. [November 2014]. Available from:
http://rsc.techres.com/Document/safetyandpharmacovigilance/DAIDS_AE_GRADING_
TABLE_v2_NOV2014.pdf  (accessed 10 September 2015).  

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12.3.
Appendix 3:  Liver Safety – Study Treatment Restart or 
Rechallenge Guidelines
VSLC GUIDELINES FOR DRUG RESTART OR RECHALLENGE AFTER STOP 
FOR LIVER CRITERIA
Drug Rechallenge refers to resuming study treatment following drug induced liver injury 
(DILI). Because of the risks associated with rechallenge after DILI (see Drug 
Rechallenge Background below) this should only be considered for a participant for 
whom there is compelling evidence of benefit from a critical or life-saving medicine, 
there is no alternative approved medicine available, and a benefit:risk assessment of 
rechallenge is considered to be favorable (Table 14, Figure 9).
Drug Restart refers to resuming study treatment following liver events meeting stopping 
criteria in which there is a clear underlying cause (other than DILI) of the liver event 
(e.g., biliary obstruction, pancreatic events, hypotension, acute viral hepatitis). 
Furthermore, there should be no evidence of alcoholic hepatitis or hypersensitivity, and 
the drug should not be associated with HLA markers of liver injury. (Table 15; Figure 
10).
As this determination can be difficult, for the purpose of these guidelines, cases 
should be treated as rechallenges if there is any reasonable likelihood that the liver 
event is related to study drug. Restarts should be limited to cases in which there is 
clear evidence that the underlying cause of the liver event is not related to study 
drug.

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DRUG RECHALLENGE
Background: Following drug-induced liver injury, drug rechallenge is associated with a 
13% mortality across all drugs in prospective studies [Andrade, 2009].  Clinical outcomes 
vary by drug, with nearly 50% fatality with halothane re-administered within one month 
of initial injury.  However, some drugs seldom result in recurrent liver injury or fatality.
Risk factors for a fatal drug rechallenge outcome include:

hypersensitivity [Andrade, 2009] with initial liver injury (e.g. fever, rash, 
eosinophilia)

jaundice or bilirubin >2xULN with initial liver injury (direct bilirubin >35% of 
total)

participant currently exhibits severe liver injury defined by: ALT3xULN, 
bilirubin 2xULN (direct bilirubin >35% of total), or INR1.5

prior serious adverse event or fatality has earlier been observed with drug 
rechallenge [Papay, 2009; Hunt, 2010]

evidence of drug-related nonclinical liability (e.g. reactive metabolites; 
mitochondrial impairment [Hunt, 2010])
VSLC Decision Process for Drug Rechallenge Approval or 
Disapproval

Principal Investigator (PI) requests consideration of drug rechallenge for a 
participant receiving compelling benefit from a critical or life-saving drug, who 
exhibits liver chemistry elevation meeting participant stopping criteria in relation 
to DILI, with no alternative treatment

By definition treatment naïve participants 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 review the participant’s rechallenge risk factors (consultation with the 
Hepatotoxicity Panel is available) and complete checklist (Table 14).

The local operating company (LOC) medical directors (ViiV and/or GSK where 
applicable) should be informed that study drug rechallenge is under consideration 
and of the final decision, whether or not to proceed.

The Medical Monitor and GCSP Physician are accountable to review and agree 
on the following prior to preparing request for rechallenge documentation for 
presentation to VSLC:
–
Compelling benefit of the investigational product (IP) for this participant and 
no alternative therapy 

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o
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)

Participant 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 is associated with known nonclinical hepatic liability/ injury

Relevant physicians (listed below) must review and agree on action to be taken 
regarding request for drug rechallenge:  

Safety Review Team Leader, Safety Development Leader, or Senior 
Safety Physician

Medicines Development Leader (MDL) and Project Physician Leader 
(PPL) 

Request is taken to full VSLC for final decision

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Table 14
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 IP for this participant 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:
fever, rash, eosinophilia, or hypersensitivity
bilirubin2xULN (direct bilirubin >35% of total)
Participant currently exhibits 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
If yes, please provide brief explanation:
IP associated with known nonclinical hepatic liability/ injury
Source data defining the patients current resistance profile
Previous drug history

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Figure 9
VSLC process for drug rechallenge approval or disapproval
Participant exhibits liver injury on drug while disease condition 
stable or improving
Medical Monitor and Safety Physician(s) to discuss benefit:risk 
and
Any fever, rash, eosinophilia, hypersensitivity with initial liver injury 
[Andrade, 2009] in this patient?
Currently ALT>3xULN and Bilirubin >2xULN or INR >1.5x in this 
patient suggesting failing liver
Any prior severe/fatal outcomes reported on drug rechallenge [Papay, 
2009; Hunt, 2010] with this drug?
Any Evidence of nonclinical hepatic liability/injury with this drug?
LOC Medical Director to be informed of rechallenge consideration and 
final decision
Relevant physicians (from Safety and Clinical functions) review and 
agree on rechallenge request
Request is 
submitted to 
VSLC
VSLC Approves Re-initiation of IP
VSLC Does NOT Approve Re-
initiation of IP
PI promptly informed of decision and 
dosing regimen
Ethics Committee or IRB review, if needed
Benefits/Risks discussed with participant 
and consent recorded in chart 
Liver chemistries obtained twice weekly for 
a minimum of one month and thereafter for 
as long as clinically indicated
Safety Review Teams record rechallenge 
outcome
VSLC notified of rechallenge outcome
PI promptly informed of decision

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DRUG RESTART
“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
•
alcoholic hepatitis
Study drug must be held while labs and evaluation are completed to assess diagnosis.
VSLC Decision Process for Drug Restart Approval or Disapproval 

Principal Investigator (PI) requests consideration of drug re-initiation for a 
participant stable or improving on IP, who exhibits liver chemistry elevation 
meeting participant stopping criteria, which is transient, non-drug-related, and 
liver chemistries have improved to normal or are within 1.5x baseline and 
ALT< 5xULN. 

GSK Medical Monitor and GCSP Physician to review the participant’s diagnosis 
restart risk factors (Hepatotoxicity Panel consultation is available) and complete 
checklist (Table 15).
–
must present source data defining the patient’s current resistance profile 
with documented evidence of extensive drug resistance and previous drug 
history.

The local operating company (LOC) medical director should be informed that 
study drug restart is under consideration and of the final decision, whether or not 
to proceed.

Relevant physicians (listed below) must review and agree on action to be taken  
regarding request for drug restart:  

Safety ReviewTeam Leader, Safety Development Leader, or Senior Safety 
Physician

MDL and PPL

Request is taken to VSLC for final decision

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Table 15
Checklist for Phase III drug restart after well-explained liver injury 
(e.g. biliary, pancreatic, hypotensive events, congestive heart failure 
(CHF), acute viral hepatitis), and improvement of liver chemistry to 
normal or 1.5x baseline & ALT<5xULN
Yes
No
Is participant stable or improving on 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
Figure 10
VSLC process for drug restart approval or disapproval
Participant exhibits transient, non-drug related liver injury while 
disease condition stable or improving
Medical Monitor and Safety Physician(s) to discuss etiology of 
liver injury and
Have liver injuries decreased to normal or to <1.5x Baseline and ALT 
<5xULN
Any fever, rash, eosinophilia in this patient or HLA genetic marker 
associated with liver injury [Andrade, 2009]?
Any evidence of alcoholic hepatitis or DILI in this patient?
Any prior sever/fatal outcomes reported on drug restart [Papay, 2009; 
Hunt, 2010] with this drug?
Any Evidence of nonclinical hepatic liability/injury with this drug?
LOC Medical Director to be informed of restart consideration and final 
decision
Relevant physicians (from Safety and Clinical functions) review and 
agree on restart request
Request is 
submitted to VSLC
VSLC Approves Re-initiation of IP
VSLC Does NOT Approve Re-
initiation of IP
PI promptly informed of decision and 
dosing regimen
Ethics Committee or IRB review, if needed
Benefits/Risks discussed with participant 
and consent recorded in chart 
Liver chemistries obtained once weekly for 
a minimum of one month and thereafter for 
as long as clinically indicated
Safety Review Teams record rechallenge 
outcome
VSLC notified of rechallenge outcome
PI promptly informed of decision

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Medical monitor, GCSP Physician and PI actions for Restart or 
Rechallenge following VSLC decision
Medical Monitor and 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 (see template below).

All severe reactions (rechallenge associated with bilirubin>2xULN or jaundice, 
or INR1.5), SAEs or fatalities which occur following a drug rechallenge (or 
restart) must be immediately reported to Line Management including, VSLC 
Chair, VP Global Medical Strategy and EU Qualified Person for 
Pharmacovigilance. 
PI Actions:

The PI must obtain Ethics Committee or Institutional Review Board approval of 
drug rechallenge or restart, as required. 

If VSLC approves drug rechallenge or restart, the patient must sign a new 
informed consent containing 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 a minimum of one month and thereafter for as 
long as clinically indicated following drug re-initiation.  If participant exhibits 
protocol-defined liver chemistry elevations, IP should be discontinued as protocol 
specified.

Medical Monitor and the Ethics Committee or Institutional Review Board must 
be informed of the patient’s outcome following drug rechallenge or restart.

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Drug Rechallenge or Drug Restart Outcomes Table Template
To be completed/updated and provided to VSLC with each event 
recorded across studies and indications
Drug Rechallenge/Restart Outcomes Table – Update with each event
Protocol#
Participant#
Rechallenge or 
Restart?
Safety 
outcome*
Drug 
benefit
Rechallenge/restart safety outcomes:
0 = no liver chemistry elevation
1 = recurrent liver chemistry elevation not meeting participant stopping criteria
2 = recurrent liver chemistry elevation meeting participant stopping criteria
3 = serious adverse event
4 = fatality

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12.4.
Appendix 4:  CDC Classification for HIV-1 Infection (2014)
Note that the CD4+ T-lymphocyte count takes precedence over the CD4+ T-lymphocyte 
percentage in HIV infection stages 1, 2, and 3.  The CD4+ T-lymphocyte should only be 
considered if the count is missing.
HIV infection, stage 0
Indicates early HIV infection, inferred from a negative or indeterminate HIV test result 
within 180 days of a positive result.  The criteria for stage 0 supersede and are 
independent of criteria used for other stages.
HIV infection, stage 1

Laboratory confirmation of HIV infection with no AIDS-defining condition, and
o
CD4+ T-lymphocyte count of ≥500 cells/L, or
o
CD4+ T-lymphocyte percentage of total lymphocytes of ≥26%.
HIV infection, stage 2

Laboratory confirmation of HIV infection with no AIDS-defining condition, and
o
CD4+ T-lymphocyte count of 200 to 499 cells/L, or
o
CD4+ T-lymphocyte percentage of total lymphocytes of 14% to 25%.
HIV infection, stage 3 (AIDS)

Laboratory confirmation of HIV infection, and
o
CD4+ T-lymphocyte count of <200 cells/L, or
o
CD4+ T-lymphocyte percentage of total lymphocytes of <14%, or
o
Documentation of an AIDS-defining condition (see below).
Documentation of an AIDS-defining condition supersedes a CD4+ T-lymphocyte count 
of >200 cells/L and a CD4+ T-lymphocyte percentage of total lymphocytes of >14%. 
HIV infection, stage unknown

Laboratory confirmation of HIV infection, and
o
No information on CD4+ T-lymphocyte count or percentage, and
o
No information on presence of AIDS-defining conditions.
Stage-3-defining opportunistic illnesses in HIV infection

Candidiasis of bronchi, trachea, or lungs 

Candidiasis of oesophagus 

Cervical cancer, invasive

Coccidioidomycosis, disseminated or extrapulmonary 

Cryptococcosis, extrapulmonary 

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
Cryptosporidiosis, chronic intestinal (>1 month's duration)

Cytomegalovirus disease (other than liver, spleen, or nodes), onset at age >1 
month

Cytomegalovirus retinitis (with loss of vision)

Encephalopathy, HIV-related 

Herpes simplex: chronic ulcers (>1 month's duration) or bronchitis, pneumonitis, 
or oesophagitis (onset at age >1 month)

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 Mycobacterium kansasii, disseminated or 
extrapulmonary 

Mycobacterium tuberculosis of any site, pulmonary, disseminated or 
extrapulmonary 

Mycobacterium, other species or unidentified species, disseminated or 
extrapulmonary

Pneumocystis jirovecii pneumonia 

Pneumonia, recurrent

Progressive multifocal leukoencephalopathy 

Salmonella septicaemia, recurrent 

Toxoplasmosis of brain, onset at age >1 month 

Wasting syndrome attributed to HIV.
Reference
CDC. Revised Surveillance Case Definition for HIV Infection – United States, 2014. 
MMWR 2014; 63 (RR-03);1-10.

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12.5.
Appendix 5:  Genetic Research
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate a relationship between genetic 
variants and: 

Response to medicine, including CAB + RPV or any concomitant medicines; 

HIV-1 susceptibility, severity and progression and related conditions. 
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a RAP prior to initiation of the 
analysis. Planned analyses and results of genetic investigations will be reported either as 
part of the clinical RAP and study report, or in a separate genetics RAP and report, as 
appropriate.
Study Population
Any participant who is enrolled in the clinical study can participate in genetic research. 
Any participant who has received an allogeneic bone marrow transplant must be excluded 
from genetic research.
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.  

A 6 mL blood sample will be taken for deoxyribonucleic acid (DNA) extraction.  
A blood sample is collected at the baseline visit, after the participant has been 
randomized and provided informed consent for genetic research. Instructions for 
collection and shipping of the genetic sample are described in the laboratory 
manual. The DNA from the blood sample may undergo quality control analyses to 
confirm the integrity of the sample.  If there are concerns regarding the quality of 
the sample, then the sample may be destroyed.  The blood sample is taken on a 
single occasion unless a duplicate sample is required due to an inability to utilize 
the original sample.
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study.   This number can be traced or linked back to 

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the participant by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number).
Samples will be stored securely and may be kept for up to 15 years after the last 
participant completes the study, or GSK may destroy the samples sooner.  GSK or those 
working with GSK (for example, other researchers) will only use samples collected from 
the study for the purpose stated in this protocol and in the informed consent 
form.  Samples may be used as part of the development of a companion diagnostic to 
support the GSK medicinal product.
Participants can request their sample to be destroyed at any time.
Informed Consent
Participants who do not wish to participate in the genetic research may still participate in 
the study.  Genetic informed consent must be obtained prior to any blood being taken.
Participant Withdrawal from Study
If a participant who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the participant will be 
given a choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA 
sample is retained 

Discontinue participation in the genetic research and destroy the genetic DNA 
sample. 
If a participant withdraws consent for genetic research or requests sample destruction for 
any reason, the investigator must complete the appropriate documentation to request 
sample destruction within the timeframe specified by ViiV/GSK and maintain the 
documentation in the site study records. 
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis.

If a participant withdraws consent for genetic research and genotype data has not 
been analyzed, it will not be analyzed or used for future research.

Genetic data that has been analyzed at the time of withdrawn consent will 
continue to be stored and used, as appropriate.
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the 
participant does not meet the entry criteria for participation in the study, then the 
investigator should instruct the participant that their genetic sample will be destroyed. No 
forms are required to complete this process as it will be completed as part of the consent 

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and sample reconciliation process.  In this instance a sample destruction form will not be 
available to include in the site files.
Provision of Study Results and Confidentiality of Participant’s Genetic Data
ViiV/GSK may summarize the genetic research results in the CSR, or separately, and 
may publish the results in scientific journals. 
ViiV/GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the 
participant, family members, insurers, or employers of individual genotyping results that 
are not known to be relevant to the participant’s medical care at the time of the 
study, unless required by law. This is due to the fact that the information generated from 
genetic studies is generally preliminary in nature, and therefore the significance and 
scientific validity of the results are undetermined.  Further, data generated in a research 
laboratory may not meet regulatory requirements for inclusion in clinical care.

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12.6.
Appendix 6:  Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.6.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
participant, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE.  However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition 
of an AE or SAE.

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Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
12.6.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
Results in death
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event.  It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or 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.

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
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption
Is a congenital anomaly/birth defect
Other situations:

Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the participant 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
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
participants receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.

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12.6.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the eCRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
12.6.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the eCRF

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all participant identifiers, with the exception of 
the participant number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.

Participant-completed Value Evidence and Outcomes questionnaires and the 
collection of AE data are independent components of the study.

Responses to each question in the Value Evidence and Outcomes questionnaire will 
be treated in accordance with standard scoring and statistical procedures detailed by 

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the scale’s developer.

The use of a single question from a multidimensional health survey to designate a 
cause-effect relationship to an AE is inappropriate.
12.6.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important 
that the investigator always make an assessment of causality for every event 
prior to the initial transmission of the SAE data to GSK.

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
The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings, including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
12.6.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the Medical Monitor.

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, the site can report this information on a paper SAE form or to the 
Medical Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.

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SAE reporting to GSK via paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the Medical Monitor or the SAE coordinator

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable, with a copy of the SAE data collection tool sent by 
overnight mail

Initial notification via the telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE receipt can be found at this beginning of the protocol on the 
Sponsor/Medical Monitor Contact Information page.

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12.7.
Appendix 7:  Pregnancy Information
12.7.1.
Modified List of Highly Effective Methods for Avoiding Pregnancy 
in FRP and Collection of Pregnancy Information
The list does not apply to FRP with same sex partners or for participants who are and will 
continue to be abstinent from penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle.  Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.

Contraceptive subdermal implant 

Intrauterine device or intrauterine system 

Combined estrogen and progestogen oral contraceptive [Hatcher, 2011])] 

Injectable progestogen [Hatcher, 2011] 

Contraceptive vaginal ring [Hatcher, 2011] 

Percutaneous contraceptive patches [Hatcher, 2011] 

Male partner sterilisation with documentation of azoospermia prior to the female 
participant's entry into the study, and this male is the sole partner for that 
participant [Hatcher, 2011].  The documentation on male sterility can come from 
the site personnel’s: review of participant’s medical records, medical examination 
and/or semen analysis, or medical history interview provided by her or her 
partner.
This is an all inclusive list of those methods that meet the GSK definition of highly 
effective: having a failure rate of less than 1% per year when used consistently and, 
correctly and, when applicable, in accordance with the product label. For non-product 
methods (e.g. male sterility), the investigator determines what consistent and correct use 
is. The investigator is responsible for ensuring that participants understand how to 
properly use these methods of contraception.
References:
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, Policar MS, editors. 
Contraceptive Technology.  20th edition. Atlanta, Georgia: Ardent Media, Inc., 2011: 50. 
Table 3-2.
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use.  ICH Harmonized Tripartite Guideline. Nonclinical 
Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for 
Pharmaceuticals.  ICH M3 (R2). 2009.
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use.  ICH Harmonized Tripartite Guideline.  Preclinical 
Safety Evaluation of Biotechnology-Derived Pharmaceuticals.  ICH S6 and Addendum 
ICH S6 (R1) 2011.

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12.7.2.
Collection of Pregnancy Information

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy.

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on mother and infant, which will be 
forwarded to GSK within 24 hours.  Generally, follow-up will not be required for 
longer than 6 to 8 weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE within 24 hours of awareness.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in this section.  While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
Any individual participant who becomes pregnant while participating will 
discontinue study medication and be withdrawn from the study.  If the female 
participant is receiving CAB LA + RPV LA, they will be followed for 52 weeks in 
the Long-Term Follow-Up Phase.
12.7.3.
Study Duration
In this study, the Extension Phase is intended to provide access to CAB LA + RPV LA 
until CAB LA + RPV LA receives local (by country) Regulatory approval, and becomes 
commercially available. Therefore, the duration of the Extension Phase will vary from 
country to country and is dependent on the recruitment time for the study and the time 
taken to achieve local approval for marketing. During this time, participants will be 
monitored every 4 weeks to ensure they continue to derive clinical benefit from CAB LA 
+ RPV LA.

2 0 1 5 N 2 5 2 0 0 7 _ 0 4
C O N FI D E N TI A L
2 0 1 5 8 5
2 1 7
1 2. 8.
A p p e n di x 8: C o u ntr y  S p e cifi c R e q uir e m e nt s
1 2. 8. 1.
S o ut h K or e a I n v e sti g ati o n al Pr o d u ct L a b el s
P a g e( s) r e m o v e d - n o n- E n gli s h t e xt r e m o v e d.
I n t his st u d y s u bject i de ntificati o n n u m ber a n d visit n u m ber will n ot be i ncl u de d i n t he I P 
la bel. H o we ver, it will be trac ke d at site p har mac y  whe n t he I P is dis pe nse d t o eac h 
s u bject. ( N ote: T his is a n o pe n la bel st u d y, t h us treat me nt n u m ber is n ot a p plica ble.)

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12.9.
Appendix 9: Protocol Changes
12.9.1.
Summary of Changes in Protocol Amendment 01 and Rationale

Changes were made to the protocol text in the following sections to reflect 
revisions to the age inclusion criteria and addition of South Korea investigational 
product labels.
Section 5.1 Inclusion Criteria #1
Appendix 8 Country Specific Requirements

Revisions were made to the protocol text to correct errors and improve accuracy 
of the text in:
Section 4.2.3.2 Participants Entering from the current ART ARM
Section 4.6.1 Risk Assessment
Section 5.2 Exclusion Criteria #32
Section 5.5.5.1 HIV-1 RNA Blips
Section 6.13.2 Prohibited Medications and Non-Drug Therapies
Section 7.1 Time and Events Table
Section 7.3.3 HIV Associated Conditions
Section 7.4.3.5 Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
Section 7.4.10 Suicidal Risk Monitoring
List of Changes
Section 4.2.3.2 Participants Entering from the current ART ARM
Previously read:
The retest should be scheduled as soon as possible (but no later than 4 weeks from the 
Week 48 visit).
Now reads:
The retest should be scheduled as soon as possible (but no later than 4 weeks from the 
Week 96 visit).
Section 4.6.1 Risk Assessment:  Oral CAB and CAB LA (GSK1265744/GSK1265744 
LA)
Inadvertent Intravenous Injection (Accidental Maladministration)
Previously read:
The clinical consequences of overdose with RPV LA are currently unknown.  HIV-1 viral 
suppression may not be effective following accidental maladministration.

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Now reads:
The clinical consequences of overdose with CAB LA are currently unknown.  HIV-1 
viral suppression may not be effective following accidental maladministration.
Section 5.1 Inclusion Criteria #1
Previously read:
AGE
1. HIV-1 infected men or women aged 18 years or greater at the time of signing the 
informed consent
Now reads:
AGE
1. Aged 18 years or older (or ≥19 where required by local regulatory agencies), at 
the time of signing the informed consent.
Section 5.2 Exclusion Criteria #32
Previously read:

Immunomodulators that alter immune responses (such as systemic corticosteroids, 
interleukins, or interferons. Note: Participants using short-term (<1 day) steroid 
tapers, topical, inhaled and intranasal corticosteroids are eligible for enrolment. 
Now reads:

Immunomodulators that alter immune responses (such as systemic corticosteroids, 
interleukins, or interferons. Note: Participants using short-term (≤14 days) steroid 
tapers, topical, inhaled and intranasal corticosteroids are eligible for enrolment. 
Section 5.5.5.1 HIV-1 RNA Blips
Previously read:
Participants who have a HIV-1 RNA >50 c/mL and < 200 c/mL at key analysis 
timepoints (Week 48Week 96) must return to the clinic as soon as possible (but no later 
than 4 weeks after the date of the Week 48 or Week 96 visit) for a repeat HIV-1 RNA test 
such that the result falls within the same analysis window.

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Now reads:
Participants who have a HIV-1 RNA ≥50 c/mL and < 200 c/mL at key analysis 
timepoints (Week 48, Week 96) must return to the clinic as soon as possible (but no later 
than 4 weeks after the date of the Week 48 or Week 96 visit) for a repeat HIV-1 RNA test 
such that the result falls within the same analysis window.
Section 6.13.2 Prohibited Medications and Non-Drug Therapies
Previously read:
Other experimental agents, antiretroviral drugs not otherwise specified in the protocol, 
cytotoxic chemotherapy, or radiation therapy may not be administered (see Exclusion 
Criteria #30, Section 5.2). 
Now reads:
Other experimental agents, antiretroviral drugs not otherwise specified in the protocol, 
cytotoxic chemotherapy, or radiation therapy may not be administered (see Exclusion 
Criteria #32, Section 5.2). 
Section 6.13.2 Prohibited Medications and Non-Drug Therapies
Previously read:
Chronic use of systemic (oral or parenteral) glucocortioids must be avoided due to 
immunosuppressive effect and potential decreases in RPV plasma concentrations; 
however, short treatment courses (e.g., 10 days or less) of oral prednisone/ 
prednisolone/methylprednisolone are allowed
Now reads:
Chronic use of systemic (oral or parenteral) glucocortioids must be avoided due to 
immunosuppressive effect and potential decreases in RPV plasma concentrations; 
however, short treatment courses (e.g., ≤ 14 days) of oral prednisone/ 
prednisolone/methylprednisolone are allowed
Section 7.1 Time and Events Table
Added check mark to IM treatment administration in column containing Weeks 64, 72,
84, and 92. 
Section 7.1 Time and Events Table footnote J.
Previously read:
j.   On Day 1, the eC-SSRS is to be administered prior to randomization.  The eC-SSRS 
will be administered at each Q4W injection visit through the Week 48 primary endpoint, 
followed by Q12W thereafter through Week 96 (Week 60, 72, 74, 96).  The eC-SSRS 
will preferably be completed at the beginning of the visit.

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Now reads:
j.   On Day 1, the eC-SSRS is to be administered prior to randomization.  The eC-SSRS 
will be administered at each Q4W injection visit through the Week 48 primary endpoint, 
followed by Q12W thereafter through Week 96 (Week 60, 72, 84, 96).  The eC-SSRS 
will preferably be completed at the beginning of the visit.
Section 7.1 Time and Events Table footnote 0.
Previously read:
o.   Only collect if the Withdrawal visit occurs at Week 24, 48, or 96.
Now reads:
o.   Only collect if the Withdrawal visit occurs at Week 48, or 96.
Section 7.3.3 HIV Associated Conditions
Previously read:
HIV-associated conditions will be recorded as per Time and Events schedule (Section 6).  
HIV-associated conditions will be assessed according to the 2014 CDC Revised 
Classification System for HIV Infection (see Section 12.4).  
Now reads:
HIV-associated conditions will be recorded as per Time and Events schedule (Section 
7.1).  HIV-associated conditions will be assessed according to the 2014 CDC Revised 
Classification System for HIV Infection (see Section 12.4).  
Section 7.4.3.5 Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
Previously read:
The investigator determines that the event or outcome qualifies as an SAE under part ‘f’ 
of the SAE definition (see Section 12.6.2)
Now reads:
The investigator determines that the event or outcome qualifies as an SAE under part 
‘other situations’ of the SAE definition (see Section 12.6.2)
Section 7.4.10 Suicidal Risk Monitoring
Section 7.4.10 has been deleted as duplicative of Section 7.4.5 Suicidal Risk Monitoring.

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Appendix 8 Country Specific Requirements:
Appendix 8 has been added including the following text: 
In this study subject identification number and visit number will not be included in the IP 
label.  However, it will be tracked at site pharmacy when the IP is dispensed to each 
subject.  (Note: This is an open label study, thus treatment number is not applicable.)
The investigational product (IP) labels have been added to Appendix 8, Section 12.8.1.
Amendment 02: A Sweden country specific amendment in response to queries from 
the Medical Products Agency. 
12.9.2.
Summary of Changes in Protocol Amendment 02 and Rationale
Changes were made to the protocol text in the following sections

Protocol Synopsis-Dose Modifications; Section 4.3.5 Dose Modifications, and 
Section 6.8.1 Oral Bridging: Text has been adjusted to indicate that consultation with 
the Medical Monitor should occur prior to the implementation of an oral bridging 
strategy and for treatment guidance in the event of a missed dose with investigational 
product.

Section 4.1 Overall Study Design:  Additional details are provided regarding the 
timing of the planned IDMC analysis prior to participant transition into the Extension 
Phase.

Section 5.1 Inclusion Criteria, Informed Consent:  Details of Informed consent 
process updated to address that enrolment of participants who are unable to provide 
direct informed consent is optional and will be based on local legal/regulatory 
requirements and site feasibility to conduct protocol procedures.

Section 6.7 Compliance with Study Treatment Administration:  Additional text has 
been added regarding Investigator and site obligations to maximize patient 
compliance for both study arms and for the duration of the trial through the Follow-up 
Phase.

Section 6.8.1 Oral Bridging: Clarifications were made within the text regarding the 
appropriate consultation procedures with the Medical Monitor for considerations of 
Oral Bridging and missed doses of the investigational product.

Section 6.13.1 Concomitant Medications and Non-Drug Therapies: Additional text 
was added for guidance on concomitant medication use with rilpivirine. 

Section 7.4.3.4 Prompt Reporting of Serious Adverse Events and Other Events; Table 
7 footnotes were updated to provide additional guidance on reporting guidelines for 
cardiovascular and death events

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
Section 10.2, Regulatory and Ethical Considerations, Including the Informed Consent 
Process: Additional language clarifications and internal protocol references are 
provided.

Section 10.4 Quality Assurance: Specification of quality assurance items required 
prior to study start has been added. 
List of Changes
Protocol Synopsis, Treatment Arms and Duration, Dose modifications; and Section 
4.2.5 Dose Modifications:
Previously Read:
In exceptional circumstances, the Medical Monitor may authorize the use of oral CAB 
and/or RPV as a short-term “bridging” strategy for participants who have begun CAB LA 
+ RPV LA.  Should a participant need “oral bridging”, sites must contact the Medical 
Monitor for authorization and guidance for treatment strategies prior to a missed CAB 
LA + RPV LA dose.  Should a participant not notify the site in advance, the Medical 
Monitor must be contacted for further treatment guidance.
Now Reads:
In exceptional circumstances, and in consultation with the Medical Monitor, Investigators 
may provide oral CAB and/or RPV as a short-term “bridging” strategy for participants 
who have begun CAB LA + RPV LA.  Should a participant need “oral bridging”, sites 
must contact the Medical Monitor for guidance on treatment strategies prior to a missed 
CAB LA + RPV LA dose.  Should a participant not notify the site in advance, the 
Medical Monitor must be contacted for further treatment guidance.
Section 4.1 Overall Study Design
Previously read:
An Independent Data Monitoring Committee (IDMC) will evaluate interim efficacy, 
tolerability, safety and PK of CAB LA + RPV LA at predefined times during the study.  
An interim futility analysis will be performed for the IDMC with the intent of having 
approximately 50% of participants reaching Week 24. 
Now reads:
An Independent Data Monitoring Committee (IDMC) will evaluate interim efficacy, 
tolerability, safety and PK of CAB LA + RPV LA at predefined times during the study.  
An interim futility analysis will be performed for the IDMC with the intent of having 
approximately 50% of participants reaching Week 24 with the intent to complete this 
analysis prior to any participants transitioning to the Extension Phase at Week 52.  In 
addition, ad hoc IDMC reviews of safety and efficacy data would also be triggered if the 
number of virologic failures exceeds pre-specified thresholds as per the IDMC charter.  

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Section 5.1 Inclusion Criteria, Informed Consent
Previously read:
Capable of giving signed informed consent as described in Section 10.2, which includes 
compliance with the requirements and restrictions listed in the consent form and in this 
protocol. Eligible participants or their legal guardians must sign a written Informed 
Consent Form before any protocol-specified assessments are conducted.
Now reads:
Capable of giving signed informed consent as described in Section 10.2, which includes 
compliance with the requirements and restrictions listed in the consent form and in this 
protocol. Eligible participants or their legal guardians (and next of kin when locally 
required), must sign a written Informed Consent Form before any protocol-specified 
assessments are conducted. Enrolment of participants who are unable to provide direct 
informed consent is optional and will be based on local legal/regulatory requirements and 
site feasibility to conduct protocol procedures.
Section 6.7 Compliance with Study Treatment Administration
The following text was removed: Treatment compliance will not be assessed during the 
Long-Term Follow-Up Phase.
Final paragraph previously read:
Due to the long acting nature of the CAB LA and RPV LA it will be imperative that the 
participant is compliant with dosing instructions.  Investigators must have plans in place 
for adherence counselling for both treatment arms of the study.  In addition, Investigators 
must have plans in place to perform visit reminders and to verify the participant’s contact 
information at each visit.
Final paragraph now reads:
Due to the long acting nature of the CAB LA and RPV LA it will be imperative that the 
participant is compliant with dosing instructions.  As part of the screening and participant 
selection, it is imperative that Investigators discuss with potential participants the long-
term commitments for the trial, and the importance of adhering to treatment regimens.  
Sites are to have plans in place for adherence counselling for both treatment arms of the 
study for the duration of the study including the Long-Term Follow-Up Phase.  In 
addition, Investigators must have plans in place to perform visit reminders, utilizing 
patient trackers provided by the study team as needed, and to verify the participant’s 
contact information at each visit.  Investigators should contact patients directly in the 
event that a participant misses any scheduled visit 

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Section 6.8.1 Oral Bridging
Previously read:
In exceptional circumstances, to address pre-planned missed CAB LA + RPV LA dosing 
visits, the medical monitor may authorize the use of daily oral CAB 30 mg and RPV 
25mg as a short-term “bridging” strategy for participants who have begun CAB LA + 
RPV LA.  In certain circumstances (e.g., prior to steady state dosing and following a >4 
week oral bridge) repeating the loading doses of CAB IM and RPV IM may be required.  
Should a participant require “oral bridging”, sites must contact the medical monitor for 
authorization and guidance for treatment and dosing strategies prior to a missed CAB LA 
+ RPV LA dose.
Now reads:
In exceptional circumstances, to address pre-planned missed CAB LA + RPV LA dosing 
visits, in consultation with the medical monitor, Investigators may provide daily oral 
CAB 30 mg and RPV 25mg as a short-term “bridging” strategy for participants who have 
begun CAB LA + RPV LA.  In certain circumstances (e.g., prior to steady state dosing 
and following a >4 week oral bridge) repeating the loading doses of CAB IM and RPV 
IM may be required.  Should a participant require “oral bridging”, sites must contact the 
medical monitor for guidance with treatment and dosing strategies prior to a missed CAB 
LA + RPV LA dose.
Section 6.13.1 Concomitant Medications and Non-Drug Therapies
The following text was added to the final paragraph of section 6.13.1:
Please refer to the local rilpivirine prescribing information for guidance regarding other 
drugs that are prohibited, should be used with caution, require dose adjustment, or 
increased clinical monitoring if taken with rilpivirine.
Section 7.4.3.4 Prompt Reporting of Serious Adverse Events and Other Events
Table 7 footnotes:
Previously Read
a.
ABC HSR eCRF only required if event meets one of the ICH E2A definitions of seriousness.
b.
GSK must be contacted at onset of liver chemistry elevations to discuss participant safety.
c.
Liver event documents (i.e., “Liver Event eCRF” and updates, “Liver Imaging eCRF” and/or “Liver 
Biopsy eCRF”, as applicable) should be completed as soon as possible.
a.
Now Reads:
a.
Additional details and time frames for reporting cardiovascular and death events are provided in Section 
7.4.3.7 and Section 7.4.3.8, respectively.
b.
ABC HSR eCRF only required if event meets one of the ICH E2A definitions of seriousness.
c.
GSK must be contacted at onset of liver chemistry elevations to discuss participant safety.

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d.
Liver event documents (i.e., “Liver Event eCRF” and updates, “Liver Imaging eCRF” and/or “Liver 
Biopsy eCRF”, as applicable) should be completed as soon as possible.
Final Paragraph- Additional text was added:
Primary and secondary Medical Monitor/SAE contact information is provided on the 
Medical Monitor/Sponsor Information Page of the current protocol.
Section 10.2, Regulatory and Ethical Considerations, Including the Informed 
Consent Process:
Paragraph 3 Bullet number 2 was removed.

Obtaining signed informed consent
Paragraph 3 Bullet 4:
Previously Bullet 5 read: 

Signed informed consent must be obtained for each participant prior to 
participation in the study.
Current Bullet 4 now reads

Signed informed consent must be obtained for each participant prior to 
participation in the study (see Inclusion Criteria, Section 5.1; Informed consent).
Section 10.4 Quality Assurance
The following language was added as the 3rd bullet:
Measures and documentation towards quality assurance that will be completed prior to 
study initiation will also include but not be limited to the study monitoring plan, study 
risk register, quality assurance plan, protocol deviation management plan,  medical 
monitoring plan, and site feasibility assessments.
12.9.3.
Summary of Changes in Protocol Amendment 03 and Rationale
The reasons for this amendment were to: update medical monitor/SAE contact 
information; provide additional clarity for assessments to be conducted during the 
Extension Phase; add text to instruct contact of the Medical Monitor upon the occurrence 
of rash during the CAB + RPV oral lead-in period; specify a secondary lipid objective 
and endpoint within the study objectives; provide clarity around dosing at the Day 1 visit; 
allow serum pregnancy testing instead of urine testing in the event that urine testing is not 
available; provide clarification that cabotegravir and rilpivirine exposure may persist for 
more than one year following IM injections, emphasize that participants should continue 
to use HAART for at least one year following the last CAB + RPV injection, and that 

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female participants of childbearing potential must continue to use adequate contraception 
for at least one year after the last CAB + RPV injection; expand the allowance of short 
treatment courses of topical, inhaled, or intranasal glucocorticoids to 21 days or less; add 
additional guidance for the definition of a change in ART regimen for inclusion/exclusion 
criteria; provide additional guidance on when to contact the Medical Monitor upon a 
serofast RPR result for screening syphilis test;  clarify language within exclusion criteria 
#9; added text regarding the treatment assignment randomization schedule;  remove a 
requirement to record within the eCRF how frequently IP was taken on average and the 
requirement to record any treatment delays or dose reductions of IP; add text to indicate 
that drugs known to cause Torsade des Pointes (TdP) should be used with caution with 
rilpivirine; remove limits on the duration for use of topical imiquimod; add clarity around 
reflexive testing for HBV DNA for participants with positive anti HBc and negative 
HBsAg and negative anti-HBs results; add temperature collection as part of vital signs to 
the Time and Events Table; add requirement that all sites should have a plan in place for 
managing possible risks for suicide related events;  clarify text regarding PK sample 
window collection; clarify text for patient reported outcome endpoints and timings for 
completion of questionnaires relative to other clinical assessments and procedures, add 
clarification for prohibited medication information; remove information in the Appendix 
requiring collection of pregnancy information for female partners of male study 
participants; incorporate updates from country-specific amendments No 1, and No 2. into 
a global protocol amendment; add text that additional details of the injection device used 
by sites for IM administration including, but not limited to functional performance, may 
also be collected within the eCRF; clarify that commercially availability of CAB LA + 
RPV LA includes availability through local public/government health sectors; add 
allowance that in exceptional circumstances, local labs can be reviewed and approved by 
the Medical Monitor for consideration of participant eligibility; add other minor 
corrections and edits to protocol text.
List of Changes
Medical Monitor/Sponsor Information Page:
The Primary Medical Monitor, Secondary Medical Monitor, and SAE Contact 
information was updated from:
 MD, MPH
ViiV Healthcare
Research Triangle Park
Five Moore Drive, Research Triangle Park, NC 27709 (USA)
Mobile: 
Office Telephone: 
Fax: 
e-mail:  
PPD
PPD
PPD
PPD
PPD

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Secondary Medical Monitor:
 MD
ViiV Healthcare
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
Research Triangle Park
Five Moore Drive, Research Triangle Park, NC 27709 (USA)
Mobile: 
Office Telephone: 
Fax: 
e-mail: 
To:
 MD, MSc
ViiV Healthcare
Research Triangle Park
Five Moore Drive, Research Triangle Park, NC 27709 (USA)
Mobile: 
Office Telephone: 
Fax: 
e-mail:  
Secondary Medical Monitor:
ViiV Healthcare
Research Triangle Park
Five Moore Drive, Research Triangle Park, NC 27709 (USA)
Mobile: 
Office Telephone: 
Fax: 
e-mail:  
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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Sponsor Serious Adverse Events (SAE) Contact Information: 
 MD, MSc
ViiV Healthcare
Research Triangle Park
Five Moore Drive, Research Triangle Park, NC 27709 (USA)
Mobile: 
Office Telephone: 
Fax: 
e-mail:  
Protocol Synopsis and Protocol Section 3.0, Objectives and Endpoints:
The following Objective and Endpoint were added.
Objective
Endpoint
To evaluate the effects of CAB LA + 
RPV LA every 4 weeks on fasting lipids 
over time compared to continuation of 
current ART over time.

Change from Baseline in fasting 
lipids over time including Week 48 
and Week 96.
The following Objectives and Endpoints were updated:
Previously Read:
To assess the acceptance of pain and injection 
site reactions following injections 

Dimension scores (“Bother of ISRs”, “Leg 
movement”, “Sleep”, and “Acceptance)_ 
and individual item scores assessing pain 
during injection, anxiety before and after 
injection, willingness to be injected in the 
future and overall satisfaction with mode of 
administration over time using the 
Perception of iNjection questionnaire (PIN)
To assess degree of health-related quality of life 
(HRQoL) using the HIV/AIDS-targeted quality of 
life (HAT-QoL) questionnaire short form

Summary statistics and between and within 
treatment group comparisons of change in 
HRQoL from Baseline and Weeks 24, 48, 
96 (or Withdrawal).
To assess the health status using the 12-item 
Short Form Health Survey (SF-12)

Summary statistics and between and within 
treatment group comparisons of change in 
health status from Baseline and Weeks 24, 
PPD
PPD
PPD
PPD
PPD

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48, 96 (or Withdrawal)
To assess treatment satisfaction of CAB LA + 
RPV LA compared to continuation of current 
ART

Change from baseline in total “treatment 
satisfaction” score, and “pain discomfort” 
and “ease of administration” sub-scores of 
the HIVTSQs over time

Change in treatment satisfaction over time 
using the HIVTSQc at Week 48 (or 
Withdrawal)
To assess treatment acceptance using the 
“General acceptance” dimension of the Chronic 
Treatment Acceptance (ACCEPT) questionnaire 
which consists of 3 items grouped into one 
single score of overall acceptance

Summary statistics and between and within 
treatment group comparisons of change in 
treatment acceptance  from Baseline and 
Weeks 8, 24, 48, 96 (or Withdrawal)
To assess tolerability of injections using the 
Numeric Rating Scale (NRS) for patients 
randomized to the CAB + RPV LA arm.

Summary statistics, within treatment group 
comparisons and change in tolerability of 
injection from Weeks 4b, 5, 40, 41, and 96.
To assess treatment acceptance using the 
“General acceptance” dimension of the Chronic 
Treatment Acceptance (ACCEPT) questionnaire 
which consists of 3 items grouped into one 
single score of overall acceptance

Summary statistics and between and within 
treatment group comparisons of change in 
treatment acceptance  from Baseline and 
Weeks 8, 24, 48, 96 (or Withdrawal)
To assess preference for CAB LA+ RPV LA 
compared to oral ARV using a single 
dichotomous preference question. 

For patients randomized to the “CAB LA + 
RPV LA” arm, preference for CAB LA + 
RPV LA compared to oral ARV regimen, at 
Week 48

For patients randomized to the “Current 
ART” arm who switched to the injectable 
treatment, preference for CAB LA + RPV LA 
compared to current ART regimen at Week 
96 (end of extension phase- secondary 
analysis)
Now Reads:
To assess the acceptance of pain and injection

Change from Week 5 in Dimension scores 

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site reactions following injections 
(“Bother of ISRs”, “Leg movement”, “Sleep”, 
and “ Injection Acceptance”) and individual 
item scores assessing pain during injection, 
anxiety before and after injection, 
willingness to be injected in the future and 
overall satisfaction with mode of 
administration over time using the 
Perception of iNjection questionnaire (PIN) 
To assess degree of health-related quality of life 
Change from Baseline in HR QoL using the 
HIV/AIDS-targeted quality of life 
questionnaire short form at Week 24, 
Week 48, Week 96 (or Withdrawal).
To assess the health status 

Change from Baseline in health status at 
Week 24, Week 48, and Week 96 (or 
Withdrawal) using the 12-item Short Form 
Survey (SF-12). 
To assess treatment satisfaction of CAB LA + 
RPV LA compared to continuation of current 
ART

Change from baseline in total “treatment 
satisfaction” score, and individual item 
scores of the HIVTSQs at Weeks 4b, 24, 
44, 96 (or Withdrawal)

Change in treatment satisfaction over time 
using the HIVTSQc at Week 48 (or 
Withdrawal)
To assess treatment acceptance 

Change from Baseline in treatment 
acceptance at Week 8, Week 24, Week 48, 
Week 96 (or Withdrawal) using the “General 
acceptance” dimension of the Chronic 
Treatment Acceptance (ACCEPT) 
questionnaire
To assess tolerability of injections 

Change from Week 4b in tolerability of 
injection at Week 5, Week 40, Week 41, 
and Week 96 using the Numeric Rating 
Scale (NRS) within the CAB + RPV LA arm.
To assess preference for CAB LA+ RPV LA 
compared to oral ARV 

For patients randomized to the “CAB LA + 
RPV LA” arm, preference for CAB LA + 
RPV LA compared to oral ARV regimen, at 
Week 48 using a single dichotomous 

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preference question

For patients randomized to the “Current 
ART” arm who switched to the injectable 
treatment, preference for CAB LA + RPV LA 
compared to current ART regimen at Week 
96 (end of extension phase- secondary 
analysis) using a single dichotomous 
preference question
Synopsis “Overall Design” and Section 4.1 Overall Design
The following text was added as the final sentence of paragraph two of the Synopsis 
“Overall Design”, and Section 4.1:
Current ART dosing on Day 1 is recommended to occur after randomization to 
avoid overlap of regimens (in the event that the participant is assigned to the CAB 
LA + RPV LA treatment arm).  However, if the participant takes current ART 
prior to coming into the clinic, randomization and initiation of oral CAB and RPV 
should continue as planned for Day 1.
The following text was added as the second sentence of paragraph three of the Synopsis 
“Overall Design”, and Section 4.1:
At visit Week 4b, participants will return to the clinic, take the last dose of oral CAB 
+ RPV, and receive the first CAB LA (600 mg) + RPV LA (900 mg) injections 
(within 2 hours of the final oral dose of CAB + RPV).  
Section 4.2.1  Screening Phase (Up to 35 days)
Second Paragraph
Previously Read
Participants will complete a screening period of up to 35 days.  A single repeat of a 
procedure/lab parameter is allowed to determine eligibility (unless otherwise specified). 
Participants may be re-screened once which requires a new participant number.  
Participants who are randomized into the trial and subsequently withdrawn from the 
study, for any reason, may not be re-screened.  Participants may be randomized as soon 
as all eligibility requirements have been confirmed at the site.  
Now Reads:

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Participants will complete a screening period of up to 35 days.  A single repeat of a 
procedure/lab parameter is allowed to determine eligibility (unless otherwise specified). 
In exceptional circumstances only, if a repeat lab is required because a central lab 
result cannot be generated, local labs can be reviewed and approved by the Medical 
Monitor for consideration of participant eligibility.  A repeat central lab will be 
submitted concurrently or at the next planned visit. Participants may be re-screened 
once which requires a new participant number.  Participants who are randomized into the 
trial and subsequently withdrawn from the study, for any reason, may not be re-screened.  
Participants may be randomized as soon as all eligibility requirements have been 
confirmed at the site.  
Section 4.2.2 Maintenance Phase (Day 1 up to Week 52)
The following text was added to the third complete paragraph:
If in the opinion of the Investigator, a participant experiences a significant safety event 
while taking oral CAB or RPV, administration of the first injections will be determined 
ONLY in consultation with the Medical Monitor.  Any rash that is possibly related to 
study drug, and is present during the CAB + RPV oral lead-in period, must be discussed 
with the Medical Monitor prior to initiation of CAB LA or RPV LA (See Section 
7.4.4.13).
Section 4.2.3.1  Participants Entering from the CAB LA + RPV LA Arm
First Paragraph
Previously Read:
All participants who successfully complete 52 weeks of CAB LA + RPV LA treatment in 
the Maintenance Phase will continue to have access to both CAB LA and RPV LA in the 
Extension Phase until study treatment is either locally approved and commercially 
available, the participant no longer derives clinical benefit, the participant meets a 
protocol-defined reason for discontinuation or until development of either CAB LA or 
RPV LA is terminated.  Visits will continue to occur every 4 weeks as per the Time and 
Events Schedule (Section 7.1) 
Now Reads:
All participants who successfully complete 52 weeks of CAB LA + RPV LA treatment in 
the Maintenance Phase will continue to have access to both CAB LA and RPV LA in the 
Extension Phase until study treatment is either locally approved and commercially 
available (including through local public/government health sectors), the participant 
no longer derives clinical benefit, the participant meets a protocol-defined reason for 
discontinuation or until development of either CAB LA or RPV LA is terminated.  Visits 
will continue to occur every 4 weeks as per the Time and Events Schedule (Section 7.1) 
Section 4.2.3.2  Participants Entering from the current ART ARM

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Second paragraph, third sentence
Previously Read:
In addition, central lab results and safety parameters from the Week 56a visit must be 
available and reviewed.
Now Reads:
In addition, central lab results and safety parameters from the Week 56a visit must be 
available and reviewed before the Week 56b visit.  
Sixth Paragraph
Previously Read:
Participants will continue study treatment in the Extension Phase until CAB LA and RPV 
LA are either locally approved and commercially available, the participant no longer 
derives clinical benefit, the participant meets a protocol-defined reason for 
discontinuation or until development of either CAB LA or RPV LA is terminated. Visits 
will continue to occur every 4 weeks. See the Time and Events Table (Section 7.1) for 
more information.
Now Reads:
Participants will continue study treatment in the Extension Phase until CAB LA and RPV 
LA are either locally approved and commercially available (including through local 
public/government health sectors), the participant no longer derives clinical benefit, the 
participant meets a protocol-defined reason for discontinuation or until development of 
either CAB LA or RPV LA is terminated. Visits will continue to occur every 4 weeks.
See the Time and Events Table (Section 7.1) for more information.
Section 4.2.4 Long-Term Follow-Up (LTFU) Phase – IM Regimen Only
Fourth paragraph, second sentence
Previously Read:
Female participants of child bearing potential must continue to use adequate 
contraception methods (see Study Procedures Manual [SPM] for list of accepted forms of 
contraception) for the entire year of follow up.
Now Reads:
Female participants of child bearing potential must continue to use adequate 
contraception methods (see Study Procedures Manual [SPM] for list of accepted forms of 
contraception) for at least 52 weeks after the last injection. 
Section 4.6.1 Risk Assessment Table; Development of Resistance following 
discontinuation of CAB LA.

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First table column:
Previously Read:
Residual concentrations of CAB would remain in the systemic circulation of participants 
who stopped CAB LA treatment for prolonged periods (up to 1 year) despite stopping 
treatment (e.g., for tolerability issues or treatment failure). 
Now Reads:
Residual concentrations of CAB would remain in the systemic circulation of participants 
who stopped CAB LA treatment for prolonged periods (more than 1 year, in some 
subjects, GlaxoSmithKline Document Number 2016N269422_00) 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. 
Section 4.6.1 Risk Assessment Table; Oral CAB and CAB LA Drug-Drug 
Interactions
First table column, third complete paragraph
Previously Read:
Chronic use of oral glucocorticoids must be avoided; however, short treatment courses 
(for example, 14 days or less) and topical, inhaled or intranasal use of glucocorticoids 
will be allowed.
Now Reads:
Chronic use of oral glucocorticoids must be avoided; however, short treatment courses 
(for example, 21 days or less) and topical, inhaled or intranasal use of glucocorticoids 
will be allowed.
Section 4.6.1 Risk Assessment Table; RPV LA; Development of Resistance
First table column, first paragraph
Previously Read:
Residual concentrations of RPV LA would remain in the systemic circulation of 
participants who stopped treatment (e.g., for tolerability issues or treatment failure) for 
prolonged periods (months).
Now Reads:

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Residual concentrations of RPV LA can remain in the systemic circulation of participants 
who stopped treatment (e.g., for tolerability issues or treatment failure) for prolonged 
periods (months to more than a year, in some subjects, McGowan, 2016).
Section 5.1 Inclusion Criteria
3rd Paragraph
Previously Read:
Laboratory results from the central laboratory services provided by this trial will be used 
to assess eligibility.  
Now Reads:
Laboratory results from the central laboratory services provided by this trial will be used 
to assess eligibility.  In exceptional circumstances only, if a repeat lab is required 
because a central lab result cannot be generated, local labs can be reviewed and 
approved by the Medical Monitor for consideration of participant eligibility.  A
repeat central lab will be submitted concurrently or at the next planned visit.
Inclusion Criteria 2
Second paragraph, bullet #3
Previously read:

Boosted PI (or atazanavir [ATV] unboosted) (either the initial or second 
PI-based cART regimen)
Now reads:

Boosted PI (or atazanavir [ATV] unboosted) (must be either the initial 
cART regimen or one historical within class switch is permitted due to 
safety/tolerability)
The following text was also added to Inclusion Criteria 2 in order to provide additional 
guidance for the definition of a change in ART regimen:
The addition, removal, or switch of a drug(s) that has been used to treat HIV based 
on antiretroviral properties of the drug constitutes a change in ART with the 
following limited exceptions: 

Historical changes in formulations of ART drugs or booster drugs, will not
constitute a change in ART regimen if the data support similar exposures 
and efficacy, and the change must have been at least 3 months prior to 
Screening.

Historical perinatal use of an NRTI when given in addition to an ongoing 
HAART will not be considered a change in ART regimen.

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
A change in dosing scheme of the same drug from twice daily to once daily 
will not be considered a change in ART regimen if data support similar 
exposures and efficacy.  
Section 5.2 Exclusion Criteria
Exclusion Criteria 13
Previously Read:
13. All participants will be screened for syphilis (rapid plasma reagin [RPR]).  
Participants with untreated syphilis infection, defined as a positive RPR without clear 
documentation of treatment, are excluded. Participants with a positive RPR test who 
have not been treated may be rescreened at least 30 days after completion of antibiotic 
treatment for syphilis
Now Reads:
13. All participants will be screened for syphilis (rapid plasma reagin [RPR]).  
Participants with untreated syphilis infection, defined as a positive RPR without clear 
documentation of treatment, are excluded. Participants with a serofast RPR result 
(persistence of a reactive nontreponemal syphilis test) despite history of adequate 
therapy and no evidence of re-exposure may enrol after consultation with the 
Medical Monitor. Participants with a positive RPR test who have not been treated may 
be rescreened at least 30 days after completion of antibiotic treatment for syphilis
Exclusion Criteria 32, 5th bullet
Previously Read:
Immunomodulators that alter immune responses such as systemic corticosteroids, 
interleukins, or interferons. Note: Participants using short-term (≤14 days) steroid tapers, 
topical, inhaled and intranasal corticosteroids are eligible for enrollment.
Now Reads:
Immunomodulators that alter immune responses such as chronic systemic corticosteroids, 
interleukins, or interferons. Note: Participants using short-term (e.g. ≤21 days) systemic 
corticosteroid treatment; topical, inhaled and intranasal corticosteroids are eligible for 
enrolment. 
Section 6.2 Treatment Assignment
The following text was added to the first paragraph:
The randomization schedule is comprised of a series of blocks, with equal treatment 
allocation within each block, which are shared across centres via central 
randomization. Given the open-label study design, central randomization was used 
to eliminate selection bias due to foreknowledge of randomized treatment. With 
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previous subjects does not predict which treatment group will be assigned to the 
next randomized subject.
Section 6.3 Dosage and Administration
Table 5 Dosage and Administration
Previously Read:
Current ART Arm*
Day 1 to Week 52
(1 tablet once daily)
Take 2 NRTIs + INI or 2 NRTIs + NNRTI or 2 NRTIs + PI 
according to approved labeling.
Now Reads:
Current ART Arm*
Day 1 to Week 52
(Tablets daily)
Take 2 NRTIs + INI or 2 NRTIs + NNRTI or 2 NRTIs + PI 
according to approved labeling.
*Take Day 1 dose after randomization
Final Paragraph
Previously Read:
The CAB + RPV oral regimen should be administered together once daily at 
approximately the same time each day with a meal.  The participant will be asked how 
often IP was taken (with a meal) on average, since the last visit, and this information will 
be recorded in the eCRF. 
Now Reads:
The CAB + RPV oral regimen should be administered together once daily at 
approximately the same time each day with a meal.  
Section 6.6.1 Dosing Considerations for CAB LA + RPV LA
The following text was added to the end of the third paragraph:
Additional details of the injection device used by sites for IM administration 
including, but not limited to functional performance, may also be collected within 
the eCRF.Section 6.7 Compliance with Study Treatment Administration

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Second Paragraph, last sentence:
Previously Read:
Treatment start and stop dates, including dates for treatment delays and/or dose 
reductions will also be recorded in the CRF.
Now Reads:
Treatment start and stop dates will also be recorded in the eCRF. 
Section 6.9.1 IM Dosing, 1st paragraph, 4th sentence:
Previously Read:
Plasma concentrations of both drugs may be measurable for approximately 52 weeks than 
following IM injections.
Now Reads:
Plasma concentrations of both LA drugs may be measurable for more than one year 
following IM injections. Any interruption in IM dosing should be discussed with the 
Medical Monitor.  Investigators should ensure that the participant initiates 
alternative highly active ART to minimize the risk of developing resistance as 
concentrations of CAB and RPV decline over time. Section 6.13.1 Permitted 
Medications and Non-Drug Therapies
The following text was added at the end of the section:
Drugs that cause Torsade des Pointes (TdP) should be used with caution when on 
rilpivirine (see SPM for list of drugs associated with TdP).
Section 6.13.2 Prohibited Medications and Non-Drug Therapies
3rd Bullet
Previously Read:
Systemically administered immunomodulators (such as interleukin and interferon agents) 
are prohibited (a list of examples is provided in the SPM).  This includes topical agents 
with substantial systemic exposure and systemic effects.  Short term use (30 days or less)
of topical imiquimod is permitted.   
Now Reads:
Systemically administered immunomodulators (such as interleukin and interferon agents) 
are prohibited (a list of examples is provided in the SPM).  This includes topical agents 

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with substantial systemic exposure and systemic effects.  Use of topical imiquimod is 
permitted.  
5th Bullet
Previously Read:
Chronic use of systemic (oral or parenteral) glucocortioids must be avoided due to 
immunosuppressive effect and potential decreases in RPV plasma concentrations;
however, short treatment courses (e.g., ≤ 14 days) of oral prednisone/ 
prednisolone/methylprednisolone are allowed. A single dose of systemic dexamethasone 
is permitted (more than a single dose may cause significant decrease in RPV plasma 
concentration and is prohibited), and topical, inhaled or intranasal use of glucocortioids 
will be allowed.  
Now Reads:
Chronic use of systemic (oral or parenteral) glucocortioids must be avoided due to their 
immunosuppressive effect and potential decreases in RPV plasma concentrations; 
however, short treatment courses with oral prednisone/ prednisolone/methylprednisolone 
(e.g. adjunctive treatment of Pneumocystis pneumonia with ≤ 21 days of tapering 
prednisone) are allowed. A single dose of systemic dexamethasone is permitted (more 
than a single dose in a treatment course may cause significant decrease in RPV plasma 
concentration and is prohibited). Topical, inhaled or intranasal use of glucocortioids will 
be allowed.  
Section 7.1 Time and Events Table
The following text was added above the Time and Events Table:
Note:  While some assessments included in the Time and Events Table are 
conducted less frequently following the secondary endpoint (Week 96), IM 
injections for participants randomized to CAB LA + RPV LA (and for participants 
who switch to CAB LA + RPV LA during the Extension Phase) will continue to be 
administered Q4W.  Beginning after Week 96, the schedule of assessments for all 
participants will be modified to collect clinical chemistries, HIV-1 RNA, and CD4+ 
cell count every 12 weeks. 
From Week 60 forward, all participants (from both originally randomized 
treatment arms), will have the same schedule of events (same visits, same 
assessments, same time frame).
Footnotes j, k, v, and aa were updated as follows:
Previously Read:

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a.
Complete all Screening assessments within 35 days.  Participants may begin the 
Maintenance Phase as soon as all Screening assessments are complete.  Participants 
may be rescreened once and will be assigned a new participant number. 
j.
On Day 1, the eC-SSRS is to be administered prior to randomization.  The eC-SSRS 
will be administered at each Q4W injection visit through the Week 48 primary 
endpoint, followed by Q12W thereafter through Week 96 (Week 60, 72, 84, 96).  The 
eC-SSRS will preferably be completed at the beginning of the visit.
k. Women of childbearing potential only.  SR=serum, UR=urine.  Pregnancy events will 
be captured starting at Day 1 following exposure to study drug.
v. With the exception of the NRS and PIN, all Patient Report Questionnaires/Surveys 
are recommended to be administered at the beginning of the visit before any other 
assessments are conducted.  NRS is to be given post injection.  Only conduct 
questionnaires/surveys at Withdrawal if occurring prior to Week 48.  
aa.  “Perception of Injection questionnaire (PIN) to be administered following injections.  
Now Reads:
a.
Complete all Screening assessments within 35 days.  Participants may begin the 
Maintenance Phase as soon as all Screening assessments are complete.  Participants 
may be rescreened once and will be assigned a new participant number. HLA-
B*5701 result is not required to inform eligibility status.
j. On Day 1, the eC-SSRS is to be administered prior to randomization.  The eC-SSRS 
will be administered at each Q4W injection visit through the Week 48 primary 
endpoint, followed by Q12W thereafter through Week 96 (Week 60, 72, 84, 96).  The 
eC-SSRS will preferably be completed at the beginning of the visit following 
administration of other PROs required prior to injections.
k. Women of childbearing potential only.  SR=serum, UR=urine.  Pregnancy events will 
be captured starting at Day 1 following exposure to study drug. Serum pregnancy 
test can substitute for urine pregnancy test if locally required but must be 
appropriately timed to confirm pregnancy status prior to randomization and 
first IM administration.
v.  With the exception of the NRS questionnaire, all Patient Report 
Questionnaires/Surveys are recommended to be administered via validated electronic 
site pad or paper instrument at the beginning of the visit before any other assessments 
are conducted and prior to administration of the eC-CSSRS.  NRS is to be given 
post injection.  Conduct questionnaires/surveys at Withdrawal if occurring prior to 
Week 96.

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Footnote aa has been removed. 
Section 7.2.1 Screening Assessments
Paragraph 5
Previously Read:
Participants infected with HBV will not be enrolled in the study.
Now Reads:
Participants infected with HBV will not be enrolled in the study.  Evidence of HBV 
infection is based on the results of testing at Screening for hepatitis B surface 
antigen (HBsAg), hepatitis B core antibody (anti-HBc), hepatitis B surface antibody 
(anti-HBs), and HBV DNA.  HBV DNA will only be performed for participants with 
positive anti-HBc and negative HBsAg and negative anti-HBs (past and/or current 
evidence).
Paragraph 7
Previously Read:
All participants will be screened for syphilis (rapid plasma reagin [RPR]) at Screening.  
Participants with untreated syphilis infection, defined as a positive RPR without clear 
documentation of treatment, are excluded.  Participants with a positive RPR test who 
have not been treated may be rescreened at least 30 days after completion of antibiotic 
treatment for syphilis.
Now Reads:
All participants will be screened for syphilis (rapid plasma reagin [RPR]) at Screening.  
Participants with untreated syphilis infection, defined as a positive RPR without clear 
documentation of treatment, are excluded.  Participants with a serofast RPR result 
despite history of adequate therapy and no evidence of re-exposure may enrol after 
consultation with the Medical Monitor. Participants with a positive RPR test who have 
not been treated may be rescreened at least 30 days after completion of antibiotic 
treatment for syphilis.
Section 7.4.1 Clinical Evaluations
Bullet 4
Previously Read:

Vital signs will include systolic and diastolic blood pressure and heart rate 
collected after resting for about 5 minutes.

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Now Reads:

Vital signs will include systolic and diastolic blood pressure and heart rate 
collected after resting for about 5 minutes.  Temperature will also be collected.
Bullet 10
Previously Read:

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). 
Now Reads:

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).  If serum testing is required locally, the 
results should be available prior to the visit where urine testing is indicated 
per the Time and Events Schedule (Section 7.1).
Table 6  Safety Laboratory Assessments
Footnote g was added to Table 6 and irrelevant abbreviations for IL-6, hs-CRP, sVCAM, 
and HOMA-IR were removed.
Now Reads:
Hematology
Platelet count 
Automated WBC differential:
RBC count
Neutrophils
WBC count (absolute) 
Lymphocytes
Hemoglobin
Monocytes
Hematocrit
Eosinophils
MCV
Basophils
Clinical Chemistry
BUN
Potassium
AST 
Total bilirubina
Creatinine
Chloride
ALT 
Albumin 
Glucosec
Total CO2
Alkaline phosphatase
Creatine phosphokinase
Sodium
Lipase
Phosphate
Creatinine clearanceb
Fasting Lipid Paneld
Total cholesterol
HDL cholesterol
LDL cholesterol
Triglycerides
Other Tests

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Plasma HIV-1 RNAe
CD4+ and CD8+ cell counts [CD4/CD8 ratio]f
Peripheral Blood Mononuclear Cells (PBMCs):  Day 1, Week 96, Withdrawal only
Hepatitis B (HBsAg), anti-HBc, anti-HBsAg, and hepatitis C antibody (Screening)g
Rapid Plasma Reagin (RPR) (Screening and Baseline)
HLA-B*5701 (Screening only)
Prothrombin Time (PT)/International Normalized Ratio (INR)/ Partial Thromboplastin Time (PTT)
Pregnancy test for women of childbearing potentialh
Urinalysis, urine albumin/creatinine ratio, and urine protein/creatinine ratio, urine phosphate
Genetics Sample 
Renal biomarkers including Cystatin-C (blood), Retinol Binding Protein (RBP, blood/urine)i
Bone biomarkers including: Bone-specific alkaline phosphatase, procollagen type 1 N-propeptide, type 1 collagen 
cross-linked C-telopeptide, osteocalcin, 25 hydroxy-Vitamin Di
Follicle stimulating hormone (FSH) and estradiol (only for instances when postmenopausal status is questionable)
MCV = mean corpuscular volume, RBC = red blood cells, WBC = white blood cells, BUN = Blood urea nitrogen, 
AST=aspartate aminotransferase, ALT = alanine aminotransferase, CO2 = carbon dioxide, HDL = high density 
lipoprotein, LDL = low density lipoprotein, HBsAg= hepatitis B virus surface antigen, PT/INR = prothrombin 
time/international normalized ratio.
a)
Direct bilirubin will be reflexively performed for all total bilirubin values >1.5 × ULN.
b)
Glomerular filtration rate (GFR) will be estimated by the central laboratory using the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) [Levey, 2009].
c)
For fasting glucose assessments, an overnight fast is preferred; however, a minimum of a 6-hour fast is 
acceptable for participants with afternoon appointments.
d)
For fasting lipids assessments, an overnight fast is preferred; however, a minimum of a 6-hour fast is acceptable 
for participants with afternoon appointments.
e)
For participants meeting virologic withdrawal criteria, plasma samples will be analyzed in attempt to obtain 
genotype/phenotype data.
f)
CD8+ cells will only be reported at Baseline, Day 1, Weeks 4b, 24, 48, and 96.
g)
HBV DNA will only be performed for participants with a positive anti-HBc and negative HBsAg and negative anti-
HBs (past and/or current evidence).
h)
Urine pregnancy test/ serum pregnancy test will be performed according to the Time and Events Table (Section 
7.1). 
i)
Since the intention is to utilize these biomarker data for research purposes, the sponsor will not be reporting the 
results of these assessments to the investigator, except for 25 hydroxy-vitamin D.
Section 7.4.5 Suicidal Risk Monitoring
First and second paragraphs
Previously Read:
Participants with HIV infection may occasionally present with symptoms of depression 
and/or suicidal ideation or behavior.  In addition, there have been some reports of 
depression, suicidal ideation and behavior (particularly in participants with a pre-existing 

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history of depression or psychiatric illness) in some patients being treated with INIs.  
Additionally, depression and anxiety has been reported in some participants being treated 
with RPV.  Therefore, it is appropriate to monitor participants prospectively for suicidal 
ideation and / or behavior before and during treatment.  It is recommended that the 
Investigator consider mental health consultation or referral for participants who 
experience signs of suicidal ideation or behavior.
Participants should be monitored appropriately and observed closely for suicidal ideation 
and behavior or any other unusual changes in behavior.  It is recommended that the 
investigator consider mental health consultation or referral for participants who 
experience signs of suicidal ideation or behavior.  Participants presenting with new 
onset/treatment emergent depression should be advised to contact the investigator 
immediately if symptoms of severe acute depression (including suicidal 
ideation/attempts) develop, because medical intervention and discontinuation of the study 
medication may be required.
Now Reads:
Participants with HIV infection may occasionally present with symptoms of depression 
and/or suicidal ideation or behavior.  In addition, there have been some reports of 
depression, suicidal ideation and behavior (particularly in participants with a pre-existing 
history of depression or psychiatric illness) in some patients being treated with INIs.  
Additionally, depression and anxiety has been reported in some participants being treated 
with RPV.  Therefore, it is appropriate to monitor and closely observe participants 
prospectively before and during treatment for suicidal ideation and/or behavior, or any 
other unusual changes in behavior.  It is recommended that the Investigator consider 
mental health consultation or referral for participants who experience signs of suicidal 
ideation or behavior.
Participants presenting with new onset/treatment emergent depression should be 
advised to contact the investigator immediately if symptoms of severe acute 
depression (including suicidal ideation/attempts) develop, because medical 
intervention and discontinuation of the study medication may be required.
The following text was added to the end of paragraph 4:
All sites should have a plan in place for managing possible risks for suicide related 
events.  
Section 7.5.1 PK Sample Collection
The first paragraph below Table 8, CAB and RPV Plasma Pharmacokinetic Sample 
Schedule
Previously Read:

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PK window for sample collection: Pre-dose visits:  3 days (1st injection), minus 7 days 
(2nd and 3rd injections), and 7days (4th and all subsequent injections);  2 hours post 
dose: one hour; one week post dose visits (Week 5 and Week 41): 3-10 days post 
injection.
Now Reads:
PK visit window and sample collection: Pre-dose visits (from projected visit date):
+/- 3 days (1st injection), minus 7 days (2nd and 3rd injection), and +/- 7days (4th and all 
subsequent injections); Pre-dose sample collection at Week 4b (and Week 56b for 
participants transitioning from the current ART arm): 20 to 28 hours after the last 
oral dose of CAB and RPV was taken; 2 hours post dose: +/-one hour; one week post 
dose visits: 3 to 10 days post injection.
Section 7.9  Value Evidence and Outcomes
First paragraph
Previously Read:
Health outcomes assessments will be conducted according to the Time and Events Table 
(Section 7.1).  Assessments are recommended to be administered at the beginning of the 
visit prior to collection of blood for analysis and other scheduled assessments. 
Now Reads:
Health outcomes assessments will be conducted according to the Time and Events Table 
(Section 7.1).  Assessments are recommended to be administered with an electronic site 
pad or paper instrument at the beginning of the visit prior to collection of blood for 
analysis and other scheduled assessments with the exception of the NRS (administered 
post injection). 
Section 7.9.1 Value Evidence and Outcomes Endpoints (Secondary)
Previously Read:

Summary statistics and between and within treatment group comparisons will be 
assessed on change in treatment satisfaction (using the HIV TSQs) from Baseline 
and Weeks 4b, 24, 48, 96 (or Withdrawal)

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
Between and within treatment group comparisons will be assessed on change in 
treatment satisfaction over time (using the HIV TSQc) at Week 48 (or Withdrawal 
from the study)

Summary statistics and between and within treatment group comparisons will be 
assessed on change in treatment acceptance from Baseline (using the ACCEPT) 
and Weeks 8, 24, 48, 96 (or Withdrawal)

Summary statistics and between and within treatment group comparisons will be 
assessed on change in the broader impact on health status (using the SF-12) from 
Baseline and Weeks 24, 48, 96 (or Withdrawal)

Summary statistics and between and within treatment group comparisons will be 
assessed on change in HRQoL (using the HAT-QoL short form) from Baseline 
and Weeks 24, 48, 96 (or Withdrawal)

Summary statistics  and within treatment group comparisons will be assessed on 
acceptance of pain and injection-site reactions following injections (using the 
PIN) at weeks 5, 41, 48, 96 (or Withdrawal from the study) on patients 
randomized to the “CAB LA + RPV LA” arm.

Summary statistics and within treatment group comparisons will be assessed on 
the tolerability of injections (using the NRS) at Weeks 4b, and 40, and 96  and for 
one week post injection visits at Weeks 5, and 41 for participants randomized to 
the CAB LA and RPV LA arm.  Change in tolerability of injection will be 
assessed from Baseline and Week 48 (primary analysis), and from Baseline and 
Week 96 (secondary analysis)
Now Reads:

Change from Week 5 in Dimension scores (e.g., “Bother of ISRs”, “Leg 
movement”, “Sleep”, and “Injection Acceptance”) and individual item scores 
assessing pain during injection, anxiety before and after injection, willingness 
to be injected in the future and overall satisfaction with mode of 
administration over time using the Perception of iNjection questionnaire 
(PIN). 

Proportion of participants considering pain and local reactions following 
injection to be extremely or very acceptable based on the acceptability score 
over time using the Perception of iNjection questionnaire (PIN).

Change from baseline in total “treatment satisfaction” score, and individual 
item scores of the HIVTSQs at Weeks 4b, 24, 44, 96 (or Withdrawal).

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
Change in treatment satisfaction over time (using the HIVTSQc) at Week 48 
(or Withdrawal).

Change from Baseline in treatment acceptance (at Weeks 8, 24, 48, 96 (or 
Withdrawal from the study) using the “General acceptance” dimension of 
the Chronic Treatment Acceptance (ACCEPT) questionnaire.

Change from Baseline in health status at Week 24, Week 48, and Week 96 (or 
Withdrawal) using the 12-item Short Form Survey (SF-12).

Change from Baseline in HR QoL (using the HAT-QoL short form) at Weeks 
24, 48, 96 (or Withdrawal from the study).

Change from Week 4b in tolerability of injections (using the NRS) at Weeks 
5, 40, 41, 96.  
Section 11, References
The following references were added:
GlaxoSmithKline Document Number 2016N269422_00: 201120: A Phase IIa Study 
to Evaluate the Safety, Tolerability and Acceptability of Long Acting Injections of 
the HIV Integrase Inhibitor, GSK1265744, in HIV Uninfected Men (ÉCLAIR) –
Week 81 Results. Effective Date: 25Oct2016.
McGowan I, Siegel A, Engstrom J, et al. Persistence of rilpivirine following single 
dose of long-acting injection. 21st International AIDS Conference (AIDS 2016). July 
18-22, 2016. Durban, South Africa. Abstract TUAC0103.
Section 12.7.2 Collection of Pregnancy Information
The following text was removed:

Investigator will attempt to collect pregnancy information on any female partner 
of a male study participant who becomes pregnant while participating in this 
study.  This applies only to participants who are randomized to receive study 
medication. 

After obtaining the necessary signed informed consent from the female partner 
directly, the investigator will record pregnancy information on the appropriate 
form and submit it to GSK within 2 weeks of learning of the partner’s pregnancy

Partner will also be followed to determine the outcome of the pregnancy.  
Information on the status of the mother and child will be forwarded to GSK. 

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date.  Any termination of the pregnancy will be reported regardless of 
fetal status (presence or absence of anomalies) or indication for procedure.

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12.9.4.
Protocol Amendment 4 Summary of Changes Table
Overall Rationale Amendment 4: Protocol amendment #4 applies to all sites. The 
reason for amendment 4 is to acknowledge the potential rollover of eligible 201585 
(ATLAS) study participants following the Week 52 visit and completion of the primary 
endpoint to the 207966 (ATLAS-2M) study. Specifications for the procedural rollover of 
201585 participants are included within amendment #4.  Due to the planned transition of 
eligible participants to ATLAS-2M following the Week 48 primary endpoint, the 
snapshot virologic response Week 96 for ATLAS is no longer valid and has been 
replaced with the proportion of participants with plasma HIV-1 RNA <50 c/mL over time 
including Week 96.  Updated references for the cabotegravir and rilpivirine investigator 
brochures have also been added.
Section # and Name
Description of Change
Brief Rationale
Section 3: Objectives 
and Endpoints and 
corresponding text in 
Sections 4.2.3, 5.5.5.1, 
9.4.9, 
Removal of secondary endpoints based on 
the snapshot virologic response and 
subgroup analyses at Week 96.  
A secondary endpoint including the 
Proportion of participants with plasma HIV-1 
RNA <50 c/mL over time including Week 96 
(Observed Case) is added to replace the 
analysis by Snapshot virologic response
Due to the planned transition of 
eligible participants following the 
primary endpoint of ATLAS to the 
207966 (ATLAS-2M) study 
examining the efficacy, safety and 
tolerability of CAB LA + RPV LA 
administered every 4 weeks (Q4W) 
compared to CAB LA + RPV LA 
administered every 8 weeks 
(Q8W), the snapshot virologic 
response Week 96 for ATLAS is no 
longer valid and has been replaced 
with the proportion of participants 
with plasma HIV-1 RNA < 50 c/mL 
over time including Week 96.  
Insufficient participant numbers are 
anticipated at Week 96 to support 
subgroup analyses as originally 
planned.
Synopsis, and Section 
4.3:  207966 (ATLAS-
2M) Rollover Option.
Addition of text describing the 207966 
(ATLAS-2M) rollover option upon individual 
participant completion of the ATLAS primary 
endpoint.
Text added acknowledges the 
potential rollover of eligible 201585 
(ATLAS) study participants 
following the Week 52 visit and 
completion of the primary endpoint 
to the 207966 (ATLAS-2M) study.
Section 4.3:1 201585 
(ATLAS) to 207966 
(ATLAS-2M) Transition 
Strategy
Addition of text describing the ATLAS to 
ATLAS-2M transition strategy for subgroups 
of patients
Offers guidance including 
appropriate timing for the transition 
of eligible ATLAS participants to 
ATLAS-2M upon local approval 
and implementation of ATLAS-2M

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251
Synopsis and Section 
5.6 Participant and 
Study Completion
Revision of the study completion definition
The definition for study completion 
has been updated to acknowledge 
and accommodate the optional 
rollover of participants from ATLAS 
to ATLAS-2M, thereby enabling 
appropriate generation of 
participant disposition data.  
Participants from either treatment 
arm who complete study Week 52 
or enter and complete the 
Extension Phase will be considered
to have completed the study. 
Sections 7.4.3.4
(Table 7), 7.4.6.3, and 
12.7.2: Reporting of 
Serious Adverse
Events and Other 
Events
Initial report of pregnancy and completion of 
Pregnancy Notification Form has been 
updated to within 24 hours of identification of 
a Pregnancy event.  Follow-up Pregnancy 
form (and SAE if required) has been updated 
to within 24 hours of investigator awareness 
of pregnancy outcome.
Text Update: Suspected ABC HSR in 
participants randomized to the current ART 
arm or receiving Oral SOC during the Long-
Term Follow-Up Phase 
Reporting timelines and 
documentation requirements have 
been updated to reflect current 
Sponsor requirements
Clarification for reporting suspected 
ABC HSR adverse event also 
applies during the Long-Term 
Follow-Up Phase for participants 
returning to Oral Standard of Care
Section 11. References
Updated references for the cabotegravir and 
rilpivirine investigator brochures have also 
been added.
Updated references
General Body Text
Minor clarifications with body text are made 
to assist with reader comprehension
Clarifications