A Phase III, Randomized, Multicenter, Parallel-group, Open-Label Study Evaluating the Efficacy, Safety, and Tolerability of Long-Acting Intramuscular Cabotegravir and Rilpivirine for Maintenance of Virologic Suppression Following Switch From an Integrase Inhibitor Single Tablet Regimen in HIV-1 Infected Antiretroviral Therapy Naive Adult Participants
Phase: PHASE3
Conditions: HIV Infections
Sponsor: ViiV Healthcare

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TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A Phase III, Randomized, Multicenter, Parallel-group, Open-
Label Study Evaluating the Efficacy, Safety, and Tolerability of 
Long-Acting Intramuscular Cabotegravir and Rilpivirine for 
Maintenance of Virologic Suppression Following Switch from 
an Integrase Inhibitor Single Tablet Regimen in HIV-1 Infected 
Antiretroviral Therapy Naive Adult Participants
Compound Number:
GSK1265744
Development Phase:
IIIA
Effective Date:
24-SEP-2018
Protocol Amendment Number:  04
Author (s):
 
 
Copyright 2018 ViiV Healthcare group of companies.  All rights reserved.  Unauthorised 
copying or use of this information is prohibited.
PPD
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Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2015N248866_00
2016-MAY-26
Original
2015N248866_01
2016-DEC-13
Amendment No. 1
The reasons for this amendment were to:  added new primary Medical Monitor contact 
information; added lipid objective and endpoint back in to the table within the Synopsis 
section; added clarification of text for patient reported outcome endpoints; added 
additional clarification regarding provision of CAB LA and RPV LA until available 
through public/government health sectors; new text added to allow use of local labs to 
determine eligibility in exceptional circumstances; updated Time and Events Table to 
provide more clarity around assessments conducted during the Extension Phase, added 
‘X’ to include collection of cardiovascular risk information at Screening, added 
temperature to Vital Signs row, added row for randomization, and clarified timings for 
completion of patient reported questionnaires relative to other clinical assessments in the 
table footnotes; clarified timing of dosing for abacavir/dolutegravir/lamivudine 
(ABC/DTG/3TC, Triumeq) for the Day 1 visit; added additional clarification that 
participants of child bearing potential must continue contraception for at least 52 weeks 
after the last injection; revised text to say that Investigators may provide ‘bridging’ 
supply after consultation with Medical Monitor (vs Medical Monitor authorizing bridging 
supply); provided clarification that cabotegravir and rilpivirine exposure may persist for 
more than one year in some participants after intramuscular administration (with added 
references); minor edits to prohibited medication information; added statement that drugs 
that cause Torsade de Pointes should be used with caution when taking rilpivirine; 
additional clarification that background NRTI therapy is not considered Investigational 
Product and accountability will not be done for NRTI background; changed film coat 
color for Tivicay (dolutegravir) from white (clinical trial material supply) to yellow 
(commercial supply) and removed statement to “protect from light” (for both Triumeq 
and Tivicay); sentence added for collection of additional details for the injection device 
used for IM administration; additional information included regarding randomization 
schedule; added text stating the investigator must discuss long-term commitment for the 
study with potential participants; added statement regarding serofast RPR results; allowed 
serum pregnancy testing where required locally (e.g. when urine testing is not available); 
removed duplicate text regarding monitoring for suicidal related events; added option for 
patient reported outcomes to be collected on paper instrument if needed; removed 
information in Appendix requiring collection of pregnancy information for female 
partners of male study participants; definition of ACCEPT, HIVTSQc, and HIVTSQs 
added to abbreviations table, duplication of ICH abbreviation removed; other minor 
corrections (e.g., updated references, adding cross reference to sections, correction of 
hyperlink to one table).
2015N248866_02
2017-JUL-19
Amendment No. 2
The reasons for this amendment are as follow:  update of contact information for 

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secondary Medical Monitor; modify text to allow dose reduction for participants who 
have a decline in creatinine clearance to <50 mL/min;  clarify that for participants not 
eligible to continue into the Maintenance Phase, only samples with HIV-1 RNA 
> 400 c/mL will be sent for resistance testing; add mitigation for ECG pad removal; 
clarify 3 day window is for all oral dosing (both Induction and Maintenance Phase); 
add "LA Arm" back to columns for Week 68, 76, 84, 92 on Time and Events Schedule 
(hidden when column was narrowed); clarify Week 104b visit is specific to those 
participants transitioning from oral IP to CAB LA + RPV LA; clarification added to 
footnote ‘p’ that genetics sample can be collected at any visit after signing informed 
consent, but Week [-20] preferred; correct footnote on Week 5 visit to reflect footnote 't'; 
add footnote 'y' back to Time and Events column for Withdrawal Visit (for Induction 
Phase); add clarification to Time and Events column that ISR assessments are only 
conducted for subjects receiving injections.  Administrative typographical errors 
corrected (e.g. clarification provided regarding genetics sample taken after participants 
are enrolled into the study [vs when participants are randomized]), and investigator 
brochure references updated, references added.
2015N248866_03
2018-JUN-25
Amendment No. 3
Changes for Amendment 3 were made to the protocol to manage and mitigate risks 
following identification of a potential safety issue related to neural tube defect in infants 
born to women with exposure to dolutegravir (DTG) at the time of conception.

A Risk Assessment table was added to include language regarding risk and mitigation 
of neural tube defects seen with DTG.

The withdrawal criteria were updated to include a reminder that females of 
reproductive potential who change their minds and desire to be pregnant should also 
be withdrawn from the study.

The Time and Events table was updated to include a reminder for investigators to 
check at every visit that females of reproductive potential are avoiding pregnancy.
Additionally, clarifications were provided for the following:
the DTG IB should be referenced for additional risks, safety information, drug 
interactions, etc.;
‘suspected’ was added to the text prior to the bulleted definition of suspected 
virologic failure in Section 5.4.5.3.;
specific storage conditions were removed from the protocol for IP, and a 
statement added to store according to product label;
insulin was removed from the section regarding clinical assessments performed 
during the study;
timeframe for pregnancy reporting and follow-up were updated to 24 hours to 
align with current reporting process;
prescribing information and IB references were updated.
2015N248866_04
2018-SEP-24
Amendment No. 4
The primary reason for protocol amendment 04 is to allow an optional (vs mandatory) 
oral lead-in for participants randomized to the ABC/DTG/3TC arm who choose to 

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continue into the Extension Phase of the study and receive CAB LA + RPV LA.  The 
Appendix for contraceptive guidance and collection of pregnancy information was 
updated to be consistent with current protocol template text.  Other minor clarifications 
were made as needed, e.g., the eCSSRs timing in the footnote for the Time and Events 
Table, updated abbreviations, etc.

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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Primary Medical Monitor/SAE Contact Information: 
 DO, MSc
ViiV Healthcare
Research Triangle Park
Five Moore Drive, Research Triangle Park, NC 27709 (USA)
Mobile: 
Office Telephone: 
Fax: 
e-mail:  
Secondary Medical Monitor:
 MD, MPH
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:
 DO, 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 supporting ViiV 
Healthcare in the conduct of this study.  
Sponsor Name and Legal Registered Address (excluding US):
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Telephone:  
PPD
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US IND Sponsor Name and Legal Registered Address
ViiV Healthcare Company
Five Moore Drive
P.O. 13398
Research Triangle Park, NC 27709-3398, USA
Telephone:  
Note: In some countries, local law requires that the Clinical Trial sponsor is a local 
company legal entity.  In these instances, the appropriate company to be identified as 
Sponsor must be agreed with the global ViiV Healthcare clinical team and signed off by 
the Vice President, Global Medical Strategy.
Regulatory Agency Identifying Number(s):  
US IND: 109,678
EudraCT #:  2016-001646-25
PPD

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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 201584
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date

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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 201584......................................................14
2.
INTRODUCTION....................................................................................................28
2.1.
Study Rationale ..........................................................................................29
2.2.
Brief Background ........................................................................................30
3.
OBJECTIVES AND ENDPOINTS...........................................................................34
4.
STUDY DESIGN ....................................................................................................37
4.1.
Overall Design ............................................................................................37
4.2.
Treatment Arms and Duration.....................................................................40
4.2.1.
Screening Phase (Up to 35 days) ................................................40
4.2.2.
Induction Phase...........................................................................41
4.2.3.
Eligibility for the Maintenance Phase ...........................................41
4.2.4.
Maintenance Phase (Day 1 to Week 100)....................................42
4.2.5.
Extension Phase..........................................................................43
4.2.5.1.
Participants Entering from the CAB LA + RPV 
LA Arm .......................................................................43
4.2.5.2.
Participants Entering from the ABC/DTG/3TC 
Arm ............................................................................43
4.2.6.
Long-Term Follow-Up Phase – IM Regimen only.........................45
4.2.7.
Dose Modifications / Permitted Treatment Substitutions ..............46
4.2.8.
Independent Data Monitoring Committee.....................................47
4.3.
Type and Number of Participants................................................................47
4.4.
Design Justification.....................................................................................48
4.5.
Dose Justification........................................................................................50
4.5.1.
Oral Lead-In Phase......................................................................50
4.5.2.
Long Acting Injectable for Maintenance Phase ............................52
4.5.3.
Modeling and Dose Simulations for CAB LA and RPV LA............58
4.5.3.1.
CAB LA ......................................................................58
4.5.3.2.
RPV LA ......................................................................60
4.6.
Benefit:Risk Assessment ............................................................................62
4.6.1.
Risk Assessment .........................................................................65
4.6.2.
Other Clinically Relevant Information...........................................79
4.6.3.
Benefit Assessment.....................................................................79
4.6.4.
Overall Benefit:Risk Conclusion...................................................79
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............80
5.1.
Inclusion Criteria.........................................................................................80
5.2.
Exclusion Criteria........................................................................................82
5.3.
Screening/Baseline/Run-in Failures............................................................85
5.4.
Withdrawal/Stopping Criteria.......................................................................85
5.4.1.
Liver Chemistry Stopping Criteria ................................................88
5.4.1.1.
Liver Chemistry Stopping Criteria, Participant 
Management and Follow-Up.......................................89
5.4.1.2.
Liver Event Adjudication Committee...........................90
5.4.1.3.
Liver Chemistry Stopping Criteria –
Restart/Rechallenge...................................................90

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5.4.2.
QTc Stopping Criteria ..................................................................92
5.4.3.
Virologic Failure...........................................................................92
5.4.4.
Definition of Virologic Failure .......................................................92
5.4.5.
Managing Virologic Failure ..........................................................93
5.4.5.1.
HIV-1 RNA Blips.........................................................93
5.4.5.2.
Suspected Virologic Failure........................................93
5.4.5.3.
Confirmed Virologic Failure ........................................94
5.5.
Participant and Study Completion...............................................................94
6.
STUDY TREATMENT ............................................................................................95
6.1.
Investigational Product and Other Study Treatment....................................95
6.1.1.
Cabotegravir (CAB) – Tablet........................................................96
6.1.2.
Rilpivirine (RPV) - Tablet .............................................................96
6.1.3.
Cabotegravir – Injectable Suspension (CAB LA)..........................96
6.1.4.
Rilpivirine – Injectable Suspension (RPV LA)...............................96
6.1.5.
ABC/DTG/3TC STR - Tablet........................................................97
6.1.6.
Dolutegravir (DTG) – Tablet.........................................................97
6.2.
Treatment Assignment................................................................................97
6.3.
Dose and Administration.............................................................................98
6.4.
Blinding.....................................................................................................100
6.5.
Packaging and Labeling............................................................................100
6.6.
Preparation/Handling/Storage/Accountability............................................100
6.6.1.
Dosing Considerations for CAB LA + RPV LA............................101
6.7.
Compliance with Study Treatment Administration.....................................102
6.8.
Protocol Permitted Substitutions...............................................................103
6.8.1.
Oral Bridging..............................................................................103
6.9.
Interruption of Study Treatment ................................................................104
6.9.1.
IM Dosing ..................................................................................104
6.9.2.
Oral Dosing................................................................................106
6.10.
Discontinuation of Study Treatment ..........................................................107
6.10.1.
Discontinuation of ABC/DTG/3TC..............................................107
6.10.2.
Discontinuation of CAB LA or RPV LA.......................................107
6.11.
Treatment of Study Treatment Overdose..................................................107
6.12.
Treatment after the End of the Study ........................................................108
6.13.
Concomitant Medications and Non-Drug Therapies..................................108
6.13.1.
Prohibited Medications and Non-Drug Therapies.......................110
7.
STUDY ASSESSMENTS AND PROCEDURES ...................................................113
7.1.
Time and Events Table.............................................................................113
7.2.
Screening and Critical Baseline Assessments ..........................................125
7.2.1.
Screening ..................................................................................125
7.2.2.
Baseline Assessments...............................................................126
7.3.
Efficacy.....................................................................................................127
7.3.1.
Plasma HIV-1 RNA....................................................................127
7.3.2.
Lymphocyte Subsets, CD4+ and CD8+ .....................................127
7.3.3.
HIV Associated Conditions ........................................................127
7.4.
Safety .......................................................................................................127
7.4.1.
Clinical evaluations ....................................................................127
7.4.2.
Laboratory Assessments ...........................................................128
7.4.3.
Adverse Events (AE) and Serious Adverse Events (SAEs)........131
7.4.3.1.
Time Period and Frequency for collecting AE 
and SAE information.................................................131

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7.4.3.2.
Method of Detecting AEs and SAEs .........................131
7.4.3.3.
Follow-up of AEs and SAEs......................................131
7.4.3.4.
Prompt Reporting of Serious Adverse Events 
and Other Events .....................................................132
7.4.3.5.
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ..............134
7.4.3.6.
Regulatory Reporting Requirements for SAEs..........134
7.4.3.7.
Cardiovascular Events..............................................135
7.4.3.8.
Death Events............................................................135
7.4.4.
Toxicity Management.................................................................135
7.4.4.1.
Treatment Interruption Due to an Adverse 
Event........................................................................136
7.4.4.2.
Grade 1 or Grade 2 Toxicity/Adverse Event .............136
7.4.4.3.
Grade 3 Toxicity/Adverse Event ...............................137
7.4.4.4.
Grade 4 Toxicity/Adverse Event ...............................137
7.4.5.
Specific Toxicities / Adverse Event Management.......................138
7.4.5.1.
Liver Chemistry Stopping Criteria .............................138
7.4.5.2.
Diarrhea ...................................................................138
7.4.5.3.
Hypertriglyceridemia / Hypercholesterolemia............139
7.4.5.4.
Seizures ...................................................................139
7.4.5.5.
Creatine Phosphokinase (CPK) Elevation ................139
7.4.5.6.
Lipase Elevations and Pancreatitis...........................139
7.4.5.7.
Decline in Renal Function.........................................140
7.4.5.7.1.
Proximal Renal Tubule 
Dysfunction...........................................140
7.4.5.8.
Proteinuria................................................................141
7.4.5.9.
QTc Prolongation .....................................................141
7.4.5.10.
Injection Site Reactions (ISRs) .................................141
7.4.5.11.
Allergic Reaction ......................................................142
7.4.5.12.
Abacavir Hypersensitivity Reaction (ABC HSR)........142
7.4.5.12.1.
Essential Participant Information ..........143
7.4.5.12.2.
Reporting of Hypersensitivity 
Reactions .............................................143
7.4.5.13.
Rash Without ABC HSR Symptoms .........................144
7.4.6.
Suicidal Risk Monitoring.............................................................145
7.4.7.
Pregnancy .................................................................................146
7.4.7.1.
Pregnancy testing.....................................................146
7.4.7.2.
Time Period for Collecting Pregnancy 
Information ...............................................................147
7.4.7.3.
Action to be Taken if Pregnancy Occurs...................147
7.4.8.
Physical Exams .........................................................................148
7.4.9.
Vital Signs..................................................................................148
7.4.10.
Electrocardiogram (ECG)...........................................................148
7.5.
Pharmacokinetics .....................................................................................148
7.5.1.
PK Sample Collection ................................................................149
7.5.2.
Rationale of PK Sampling Strategy............................................151
7.5.3.
Sample Analysis ........................................................................151
7.5.3.1.
CAB Sample Analysis...............................................151
7.5.3.2.
RPV Sample Analysis...............................................151
7.6.
Biomarker(s).............................................................................................151
7.6.1.
Biomarker Endpoints (Exploratory) ............................................151
7.7.
Genetics ...................................................................................................152

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7.8.
Viral Genotyping and Phenotyping............................................................152
7.8.1.
HIV-1 pol Viral Genotyping and Phenotyping .............................152
7.8.2.
HIV-1 Exploratory Analysis ........................................................152
7.9.
Value Evidence and Outcomes.................................................................153
7.9.1.
Value Evidence and Outcomes Endpoints (Secondary).............154
7.9.2.
Value Evidence and Outcomes Endpoints (Exploratory)............155
8.
DATA MANAGEMENT .........................................................................................155
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES ...............................155
9.1.
Hypotheses...............................................................................................155
9.2.
Sample Size Considerations.....................................................................156
9.2.1.
Sample Size Assumptions .........................................................156
9.2.1.1.
Rationale for non-inferiority margin...........................156
9.2.1.2.
Assumption for Virologic Failure Rate at Week 
48 (Primary Endpoint)...............................................157
9.2.1.2.1.
Control Arm ..........................................157
9.2.1.2.2.
CAB LA + RPV LA arm.........................158
9.2.1.3.
Assumption for Response Rate at Week 48 
(Secondary Endpoint)...............................................159
9.2.2.
Sample Size Sensitivity..............................................................159
9.2.3.
Sample Size Re-estimation or Adjustment.................................162
9.2.4.
Sample Size Considerations for Week 124 Extension 
Switch Analysis..........................................................................162
9.3.
Data Analysis Considerations ...................................................................162
9.3.1.
Analysis Populations..................................................................162
9.3.1.1.
All Participants Enrolled............................................162
9.3.1.2.
Intent-to-Treat Exposed Population (ITT-E)..............162
9.3.1.3.
Per-Protocol Exposed Population (PP).....................163
9.3.1.4.
Safety Population .....................................................163
9.3.1.5.
PK Population...........................................................163
9.3.1.6.
Extension Switch Population (ES) ............................163
9.3.2.
Treatment Comparisons ............................................................163
9.3.2.1.
Primary Comparison of Interest ................................163
9.3.2.2.
Other Comparisons of Interest..................................163
9.3.2.3.
Secondary comparisons ...........................................164
9.3.3.
Planned Analyses......................................................................164
9.4.
Key Elements of Analysis Plan .................................................................164
9.4.1.
Primary Analyses.......................................................................165
9.4.2.
Secondary Analyses ..................................................................166
9.4.2.1.
Week 124 Extension Switch Analysis .......................167
9.4.3.
Pharmacokinetic Analyses.........................................................168
9.4.4.
Pharmacokinetic/Pharmacodynamic Analyses...........................168
9.4.5.
Viral Genotyping/Phenotyping Analyses ....................................169
9.4.6.
Health Outcomes Analyses........................................................169
9.4.7.
Other Analyses ..........................................................................169
10. STUDY GOVERNANCE CONSIDERATIONS......................................................169
10.1.
Posting of Information on Publicly Available Clinical Trial Registers..........169
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ......................................................................................170
10.3.
Quality Control (Study Monitoring) ............................................................170

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10.4.
Quality Assurance.....................................................................................171
10.5.
Study and Site Closure .............................................................................171
10.6.
Records Retention....................................................................................171
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication ...............172
10.8.
Review Committee....................................................................................173
10.8.1.
Independent Data Monitoring Committee...................................173
11. REFERENCES.....................................................................................................174
12. APPENDICES......................................................................................................178
12.1.
Appendix 1: Abbreviations and Trademarks..............................................178
12.2.
Appendix 2: Division Of AIDS Table For Grading The Severity Of 
Adult And Pediatric Averse Events Version 2.0, November 2014..............183
12.3.
Appendix 3:  Liver Safety – Study Treatment Restart or Rechallenge 
Guidelines.................................................................................................221
12.4.
Appendix 4: CDC Classification System for HIV-1 Infections (2014) .........229
12.5.
Appendix 5: Genetic Research .................................................................231
12.6.
Appendix 6: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events.............................................234
12.6.1.
Definition of Adverse Events......................................................234
12.6.2.
Definition of Serious Adverse Events.........................................235
12.6.3.
Definition of Cardiovascular Events ...........................................237
12.6.4.
Recording of AEs and SAEs ......................................................237
12.6.5.
Evaluating AEs and SAEs..........................................................238
12.6.6.
Reporting of SAEs to ViiV Healthcare / GSK..............................239
12.7.
Appendix 7:  Contraceptive Guidance and Collection of Pregnancy 
Information................................................................................................240
12.7.1.
Contraception Guidance ............................................................240
12.7.2.
Collection of Pregnancy Information ..........................................242
12.8.
Appendix 8: Country Specific Requirements.............................................243
12.8.1.
United Kingdom (UK).................................................................243
12.8.2.
Japan.........................................................................................243
12.9.
Appendix 9:  Protocol Amendments..........................................................244
12.9.1.
Amendment 01 (All Countries)...................................................244
12.9.2.
Amendment 02 (All Countries)...................................................272
12.9.3.
Amendment 03 (All Countries)...................................................279
12.9.4.
Amendment 04 (All Countries)...................................................289

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1.
PROTOCOL SYNOPSIS FOR STUDY 201584
Rationale
201584 (the First Long-Acting Injectable Regimen – FLAIR study) is being conducted to 
establish if human immunodeficiency virus type-1 (HIV-1) infected adult participants 
whose virus is virologically suppressed on an integrase inhibitor single tablet regimen 
(INI STR) will remain suppressed after switching to a two-drug intramuscular (IM) long-
acting (LA) regimen of cabotegravir (CAB) and rilpivirine (RPV).  In this study, the INI 
STR will be limited to abacavir/dolutegravir/lamivudine (ABC/DTG/3TC).  This study is 
designed to demonstrate the non-inferior antiviral activity of switching to a two drug 
CAB LA 400 mg + RPV LA 600 mg regimen every 4 weeks (Q4W: monthly) compared 
to remaining on ABC/DTG/3TC over 48 weeks (4 weeks oral CAB + RPV, 44 weeks LA 
therapy).  201584 (FLAIR) will also allow for characterization of long-term antiviral 
activity, safety, and tolerability and participant satisfaction of the regimens through 
Week 96.  Additionally, participants randomized to continue ABC/DTG/3TC will be 
given an option to switch to LA therapy at Week 100.  Eligible participants (HIV-1 
ribonucleic acid [RNA] <50 c/mL at Week 96) would transition to LA dosing, beginning 
with the first IM CAB LA + RPV LA injections at either Week 100 (direct to injection) 
or Week 104b (following optional oral lead-in with CAB 30 mg and RPV 25 mg).
201584 (FLAIR) is being conducted in parallel with the 201585 (ATLAS) study with the 
aim to pool data generated from the current study with study 201585, 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 ABC/DTG/3TC over 48 weeks in 
HIV-1 antiretroviral naïve participants.

Proportion of participants with a ‘virologic 
failure’ endpoint as per FDA Snapshot 
algorithm at Week 48 (Missing, Switch, or 
Discontinuation = Failure, 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 ABC/DTG/3TC.

Proportion of participants with plasma HIV-1 
RNA <50 copies/mL (c/mL) at Week 48 
using the FDA Snapshot algorithm (Intent-
to-Treat Exposed [ITT-E] population).

Proportion of participants with plasma HIV-1 
RNA <200 c/mL at Week 48 using the FDA 
Snapshot algorithm (ITT-E population).

Proportion of participants with plasma HIV-1 
RNA <200 c/mL and HIV-1 RNA <50 c/mL 
at Week 96 using the FDA Snapshot 
algorithm (ITT-E population).

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Objectives
Endpoints

Proportion of participants with a ‘virologic 
failure’ endpoint as per FDA Snapshot 
algorithm at Week 96.

Proportion of participants with confirmed 
virologic failure at Week 48 and Week 96.

Absolute values and change from Baseline 
in plasma HIV-1 RNA (log10 copies/mL) at 
Week 48 and Week 96.

Absolute values and changes from Baseline 
in CD4+ cell counts over time including 
Week 48 and Week 96.

Incidence of disease progression (HIV-
associated conditions, acquired 
immunodeficiency syndrome [AIDS] and 
death).
To evaluate the safety and tolerability of 
switching to CAB LA + RPV LA every 4 weeks 
(monthly) compared to continuation of 
ABC/DTG/3TC over time.

Incidence and severity of adverse events 
(AEs) and laboratory abnormalities over 
time including Week 48 and Week 96.

Proportion of participants who discontinue 
treatment due to AEs over time including 
Week 48 and Week 96.

Absolute values and changes in laboratory 
parameters over time including Week 48 
and Week 96.
To evaluate the effects of CAB LA + RPV LA 
every 4 weeks on fasting lipids over time 
compared to continuation of ABC/DTG/3TC 
over time.

Change from Baseline in fasting lipids over 
time including Week 48 and Week 96.
To assess the development of 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 and 
Week 96.
To characterize CAB and RPV concentrations 
and population pharmacokinetics (PK) 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 (BMI), and relevant laboratory 
parameters will be evaluated as potential 
predictors of inter- and intra-participant 

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Objectives
Endpoints
variability for pharmacokinetic parameters.  
To assess the acceptance of pain and injection 
site reactions following injections.

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).
To assess treatment satisfaction of CAB LA + 
RPV LA compared to continuation of 
ABC/DTG/3TC.

Change from baseline in total “treatment 
satisfaction” score, and individual item 
scores of the HIV Treatment Satisfaction 
Questionnaire (status version) (HIVTSQs) 
at Week 4b, Week 24, Week 44, Week 96 
(or Withdrawal).

Change in treatment satisfaction over time 
(using the HIVTSQc change version 
[HIVTSQc]) at Week 48 (or Withdrawal).
To assess degree of health-related quality of life 
(HR QoL).

Change from Baseline in HR QoL using the 
HIV/AIDS targeted quality of life 
questionnaire (HAT-QoL) short format 
Week 24, Week 48, Week 96 (or 
Withdrawal).
To assess 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 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 
injections at Week 5, Week 40, Week 41, 
and Week 96 using the Numeric Rating 

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Objectives
Endpoints
Scale (NRS) within the CAB LA + RPV LA 
arm.
To evaluate the antiviral and immunologic 
effects, safety and tolerability, and development 
of viral resistance to CAB LA + RPV LA at 
Week 124 and over time for participants 
switching from ABC/DTG/3TC in the Extension 
Phase, with and without optional oral lead-in.

Proportion of participants with HIV-1 RNA 
50 c/mL at Week 124, with and without 
oral lead-in (FDA Snapshot algorithm, 
Extension Switch population).

Proportion of participants with plasma HIV-1 
RNA <50 c/mL and HIV-1 RNA <200 c/mL
over time.

Proportion of participants with confirmed 
virologic failure over time.

Incidence of treatment emergent genotypic 
and phenotypic resistance to CAB and RPV 
over time.

Absolute values and change from Baseline 
in CD4+ cell counts over time.

Incidence and severity of AEs and 
laboratory abnormalities over time.

Proportion of participants who discontinue 
treatment due to AEs over time.

Absolute values and change in laboratory 
parameters over time.
To evaluate the pharmacokinetics of CAB and 
RPV in the setting of no oral lead-in for 
participants switching from ABC/DTG/3TC in the 
Extension Phase.

To evaluate plasma CAB and RPV 
concentrations over time (Week 100 [direct 
to inject without oral lead-in] and Week 104 
[both direct to inject and optional oral lead-
in participants])
Exploratory
To explore the effect of participant 
characteristics on the virologic and immunologic 
response of CAB LA and RPV LA compared to 
continuation of ABC/DTG/3TC.

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, and 96 using the Snapshot algorithm for 
the ITT-E population.

Proportion of participants by subgroup(s) 
(e.g. by age, gender, BMI, race, HIV-1 
subtype, Baseline CD4+) with plasma HIV-1 
RNA <50 c/mL at Week 48 and Week 96.

Change from Baseline in CD4+ cell counts 

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Objectives
Endpoints
by subgroups at Week 48 and Week 96.
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 receiving CAB LA and RPV LA 
compared to continuation of ABC/DTG/3TC 
over time.

Absolute values and change from Baseline 
in renal (in urine and blood) and bone (in 
blood) biomarkers over time including Week 
48 and Week 96.
To assess preference for CAB LA + RPV LA 
compared to oral antiretroviral (ARV) therapy 
using a single dichotomous preference 
question.

For participants randomized to the “CAB 
LA + RPV LA” arm, preference for CAB LA 
+ RPV LA compared to oral ARV regimen, 
at Week 48.
Overall Design
201584 (FLAIR) is a 120-week Phase 3, multi-phase, randomized, open label, active-
controlled, multicenter, parallel-group, non-inferiority study in HIV-1, ART-naïve adult 
participants.  Participants who fulfill eligibility requirements will enroll into the Induction 
Phase of the study and receive ABC/DTG/3TC for 20 weeks (Week [-20] to Day 1).  
Participants who have an HIV-1 RNA <50 c/mL at Week (-4) will be randomized (1:1) 
into the Maintenance Phase at Day 1 to either continue ABC/DTG/3TC or to discontinue 
ABC/DTG/3TC and begin oral therapy with CAB 30 mg + RPV 25 mg once daily.  
ABC/DTG/3TC dosing on Day 1 should 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 ABC/DTG/3TC prior to coming into 
the clinic, randomization and initiation of oral CAB and RPV should continue as planned 
for Day 1.  Participants who are not eligible to continue into the Maintenance Phase will 
be withdrawn from the study.  At the Week 4a visit, assessments (including e.g., clinical 
chemistries) will be performed.  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 Week 4b 
visit can be performed as soon as central laboratory results become available and safety 
parameters are reviewed.  The second and third IM injections (CAB LA 400 mg + 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 injections occur 
within the window of Week 7 to Week 8, but not later than Week 8, and the third 
injections occur within the window of Week 11 to Week 12, but no later than Week 12.  
Subsequent injections (CAB LA 400 mg + RPV LA 600 mg) will occur every 4 weeks 
(monthly) thereafter, with a 7 day dosing window being allowed (but not preferred).  In 
addition, starting at the Week 12 injections, the interval between injection visits should 
be limited to a maximum of 5 weeks.  If the length of time between injections exceeds, or 
is projected to exceed 5 weeks, the Medical Monitor must be contacted to discuss 
individual participant case management.  

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Participants randomized to ABC/DTG/3TC during the Maintenance Phase will continue 
ABC/DTG/3TC for at least an additional 100 weeks.  Participants who successfully 
complete Week 100 (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.
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 will enter a 52 week Long-
Term Follow-Up Phase.  Participants must remain on suppressive highly active 
antiretroviral therapy (HAART) for at least 52 weeks after the last dose of CAB LA 
and/or RPV LA.
In order to achieve balance across the two treatment arms, randomization will be 
stratified by participants’ Baseline HIV-1 RNA (<100,000, 100,000 c/mL) and gender at 
birth.  The primary endpoint for the study is the proportion of participants who meet the 
Snapshot virologic failure criterion at Week 48.  The proportion of participants with 
plasma HIV-1 RNA <50 c/mL at Week 48 of maintenance treatment using the FDA 
Snapshot algorithm (Missing, Switch or Discontinuation = Failure, Intent-to-Treat 
Exposed [ITT-E] population) is a key secondary endpoint comparison.
Assuming a 20% screen failure rate, sufficient ART-naïve participants will be screened 
(approximately 775) in order to ensure that a total of approximately 620 participants are 
enrolled at the beginning of the Induction Phase.  Assuming 7.5% of enrolled participants 
will not participate in the Maintenance Phase, this will ensure approximately 
570 participants continue into the Maintenance Phase.  The sample size of 285 per arm 
(at Day 1) is such that the study has approximately 97% power to demonstrate non-
inferiority in the proportion of participants with snaphot virologic failure at Week 48 
using an 6% margin, assuming a true 3% failure rate for CAB LA + RPV LA and a 2% 
failure rate for the ABC/DTG/3TC control arm and using a 2.5% one-sided alpha level. 
This sample size is primarly chosen so that the pooled analysis of data from this study 
and study 201585 (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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201584 (FLAIR) Study Schematic
¥Subjects who withdraw from IM CAB LA + RPV LA must enter the 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.
All participants will complete the Screening Phase of up to 35 days prior to Baseline 
(Week [-20]) during which all clinical and laboratory assessments of eligibility must be 
performed and reviewed.  Participants may be re-screened once.  Participants who are 
enrolled into the trial and subsequently withdrawn from the study, for any reason, may 
not be re-screened.  Participants may be enrolled as soon as all eligibility requirements 
have been confirmed at the site.
Induction Phase (Week [-20] to Day 1)
Following the Screening Phase, eligible participants will be enrolled into the study and 
begin a 20 week Induction Phase on ABC/DTG/3TC.  Participants who have 
demonstrated tolerability to the Induction Phase regimen and with an undetectable HIV-1 
RNA (<50 c/mL) at the Week (-4) visit are eligible to enter the Maintenance Phase. A 
single repeat HIV-1 RNA test to determine eligibility may be allowed ONLY after 
consultation with the Medical Monitor.  The retest should be scheduled as soon as 
possible as results of this retest must be available prior to the Day 1 visit.  Participants 
with HIV-1 RNA 400 c/mL at Week (-4) are not eligible to enter the Maintenance 
Phase, will not be allowed a repeat to determine eligibility, and will therefore be 
withdrawn from the study.  Note:  ABC/DTG/3TC dosing on Day 1 should occur after 

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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 
ABC/DTG/3TC prior to coming into the clinic, randomization and initiation of oral CAB 
and RPV should continue as planned for Day 1.
Maintenance Phase (Day 1 to Week 100)
At Day 1, the Maintenance Phase begins.  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 
will have the assessments completed, 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 Week 4b visit can be 
performed as soon as central laboratory results become available and safety 
parameters are reviewed.  The second and third IM injections (CAB LA 400 mg + 
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 
injections occur within the window of Week 7 to Week 8, but not later than 
Week 8), and the third injections occur within the window of Week 11 to 
Week 12, but no later than Week 12.  Subsequent injections (CAB LA 400 mg + 
RPV LA 600 mg) will occur every 4 weeks thereafter, with a (+ or -) 7 day dosing 
window, from the projected visit date, being allowed (but not preferred).  
Following the Week 12 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.
OR

Continue on the oral ABC/DTG/3TC initiated during the Induction Phase for at 
least an additional 100 weeks.  Participants who successfully complete Week 100 
(without meeting study defined withdrawal criteria and who remain virologically 
suppressed through Week 96:  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.

ABC/DTG/3TC dosing on Day 1 should occur after randomization to avoid 
overlap of regimens (in the event that the participant is assigned to begin oral 
CAB and RPV on Day 1).  However, if the participant takes ABC/DTG/3TC prior 
to coming into the clinic, randomization and initiation of oral CAB and RPV 
should continue as planned on Day 1.
Randomization will be stratified by participants’ Baseline HIV-1 RNA (<100,000, 
100,000 c/mL) and gender at birth. 

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Extension Phase
All eligible participants who transition into the Extension Phase 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.
Participants not eligible to enter the Extension Phase will end their study participation 
(Week 100 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.
Participants Entering from the CAB LA + RPV LA Arm
All participants who successfully complete Week 100 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.  
Participants Entering from the ABC/DTG/3TC Arm
Participants randomized to continue ABC/DTG/3TC 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 100.  
The transition from ABC/DTG/3TC to CAB LA + RPV LA within the Extension Phase 
can be completed with or without an oral lead-in prior to commencement of injectable 
treatment.  The oral lead-in decision will be made by the participant in consultation with 
the investigator and must be appropriately documented. As participants approach the 
Week 100 visit, sites must ensure sufficient CAB and RPV supply are available to 
support the participant’s decision for transition to LA.
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 
ABC/DTG/3TC while eligibility is being confirmed.  
All participants with an undetectable HIV-1 RNA (<50 c/mL) result from the Week 96 
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 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 with a 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 96 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 Transitioning Direct to Injection in the Extension Phase
Central lab results and safety parameters from the Week 96 visit must be available and 
reviewed for participants who choose to transition direct to injection.  Participants with 
ongoing safety issues or laboratory abnormalities of clinical concern (e.g., Grade 3 or 

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Grade 4 liver enzyme elevations), will require consultation and agreement with the 
Medical Monitor prior to proceeding directly to injections in the Extension Phase. 
If a clinical chemistry retest is required based on Week 96 labs, the retest should be 
performed as soon as possible (and preferably no later than 7 days following Week 96).
Participants will remain on oral ABC/DTG/3TC until the Week 100 injection visit, and 
until any required Week 96 retest results are available for review.
At Week 100, eligible participants will take the last dose of ABC/DTG/3TC (or DTG + 
2 NRTIs), and receive the first injections of CAB LA (600 mg) + RPV LA (900 mg) as 
initial loading doses.  Clinical chemistries will also be assessed at Week 100.  At 
Week 101, participants will return to the clinic for PK and safety assessments including 
clinical chemistries.  The second and third injections (CAB LA 400 mg + RPV LA 
600 mg) will be administered at Week 104a and Week 108.  There will be a one week 
dosing window for the second and third IM injections such that the second injections 
occur within the window of Week 103 to Week 104a, but not later than Week 104a, and 
the third injections occur within the window of Week 107 to Week 108, but no later than 
Week 108.  Subsequent injections (CAB LA 400 mg + RPV LA 600 mg) will occur 
every 4 weeks thereafter, from the projected visit date, with a (+ or -) 7 day dosing 
window being allowed (but not preferred).  Following the Week 108 injection, the 
interval between injection visits should be limited to a maximum of 5 weeks.  The 
Medical Monitor must be contacted if the length of time between injections exceeds, or is 
projected to exceed, 5 weeks.
Participants Receiving Optional Oral Lead-In in the Extension Phase
At Week 100, eligible participants who after discussion with the investigator, choose to 
receive the optional oral lead-in will initiate a 4 week lead-in of oral CAB 30 mg + oral 
RPV 25 mg once daily. It is not necessary to dose ABC/DTG/3TC on the day the 
participant begins the oral lead-in with CAB + RPV.  However, if the participant takes 
ABC/DTG/3TC prior to coming into the clinic, initiation of oral CAB and RPV should 
continue as planned.  Clinical chemistries will also be assessed at Week 100.  At Week 
104a, following the 4 week CAB + RPV oral lead-in, participants will have additional 
safety assessments including clinical chemistries.  In addition, central lab results and 
safety parameters from the Week 104a visit must be available and reviewed.  If a clinical 
chemistry retest is required based on Week 104a labs, the retest should be performed as 
soon as possible (and preferably no later than 7 days following Week 104a). Participants 
will remain on oral CAB 30 mg + RPV 25 mg until the Week 104b injection visit, and 
until any required Visit 104a retest results are available for review.  An HIV-1 RNA 
sample will not be collected at Week 104a for participants receiving the optional oral 
lead-in, but will be obtained at the Week 104b visit to serve as the injection baseline viral 
load.
At visit Week 104b, 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 Week 104b visit can be performed as 
soon as central lab results from the Week 104a visit become available and safety 
parameters are reviewed.  The second and third injections (CAB LA 400 mg + RPV LA 
600 mg) will be administered at Week 108 and Week 112.  There will be a one week
dosing window for the second and third IM injections such that the second injections 

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occur within the window of Week 107 to Week 108, but not later than Week 108, and the 
third injections occur within the window of Week 111 to Week 112, but no later than 
Week 112.  Subsequent injections (CAB LA 400 mg + RPV LA 600 mg) will occur 
every 4 weeks thereafter, from the projected visit date, with a (+ or -) 7 day dosing 
window being allowed (but not preferred).  Following the Week 112 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.
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 highly active antiretroviral therapy (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 non-nucleoside reverse transcriptase inhibitor (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 four weeks of the last injection.

The 52 weeks follow up phase will begin the day of the last CAB LA and/or RPV LA 
dose.  These participants will not complete a Withdrawal visit, but will instead move 
directly into the Long-Term Follow Up Phase.

Participants will be assessed with clinic visits at Months 1, 3, 6, 9 and 12.  Female 
participants of child bearing potential must continue to use adequate contraception 
methods for at least 52 weeks after the last injection.  

In order to assure that participants have access to HAART during the Long-Term 
Follow-Up Phase, GlaxoSmithKline (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 
the withdrawal visit.
Protocol Permitted Substitutions
Participants who are HLA-B*5701 positive at the Screening visit are allowed to enter the 
study on DTG and an approved dual-nucleoside reverse transcriptase inhibitor (NRTI) 
backbone that does not contain abacavir (e.g. tenofovir/emtricitabine [TDF/FTC] or 
tenofovir alafenamide/emtricitabine [TAF/FTC]).  This regimen may be supplied 
regionally by GSK or reimbursement will be provided as needed. 

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During the Induction Phase, prior to randomization into the Maintenance Phase at Day 1, 
one switch to an alternate approved background NRTI therapy is allowed for toxicity or 
tolerability management.  The date of a decision to switch the NRTI background therapy 
for toxicity or tolerability management must be documented in the electronic case report 
form (eCRF).  Switches of a background NRTI for any other reason are not permitted in 
the study.  Local prescribing information should be consulted for information regarding 
use of these medications.  
For consistency with prescribing information, dose reductions of lamivudine (or 
emtricitabine if used as alternate NRTI) are permitted as needed for creatinine clearance 
<50 mL/min (throughout the study).  No other dose reductions, modifications, or changes 
in the frequency of any components of any regimen will be allowed during the 
Maintenance and Extension Phases of the study.  
Following the Induction Phase, in exceptional circumstances, and in consultation with the 
Medical Monitor, Investigators may provide oral CAB and RPV as a short-term 
“bridging” strategy for participants who have begun CAB LA + RPV LA and who will 
miss a subsequent scheduled LA injection.  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.
Protocol waivers or exemptions are not allowed.  Therefore, adherence to the study 
design requirements are essential and required for study conduct.
Study Completion
Participants are considered to have completed the study if they satisfy one of the 
following: 

Randomly assigned to either treatment group, completed the randomized 
Maintenance Phase including the Week 100 visit, and did not enter the Extension 
Phase;

Randomly assigned to either treatment group, completed the randomized 
Maintenance Phase including the Week 100 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).
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.
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 

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ethical interests and well-being of subjects and to protect the scientific validity of this 
study and study 201585. 
The IDMC will evaluate accumulating efficacy, tolerability and 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/safety/PK 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 ABC/DTG/3TC arm given the partial data set.  The sponsor will remain 
blinded to this analysis.
In addition, the IDMC may also continuously monitor the incidence of participants 
meeting the confirmed virologic failure 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 into the study is HIV-1 infected antiretroviral (ART) 
naïve participants.
Assuming a 20% screen failure rate, sufficient ART-naïve participants will be screened 
(approximately 775) in order to ensure that a total of approximately 620 participants are 
enrolled at the beginning of the Induction Phase.  Assuming 7.5% of enrolled participants 
will not participate in the Maintenance Phase, this will ensure approximately 
570 participants continue into the Maintenance Phase.  Participants will be enrolled from 
multiple sites which may include sites in Canada, France, Germany, Italy, Japan, the 
Netherlands, Russia, South Africa, Spain, the United Kingdom, and the United States.
Randomization will be stratified by participants’ Baseline HIV-1 RNA (<100,000, 
100,000 c/mL) and gender at birth.
A goal of this study is to enroll approximately 20% women, who are typically under-
represented in clinical studies.  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.  
Participants who prematurely discontinue from the study will not be replaced.

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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 participants’ Baseline HIV-1 RNA 
(<100,000, 100,000 c/mL) and gender at birth.  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 INI STR arm, this would provide approximately 97% to show 
non-inferiority at a 2.5% one-sided significance level.  If we observe a 2% failure rate for 
the INI STR 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] – INI STR).
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, 201585, 
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.
In descriptive analyses, antiviral response will be assessed according to the proportion of 
participants with and without oral lead-in who have HIV-1 RNA ≥50 c/mL at Week 124 
(i.e., 24 weeks from initiation of CAB LA + RPV LA at Week 100, 6 week analysis 
window, using the FDA Snapshot algorithm), with corresponding 95% confidence 
interval.  No formal statistical comparison with respect to safety and efficacy outcomes 
will be performed.  
201584 (FLAIR) is being conducted in parallel with study 201585 (ATLAS) with the aim 
to pool data generated from the current study with study 201585, in order to evaluate key 
program objectives.

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2.
INTRODUCTION
Advances in antiretroviral therapies (ART) have led to significant improvements in 
morbidity and mortality among Human Immunodeficiency Virus (HIV)-infected persons, 
and has transformed HIV into a chronic manageable disease. Suppression of viral 
replication is the cornerstone of ART’s success and this in turn, is dependent on a 
participant’s ability to adhere to life-long therapy with 3 or more antiretrovirals (ARVs). 
Fixed-dose combinations (FDCs) have greatly advanced HIV treatment by allowing 
simplification of dosing and reducing pill burden.  Among regimens of comparable 
efficacy, physicians and HIV-1-infected participants who receive ART rate total pill 
burden, dosing frequency, and safety concerns among the greatest obstacles to achieving 
adherence. Incomplete adherence may lead to the emergence of drug-resistant virus that 
can lead to the loss of virologic control and reverse the benefits of ART.  Different HIV 
treatment modalities are being developed to help improve adherence and participant 
outcomes, and prevent the emergence of resistance and transmission of the virus. 
There is also an increasing desire to develop nucleoside reverse transcriptase inhibitor 
(NRTI)-sparing regimens that avoid long-term NRTI-associated adverse drug reactions, 
including renal, hepatic, bone and cardiovascular 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 
participants 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),
which can also be formulated as a LA product, is a diarylpyrimidine derivative and a 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 profile, as well as improved adherence 
and treatment satisfaction in virologically suppressed patients.
To date, there are three integrase inhibitors approved in the US and EU for the treatment 
of HIV-infection: raltegravir (RAL) (Merck), elvitegravir (EVG) (Gilead), and 
dolutegravir (DTG) (ViiV Healthcare).  Two of these three (DTG, EVG) are currently 
available as components of a once daily single tablet regimen.  In April, 2015, the 
Department of Health and Human Services (DHHS) updated treatment guidelines to 
include five recommended choices for initial treatment of HIV infection.  Four of these 
five include integrase based therapy as the first line recommended regimen for ART-
naïve participants [DHHS, 2015].
DTG is a potent dual cation binding integrase inhibitor, exhibiting rapid reduction in viral 
load, best in class efficacy, and a high barrier to resistance.  DTG is a once daily, 
unboosted integrase inhibitor that has demonstrated sustained antiviral activity 
comparable or superior to standard of care in combination with dual NRTIs [Raffi, 2013; 
Walmsley, 2015].  In addition, due to its mechanism of metabolism, DTG lacks many of 
the frequent drug interactions associated with other medications commonly taken by 
HIV-positive patients.  To date, the efficacy, PK, safety and drug interaction potential of 

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DTG has been evaluated in an extensive program of Phase 1 to 3B clinical trials 
[TIVICAY Prescribing Information, 2017].  DTG has also demonstrated significant 
improvements over the first marketed INI (RAL), including activity in the presence of 
integrase (IN)-resistant viruses and an improved dosing regimen (unboosted once daily 
administration) with similar or improved safety. 
Abacavir (ABC)/DTG/lamivudine (3TC) is a combination product of an INI and 
two NRTIs formulated into a fixed dose combination (FDC) single tablet regimen (STR) 
that offers the simplicity of a once-daily well-tolerated regimen, with a high genetic 
barrier for resistance.  It may be taken with or without food, and demonstrates few drug-
drug interactions in treatment-naïve participants. 
The overall objective of this study will be to demonstrate the non-inferior antiviral 
activity of switching to intramuscular CAB LA + RPV LA every 4 weeks compared to 
continuation of ABC/DTG/3TC over 48 weeks (44 weeks of LA maintenance treatment) 
in HIV-1 antiretroviral naïve participants.
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 compliance, treatment convenience, and improved 
quality of life for individuals with HIV compared to current standard of care.  201584 
(FLAIR) is being conducted to establish if human immunodeficiency virus type-1 
(HIV-1) infected adult participants whose virus is virologically suppressed on an 
integrase inhibitor single tablet regimen (INI STR), will remain suppressed after 
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 a two drug CAB LA + RPV LA regimen every 4 weeks 
(monthly) compared to remaining on a single tablet integrase based regimen 
(ABC/DTG/3TC) over 48 weeks.  201584 (FLAIR) will also allow for characterization of 
long-term antiviral activity, safety, tolerability, and participant satisfaction of the 
regimens through Week 96.  
Additionally, participants initially randomized to continue ABC/DTG/3TC will have an 
option to switch to CAB LA + RPV LA at, or after, completion of the Week 100 visit.  
Amendment 04 of the FLAIR study will provide an opportunity to access an optional (vs 
mandatory) oral lead-in for these participants who transition to LA treatment at 
Week 100.  Eligible participants (HIV-1 RNA <50 c/mL at Week 96) would transition to 
LA dosing, beginning at either Week 100 (direct to injection) or Week 104b (following
optional oral lead-in with CAB 30 mg and RPV 25 mg).
Importantly, the oral lead-in during the early development program for CAB LA and 
RPV LA was instituted to minimize the risk of severe adverse drug reactions during LA 
dosing (e.g. acute hypersensitivity).  The 4 week oral lead-in allowed for an evaluation of 
any untoward adverse events and an assessment of safety labs prior to initiation of LA 
therapy.  To date, the principal safety risk identified with cabotegravir, following 3145
exposures to drug (oral and/or LA), is suspected DILI, which has occurred in a few 

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individuals, all of whom were receiving oral CAB. The time to onset ranged between 
4 weeks and one year and manifested as asymptomatic elevations of ALT, without 
compromise to hepatic function.  Each participant fully recovered, with removal of 
investigational product, without hospitalization or intervention.  During the Phase 3 
ATLAS and FLAIR studies, no cases of DILI have been identified, during the oral lead-
in period, or following initiation of LA dosing.  There has been no evidence to date of a 
risk for clinically significant hepatotoxicity observed with cabotegravir.  Additionally, 
throughout the development program to date, no cases of severe drug hypersensitivity or 
severe drug allergy have been observed.  While the risk of idiosyncratic severe drug 
reactions cannot be fully excluded, the risk of occurrence is felt to be low, on the basis of 
safety data generated to date.
Based on blinded, instream review of ongoing Phase 3 aggregate AE data (from FLAIR, 
and ATLAS) and of individual case reports (SAEs), no new, emerging, drug related 
safety issues have been identified within the four week oral lead-in dosing period (e.g., 
hypersensitivity, Drug Reaction with Eosinophilia and Systemic Symptoms [DRESS], 
severe drug induced liver injury [DILI]) that would have precluded participants from 
proceeding to CAB LA + RPV LA injections during the Maintenance Phase of the 
studies.  Additionally, review of accumulating data has not identified any new safety 
issues occurring on CAB LA + RPV LA that were otherwise predictable based on oral 
exposure experience.
As a result of the accumulated safety data, which has been generated over the course of 
the Phase 1, 2 and 3 clinical studies, this amendment has been developed to generate 
safety, efficacy and PK data for the transition from oral ART to CAB LA + RPV LA 
without receiving an oral lead-in.  These data are intended to inform regulatory 
discussions around the safe and effective direct to inject dosing option with CAB LA + 
RPV LA.  The decision to dose with or without an oral-lead-in will be optional in this 
study, as elected by the study participant following informed consent discussions with the 
investigator.
At Week 124, a descriptive analysis will be conducted to assess antiviral response (HIV-1 
RNA 50 c/mL) for participants who choose no oral lead-in.  No formal statistical 
comparison will be performed with respect to safety and efficacy outcomes at Week 124.
Data from this optional oral lead in will provide valuable knowledge/insight into the 
evolution of the ‘direct to injection’ concept. 
2.2.
Brief Background

Various approaches to simplify a patient's antiretroviral therapy (ART) regimen, after 
achieving virologic suppression, have been studied.  Previous studies have evaluated 
switches to ritonavir-boosted PI monotherapy in virologically suppressed participants 
[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 

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option for the majority of participants studied who have effectively maintained 
virologic suppression. 

Other approaches have looked at two nucleoside reverse transcriptase inhibitors 
(NRTIs) with a ritonavir-boosted protease inhibitor (PI/r) compared to a PI/r + single 
NRTI.  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.  The primary endpoint was the proportion of participants without 
virologic failure at Week 48.  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 2b studies (LAI116482 [LATTE] and 200056 [LATTE-2]) have been 
conducted with oral CAB and/or intramuscular (IM) CAB 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) once daily 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 virologic 
suppression for the CAB groups compared with the EFV group (each p<0·001; log-rank 
test).  A planned Week 48 analysis (24 weeks of CAB + 2 NRTIs Induction, followed by 
24 weeks of CAB + RPV Maintenance) demonstrated that 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 participants and 39 (63%) of EFV plus dual NRTI participants 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%]).  

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The 200056 study (LATTE-2) evaluated a 20 week induction of HIV-1 RNA suppression 
with a three drug oral antiretroviral regimen consisting of CAB + ABC / 3TC Fixed Dose 
Combination (FDC) followed by randomization to a two-drug regimen consisting of 
intramuscular (IM) long-acting (LA) CAB LA + RPV LA compared to continuation of 
oral CAB + ABC / 3TC for the maintenance of HIV-1 RNA suppression.  A total of 309 
participants were enrolled and treated.
During the Induction Period there was a rapid and sustained decline in HIV-1 RNA, with 
91% of participants (282/309) achieving HIV-1 RNA <50 c/mL through 20 weeks of 
therapy.  There was a single participant (with known compliance issues) with confirmed 
virologic failure during the Induction Period.  Virologic testing revealed no treatment 
emergent phenotypic or genotypic resistance in this participant.
The primary endpoint for 200056 was the Week 32 proportion of participants with HIV-1 
RNA < 50 c/mL (Snapshot, Intent-to-Treat Maintenance Exposed population [ITT-ME]). 
Following virologic suppression on three drug oral therapy in the Induction Period, 
286 participants qualified to enter randomization at the Day 1 visit, and were 
subsequently randomized 2:2:1 onto every 4 week intramuscular (IM) injections with 
CAB LA + RPV LA (Q4W), every 8 week IM injections with CAB LA + RPV LA 
(Q8W) or continuation of oral CAB + NRTIs, respectively.  At the time of randomization 
at Day 1, participants entering one of the IM arms discontinued all oral ART. Through 
32 weeks of two-drug maintenance therapy, 95% (Q8W) and 94% (Q4W) of participants 
on injectable dosing were virologic successes, compared to 91% of participants 
continuing three drug oral CAB + NRTIs, meeting pre-specified criteria for comparability 
between the dosing arms. Through 32 weeks of Maintenance therapy, there was one 
participant each on Q8W and oral dosing with confirmed virologic failure (CVF), without 
any evolution of viral resistance. The CVF on Q8W dosing occurred following an 
aberrant RPV injection, without measurable plasma RPV concentrations 4 weeks post 
dosing.  
Week 48 data was a secondary endpoint for 200056, and permitted the evaluation of the 
two-drug long-acting combinations’ ability to maintain the virologic suppression 
demonstrated at Week 32.  At Week 48, 92% (Q8W) and 91% (Q4W) of participants 
receiving injectable dosing had a sustained virologic response (HIV-1 RNA <50 c/mL) 
compared to 89% of participants continuing oral CAB + 2 NRTIs.  Although the 
proportion of participants with virologic success was similar for Q8W and Q4W dosing, 
the reason for Snapshot failure was different between the arms.  There were more 
Snapshot failures for virologic reasons on the Q8W arm (n=8, 7%) than in the Q4W arm 
(n=1, <1%), and more participants with no virologic data (discontinued due to AE or 
other reasons) on the Q4W arm (n=9, 8%) compared to the Q8W arm (n=1, <1%).  
Between Week 32 and Week 48, one additional participant (Q8W) had confirmed 
virologic failure.  This participant had a Baseline HIV-1 RNA of 444,489 c/mL.  At 
Week 48, the participant was a suspected virologic failure with HIV-1 RNA = 463 c/mL.  
Upon retest, ten days later, the virologic failure was confirmed with HIV-1 RNA of 
205 c/mL.  At the time of CVF, this participant had treatment emergent NNRTI 
resistance K103N, E138G, and E238T, with high level phenotypic resistance to 
delaviridine (>MAX), efavirenz (48 fold change [FC]), nevirapine (>Max), and 

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rilpivirine (3.34 FC). The fold change to etravirine (1.91) was below the lower cutoff.
Week 48 integrase genotype had the treatment emergent integrase resistance mutation 
Q148R, with accompanying resistance to raltegravir (29 FC), elvitegravir (138 FC), and 
cabotegravir (6.06 FC). The Week 48 sample was not resistant to dolutegravir (1.38 FC).
Overall, AEs and clinical chemistries were similar to those observed in prior studies with 
CAB, without discernible trends between Q8W, Q4W, and oral. Injections were well 
tolerated with two participants discontinuing due to injection tolerability through 48 
weeks (both on Q8W dosing). The vast majority of injection site reactions were due to 
pain/discomfort with nearly all injection site reactions classified as mild (82%) or 
moderate (17%), with <1% of reactions classified as severe. There was no discernible 
tolerability difference between Q4W (2 mL) dosing and Q8W (3 mL dosing).  The most 
common non-ISR AEs during the Maintenance Phase were nasopharyngitis (24%), 
headache (16%), and diarrhea (13%) on IM arms and nasopharyngitis (30%), headache 
(11%), and diarrhea (5%) on oral CAB.  Through Week 48, SAEs during the 
Maintenance Period occurred in 7% of participants randomized to CAB LA + RPV LA 
and 5% of participants randomized to remain on oral treatment, none were drug related.  
Based on the data from the Week 48 endpoint, Q4W dosing was chosen to progress for 
further clinical development.
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 people with living with HIV.  
201584 (FLAIR) is being conducted in parallel with study 201585 with the aim to pool 
data generated from the current study with study 201585, 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 compared to continuation of 
ABC/DTG/3TC over 48 weeks in HIV-1 
antiretroviral naïve participants.

Proportion of participants with a ‘virologic 
failure’ endpoint as per FDA Snapshot 
algorithm at Week 48 (Missing, Switch or 
Discontinuation = Failure, 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 compared to 
continuation of ABC/DTG/3TC.

Proportion of participants with plasma HIV-1 
RNA <50 copies/mL (c/mL) at Week 48 
using the FDA Snapshot algorithm (Intent-
to-Treat Exposed [ITT-E] population).

Proportion of participants with plasma HIV-1 
RNA <200 c/mL at Week 48 using the FDA 
Snapshot algorithm (ITT-E population).

Proportion of participants with plasma HIV-1 
RNA <200 c/mL and HIV-1 RNA <50 c/mL 
at Week 96 using the FDA Snapshot 
algorithm (ITT-E population).

Proportion of participants with a ‘virologic 
failure’ endpoint as per FDA Snapshot 
algorithm at Week 96.

Proportion of participants with confirmed 
virologic failure at Week 48 and Week 96.

Absolute values and change from Baseline 
in plasma HIV-1 RNA at Week 48 and 
Week 96.

Absolute values and changes from Baseline 
in CD4+ cell counts over time including 
Week 48 and Week 96.

Incidence of disease progression (HIV-
associated conditions, acquired 
immunodeficiency syndrome [AIDS] and 
death).
To evaluate the safety and tolerability of 
switching to CAB LA + RPV LA every 4 weeks 
compared to continuation of ABC/DTG/3TC 
over time.

Incidence and severity of AEs and 
laboratory abnormalities over time including 
Week 48 and Week 96.

Proportion of participants who discontinue 
treatment due to AEs over time including 
Week 48 and Week 96.

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Objectives
Endpoints

Absolute values and changes in laboratory 
parameters over time including Week 48 
and Week 96.
To evaluate the effects of CAB LA + RPV LA 
every 4 weeks on fasting lipids over time 
compared to continuation of ABC/DTG/3TC 
over time.

Change from Baseline in fasting lipids over 
time including Week 48 and Week 96.
To assess the development of 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 and 
Week 96.
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 assess the acceptance of pain and injection 
site reactions following injections.

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).
To assess degree of health-related quality of life 
(HR QoL).

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 treatment satisfaction of CAB LA + 

Change from baseline in total “treatment 

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Objectives
Endpoints
RPV LA compared to continuation of 
ABC/DTG/3TC.
satisfaction” score, and individual item 
scores of the HIV Treatment Satisfaction 
Questionnaire (status version) (HIVTSQs) 
at Week 4b, Week 24, Week 44, Week 96 
(or Withdrawal).

Change in treatment satisfaction over time 
(using the HIVTSQ change version 
[HIVTSQc]) at Week 48 (or Withdrawal).
To assess 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 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 
injections at Week 5, Week 40, Week 41, 
and Week 96 using the Numeric Rating 
Scale (NRS) within the CAB LA + RPV LA 
arm.
To evaluate the antiviral and immunologic 
effects, safety and tolerability, and viral 
resistance of CAB LA + RPV LA at Week 124 
and over time for participants switching from 
ABC/DTG/3TC in the Extension Phase, with and 
without oral lead-in.

Proportion of participants with HIV-1 RNA 
50 c/mL at Week 124, with and without 
oral lead-in (FDA Snapshot algorithm, 
Extension Switch population).

Proportion of participants with plasma HIV-1 
RNA <50 c/mL and HIV-1 RNA <200 c/mL 
over time.

Proportion of participants with confirmed 
virologic failure over time.

Incidence of treatment emergent genotypic 
and phenotypic resistance to CAB and RPV 
over time.

Absolute values and change from Baseline 
in CD4+ cell counts over time.

Incidence and severity of AEs and 
laboratory abnormalities over time.

Proportion of participants who discontinue 

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Objectives
Endpoints
treatment due to AEs over time.

Absolute values and change in laboratory 
parameters over time.
To evaluate the pharmacokinetics of CAB and 
RPV in the setting of no oral lead-in for 
participants switching from ABC/DTG/3TC in the 
Extension Phase.

To evaluate plasma CAB and RPV 
concentrations over time (Week 100 [direct 
to inject without oral lead-in] and Week 104 
[both direct to inject and optional oral lead-
in participants])
Exploratory
To explore the effect of participant 
characteristics on the virologic and immunologic 
response of CAB LA and RPV LA compared to 
continuation of ABC/DTG/3TC.

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, and 96 using the Snapshot algorithm for 
the ITT-E population.

Proportion of participants by subgroup(s) 
(e.g. by age, gender, BMI, race, HIV-1 
subtype, Baseline CD4+) with plasma HIV-1 
RNA <50 c/mL at Week 48 and Week 96.

Change from Baseline in CD4+ cell counts 
by subgroups at Week 48 and Week 96.
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 receiving CAB LA and RPV LA 
compared to continuation of ABC/DTG/3TC 
over time.

Absolute values and change from Baseline 
in renal (in urine and blood) and bone (in 
blood) biomarkers over time including Week 
48 and Week 96.
To assess preference for CAB LA + RPV LA 
compared to oral antiretroviral (ARV) therapy 
using a single dichotomous preference 
question.

For participants randomized to the “CAB 
LA + RPV LA” arm, preference for CAB LA 
+ RPV LA compared to oral ARV regimen, 
at Week 48.
4.
STUDY DESIGN
4.1.
Overall Design
201584 (FLAIR) is a 120-week Phase 3, multi-phase, randomized, open label, active-
controlled, multicenter, parallel-group, non-inferiority study in HIV-1, ART-naïve adult 
participants.  Participants who fulfill eligibility requirements will enroll into the Induction 

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Phase of the study and receive ABC/DTG/3TC for 20 weeks (Week [-20] to Day 1).  
Participants who have an HIV-1 RNA <50 c/mL at Week (-4) will be randomized (1:1) 
into the Maintenance Phase at Day 1 to either continue ABC/DTG/3TC or to discontinue 
ABC/DTG/3TC 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).  ABC/DTG/3TC dosing on Day 1 should 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 ABC/DTG/3TC prior to coming into 
the clinic, randomization and initiation of oral CAB and RPV should continue as planned 
for Day 1.  Participants who are not eligible to continue into the Maintenance Phase will 
be withdrawn from the study.  At the Week 4a visit, assessments (including e.g. clinical 
chemistries) will be performed as per the Time and Events Table (Table 5).  At the 
Week 4b visit, 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 4b visit can be performed as soon as central laboratory 
results become 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 period 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.  The second and third IM injections (CAB LA 400 mg + 
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 injections 
occur within the window of Week 7 to Week 8, but not later than Week 8), and the third 
injections occur within the window of Week 11 to Week 12, but no later than Week 12.  
Subsequent injections (CAB LA 400 mg + RPV LA 600 mg) will occur every 4 weeks 
thereafter, with a 7 day dosing window being allowed (but not preferred).  In addition, 
starting at the Week 12 injection (third injection), the interval between injection visits 
should be limited to a maximum of 5 weeks.  If the length of time between injections 
exceeds, or is projected to exceed 5 weeks, the Medical Monitor must be contacted to 
discuss individual participant case management.  
Participants randomized to ABC/DTG/3TC during the Maintenance Phase will continue 
ABC/DTG/3TC for at least an additional 100 weeks.  Participants who successfully 
complete Week 100 (without meeting study defined withdrawal criteria and who remain 
virologically suppressed through Week 96:  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.  
The transition from ABC/DTG/3TC to CAB LA + RPV LA within the Extension Phase 
can be completed with or without an oral lead-in prior to commencement of injectable 
treatment.  The oral lead-in decision will be made by the participant in consultation with 
the investigator and must be appropriately documented.
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 will enter a 52 week Long-
Term Follow-Up Phase.  Participants must remain on suppressive highly active 

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antiretroviral therapy (HAART) for at least 52 weeks after the last dose of CAB LA 
and/or RPV LA.
In order to achieve balance across the two treatment arms, randomization will be 
stratified by participant’s Baseline HIV-1 RNA (<100,000, 100,000 c/mL) and gender at 
birth.  The primary endpoints for the study is the proportion of participants who meet the 
Snapshot virologic failure criteria at Week 48 (48 weeks of two drug maintenance 
treatment, 44 weeks of LA therapy).  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 comparison.  
Approximately 620 subjects will be enrolled into the Induction Phase of the study. 
Assuming 7.5% of enrolled participants will not participate in the Maintenance Phase, 
this will ensure approximately 570 participants continue into the Maintenance Phase.  
The sample size of 285 per arm (at Day 1 randomization) is such that the study has 
approximately 97% power to demonstrate non-inferiority in the proportion of participants 
with snaphot virologic failure at Week 48 using an 6% margin, assuming a true 3% 
failure rate for CAB and a 2% failure rate for the ABC/DTG/3TC control arm and using a 
2.5% one-sided alpha level.
An Independent Data Monitoring Committee (IDMC) will evaluate interim efficacy, 
tolerability and 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.  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 LA + RPV LA 
arm.  Additional details are provided in Section 9.3.3, and in the IDMC charter, which is 
available upon request.

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Figure 1
201584 (FLAIR) Study Schematic
¥Subjects who withdraw from IM CAB LA + RPV LA must enter the 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.
All participants will complete the Screening phase of up to 35 days prior to Baseline 
(Week [-20]) during which all clinical and laboratory assessments of eligibility must be 
performed and reviewed.  All Screening results must be available prior to enrolment.  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.  Similarly, if a central 
laboratory result cannot be generated for genotype/phenotype, a local result can be 
considered following review and approval by the study virologist.
Participants not meeting all inclusion and exclusion criteria at initial screen may be re-
screened one time with a new participant number.  Participants who are enrolled into the 
trial and subsequently withdrawn from the study, for any reason, may not be re-screened.  
Participants may be enrolled as soon as all eligibility requirements have been confirmed 
at the site.

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4.2.2.
Induction Phase
Following the Screening Phase, eligible participants will be enrolled into the study and 
begin a 20 week Induction Phase study on ABC/DTG/3TC (Week [-20] to Day 1). 
ABC/DTG/3TC dosing on Day 1 should 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 ABC/DTG/3TC prior to coming into 
the clinic, randomization and initiation of oral CAB and RPV should continue as planned 
on Day 1. 
4.2.3.
Eligibility for the Maintenance Phase
Participants with an undetectable HIV-1 RNA (<50 c/mL) at the Week (-4) visit are 
eligible to enter the Maintenance Phase.  A single repeat HIV-1 RNA test to determine 
eligibility may be allowed ONLY after consultation with the medical monitor.  
Participants with HIV-1 RNA 400 c/mL at Week (-4) are not eligible to enter the 
Maintenance Phase, will not be allowed a repeat to determine eligibility, and will 
therefore be withdrawn from the study.
Result of HIV-1 RNA at Week (-4)
Action
<50 c/mL
Begin Maintenance Phase at Day 1.
50 c/mL but <400 c/mL
Single repeat allowed only after consultation 
and approval from Medical Monitor.
Single repeat <50 c/mL
Begin Maintenance Phase at Day 1.
Single repeat 50 c/mL
Cannot begin Maintenance Phase and must be 
withdrawn from study; Complete withdrawal visit 
instead of Day 1.
400 c/mL
Cannot begin Maintenance Phase and must be 
withdrawn from study; Complete withdrawal visit 
instead of Day 1.
Should a participant be allowed a repeat, results of this repeat must be available prior to 
Day 1, therefore the time needed for scheduling the visit, lab draws and lab analysis 
should be considered.  
The Medical Monitor may advise the site to withdraw a participant from the study prior 
to Week (-4) if the participant is unlikely to be eligible for the Maintenance Phase.
Participants ineligible for the Maintenance Phase will be withdrawn.  
If the participant is ineligible for the Maintenance Phase, samples with a HIV-1 RNA 
>400 c/mL will be sent to a central laboratory for resistance testing and results provided 
to the Investigator once available.

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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 
Maintenance Phase.
4.2.4.
Maintenance Phase (Day 1 to Week 100)
At Day 1, the Maintenance Phase begins.  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 (Section 
7.1.), including clinical chemistries.  At the Week 4b visit, 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 Week 4b visit can be performed as soon as central laboratory 
results from the Week 4a visit become 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 period 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.  The second and third 
IM injections (CAB LA 400 mg + 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 injections occur within the window of Week 7 
to Week 8, but not later than Week 8), and the third injections occur within the 
window of Week 11 to Week 12, but no later than Week 12.  Subsequent 
injections (CAB LA 400 mg + RPV LA 600 mg) will occur every 4 weeks 
(monthly) thereafter, with a 7 day dosing window being allowed (but not 
preferred).  In addition, following the Week 12 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.  The dosing window (7 days) for injections after 
Week 12 is allowed, but also not preferred.  
OR

Continue on oral ABC/DTG/3TC initiated during the Induction Phase for at least 
an additional 100 weeks.  Participants who successfully complete Week 100 
(without meeting study defined withdrawal criteria and who remain virologically 
suppressed through Week 96:  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.

ABC/DTG/3TC dosing on Day 1 should 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 ABC/DTG/3TC prior 
to coming into the clinic, randomization and initiation of oral CAB and RPV 
should continue as planned on Day 1.

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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 between Day 1 and Week 4b, must be discussed with the 
Medical Monitor prior to initiation of CAB LA or RPV LA (See Section 7.4.5.13).
Participant randomization will be stratified by participants’ Baseline HIV-1 RNA 
(<100,000, 100,000 c/mL) and gender at birth.  
4.2.5.
Extension Phase
All eligible participants who transition into the Extension Phase 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.
Participants not eligible to enter the Extension Phase will end their study participation 
(Week 100 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.
4.2.5.1.
Participants Entering from the CAB LA + RPV LA Arm
All participants who successfully complete 100 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. See the Time and Events Table (Section 7.1) for more information.
4.2.5.2.
Participants Entering from the ABC/DTG/3TC Arm
Participants randomized to continue ABC/DTG/3TC 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 100 (no withdrawal visit needed). The 
transition from ABC/DTG/3TC to CAB LA + RPV LA within the Extension Phase can 
be completed with or without an oral lead-in prior to commencement of injectable 
treatment.  The participant’s decision will be taken in consultation with the investigator 
and must be appropriately documented. As participants approach the Week 100 visit, 
sites must ensure sufficient CAB and RPV supply are available to support the 
participant’s decision for transition to LA.
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 
ABC/DTG/3TC while eligibility is being confirmed.
All participants with an undetectable HIV-1 RNA (<50 c/mL) result from the Week 96 
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 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 with a 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 96 are not 

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eligible to enter the Extension Phase, will not be allowed a repeat to determine eligibility, 
and will therefore be withdrawn from the study.
Result of HIV-1 RNA at Week 96
Action
<50 c/mL
Begin Extension Phase at Week 100
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 at Week 100
Single repeat 50 c/mL
Cannot begin Extension Phase and must be 
withdrawn from study; Complete Week 100 visit 
(no withdrawal visit required)
400 c/mL
Cannot begin Extension Phase and must be 
withdrawn from study; Complete Week 100 visit 
(no withdrawal visit required)
Participants Transitioning Direct to Injection in the Extension Phase:  
Central lab results and safety parameters from the Week 96 visit must be available and 
reviewed for participants who choose to transition directly to injections.  Participants 
with ongoing safety issues or laboratory abnormalities of clinical concern (e.g. Grade 3 or 
Grade 4 liver chemistry elevations) will require consultation and agreement with the 
Medical Monitor prior to proceeding directly to injections in the Extension Phase.
If a clinical chemistry retest is required based on Week 96 labs, the retest should be 
performed as soon as possible (and preferably no later than 7 days following Week 96).
Participants will remain on oral ABC/DTG/3TC until the Week 100 injection visit, and 
until any required Week 96 retest results are available for review.
At Week 100, eligible participants will take the last dose of ABC/DTG/3TC (or DTG + 
2 NRTIs), and receive the first injections of CAB LA (600 mg) + RPV LA (900 mg) as 
initial loading doses.  Clinical chemistries will also be assessed at Week 100.  At 
Week 101, participants will return to the clinic for PK and safety assessments including 
clinical chemistries.  The second and third injections (CAB LA 400 mg + RPV LA 
600 mg) will be administered at Week 104a and Week 108.  There will be a one week 
dosing window for the second and third IM injections such that the second injections 
occur within the window of Week 103 to Week 104a, but not later than Week 104a, and 
the third injections occur within the window of Week 107 to Week 108, but no later than 
Week 108.  Subsequent injections (CAB LA 400 mg + RPV LA 600 mg) will occur 
every 4 weeks thereafter, from the projected visit date, with a (+ or -) 7 day dosing 
window being allowed (but not preferred).  Following the Week 108 injection, the 
interval between injection visits should be limited to a maximum of 5 weeks.  The 
Medical Monitor must be contacted if the length of time between injections exceeds, or is 
projected to exceed, 5 weeks.

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Participants Receiving Optional Oral Lead-In in the Extension Phase:
As participants approach the Week 100 visit, sites must ensure sufficient oral CAB and 
RPV are available for participants who choose to use the oral lead-in.
At Week 100, eligible participants who after discussion with the investigator, choose to 
receive the optional oral lead-in will initiate a 4 week lead-in of oral CAB 30 mg + oral 
RPV 25 mg once daily.  It is not necessary to dose ABC/DTG/3TC on the day the 
participant begins the oral lead-in with CAB + RPV.  However, if the participant takes 
ABC/DTG/3TC prior to coming into the clinic, initiation of oral CAB and RPV should 
continue as planned.  Clinical chemistries will be assessed at Week 100.  At Week 104a, 
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 104a visit must 
be available and reviewed before the Week 104b visit. If a clinical chemistry retest is 
required based on Week 104a labs, the retest should be performed as soon as possible 
(and preferably no later than 7 days following Week 104a). Participants will remain on 
oral CAB 30 mg + RPV 25 mg until the Week 104b injection visit, and until any required 
Visit 104a retest results are available for review.
At Week 104b visit, 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 Week 104b visit can be performed as 
soon as central lab results from the Week 104a visit become available and safety 
parameters are reviewed.  The second and third injections (CAB LA 400 mg + RPV LA 
600 mg) will be administered at Week 108 and Week 112.  There will be a one week 
dosing window for the second and third IM injections such that the second injections 
occur within the window of Week 107 to Week 108, but not later than Week 108, and the 
third injections occur within the window of Week 111 to Week 112, but no later than 
Week 112.  Subsequent injections (CAB LA 400 mg + RPV LA 600 mg) will occur 
every 4 weeks (monthly) thereafter, from the projected visit date, with a (+ or -) 7 day 
dosing window being allowed (but not preferred).  Following the Week 112 injection, the 
interval between injection visits should be limited to a maximum of 5 weeks.  If the 
length of time between injections exceeds, or is projected to exceed 5 weeks, the Medical 
Monitor must be contacted to discuss individual participant case management.
4.2.6.
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 highly active antiretroviral therapy (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 four weeks of the last injection.

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
The 52 weeks follow up phase will begin the day of the last CAB LA and/or RPV LA 
dose.  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 Table 
(Section 7.1.).   

Participants will be assessed with clinic visits at Months 1, 3, 6, 9 and 12.  Female 
participants of child bearing potential must continue to use adequate contraception 
methods for at least 52 weeks after the last injection. 

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 participating in the 
Long-Term Follow-Up Phase.  The participants’ last on study visit will be considered the 
withdrawal visit.
4.2.7.
Dose Modifications / Permitted Treatment Substitutions
Participants who are HLA-B*5701 positive at the Screening visit are allowed to enter the 
study on DTG and an approved dual-NRTI backbone that does not contain abacavir (e.g. 
tenofovir/emtricitabine [TDF/FTC] or tenofovir alafenamide/emtricitabine [TAF/FTC]).  
This regimen may be supplied regionally by GSK or reimbursement will be provided as 
needed. 
During the Induction Phase, prior to randomization into the Maintenance Phase at Day 1, 
one switch to an alternate approved background NRTI therapy is allowed for toxicity or 
tolerability management.  The date of a decision to switch the NRTI background therapy 
for toxicity or tolerability management must be documented in the eCRF.  Switches of a 
background NRTI for any other reason are not permitted in the study.  Local prescribing 
information should be consulted for information regarding use of these medications.
A short term bridging supply for participants on the CAB LA + RPV LA arm may be 
permitted following discussion with the Medical Monitor (see Section 6.8.1).
For consistency with prescribing information, dose reductions of lamivudine (or 
emtricitabine if used as alternate NRTI) are permitted in the context of renal insufficiency 
(throughout the study), e.g. as needed for creatinine clearance <50 mL/min.  

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If a dose reduction of lamivudine, a component of TRIUMEQ, is required for participants 
with creatinine clearance less than 50 mL/min, the individual entities should be used (e.g. 
DTG tablets, ABC tablets, 3TC tablets as separate medications, with dosing consistent 
with prescribing information).  DTG can be provided centrally through the study.  Single 
entity products will need to be sourced locally and can be reimbursed by the Sponsor as 
needed.  Lamivudine (3TC) dose reduction will be allowed throughout the study, and is 
not considered to be a “switch to an alternative approved background NRTI therapy”, but 
rather an alignment with prescribing information to maintain consistent 3TC plasma 
exposure for participants with renal insufficiency.
No other dose reductions, modifications, or changes in the frequency of any components 
of any regimen will be allowed during the Maintenance and Extension Phases of the 
study.
Protocol waivers or exemptions are not allowed.  Therefore, adherence to the study 
design requirements are essential and required for study conduct.
4.2.8.
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 (201584) and study 201585. 
An IDMC will evaluate accumulating efficacy, tolerability / safety, and PK of CAB LA + 
RPV LA at predetermined times during the study.  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 ABC/DTG/3TC 
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 criteria through Week 48 to ensure that participants are not being sub-
optimally treated in the CAB + RPV arm.
Additional ad hoc analyses may be scheduled if needed.  
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.
4.3.
Type and Number of Participants
Assuming a 20% screen failure rate, sufficient ART-naïve participants will be screened 
(approximately 775) in order to ensure that a total of approximately 620 participants are 
enrolled at the beginning of the Induction Phase.  Assuming 7.5% of enrolled participants 
will not participate in the Maintenance Phase (based on the rate of withdrawals observed 
during the Induction Period of study 200056), 620 participants enrolled into the Induction 

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Phase will ensure approximately 570 participants continue into the Maintenance Phase.  
Participants will be enrolled from multiple sites which may include sites in Canada, 
France, Germany, Italy, Japan, the Netherlands, Russia, South Africa, Spain, the UK, and 
the US.
Randomization will be stratified by participants’ Baseline HIV-1 RNA (<100,000, 
100,000 c/mL) and gender at birth.
A goal of this study is to enroll approximately 20% women who are typically under-
represented in clinical studies.  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 key study populations.
Participants who prematurely discontinue from the study will not be replaced.
4.4.
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 with virologic failure per Snapshot algorithm at Week 48 is the 
FDA recommended endpoint for switch design studies (Center for Drug Evaluation and 
Research, Human Immunodeficiency Virus-1 Infection: Developing Antiretroviral Drugs 
for Treatment, 2015).

Various approaches to simplify a participant's antiretroviral therapy (ART) regimen, 
after achieving virologic suppression, have been studied.  Previous studies have 
evaluated switches to ritonavir-boosted PI monotherapy therapy in virologically 
suppressed participants [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 virologic suppression. 
In addition, the 200056 (LATTE-2) clinical trial, evaluated a different simplification 
approach and served as proof of concept for 201584 (FLAIR).  In 200056, HIV-1 RNA 
suppression was induced with a three drug antiretroviral regimen consisting of CAB + 
ABC/3TC FDC, and then participants transitioned to a two-drug two-class regimen 
consisting of CAB LA + RPV LA for the maintenance of HIV-1 RNA suppression.  
Through 32 weeks on 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. During the Maintenance Period, there was 
one protocol confirmed virologic failure (CVF) on Q8W dosing and one CVF on oral 
dosing, without any evolution of resistance. The CVF on Q8W dosing occurred 

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following an aberrant RPV injection, without measurable RPV concentrations 4 weeks 
post dosing.  Overall AEs and clinical chemistries, were in line with 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 32 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 Week 48 data demonstrated similar virologic success between the Q4W and Q8W 
arms, with 92% (Q8W) and 91% of participants remaining suppressed (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, there were more Snapshot failures for virologic reasons on the Q8W arm 
(7%) compared to the Q4W arm (<1%), and more participants with Snapshot failure for 
non-virologic reasons (discontinued due to AE or other reasons) on the Q4W arm (8%) 
compared to the Q8W arm (<1%).  Additionally, between Week 32 and Week 48, one 
additional participant (Q8W) had confirmed virologic failure, with treatment emergent 
NNRTI (K103N, E138G, and E238T) and integrase (Q148R).  See Section 2 for 
additional information on this participant.
On the basis of these 200056 data, Q4W dosing was selected to progress into Phase 3 for 
further clinical development.
The open-label design for 201584 (FLAIR) best suits the objectives of this study.  A 
double-blind, double-dummy design for this study would result in an increased pill 
burden in all participants, a requirement for placebo injections across the comparator 
arms, elevated risk of oral ART non-adherence in participants receiving placebo 
injections, limitations to patient reported preference data comparing injectable and oral 
ART, as well as considerable trial design complexities.
A blinded design is also complicated by the requirement for an oral lead-in, in the CAB 
LA + RPV LA arm only.  Blinding the oral lead-in would require additional placebo pills 
for 5 weeks in the ART continuation arm, that otherwise would not be required.  
In addition to study design challenges, the impact of blinding in both studies carries the 
potential risk of oral regimen non-compliance, in participants on the ART continuation 
arm, who may believe that they are receiving active drug via injection (and therefore 
possibly increased risk of HIV 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.

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Due to the complexities, limitations and risks of blinding each switch study, both Phase 3 
studies are planned as open label studies.  
4.5.
Dose Justification
4.5.1.
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 
been administered to HIV-infected participants in both LATTE and 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 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 2b, 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 compared to efavirenz (EFV) 600 mg once daily with two NRTIs.  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 2b 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.  

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Table 1
LAI116482:  Proportion (95% CI) of Participants with Plasma HIV-1 
RNA <50 c/mL at Key Visits- Snapshot (MSDF) Analysis (ITT-E 
Population)
Visit
CAB
10 mg
N=60
CAB
30 mg
N=60
CAB
60 mg
N=61
CAB 
Subtotal
N=181
EFV 
600 mg
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 two NRTIs during the 24 week Induction Period.
95% CIs are normal approximation confidence intervals.
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 4.5.2, 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.  
The oral lead-in for participants randomized to the ABC/DTG/3TC arm who choose to 
receive CAB LA + RPV LA during the Extension Phase of the study is optional.  Without 
oral lead-in dosing, CAB LA and RPV LA achieve concentrations following their initial 
injections similar to induction doses of their respective efficacious oral products.  Oral 
ABC/DTG/3TC administered up to and including the day of the initial CAB LA + RPV 
LA injections will provide additional exposure to active antiviral agents during the 

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transition from oral to LA treatment (e.g., exposure that would replace oral CAB + RPV 
exposure).
4.5.2.
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 every 4 week 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 4.5.1, 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 Period (16 weeks of oral CAB + 
2 NRTIs, 4 weeks of CAB + 2 NRTIs + oral RPV).  Subjects who were eligible to 
continue into the Maintenance Period 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 
continue on their triple ART regimen.
The Q4W dosing strategy was selected for further investigation in Phase 3 based on the 
efficacy, safety and tolerability at Week 48, 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 subjects 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 subject, 
randomized to the Q8W regimen and one subject 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
LATTE-2:  Proportion (95% CI) of Subjects with Plasma HIV-1 RNA 
<50 c/mL at Week 48 - Snapshot (MSDF) Analysis (ITT-E Population)
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 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, 
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 CAB PK Parameters following Repeat Dose 
Administration of Cabotegravir LA to HIV-infected Subjects 
(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(Week 40 to Week 44) for Q4W (n=80) and AUC(Week 40 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 Week 24 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 Week 40 using 
troughs at Week 40, Week 44, and Week 48 for Q4W (n=98) and Week 16, Week 24, Week 32, Week 40 and 
Week 48 for Q8W (n=112).
e.
Tmax presented as median (range) in days, (Week 24 to Week 32:  n=97 Q4W arm, n=98, Q8W arm; Week 40 to 
Week 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 CAB 30 mg 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 RPV LA to HIV-infected Subjects (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 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(Week 40 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 Week 24 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 Week 40 using troughs at 
Week 36, Week 40, Week 44, and Week 48 for Q4W (n=102) and Week 40 and Week 48 for Q8W (n=100)
e.
Tmax presented as median (range), (Week 24 to Week 32: n=96 Q4W arm, n=97 Q8W arm; Week 40 to Week 
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 and C(following RPV 25 mg 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 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 have been optimized for the 
present study.  In LATTE-2, the Q4W dosing regimen for CAB LA included a 1st dose of 
800 mg (two 2 mL 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 600 mg 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 600 mg 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 Q4W thereafter = Study Week 4b, Week 8, and Q4W thereafter, 
respectively. 

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In summary, a modified Q4W 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 3 mL each, at doses of 
600 mg and 900 mg, respectively.  Subsequent injections of CAB LA and RPV LA will 
be 2 mL each, at doses of 400 mg and 600 mg, respectively (see also Section 4.5.3). 
4.5.3.
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.
4.5.3.1.
CAB LA
For CAB LA, the model included data from 416 subjects who received CAB LA as single 
or repeat administration, with approximately 50% of data obtained from 200056 
(LATTE-2), approximately 20% from 201120 (CAB LA PrEP study), and approximately 
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 PA-IC90, and 88% is predicted to achieve trough 
concentrations above the geometric mean trough following the 10 mg oral dose in 
LATTE of 1.35 g/mL (8x PA-IC90).  

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Figure 4
Simulated* Median (90% Prediction Interval [PI]) CAB Plasma 
Concentrations versus Time for the CAB LA Q4W Regimen (600 mg 
IM Day 1, then 400 mg IM Q4W thereafter^)
* Note: current simulations based on interim plasma concentration dataset
^Study Time and Events include a 4 week oral lead in.  Therefore, Day 1 = day of first injections (Week 4b study 
visit); Week 4 = second injections (Week 8 study visit)
Medium dashed line at 1.35 g/mL corresponds to the geometric mean Ctrough concentration following oral CAB 
10 mg once daily (LATTE) and is equivalent to 8x PA-IC90 
Dotted line at 0.664 g/mL corresponds to 4x PA-IC90 
Long dashed line at 0.166 g/mL corresponds to the PA-IC90.
At steady state, a one week delay in dosing of the Q4W regimen results in approximately 
15% reduction in median CAB trough.  With this delay, 95% are predicted to remain 
above 4x PA-IC90, and 79% are predicted to remain above the 10 mg oral target (Figure 
5).  Simulations including delays greater than one week have been explored (not shown), 
with <70% of subjects remaining above the 10 mg oral target.  Therefore, a 1-week delay 
is the maximum allowed per the protocol.  

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Figure 5
Impact of 1-week Delay in Dosing at Steady State (Week 40 delayed 
to Week 41) on Simulated* Median (90% PI) CAB Plasma 
Concentrations versus Time for the CAB LA Q4W regimen (600 mg 
IM Day 1, then 400 mg IM Q4W thereafter^)
* Note: current simulations based on interim plasma concentration dataset
^Study Time and Events include a 4 week oral lead in.  Therefore, Day 1 = day of first injections (Week 4b study 
visit); Week 4 = second injections (Week 8 study visit)
Medium dashed line at 1.35 g/mL corresponds to the geometric mean Cfollowing oral CAB 10 mg once daily  
(LATTE) and is equivalent to 8x PA-IC90 
Dotted line at 0.664 g/mL corresponds to 4x PA-IC90 
Long dashed line at 0.166 g/mL corresponds to the PA-IC90.
4.5.3.2.
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 
median RPV Cat Week 4 is 42 ng/mL, with >98% of participants above the RPV PA-
IC90.

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Figure 6
Simulated* Median (90% PI) RPV Plasma Concentrations versus 
Time Profile for the RPV LA Q4W regimen (900 mg IM Day 1, then 
600 mg IM Q4W thereafter^)
* Note: current simulations based on interim plasma concentration dataset
^Study Time and Events include a 4 week oral lead in.  Therefore, Day 1 = day of first injections (Week 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)
At steady-state, a one week delay in dosing for the Q4W regimen is predicted to result in 
a median steady-state Cthat remains above the median trough for RPV 25 mg (Figure 
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 25 mg once daily in LATTE-2 (oral lead-in) 
and is similar to median RPV Cin other studies in HIV-infected patients (LATTE, ECHO/THRIVE)
4.6.
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 Brochures (GlaxoSmithKline 
Document Number RH2009/00003/07; 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 Prescribing Information, 2018).  

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ABC/DTG/3TC is an established regimen that has been in clinical use for several years 
and has an established benefit/risk profile described in detail in the DTG IB 
(GlaxoSmithKline Document Number RM2007/00683/11) and respective country 
product labels (TRIUMEQ Prescribing Information, 2018).
A potential safety issue related to neural tube defects in infants born to women with 
exposure to dolutegravir (DTG) at the time of conception has been recently identified as 
noted below:
Potential Risk
of Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [ABC/DTG/3TC, DTG]
Refer to DTG IB and country product labels for additional information
DTG: Neural 
tube defects
In one ongoing birth outcome surveillance
study in Botswana, early results from an 
unplanned interim analysis show that 4/426 
(0.9%) of women who were taking DTG 
when they became pregnant had babies 
with neural tube defects compared to a 
background rate of 0.1%.
1. A female subject is eligible to 
participate if she is not pregnant, 
not lactating, and, if she is a 
female of reproductive potential, 
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) from 30 days 
prior to the first dose of study 
medication 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.
2. Women who are breastfeeding or 
plan to become pregnant or 
breastfeed during the study are 
excluded;
3. Women who become pregnant, 
or who desire to be pregnant 
while in the study will have study 
treatment discontinued and 
withdrawn from the study.
4. Females of reproductive potential 
are reminded re: pregnancy 
avoidance and adherence to 
contraception requirements at 
every study visit.
5. Pregnancy status is monitored at 
every study visit
The most significant toxicity associated with ABC is the well-characterized drug-related 
hypersensitivity reaction (HSR).  Studies have shown that carriage of the HLA-B*5701

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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 
participants, 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., TRIUMEQ, ZIAGEN, EPZICOM / KIVEXA 
or TRIZIVIR) if a HSR cannot be ruled out on clinical grounds, due to the potential for a 
severe or even fatal reaction.
A detailed clinical description of this reaction (including the type and severity of events 
that can occur on re-challenge or reintroduction following ABC interruption for non-HSR 
reasons) and guidance regarding its management are included in the Local Country 
Prescribing Information for TRIUMEQ (or EPZICOM if TRIUMEQ is not available 
within country).  
Mitigation for ABC HSR:  Every potential participant will be screened for the carriage 
of the HLA-B*5701 allele.  Participants who are HLA-B*5701 positive at the Screening 
visit are allowed to enter the study on a dual-NRTI backbone that does not contain 
abacavir (see Section 6.8).
The following section outlines the risk assessment and mitigation strategy for CAB and 
RPV in this protocol.

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4.6.1.
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.
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Drug Induced Liver Injury
A small proportion of participants in the CAB 
program to date (total exposure >3100 participants) 
have developed transaminitis (elevated liver 
transaminases characterised by predominant ALT 
elevation).  In some of these participants’ transient 
transaminitis were explained by acute hepatitis C 
infection and whilst a small number of others did not 
have alternative explanations, suggesting a mild form 
of DILI without hepatic dysfunction which resolved 
upon withdrawal of treatment with CAB. 
Of the four participants with possible or probable 
cases of DILI identified in Phase 2 studies, all were 
receiving oral CAB.

Exclusion criteria as described in Section 5.2
will prohibit participants with significant liver 
impairment based on screening liver chemistry 
including transaminases (ALT and 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 period was
implemented at the beginning of this study, 
where all participants will receive oral CAB 
prior to the administration of CAB LA to 
determine individual safety and tolerability.  
During the Extension Phase of the study, 
following review of available oral lead-in and 
Maintenance Phase safety data, the protocol 
was amended to allow an optional oral lead-in 
for the participants transitioning from 

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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
ABC/DTG/3TC to CAB LA+RPV LA.

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 7.4.5.1 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 ULN 
while on study must consult with Medical 
Monitor prior to initiation or continuation of 
CAB LA.  

All instances of liver transaminase elevations 
of Grade 2 and above will be followed to 
resolution.  Participants withdrawn from CAB 
treatment due to meeting liver chemistry 
stopping criteria will be regularly monitored 
both clinically and using liver chemistries to 
determine progress towards resolution of the 
liver event.

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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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 receiving multiple injections. 
Although some Grade 3 ISRs were reported, the 
majority of ISRs 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 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 will be given 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.

Specialist dermatology consultation will be 
sought if warranted for individual participants.
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, 

The risk of developing a hypersensitivity 
reaction post administration of CAB LA was  
minimized at the start of the study by the use 
of a mandatory 4-week oral lead-in of CAB to 
determine individual safety and tolerability 

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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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 
CAB LA. The long exposures anticipated after CAB 
LA injection may complicate the management of a 
drug hypersensitivity reaction, were it to occur.
prior to the introduction of CAB LA. During 
the Extension Phase of the study, following 
review of available oral lead-in and 
Maintenance Phase safety data, the protocol 
was amended to allow an optional oral lead-in 
for the participants transitioning from 
ABC/DTG/3TC to CAB LA+RPV LA.

Clinical assessments, laboratory tests 
(including liver transaminases) and vital signs 
will be performed throughout this study (refer 
to Time & Events Table).  Results from these 
assessments may aid early detection of HSR.

Oral CAB will be withdrawn immediately for 
cases with suspected HSR during the oral 
lead-in phase.  During oral and CAB LA 
treatment, any HSR reactions that occur 
would be managed supportively

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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Development of 
Resistance following 
discontinuation of CAB 
LA
Residual concentrations of CAB would remain in the 
systemic circulation of participants for prolonged 
periods (more than 1 year in some participants, 
GlaxoSmithKline Document Number 
2016N269422_00, Study 201120) 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. 

Alternative oral HAART regimens will be 
prescribed within four weeks after participants 
stop CAB LA.  This would be anticipated to 
result in rapid resuppression of HIV-1 RNA 
thus minimizing of the risk of emergent 
resistance.

The participants in this study who discontinue 
CAB LA for any reason will be monitored for 
a minimum of 52 weeks from the time of the 
last CAB LA injection.
Drug-Drug Interactions 
(DDIs)
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

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
-
the antimycobacterials rifampicin, 
rifampin, 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.
Residual concentrations of CAB could remain in the 
systemic circulation of participants who stopped 
treatment (e.g. for tolerability issues or treatment 
failure) for prolonged periods (months).  
Participants discontinuing a LA regimen may be at 
risk for developing DDIs many weeks after 
discontinuing injectable therapy.  

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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 
CAB LA can be inadvertently administered 
intravenously instead of intramuscularly resulting in 
higher than expected concentrations of CAB.  This 
could be due to administrator error, improper 
injection technique and / or improper needle length 
used based on body type.
The clinical consequences of overdose with CAB are 
currently unknown. HIV-1 viral suppression may not 
be effective following accidental maladministration.

Training will be provided to all sites on proper 
injection technique.  

Should IM maladministration be suspected at 
any time (e.g., suspected under or overdose or 
inadvertent IV dosing), a PK sample, post 
dose ECG, vital signs or any other supportive 
testing may be obtained at the discretion of the 
investigator, and the Medical Monitor 
notified.  

Laboratory samples for safety parameters and 
HIV-1 RNA will be closely monitored in all 
participants.  Additionally, 2 hour post dose 
PK samples will be obtained at a few 
timepoints (Week 4b; Week 48; Week 96; 
Week 104b [participants transitioning from 
ABC/DTG/3TC]) 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.

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ORAL RPV
For safety and risk mitigation for oral RPV refer to the RPV prescribing information [Edurant Prescribing Information, 2018].  
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:
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, the majority of 
ISRs have not, to date, been associated with an excess of 
participants’ withdrawal due to ISRs.

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 

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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
infections (abscess, cellulitis) and 
collections of fluid requiring drainage 
will be monitored.

Specialist dermatology consultation 
will be sought if warranted for 
individual participants.
Rash
Some observations of rash with oral RPV have been reported 
in clinical studies executed to date (the majority are Grade 1 
or Grade 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.

At the beginning of this study, RPV 
LA administration was preceded by a 
four week oral RPV lead-in to 
evaluate safety and tolerability in 
individual participants.  During the 
Extension Phase of the study, 
following review of available oral 
lead-in and Maintenance Phase safety 
data, the protocol was amended to 
allow an optional oral lead-in for the 
participants transitioning from 
ABC/DTG/3TC to CAB LA+RPV 
LA.

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.

Participants experiencing a grade 3 or 

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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
4 rash should discontinue their ART 
medication and will be withdrawn 
from the study.

All rash events should be assessed 
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.
Development of 
Resistance
Residual concentrations of RPV can remain in the systemic 
circulation of participants who stopped treatment (e.g. for 
tolerability issues or treatment failure) for more than one year 
in some participants [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 four weeks 
after participants stop RPV LA.  This 
would be anticipated to result in rapid 
resuppression of HIV-1 RNA thus 
minimizing of 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 

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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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 and 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 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.
Residual concentrations of RPV could remain in the systemic 
circulation of participants who stopped treatment (e.g. for 
tolerability issues or treatment failure) for prolonged periods 
(months).

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
Participants discontinuing a LA regimen may be at risk for 
developing resistance to RPV many weeks after 
discontinuing injectable therapy. 
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.  
The clinical consequences of overdose with RPV LA are 
currently unknown.  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), a PK sample, post dose ECG 
monitoring and vital signs or any 
other supportive testing may be 
obtained at the discretion of the 
investigator, and the Medical Monitor 
notified.

Laboratory samples for safety 
parameters and HIV-1 RNA will be 
closely monitored in all participants.  
Additionally, 2 hour post dose PK 
samples will be obtained at a few 
timepoints (Week 4b; Week 48; 
Week 96; Week 104b [participants 
transitioning from ABC/DTG/3TC]) 
for determination of RPV 
concentration and possible 
pharmacokinetic correlation with 
safety parameters such as ECG 
changes and virologic response.  

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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Additionally, an unscheduled PK 
sample may be drawn approximately 2 
hours post dosing for future evaluation 
of RPV concentrations.
Study Procedures
Risks of complications 
from venipuncture for 
blood sampling
Complications from with venipuncture include swelling, 
bleeding, bruising and infection 

These risks will be minimized using 
current standard of care techniques for 
venipuncture.
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.

ECGs will be conducted by appropriately 
trained personnel and effort made to 
minimise contact time for application of 
the pads.
Other
Risk of Treatment 
Failure
This study employs a novel maintenance approach to the 
treatment of HIV-1 infection.  Following virologic 
suppression, participants will be transitioned off of a 3 drug 
ART regimen to a 2 drug LA ART regimen that remains 
experimental.  CAB and RPV have demonstrated antiviral 
activity in the Phase 2b studies LAI116482 (oral two drug 
treatment) and 200056 (two drug LA treatment).  
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 

HIV-1 RNA will be closely monitored 
throughout the study. 

Plasma samples will be collected 
throughout the Maintenance Phase for 
determination of CAB and RPV 
concentration and possible 
pharmacokinetic correlation with 

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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
formulations and LA data from 200056.  
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.  
virologic response.  

HIV-1 RNA will be closely monitored 
throughout the study. 

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4.6.2.
Other Clinically Relevant Information
Additional details concerning safety observations from clinical studies and for which a 
causal association has not been established or which are of minimal clinical significance 
may be found in the Investigator’s Brochure (please refer to Section 6 of the IB: 
‘Summary of Data and Guidance for the Investigator.’)
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.
4.6.3.
Benefit Assessment
The antiviral activity of CAB against HIV-1 has been well established through Phase 2a 
and Phase 2b studies.  RPV is an established antiviral agent against HIV-1 in treatment 
naive participants, with long term durability (>96 weeks in Phase 3 and >240 weeks in 
Phase 2b).
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 Q4W dosing without the need to take concomitant daily 
oral therapy.  Adherence in these participants is expected to be improved and will be 
directly observed.  Efficacy of the two-drug regimen, as oral agents, has been 
demonstrated through Week 96 of the ongoing LAI116482 study.  Efficacy of the two-
drug regimen, as LA agents, has been demonstrated through Week 32 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.
4.6.4.
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 the CAB + RPV are justified 
by the anticipated benefits that may be afforded to study participants switching to a Long-
Acting, NRTI-sparing regimen.

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5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the investigational product or other study treatment 
that may impact participant eligibility is provided in the current Investigator Brochures 
for CAB (GlaxoSmithKline Document Number RH2009/00003/07) and RPV (RPV IB, 
2017), and the RPV product label (Edurant Prescribing Information, 2018).  Information 
for ABC/DTG/3TC or DTG is provided in the current DTG IB (GlaxoSmithKline 
Document Number: RM2007/00683/11) and US or country product label (TRIUMEQ
Prescribing Information, 2018; TIVICAY Prescribing Information, 2017).
5.1.
Inclusion Criteria
Deviations from inclusion criteria are not allowed because they can potentially jeopardise 
the scientific integrity of the study, regulatory acceptability or participant safety.  
Therefore, adherence to the criteria as specified in the protocol is essential.
In general, participants screened for this study must:

be able to understand and comply with protocol requirements, instructions, and 
restrictions, 

be likely to complete the study as planned, 

understand the long term commitment to the study,

and be considered appropriate candidates for participation in an investigative 
clinical trial with oral and intramuscularly injectable medications (e.g., no active 
substance abuse, acute major organ disease).
Laboratory results from the central laboratory services provided by this trial will be used 
to assess eligibility.  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.  Similarly, if a central laboratory result cannot be generated for 
genotype/phenotype, a local result can be considered following review and approval by 
the study virologist.
Participants are allowed to re-screen for this study one time.  This will require a new 
participant number.
The following are study specific eligibility criteria unless stated otherwise.  In addition 
to these criteria, Investigators must exercise clinical discretion regarding selection of 
appropriate study participants, taking into consideration any local treatment 
practices or guidelines and good clinical practice (GCP).  All participants must be 
considered appropriate candidates for initiation of antiretroviral therapy in 
accordance with local treatment guidelines.

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Participants eligible for enrolment in the study must meet all of the following criteria:
AGE
HIV-1 infected, ART-naive men or women aged 18 years or greater at the time of signing 
the informed consent.
TYPE OF PARTICIPANT AND DIAGNOSIS INCLUDING DISEASE SEVERITY 
HIV-1 infection as documented by Screening plasma HIV-1 RNA 1000 c/mL;
Antiretroviral-naïve (10 days of prior therapy with any antiretroviral agent following a 
diagnosis of HIV-1 infection).  Any previous exposure to an HIV integrase inhibitor or 
non-nucleoside reverse transcriptase inhibitor will be exclusionary.
SEX
Female Participants:
A female participant is eligible to participate if she is not pregnant at Screening and first 
day of Induction Phase (as confirmed by a negative serum human chorionic 
gonadotrophin [hCG] test), 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 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 Appendix 7.) 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.
ALL participants in the study should be counseled on safer sexual practices including 

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the use and benefit/risk of effective barrier methods (e.g., male condom) and on the risk 
of HIV transmission to an uninfected partner.
INFORMED CONSENT
Capable of giving signed informed consent as described in Section 6.2 which includes 
compliance with the requirements and restrictions listed in the consent form and in this 
protocol.
OTHER
French participants: In France, a participant will be eligible for inclusion in this study 
only if either affiliated to or a beneficiary of a social security category.
5.2.
Exclusion Criteria
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardise 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 Medical Conditions 
a.
Women who are pregnant, breastfeeding, or plan to become pregnant or breastfeed 
during the study.
b. Any evidence at Screening of an active Centers for Disease and Prevention Control 
(CDC) Stage 3 disease [CDC, 2014], except cutaneous Kaposi’s sarcoma not 
requiring systemic therapy or historic or current CD4+ cell count <200 cells/mm3 are 
not exclusionary (local guidelines dictate).
Participants with known moderate to severe hepatic impairment.
Any pre-existing physical or mental condition (including substance abuse 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.
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. 
Participant who, in the investigator's judgment, poses a significant suicide risk.  
Participant’s recent history of suicidal behavior and/or suicidal ideation should be 
considered when evaluating for suicide risk.
The participant has a tattoo or other dermatological condition overlying the gluteus 

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region which may interfere with interpretation of injection site reactions.
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.
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 prior to 
Week 48 of the Maintenance Phase 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, HCV 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 is inconclusive, 
the Fib-4 score will be used to verify eligibility.  

A 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 (√ALT))
Unstable liver disease (as defined by any of the following:  presence of ascites, 
encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or 
persistent jaundice), known biliary abnormalities (with the exception of Gilbert's 
syndrome or asymptomatic gallstones or otherwise stable chronic liver disease per 
investigator assessment). 
History of liver cirrhosis with or without hepatitis viral co-infection.
Ongoing or clinically relevant pancreatitis.
All participants will be screened for syphilis (rapid plasma reagin [RPR]). Participants 
with untreated syphilis infection, defined as a positive RPR without clear documentation 

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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.
Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or 
resected, non-invasive cutaneous squamous cell carcinoma, or cervical, anal or penile 
intraepithelial neoplasia; other localized malignancies require agreement between the 
investigator and the study Medical Monitor for inclusion of the participant prior to 
enrolment.
Any condition which, in the opinion of the Investigator, may interfere with the 
absorption, distribution, metabolism or excretion of the drug or render the participant 
unable to receive study medication.
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.
Current or anticipated need for chronic anti-coagulation.
Alanine aminotransferase (ALT) 3 times ULN.  
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.
CONCOMITANT MEDICATIONS
Exposure to an experimental drug and/or experimental vaccine within 28 days or 5 half-
lives of the test agent, or twice the duration of the biological effect of the test agent, 
whichever is longer, prior to the first dose of IP.
Treatment with any of the following agents within 28 days of Screening:

radiation therapy

cytotoxic chemotherapeutic agents

tuberculosis (TB) therapy, with the exception of treatment of latent TB with 
isoniazid

Immunomodulators that alter immune responses (such as chronic systemic 
corticosteroids, interleukins, or interferons).  Note: Participants using short-term 
(e.g. 21 day) systemic corticosteroid treatment; topical, inhaled or intranasal 
corticosteroids are eligible for enrolment.
Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening.
Treatment with any agent, except recognized ART as allowed above, with documented 
activity against HIV-1 within 28 days of the first dose of IP.
Use of medications which are associated with Torsades de Pointes (See SPM for a list of 
relevant medications).

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DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
Any evidence of primary resistance to NNRTIs (except for K103N which is allowed), or 
any known resistance to INIs from historical resistance test results (International 
AIDS Society [IAS]-USA, 2015).  Note:  re-tests of Screening genotypes are allowed 
only at the discretion of the study virologist.
Participants who are HLA-B*5701 positive and are unable to use an NRTI backbone that 
does not contain abacavir (participants who are HLA-B*5701 positive may be enrolled if 
they use a NRTI backbone that does not contain abacavir; HLA-B*5701 positive 
participants may be excluded from the study if local provision of an alternate NRTI 
backbone is not possible).
Any verified Grade 4 laboratory abnormality.  A single repeat test is allowed during the 
Screening Phase to verify a result.
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.
Participant has estimated creatinine clearance <50 mL/min/1.73m2 via the Chronic 
Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (Levey, 2009).
Participants who are currently participating in or anticipate to be selected for any other 
interventional study. 
5.3.
Screening/Baseline/Run-in Failures
Screen failures are defined as participants who consent to participate in the clinical trial 
but are never subsequently enrolled or 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 7.4.3.6).
5.4.
Withdrawal/Stopping Criteria
Participants permanently discontinuing study treatments prior to Week 100 are 
considered to be withdrawn from the study treatments.  Similarly, participants 
permanently discontinuing participation from the Extension Phase prior to commercially 
available CAB LA + RPV LA drug supply are considered to be withdrawn from the study 
treatments, and will move directly into the Long-Term Follow-Up Phase.  Participants 
permanently discontinuing participation from the Long-Term Follow-Up Phase are 
considered to be withdrawn from the study treatments and from the study.
A participant may withdraw consent and discontinue participation in this study at any 
time.  The Investigator may also, at their discretion, discontinue the participant from 
participating in this study at any time (e.g., safety, behavioral 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.  Participants who 
are withdrawn from the study will not be replaced.

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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.
Reasons for study withdrawal may include:

Adverse event / Serious adverse event

Protocol deviation

Intolerability of injections

Participant lost to follow-up

Participant withdrew consent

Investigator discretion

Participant or investigator non-compliance

Termination of the study by the Sponsor

At the request of the participant, Investigator, GSK, or ViiV Healthcare

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 withdrawn 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.

Participants who cannot or do not wish to continue on to the Long-Term Follow Up 
Phase.

Confirmed virologic failure.

Pregnancy (intrauterine), regardless of termination status of the pregnancy.  (If 
receiving CAB LA + RPV LA, the participant would discontinue LA study treatment 
and continue to be followed in the Long-Term Follow-Up Phase.)  As a reminder, 
females of reproductive potential who changed their minds and desire to be 
pregnant, or who state they are no longer willing to comply with the approved 
pregnancy avoidance methods, should also be withdrawn from the study.

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
Participant requires a second switch or a dose adjustment of any component of the 
ABC/DTG/3TC (with exception of dose reduction for renal insufficiency as noted in 
Section 4.2.7).  A substitution for NRTI backbone is allowed at Screening, e.g. 
ABC/3TC to TDF/FTC or TAF/FTC for participants who are HLA-B*5701 positive. 
During the Induction Phase, prior to randomization into the Maintenance Phase at 
Day 1, one switch to an alternate approved background NRTI therapy is allowed for 
toxicity or tolerability management.  

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).

Grade 4 clinical AE or toxicity in the absence of compelling evidence that the AE is 
not causally related to the IP.

Liver toxicity where Stopping Criteria are met and no compelling alternative cause is 
identified (See Section 5.4.1).

Renal toxicity is met and no compelling alternate cause is identified.

Participant has a Grade 3 or higher rash or Grade 2 rash with evidence of systemic 
involvement.

The following QT criteria:

Corrected QT interval (QTc) >550 msec considered causally related to IP (See 
Section 5.4.2).
This criterion must be based on the average QTc value of triplicate ECGs.  For example, 
if an ECG demonstrates a prolonged QT interval, obtain two more ECGs over a brief 
Phase, and then use the averaged QTc values of the three ECGs to determine whether the 
participant should be discontinued from the study.  
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 (Table 5) 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) 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.   

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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”. 
5.4.1.
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.

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).

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
ALT ≥5xULN but <8xULN and cannot be monitored weekly for >2 weeks.
5.4.1.1.
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 critera is met, do the following:

Immediately hold IP.  If receiving 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, Table 7).

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);
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;

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
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 eCRF 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.
5.4.1.2.
Liver Event Adjudication Committee
A liver safety panel will be used to evaluate all subjects 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 analyses, estimated timing and the decision criteria will be pre-
specified in an Adjudication Committee Charter.
5.4.1.3.
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.

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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.
Drug Restart Following Transient Resolving Liver Events Not Related to IP
Approval by the VSLC for drug restart or additional IM administration can be considered 
where:

Liver chemistries have a clear underlying cause (e.g., biliary obstruction, 
hypotension and liver chemistries have improved to normal or are within 
1.5 x baseline and ALT <3xULN).  Ethics Committee or Institutional Review 
Board approval of drug restart/rechallenge must be obtained, as required.

If restart of drug or continuation of LA dosing is approved by the VSLC in 
writing, the 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 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.  

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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.
5.4.2.
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.  
5.4.3.
Virologic Failure
Following randomization into the Maintenance Phase, no changes, or intensification of 
ART will be permitted prior to protocol-defined virologic failure (one switch allowed 
during Induction Phase for toxicity / tolerability management – See Section 6.8).  Only 
plasma HIV-1 RNA values determined by the central laboratory will be used to assess 
virologic failure.  Baseline plasma HIV-1 RNA is the assessment completed on the first 
day of the Induction Phase.  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 potential emergence of virologic resistance only. 
5.4.4.
Definition of Virologic Failure
For the purposes of clinical management in this study, virologic failure is defined as any
of the following:

Non-response as indicated by a less than a 1.0 log10 copies/mL decrease in plasma 
HIV-1 RNA after 4 weeks of starting the Induction Phase, which is subsequently 
confirmed, unless the plasma HIV-1 RNA is < 400 c/mL (Induction Phase 
criteria).

Rebound as indicated by two consecutive plasma HIV-1 RNA that are > 0.5 log10
c/mL increase in plasma HIV-1 RNA from the nadir value on study, where the 

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lowest HIV-1 RNA value is 200 c/mL (Induction Phase criteria).

Rebound as indicated by two consecutive plasma HIV-1 RNA levels 200 c/mL 
after prior suppression to < 200 c/mL. 
5.4.5.
Managing Virologic Failure
Inadequate adherence is a common cause for virologic failure, and should be explored as 
a first step in the management of study participants (e.g., at the first indication of 
inadequate virologic response or rebound).
5.4.5.1.
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 key analysis 
timepoints (Week 48, Week 96) must return to the clinic as soon as possible (but no more 
than 4 weeks from 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 (e.g. if additional injections should be 
administered).
5.4.5.2.
Suspected Virologic Failure
Upon notification that a participant’s HIV-1 RNA plasma level meets any of the 
definitions of suspected virologic failure, the Investigator should confirm the definition is 
met by initiating a repeat of the HIV-1 RNA assessment.  
The following guidelines should be followed for scheduling confirmatory HIV-1 RNA 
testing in an effort to avoid false-positive results: 

Confirmatory testing should be scheduled 2 to 4 weeks following resolution of 
any intercurrent illness, during which time the participant should receive full dose 
of all IP.

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
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.
5.4.5.3.
Confirmed Virologic Failure
Participants who have confirmed virologic failure must be discontinued from the 
Induction, Maintenance or Extension Phase of 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 4.2.6).
A plasma sample from the suspected virologic failure visit as well as the first day of the 
Induction Phase (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.
5.5.
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. 
Participants are considered to have completed the study if they satisfy one of the 
following: 

Randomly assigned to either treatment group, completed the randomized 
Maintenance Phase including the Week 100 visit, and did not enter the Extension 
Phase;

Randomly assigned to either treatment group, completed the randomized 
Maintenance Phase including the Week 100 visit, and entered and completed the 
Extension Phase (defined as remaining on study until commercial supplies of 

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CAB LA + RPV LA become locally available or development of CAB LA + RPV 
LA is terminated).
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 Long-Term 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 ABC/DTG/3TC with ongoing AEs, 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.
In this study, investigational product (IP) refers to oral ABC/DTG/3TC single tablet 
regimen (or alternately DTG), oral CAB, and CAB LA, which will be supplied by 
GlaxoSmithKline and oral RPV and RPV LA which will be supplied by Janssen 
Pharmaceuticals.  The dual NRTI background therapy that is administered with single 
entity DTG is not considered IP.
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 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.

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6.1.1.
Cabotegravir (CAB) – Tablet
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 according to the 
product label.
CAB Tablet is composed of cabotegravir sodium, lactose monohydrate, microcrystalline 
cellulose, hypromellose, sodium starch glycolate, magnesium stearate, and white film-
coat.  The white film-coating contains hypromellose, titanium dioxide and polyethylene 
glycol.
6.1.2.
Rilpivirine (RPV) - Tablet
RPV [Edurant Prescribing Information, 2018) is provided by Janssen Research & 
Development, LLC, a division of Janssen Pharmaceuticals as 25 mg tablets that are off-
white, round, biconvex, film-coated and debossed on one side with “TMC” and the other 
side with “25”. RPV is manufactured by Janssen -Cilag S.p.A, Latina, Italy. RPV will 
be provided as globally marketed product, including US and the European Union.  RPV 
will be overlabeled and packaged in bottles of 30 tablets.  RPV tablets are to be stored 
according to the product label.
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.
6.1.3.
Cabotegravir – Injectable Suspension (CAB LA)
CAB LA is manufactured by GlaxoSmithKline and is a sterile white to slightly pink 
suspension containing 200 mg/mL of CAB as free acid for administration by 
intramuscular (IM) injection.  The product is packaged in a 3 mL USP Type I glass vial 
with a 13 mm gray stopper and aluminium seal.  Each vial is for single-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 according to the product 
label.
CAB LA is composed of cabotegravir free acid, polysorbate 20, polyethylene glycol 
3350, mannitol, and water for injection.
6.1.4.
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 

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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 
aluminium 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 stored 
according to the product label and should 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.
6.1.5.
ABC/DTG/3TC STR - Tablet
ABC/DTG/3TC STR is manufactured by GlaxoSmithKline.  Each film-coated tablet 
contains abacavir sulphate equivalent to 600 mg of abacavir, dolutegravir sodium 
equivalent to 50 mg dolutegravir, and 300 mg of lamivudine.  ABC/DTG/3TC tablets are 
purple, biconvex, oval, debossed with “572 Tri” on one side.  ABC/DTG/3TC will be 
packaged in bottles of 30 tablets.  ABC/DTG/3TC should be stored and dispensed in the 
original container, protected from moisture, are packaged with a desiccant which should 
not be removed.  ABC/DTG/3TC tablets are to be stored according to the product label.
The inactive ABC/DTG/3TC tablet ingredients include D-mannitol, magnesium stearate, 
microcrystalline cellulose, povidone, and sodium starch glycolate.  The tablet film-
coating contains the inactive ingredients iron oxide black, iron oxide red, macrogol/PEG, 
polyvinyl alcohol – part hydrolyzed talc, and titanium oxide.
6.1.6.
Dolutegravir (DTG) – Tablet
Dolutegravir is manufactured by GlaxoSmithKline and will be provided to participants 
who are HLA-B*5701 positive (to be used in combination with 2 NRTIs). DTG 50 mg 
tablets are yellow, round, biconvex, film-coated tablets. The tablets contain 52.62 mg 
dolutegravir sodium salt, which is equivalent to 50 mg dolutegravir free acid. Each tablet 
is debossed with “SV 572” on one side and “50” on the other side.  The tablets are 
packaged into high density polyethylene (HDPE) bottles with induction seals and child-
resistant closures. Each bottle contains 30 tablets and a desiccant. DTG tablets are to be 
stored according to the product label.
Each tablet of DTG also contains the following inactive ingredients: D-mannitol, 
microcrystalline cellulose, povidone K29/32, sodium starch glycolate, and sodium stearyl 
fumarate.  The tablet film-coating contains the inactive ingredients iron oxide yellow, 
macrogol/PEG, polyvinyl alcohol-part hydrolyzed, talc, and titanium dioxide.
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.  
At the beginning of the Maintenance Phase, 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 eligibility to continue into the Maintenance 
Phase, 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 LA + RPV LA or to remain on 
ABC/DTG/3TC through Week 100, in accordance with the computer generated 
randomization schedule.  Randomization will be stratified by participants’ Baseline 
HIV-1 RNA (<100,000, 100,000 c/mL) and gender at birth.  In addition, RAMOS NG 
will facilitate the initial supply and subsequent resupply of IP to study sites.
6.3.
Dose and Administration
At Day 1 (beginning of Maintenance Phase), participants will be randomly assigned to 
receive treatment with CAB LA + RPV LA or to remain on ABC/DTG/3TC.  
ABC/DTG/3TC dosing on Day 1 should 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 ABC/DTG/3TC prior to coming into 
the clinic, randomization and initiation of oral CAB and RPV should continue as planned 
on Day 1. Regardless of treatment arm assignment, the investigator should instruct all 
participants on the importance of treatment adherence.  This study has an open-label 
design.  Following is a table of dosing and administration for all treatment arms:
Induction Phase (Week [-20] to Day 1) – All Subjects
Week (-20) to Day 1
(1 tablet once daily)
Take 1 tablet ABC 600 mg / DTG 50 mg / 3TC 300 mg once daily 
with or without food
*Take Day 1 dose after randomization.
Maintenance Phase (Day 1 to Week 100)
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 

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time each day, with a meal.
First Injection (Loading Dose) – Week 4b^
Week 4b^
(two 3 mL injections once)
Receive last dose of oral CAB + RPV
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 following Week 4b
Week 8 to Week 100
(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
ABC/DTG/3TC Once Daily Arm*
Day 1 to Week 100
(1 tablet once daily)
Take 1 tablet ABC 600 mg / DTG 50 mg / 3TC 300 mg once daily 
with or without food
*Take Day 1 dose after randomization.
Extension Phase (Week 100 through End of Study) 
CAB LA + RPV LA Arm – continue IM dosing Every 4 Weeks+
ABC/DTG/3TC Arm (Transition to CAB LA + RPV LA)* - Optional Oral Lead-In
Dosing If Using Optional Oral Lead-In
Week 100 to Week 104b
(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 Injection (Loading Dose) – Week104b^ - Optional Oral Lead-In
Week 104b^
(two 3 mL injections once)
Receive last dose of oral CAB + RPV
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 following Week 104b – Optional Oral Lead-In
Week 108 forward
(two 2 mL injections every 4 
Receive CAB LA 400 mg given as 1 X 2 mL IM injection

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weeks)
Receive RPV LA 600 mg given as 1 X 2 mL IM injection
ABC/DTG/3TC Arm (Transition to CAB LA + RPV LA)*
Direct to Inject Dosing - if Not Using Oral Lead-In
First Injection (Loading Dose) – Week100^ - No Oral Lead-In
Week 100^
(two 3 mL injections once)
Receive last dose of oral ABC/DTG/3TC
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 following Week 100 – No Oral Lead-In
Week 104a 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 ABC/DTG/3TC will be given an option to switch to CAB LA + RPV LA (or be discontinued 
from the study) at Week 100.  If the participant decides not to continue participation in the study, arrangements for 
off-study ART should be made in advance of this Week 100 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 study 
summary data, according to actual randomized treatment groups, will be available to 
sponsor staff prior to the planned Week 48 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 

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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.
IP accountability will be evaluated using pill counts of unused IP for participants 
receiving oral treatment (ABC/DTG/3TC [or alternate DTG], oral CAB, oral RPV).  Pill 
counts will not be done for the dual NRTIs taken with DTG, as these will not be provided 
centrally.  IP accountability will be conducted each time the participant receives a 
new/refill supply of IP, when the participant completes oral CAB and RPV (including 
oral bridging supply), and through the Withdrawal visit, study completion, or Week 104b 
of the Extension 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 SPM. 
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.  Sites should gently 
invert the vials a few times to re-suspend sediments and allow bubbles to subside, and 
then use a syringe to withdraw the required volume of suspension for IM injection.  
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, CAB and RPV injections should be 
given on different sides of the body (e.g. left or right gluteus medius), or spaced 
approximately 2 cm from one another, from the site of any previous injection or any 
injection site reaction.  The time, side, and location of injections will be captured in the 
eCRF.  

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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 type.  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 
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 loading dose IM regimen 
(CAB LA 600 mg + RPV LA 900 mg) within 2 hours of taking the last oral CAB + RPV 
dose where possible.  The same should apply to participants switching from the oral 
regimen to an IM regimen at Week 104b.
Should IM maladministration, specifically overdose or inadvertent IV dosing, be 
suspected at any time, the participant will stay onsite for approximately 2 to 3 hours post 
dose for safety monitoring.  An ECG will be performed at approximately 2 hours post 
dose.  The Medical Monitor will be notified in the event of a suspected 
maladministration.  
In the event of suspected intravenous administration, a PK sample will also be drawn 
approximately 2 hours post dose for evaluation of CAB and RPV plasma concentrations.
Appropriate, confirmation of successful IM administration will also be captured in the 
eCRF. 
Additional dosing instructions and considerations can be found in the SPM.
6.7.
Compliance with Study Treatment Administration
IP accountability will be evaluated using pill counts of unused IP (CAB and RPV tablets 
at the end of oral dosing [including bridging supply], and ABC/DTG/3TC [or alternate 
DTG]).  This assessment will be conducted each time the participant receives a supply of 
oral study medication.  These data will be recorded in the participant’s eCRF.  Treatment 
start and stop dates will also be recorded in the eCRF.
When participants are dosed with CAB LA and RPV LA at the site, they will receive IM 
injections directly from the investigator or designee, under medical supervision.  The date 
and time of each injection of CAB LA and RPV LA administered in the clinic will be 
recorded in the source documents.  These data 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.  

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IP accountability (e.g. pill counts) will not be assessed for alternate NRTIs taken with 
single entity DTG, or during the Long-Term Follow-Up Phase.
Due to the long acting nature of the CAB LA and RPV LA, it will be imperative that the 
participant is compliant with dosing visits.  As part of the screening and participant 
selection process, Investigators must discuss with potential participants the long-term 
commitments for the study, and the importance of adhering to treatment regimens.
Investigators must have plans in place for adherence counselling for both treatment arms.  
6.8.
Protocol Permitted Substitutions
Participants who are HLA-B*5701 positive at the Screening visit are allowed to enter the 
study on DTG and an approved dual-NRTI backbone that does not contain abacavir (e.g. 
TDF/FTC or TAF/FTC).  This regimen may be supplied regionally by GSK or 
reimbursement will be provided as needed. 
During the Induction Phase, prior to randomization into the Maintenance Phase at Day 1, 
one switch to an alternate approved background NRTI therapy is allowed for toxicity or 
tolerability management.  The date of a decision to switch the NRTI background therapy 
for toxicity or tolerability management must be documented in the eCRF.  Switches of a 
background NRTI for any other reason are not permitted in the study.  Local prescribing 
information should be consulted for information regarding use of alternative background 
medications.  
For consistency with prescribing information, dose reductions of lamivudine (or 
emtricitabine if used as alternate NRTI) are permitted throughout the study in the context 
of renal insufficiency, e.g. as needed for creatinine clearance <50 mL/min  (See 
Section 4.2.7. for additional information).
No other dose reductions, modifications, or changes in the frequency of any components 
of any regimen will be allowed during the Maintenance and Extension Phases of the 
study.  
Protocol waivers or exemptions are not allowed.  Therefore, adherence to the study 
design requirements are essential and required for study conduct.
6.8.1.
Oral Bridging
In exceptional circumstances, to address pre-planned missed CAB LA + RPV LA dosing 
visits, following consultation with the Medical Monitor, Investigators may provide daily 
oral CAB 30 mg and RPV 25 mg as a short-term “bridging” strategy for subjects who 
have begun CAB LA + RPV LA and who will miss a subsequent scheduled LA injection.  
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 
subject 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.  

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6.9.
Interruption of Study Treatment
IP 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 RPV LA are anticipated to be at high 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 in 
some participants 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 (e.g. in the Long-Term Follow-Up Phase) 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 injections [Week 4b]).  The first injections of 
CAB LA (600 mg) and RPV LA (900 mg) are administered at Week 4b (can be 
performed as soon as lab results from Week 4a become available).  The second and third 
IM injections (CAB LA 400 mg + 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 injections occur within the window of Week 7 to Week 8, 
but not later than Week 8, and the third injections occur within the window of Week 11 to 
Week 12, but no later than Week 12.  Subsequent injections (CAB LA 400 mg + RPV 
LA 600 mg) will occur every 4 weeks thereafter, with a (+ or -) 7 day dosing window, 
from the projected visit date, being allowed (but not preferred).  In addition, following 
the Week 12 injections, time 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.  For the duration of the study, the injection 
visit schedule should be maintained according to the first IM injections given at Week 4b.

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At one-week post dose visits (Week 5, Week 41, and Week 101), 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.
Transition from ABC/DTG/3TC to IM Dosing into the Extension Phase:
Participants who were randomized to ABC/DTG/3TC and are eligible to enter the 
Extension Phase will transition to IM dosing at or after Week 100.  The transition from 
ABC/DTG/3TC to CAB LA + RPV LA can be completed with or without an oral lead-in 
prior to commencement of injectable treatment.  The participant decision will be taken in 
consultation with the investigator and appropriately documented.  In order to ensure no 
interruption in study treatment, the transition into Extension should be performed as 
follows:
Participants Transitioning Directly to Injections in the Extension Phase:  
Central lab results and safety parameters from the Week 96 visit must be available and 
reviewed for participants who choose to transition direct to injection.  If a clinical 
chemistry retest is required based on Week 96 labs, the retest should be performed as 
soon as possible (and preferably no later than 7 days following Week 96). Participants 
will remain on oral ABC/DTG/3TC until the Week 100 injection visit, and until any 
required Week 96 retest results are available for review.
At Week 100, eligible participants will take the last dose of ABC/DTG/3TC (or DTG + 
2 NRTIs), and receive the first injections of CAB LA (600 mg) + RPV LA (900 mg) as 
initial loading doses.  Clinical chemistries will also be assessed at Week 100.  At 
Week 101, participants will return to the clinic for PK and safety assessments including 
clinical chemistries.  The second and third injections (CAB LA 400 mg + RPV LA 
600 mg) will be administered at Week 104a and Week 108.  There will be a one week 
dosing window for the second and third IM injections such that the second injections 
occur within the window of Week 103 to Week 104a, but not later than Week 104a, and 
the third injections occur within the window of Week 107 to Week 108, but no later than 
Week 108.  Subsequent injections (CAB LA 400 mg + RPV LA 600 mg) will occur 
every 4 weeks thereafter, from the projected visit date, with a (+ or -) 7 day dosing 
window being allowed (but not preferred).  Following the Week 108 injection, the 
interval between injection visits should be limited to a maximum of 5 weeks.  The 

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Medical Monitor must be contacted if the length of time between injections exceeds, or is 
projected to exceed, 5 weeks.
Participants Receiving Optional Oral Lead-In in the Extension Phase:
At Week 100, eligible participants who after discussion with the investigator, choose to 
receive the optional oral lead-in will begin a 4 week lead-in of oral CAB 30 mg + oral 
RPV 25 mg once daily.  It is not necessary to dose ABC/DTG/3TC on the day the 
participant begins the oral lead-in with CAB + RPV.  However, if the participant takes 
ABC/DTG/3TC prior to coming into the clinic, initiation of oral CAB and RPV should 
continue as planned.
At Week 104a, assessments including clinical chemistries will be performed.  At 
Week 104b, participants will return to clinic, take the last dose of oral CAB + RPV, and 
receive the first injections of CAB LA (600 mg) + RPV LA (900 mg) (within 2 hours of 
the final oral dose of CAB + RPV).  The Week 104b visit can be performed as soon as 
lab results from Week 104a become available.  The second and third IM injections (CAB 
LA 400 mg + RPV LA 600 mg) will be performed at Week 108 and Week 112.  There 
will be a one week dosing window for the second and third IM injections such that the 
second injections occur within the window of Week 107 to Week 108, but not later than 
Week 108, and the third injections occur within the window of Week 111 to Week 112, 
but no later than Week 112.  Subsequent injections (CAB LA 400 mg + RPV LA 
600 mg) will occur every 4 weeks (monthly) thereafter, with a (+ or -) 7 day dosing 
window, from the projected visit date, being allowed (but not preferred).  In addition, 
following the Week 112 injections, time 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.  For the duration of the 
study, the injection visit schedule should be maintained according to the first IM 
injections given at Week 104b.
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 
(for all oral dosing in the Induction, Maintenance, and Extension Phases of the study).  
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 the Long Term Follow Up are expected to occur as projected 
according to the last injection.  There is no calendar defined visit window in the Long 
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6.10.
Discontinuation of Study Treatment
Participants unable to manage drug toxicity or tolerate investigational product must have 
IP discontinued.
6.10.1.
Discontinuation of ABC/DTG/3TC
In the event of a discontinuation of an ABC-containing product for any reason, re-
initiation of this drug should be undertaken with caution.  Health care providers should 
obtain a complete history of the events surrounding the discontinuation of the ABC-
containing product.  If there are symptoms consistent with a hypersensitivity reaction, 
ABC must not be reinitiated.  If there is no evidence of a prior reaction, the participant 
may restart treatment with the ABC-containing product.  The participant and health care 
provider must be aware of the possibility of a rapid-onset hypersensitivity reaction upon 
reinitiation of ABC, which may be life-threatening or fatal, and the participant must be 
able to, if necessary, receive prompt medical evaluation (see also Section 7.4.5.12).
6.10.2.
Discontinuation of CAB LA or RPV LA
Any participant receiving at least one dose of CAB LA and /or RPV LA who 
discontinues IP must initiate treatment with HAART and enter the Long-Term Follow-
Up Phase for 52 weeks of follow up (see Section 4.2.6.).
6.11.
Treatment of Study Treatment Overdose
For this study, any tablet intake exceeding a total daily dose of CAB 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 participants receiving 
ABC/DTG/3TC, any tablet intake exceeding the protocol defined daily number of tablets 
(one tablet daily) will be considered an overdose.  For participants receiving DTG + 
NRTIs, any tablet count exceeding the marketed dose in local prescribing information 
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 to 3 hours post 
dose for safety monitoring.  An ECG will be performed approximately 2 hours post dose.  
The Medical Monitor will be notified in the event of a suspected maladministration.  
In the event of suspected intravenous administration, a PK sample will also be drawn 
approximately 2 hours post dose for evaluation of CAB and RPV plasma 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).

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If an overdose occurs and is associated with an adverse event requiring action, all study 
medications must be temporarily discontinued until the adverse event resolves. 
The Investigator should use clinical judgement in treating overdose, as GSK is unable to 
recommend specific treatment.
In the event of an overdose the investigator or treating physician should:
a.
contact the Medical Monitor immediately.
closely monitor the participant for adverse events (AEs)/serious adverse events (SAEs) 
and laboratory abnormalities until IP can no longer be detected systemically (number of 
days will vary by compound – Medical Monitor / study team can advise).
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).
document the quantity of the excess dose as well as the duration of the overdosing in the 
eCRF.
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 (see Section 4.2.7 for information regarding dose modifications).
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.
6.13.
Concomitant Medications and Non-Drug Therapies
Participants should be advised to notify their investigator of any current or proposed 
concomitant medication, whether prescribed or over-the-counter, because of the potential 
drug:drug interactions between such treatments and the study drugs.  The investigator 
should evaluate any potential drug:drug interactions at every visit, including reviewing 
the most current version of the investigator brochures, the U.S and/or local prescribing 
information for RPV, and ABC/DTG/3TC (or DTG + NRTIs), especially if any new 
concomitant medications are reported by participants.  All concomitant medications, 
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.
Concomitant medications (prescription and non-prescription) should be administered 
only as medically necessary during the study (except prohibited medications described in 
Section 6.13.1).  Chemoprophylaxis for HIV-associated conditions is encouraged, if 
appropriate, at the discretion of the participant and their physician.  
Because non-HIV vaccines may cause a temporary increase in the level of plasma HIV-1 
RNA, it is highly recommended that a vaccine, if necessary, be given during or 

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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 if possible (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 
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.
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-Receptor antagonists (e.g. cimetidine, famotidine, nizatidine, ranitidine) may 
cause significant decreases in RPV plasma concentrations.  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.
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.
Drugs that cause Torsade de Pointes (TdP) should be used with caution when taking 
rilpivirine (see SPM for list of drugs associated with TdP).
ABC/DTG/3TC:  DTG should be administered 4 hours before or 6 hours after taking 
antacid or laxative products or sucralfate containing polyvalent cations (e.g., aluminum 
and magnesium) or calcium supplements.  Proton pump inhibitors and H2-Receptor 
antagonists (e.g. cimetidine, famotidine, nizatidine, ranitidine) may be used in place of 
antacids with no dosing restrictions.  Iron supplements can be taken with DTG provided 
that all three are taken together with a meal.  Under fasting conditions, DTG should be 
given 2 hours prior to OR 6 hours after iron supplements.

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Metformin concentrations may be increased by DTG.  For participants starting metformin 
after DTG, titrate as recommended in local prescribing information for DTG and monitor 
glucose control.  If starting DTG after metformin, consider dose reduction of metformin 
as needed if glucose is well controlled.
Clinical monitoring is recommended for participants taking methadone as methadone 
maintenance therapy may need to be adjusted in some participants.
Approved hormonal contraception may be administered. However, the investigator 
should consult local prescribing information for guidance on the use of hormonal 
contraceptives with background ART as some antiretrovirals have clinically significant 
drug interactions with these products.
Please refer to the local prescribing information for other drugs that should be used with 
caution, require dose adjustment, or increased clinical monitoring if taken with 
ABC/DTG/3TC.
DTG + 2 NRTIs: For participants who are HLA-B*5701 positive and are receiving 
DTG +alternate NRTI background therapy or who have switched to alternate NRTI 
background therapy during the Induction Phase for tolerability, refer to local prescribing 
information for details regarding concurrent therapies.
6.13.1.
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 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 participants with acute viral 
hepatitis (James, 2009).

Chronic use of systemic (oral or parenteral) glucocorticoids must be avoided due 
to the 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, but more than a single dose in a treatment 
course may cause a significant decrease in RPV plasma concentration and is 
prohibited.  Topical, inhaled or intranasal use of glucocorticoids will be allowed.  

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
Hepatitis C infection therapy is prohibited during the Induction and Maintenance 
Phase before the Week 48 primary endpoint, and interferon-based HCV therapy is 
prohibited throughout the entire study.  Options for treatment of hepatitis C 
should be discussed with the Medical Monitor prior to initiation of therapy.
Note: Any prohibited medications 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.
For additional information on concurrent therapies and interactions suspected to be 
relevant to other antiretroviral therapy used during the study (e.g. ABC/DTG/3TC), 
please consult the current DTG Investigator brochure and local prescribing information.
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 RPV:

Oral RPV:  proton pump inhibitors, such as esomeprazole, lansoprazole, 
omeprazole, pantoprazole, rabeprazole;

Both Oral and RPV LA:  systemic dexamethasone (more than a single dose).
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.
Please refer to the current RPV Investigator brochure and local prescribing information 
for other drugs that are prohibited, should be used with caution, require dose adjustment, 
or increased clinical monitoring if taken with oral RPV.

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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 aspirin (daily doses 325mg).  Systemic anticoagulation (including prophylaxis 
doses) on the day of an IM injection should be avoided.
Concurrent with ABC/DTG/3TC
The following medications or their equivalents may cause decreased concentrations of 
DTG.  Therefore, the following medications must not be administered concurrently with 
DTG:

Carbamazepine

Oxcarbazepine

Phenobarbital

Phenytoin

Rifampin 

Rifapentine 

St. John’s wort (Hypericum perforatum)
Dofetilide and pilsicainide are prohibited as DTG may inhibit their renal tubular secretion 
resulting in increased dofetilide/pilsicainide concentrations and potential for toxicity.
Note:  Any prohibited medication that decrease DTG 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.  Any other prohibited medication should be discontinued 
for a minimum of two weeks or a minimum of three half-lives (whichever is longer) prior 
to the first dose.
Please refer to the current DTG IB and local prescribing information for other drugs that 
should be used with caution, require dose adjustment, or increased clinical monitoring if 
taken with ABC/DTG/3TC (or DTG with alternate NRTI background therapy).
Concurrent with DTG + NRTIs
In addition to the prohibited medications noted for DTG above (as a component of 
ABC/DTG/3TC), for participants who are HLA-B*5701 positive and who are receiving 
DTG + alternate NRTI background therapy, refer to the current DTG IB and local 
prescribing information for details regarding concurrent therapies.

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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 may be altered during the 
course of the study based on newly available data to ensure appropriate 
monitoring.

The change in timing or addition of time points for any planned study 
assessments must be documented in a Note to File which is approved by the 
relevant study team member and then archived in the study sponsor and site 
study files, but this will not constitute a protocol amendment. 

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. 
7.1.
Time and Events Table
Note:  While some assessments included in the Time and Events Table are conducted less 
frequently following the primary endpoint (Week 48), 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 at 
Week 112, the schedule of assessments for participants continuing in the Extension Phase 
from the CAB LA + RPV LA arm will be modified to collect clinical chemistries, HIV-1 
RNA, and CD4+ cell count every 12 weeks. 
Participants originally randomized to ABC/DTG/3TC at Day 1, who choose to continue 
into the Extension Phase and transition to CAB LA + RPV LA, will have all assessments 
noted in the Time and Events table below performed Q4W through Week 124.  
Beginning at Week 124, the schedule of assessments for these participants transitioning 
from ABC/DTG/3TC into the Extension Phase will be modified to collect clinical 
chemistries, HIV-1 RNA, and CD4+ cell count every 12 weeks as noted in the Time and 
Events schedule below.

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From Week 124 forward, all participants (from both originally randomized treatment 
arms), will have the same schedule of events (same visits, same assessments, same time 
frame).

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Table 5
201584 (FLAIR) Time and Events Table
Procedures
Screening a
Induction Phase 
by Week
Maintenance Phase by Week
Extension Phase 
by Week
WithdrawalY
Long-Term Follow-Up
Baseline (-20)
(-16)
(-12 -8)
(-4)
WDy
Day 1
4a
4b – LA arm
5t – LA arm
8, 12, 16, 20
24
28, 32, 36
40, 44
41 – LA arm
48
52 - LA Arm
56
60 – LA Arm
64, 72, 80, 88
68,76, 84, 92
- LA Arm
96
100
101 – Direct to Inject Arm
104a – Direct to Inject Arm
104a LA and Oral Lead-In 
Arm
104b - Oral Lead-In Arm
108
112, 116, 120,124 
ABC/DTG/3TC Switch Arm
Q4W after 108 (LA Arm) or 
after 124 (Switch Arm)
Q12W beginning 112 (LA 
Arm) or 124 (Switch Arm)j
Clinical and Other Assessments
Written Informed 
Consent 
X
Eligibility 
Verification 
(Inclusion / 
Exclusion Criteria)
X
X
X
b
X
b
Randomization
X
Demography
X
Medical Historyc
X
Medication History 
/ Prior ART 
History
X
Symptom Directed 
Physical Exam 
and Medical 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

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Procedures
Screening a
Induction Phase 
by Week
Maintenance Phase by Week
Extension Phase 
by Week
WithdrawalY
Long-Term Follow-Up
Baseline (-20)
(-16)
(-12 -8)
(-4)
WDy
Day 1
4a
4b – LA arm
5t – LA arm
8, 12, 16, 20
24
28, 32, 36
40, 44
41 – LA arm
48
52 - LA Arm
56
60 – LA Arm
64, 72, 80, 88
68,76, 84, 92
- LA Arm
96
100
101 – Direct to Inject Arm
104a – Direct to Inject Arm
104a LA and Oral Lead-In 
Arm
104b - Oral Lead-In Arm
108
112, 116, 120,124 
ABC/DTG/3TC Switch Arm
Q4W after 108 (LA Arm) or 
after 124 (Switch Arm)
Q12W beginning 112 (LA 
Arm) or 124 (Switch Arm)j
Assessment d
Weight, BMI, and 
Height e
X
X
X
X
X
X
Cardiovascular 
Risk Assessment
X
X
Vital Signs (BP, 
HR, temperature) f
X
X
X
X
X
X
X
X
12-Lead ECG g
X
X
pr
e-
do
se 
x3
X
X
X
g
X
g
X
X
X
CDC 
Classification
X
X

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Procedures
Screening a
Induction Phase 
by Week
Maintenance Phase by Week
Extension Phase 
by Week
WithdrawalY
Long-Term Follow-Up
Baseline (-20)
(-16)
(-12 -8)
(-4)
WDy
Day 1
4a
4b – LA arm
5t – LA arm
8, 12, 16, 20
24
28, 32, 36
40, 44
41 – LA arm
48
52 - LA Arm
56
60 – LA Arm
64, 72, 80, 88
68,76, 84, 92
- LA Arm
96
100
101 – Direct to Inject Arm
104a – Direct to Inject Arm
104a LA and Oral Lead-In 
Arm
104b - Oral Lead-In Arm
108
112, 116, 120,124 
ABC/DTG/3TC Switch Arm
Q4W after 108 (LA Arm) or 
after 124 (Switch Arm)
Q12W beginning 112 (LA 
Arm) or 124 (Switch Arm)j
HIV Associated 
Conditions
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE and SAE 
Assessment, Con 
Meds
X 
h
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ISR Assessment 
(LA Arm Only)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 
If 
appl
i-
cabl
e
Columbia Suicide 
Severity Rating 
Scale (eC-SSRS) i
X
X
X
X
X
X
X
X
X
X
X
X
W7
2
W84
X
X
Clinical Chemistry 
and Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Rapid Plasma 
Reagin (RPR)
X
X

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Procedures
Screening a
Induction Phase 
by Week
Maintenance Phase by Week
Extension Phase 
by Week
WithdrawalY
Long-Term Follow-Up
Baseline (-20)
(-16)
(-12 -8)
(-4)
WDy
Day 1
4a
4b – LA arm
5t – LA arm
8, 12, 16, 20
24
28, 32, 36
40, 44
41 – LA arm
48
52 - LA Arm
56
60 – LA Arm
64, 72, 80, 88
68,76, 84, 92
- LA Arm
96
100
101 – Direct to Inject Arm
104a – Direct to Inject Arm
104a LA and Oral Lead-In 
Arm
104b - Oral Lead-In Arm
108
112, 116, 120,124 
ABC/DTG/3TC Switch Arm
Q4W after 108 (LA Arm) or 
after 124 (Switch Arm)
Q12W beginning 112 (LA 
Arm) or 124 (Switch Arm)j
Pregnancy 
Testingj
S
U
S
S
S
S
U
S
U
S
S
S
S
S
S
S
S
S
S
S
S
Uj
S
S
U
S
S
S -
Q4
W
S
S
HIV-1 RNA and 
sample for 
storagek 
Xk
X
X
X
X
X
X
X
X
X
X
X
X
S
k
X
X
X
X
Sk
X
X
X
X
X
X
X
CD4+ 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CD8+
X
X
X
X
X
X
X
X
X
Urinalysisl 
X
X
X
X
X
X
X
X
Fasting Lab 
Assessments:  
Glucose, 
Cholesterol (Total, 
HDL and LDL) 
and Triglycerides 
m
X
X
X
X
X
X

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Procedures
Screening a
Induction Phase 
by Week
Maintenance Phase by Week
Extension Phase 
by Week
WithdrawalY
Long-Term Follow-Up
Baseline (-20)
(-16)
(-12 -8)
(-4)
WDy
Day 1
4a
4b – LA arm
5t – LA arm
8, 12, 16, 20
24
28, 32, 36
40, 44
41 – LA arm
48
52 - LA Arm
56
60 – LA Arm
64, 72, 80, 88
68,76, 84, 92
- LA Arm
96
100
101 – Direct to Inject Arm
104a – Direct to Inject Arm
104a LA and Oral Lead-In 
Arm
104b - Oral Lead-In Arm
108
112, 116, 120,124 
ABC/DTG/3TC Switch Arm
Q4W after 108 (LA Arm) or 
after 124 (Switch Arm)
Q12W beginning 112 (LA 
Arm) or 124 (Switch Arm)j
Hepatitis B 
(HBsAg), Anti-
HBc, and Anti-
HBsAG
Hepatitis C 
(anti-HCV Ab)
X
HLA-B*5701
X
PT/PTT/INR
X
X
Renal and Bone 
marker analytes 
(blood/urine)n
X
X
X
X
Peripheral Blood 
Mononuclear Cells 
(PBMCs) o
X
X
X
Genetic Samplep
X

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Procedures
Screening a
Induction Phase 
by Week
Maintenance Phase by Week
Extension Phase 
by Week
WithdrawalY
Long-Term Follow-Up
Baseline (-20)
(-16)
(-12 -8)
(-4)
WDy
Day 1
4a
4b – LA arm
5t – LA arm
8, 12, 16, 20
24
28, 32, 36
40, 44
41 – LA arm
48
52 - LA Arm
56
60 – LA Arm
64, 72, 80, 88
68,76, 84, 92
- LA Arm
96
100
101 – Direct to Inject Arm
104a – Direct to Inject Arm
104a LA and Oral Lead-In 
Arm
104b - Oral Lead-In Arm
108
112, 116, 120,124 
ABC/DTG/3TC Switch Arm
Q4W after 108 (LA Arm) or 
after 124 (Switch Arm)
Q12W beginning 112 (LA 
Arm) or 124 (Switch Arm)j
Pharmacokinetics (CAB + RPV only)
PK Sample 
(S)= Storage 
sample
X
v 
w
X
t 
v
X
X
X
X
X
v
X
v
X
X
X
S
X
v
X
X
v
X
v
X
v 
w
S
X
S
Investigational Products
Oral CAB and 
Oral RPV 
Dispensation 
X
X
Xx
OLI 
Onl
y
Xx
OLI 
Onl
y
ABC/DTG/3TC 
Dispensation (or 
DTG alternate)
X
X
X
X
q 
r
X
X
X
X
X
X
X
X
X
X
Study Treatment 
Accountability 
(pill counts)
X
X
X
r
X
X
X
X
u
X
X
X
X
X
X
X
X
X
OLI 
Onl
y
X
OLI 
Onl
y
X
u
IM Study 
Treatment 
Administration –
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
s
X
X
X –
con
t 

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Procedures
Screening a
Induction Phase 
by Week
Maintenance Phase by Week
Extension Phase 
by Week
WithdrawalY
Long-Term Follow-Up
Baseline (-20)
(-16)
(-12 -8)
(-4)
WDy
Day 1
4a
4b – LA arm
5t – LA arm
8, 12, 16, 20
24
28, 32, 36
40, 44
41 – LA arm
48
52 - LA Arm
56
60 – LA Arm
64, 72, 80, 88
68,76, 84, 92
- LA Arm
96
100
101 – Direct to Inject Arm
104a – Direct to Inject Arm
104a LA and Oral Lead-In 
Arm
104b - Oral Lead-In Arm
108
112, 116, 120,124 
ABC/DTG/3TC Switch Arm
Q4W after 108 (LA Arm) or 
after 124 (Switch Arm)
Q12W beginning 112 (LA 
Arm) or 124 (Switch Arm)j
Q4W throughout 
Maintenance and 
Extension Phase
dos
-ing 
Q4
W
Patient Reported Outcomesz
HAT-QoL (short 
form)
X
X
X
X
X
SF-12
X
X
X
X
X
ACCEPT
X
W
8
X
X
X
X
HIVTSQ(s)
X
X
X
W
4
4
X
X
HIVTSQ(c)
X
X
PIN (LA Arm 
Only)aa
X
X
X
X
X
NRS (LA Arm 
X
X
W
X
X

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Procedures
Screening a
Induction Phase 
by Week
Maintenance Phase by Week
Extension Phase 
by Week
WithdrawalY
Long-Term Follow-Up
Baseline (-20)
(-16)
(-12 -8)
(-4)
WDy
Day 1
4a
4b – LA arm
5t – LA arm
8, 12, 16, 20
24
28, 32, 36
40, 44
41 – LA arm
48
52 - LA Arm
56
60 – LA Arm
64, 72, 80, 88
68,76, 84, 92
- LA Arm
96
100
101 – Direct to Inject Arm
104a – Direct to Inject Arm
104a LA and Oral Lead-In 
Arm
104b - Oral Lead-In Arm
108
112, 116, 120,124 
ABC/DTG/3TC Switch Arm
Q4W after 108 (LA Arm) or 
after 124 (Switch Arm)
Q12W beginning 112 (LA 
Arm) or 124 (Switch Arm)j
Only)
4
0
Preference (LA 
Arm Only)
X
Follow Up Visit:  Conduct ~4 weeks after the last dose of oral IP.  Required only if the participant has ongoing AEs / lab abnormalities at the last on-study visit.  This visit may be 
conducted by telephone.
Direct to Inject:  Participants transitioning into the Extension Phase who do not use the optional CAB + RPV oral lead-in beginning at Week 100.
Oral Lead-In:  Participants transitioning into the Extension Phase who do use the optional CAB + RPV oral lead-in beginning at Week 100.
LA Arm:  Participants who were originally randomized to CAB LA + RPV LA at Day 1.
Switch Arm:  All participants who transition into the Extension Phase from ABC/DTG/3TC (or DTG + 2 NRTI’s) at Week 100 – e.g., both direct to inject and oral lead-in participants.
a.
Complete all Screening assessments within 35 days.  Participants may begin the Induction Phase as soon as all Screening assessments are complete.  Participants may be 
rescreened once and will be assigned a new participant number.
b.
Confirmation of eligibility to enter the Maintenance Phase (Section 4.2.4), eligibility to enter the Extension Phase (Section 4.2.5).
c.
Collect full routine medical history plus (report at Baseline visit): HIV risk factors (may be collected at a later study visit), cardiovascular risk factors (assessments include smoking 
status and history, family history of cardiac events), recent [6 months] illicit drug use, intravenous drug use, gastrointestinal disease, metabolic, psychiatric, renal and neurologic 
disorders.
d.
Physical exams should be conducted as part of normal routine clinical care but data will not be collected in the eCRF. Medical assessments include any decisions the study staff 
must make for participant management and / or care. 
e.
Height collected at Baseline only.
f.
Measure vital signs after about 5 minutes of rest in a semi-supine position.

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g.
A 12-lead ECG will be performed after resting in a semi-supine position for at least 5 minutes.  Perform ECG at Baseline (Week [-20]) in triplicate prior to dosing.  For subjects 
randomized to CAB LA + RPV LA, at Week 4b and Week 48, a second ECG will be obtained approximately 2 hours after the last injection and just prior to the 2 hour post dose PK 
sampling.
h.
Collect SAEs at Screen only if associated to study participation.
i.
On Day 1, the eC-SSRS is to be administered prior to randomization.  During the Maintenance Phase, the eC-SSRS will be administered at each Q4W visit through the Week 48 
primary endpoint, and then followed by Q12W assessments for CAB LA + RPV LA arm, thereafter through Week 96 (LA:  Week 60, 72, 84, 96).  The ABC/DTG/3TC arm will have 
assessments at Week 72 and Week 96).  Preferably completed at the beginning of the visit following administration of other patient reported questionnaires required prior to
injections.
j.
Conduct pregnancy tests for only women of childbearing potential at every visit throughout the study, including Q4W during the Extension Phase.  Remind females of reproductive 
potential of the need to avoid pregnancy while in study and adherence to the study’s contraception requirements.  A negative urine pregnancy test is required prior to beginning the 
Induction Phase (Week [-20]), on Day 1 (preferably prior to randomization), and at Week 4b (or Week 104b for subjects transitioning from ABC/DTG/3TC) prior to the first injection.
Serum pregnancy test can substitute for urine pregnancy test if locally required, but must be appropriately timed to confirm pregnancy status prior to e.g. randomization and first IM 
administration. S=Serum/U=Urine.
k.
Plasma for storage will be used: to determine genotypic eligibility at Screen, for possible future analyses, as back- up in case samples are lost or damaged in transit to the lab and 
for genotypic and phenotypic analyses in cases of virologic failure.  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.
l.
A morning specimen is preferred.  To assess biomarkers: urine albumin/creatinine ratio; urine protein/creatinine ratio; and urine phosphate.
m.
Overnight fast is preferred; however, a minimum of a 6 hour fast is acceptable.
n.
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
o.
Whole blood/Peripheral Blood Mononuclear Cell collection samples may be used for virologic analyses as described in Section 7.8.  PBMCs will be collected at Day 1, Week 96, 
Withdrawal visits.
p.
Informed consent for genetic research must be obtained before sample collection.  Sample may be collected at any visit after signing informed consent, but preferably at the 
Week [-20] visit.
q.
Instruct participants to continue to take the ABC/DTG/3TC regimen until Day 1 of the Maintenance Phase.  Participants will be randomized at Day 1 to continue on ABC/DTG/3TC 
arm or begin oral CAB + oral RPV.  Day 1 dosing should occur after randomization to determine defined treatment for the Maintenance Phase.
r.
Remind participants of the potential change in study treatment and visit frequency beginning at Day 1.
s.
Visit Week 104b is only required for participants transitioning from the ABC/DTG/3TC arm.
t.
The Week 5 visit should be performed approximately 7 days after the first injections at Week 4b (3 to 10 day window allowed).
u.
For oral CAB + RPV only.
v.
Take PK samples pre-dose.  At Week 4b (and Week 104b for participants transitioning to LA from ABC/DTG/3TC using the optional oral lead-in), the pre-dose PK sample should 
be taken after review of the PK diary and prior to the final oral CAB + RPV dose.  A sample will be also be taken at Week 4b, Week 48, and Week 96 (and Week 100 [direct to 
inject] or Week 104b [using CAB + RPV oral lead-in]), approximately 2 hours post-injections.  The Week 5, Week 41, and Week 101 visit can be performed at any time from 3 to 10 
days after the Week 4b, Week 40, and Week 100 injection, respectively. PK samples at Week 5, Week 41, and Week 101 can be taken at any time during the visit.
w.
Participants should take the last dose of oral CAB+RPV at Week 4b (and Week 104b for participants transitioning to LA from ABC/DTG/3TC if using the optional oral lead-in) in the 
clinic after PK sampling. Participants should take the last dose of ABC/DTG/3TC at Week 100 if transitioning directly to injections at Week 100. Injections should be administered 
within 2 hours of the last oral dose where possible.

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x.
For participants transitioning to CAB LA + RPV LA from ABC/DTG/3TC only.
y.
Follow Up Visit:  Conduct approximately 4 weeks after the last dose of oral 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.
z.
With the exception of the NRS questionnaire, patient reported questionnaire/surveys are recommended to be administered at the beginning of the visit before any other clinical 
assessments are conducted, and prior to completion of the eCSSRs assessments.  Only conduct questionnaires/surveys at Withdrawal if occurring prior to Week 96 (The NRS will 
not be collected at Withdrawal).
aa. The PIN, Preference, and NRS questionnaires are to be administered only to participants receiving CAB LA + RPV LA injections. The NRS should be collected 30 to 60 minutes 
post-injection (and at Week 5 and Week 41, one week post-injections) - the participant should record the maximum level of pain experienced with the most recent injections.
Note: BMI- Body mass Index, 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.
Participants must be counseled on the practice of safer sexual practices including the use 
of effective barrier methods (e.g. male condom/spermicide) and the length of time in 
which they are required for participation in this study as part of the eligibility process.
7.2.1.
Screening
All participants will complete the Screening phase of up to 35 days prior to Baseline 
(Week [-20]) during which all clinical and laboratory assessments of eligibility must be 
performed and reviewed.  All Screening results must be available prior to enrolment.  A 
single repeat of a procedure/lab parameter is allowed to determine eligibility (unless 
otherwise specified).  
Eligibility criteria must be carefully assessed at the Screening visit and confirmed at the 
first Induction Phase visit prior to enrolment.  Participants may enroll and begin the 
Induction Phase as soon as all Screening assessments are complete and the results are 
available and documented.  
Laboratory results from the central laboratory services provided by this trial will be used 
to assess study eligibility.  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.  
Each participant screened will be assigned a participant number.  Participants not meeting 
all inclusion and exclusion criteria at initial screen may be re-screened one time with a 
new participant number.  Participants who are enrolled into the trial and subsequently 
withdrawn from the study for any reason may not be rescreened.
At Screening, samples for HIV-1 genotypic and phenotypic resistance testing and plasma 
HIV-1 RNA measurement will be obtained. If a central laboratory result cannot be 
generated for Screening genotype/phenotype, a local result can be considered following 
review and approval by the study virologist.
Physical exams should be conducted as part of normal routine clinical care but will not be 
collected systematically in the eCRF. 

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Participants infected with hepatitis B virus (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).
Participants with an anticipated need for HCV therapy prior to Week 48 of the 
Maintenance Phase of the study must not be enrolled into this study, as HCV therapy may 
include the prohibited medication interferon.  The length of this study should be 
considered when assessing the potential need for therapy.
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.  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.
The electronic Columbia Suicidality Severity Rating Scale (eC-SSRS) (see Section 7.4.6) 
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 is not 
necessarily exclusionary, rather a means to assess overall risk.
7.2.2.
Baseline Assessments
Participants will have “Baseline” assessments completed at the beginning of the 
Induction Phase (Week [-20] visit).
Any changes to the eligibility parameters must be assessed and any results required must 
be available and reviewed prior to enrolment (e.g. urine pregnancy test for women of 
child bearing potential).
HIV-1 genotypic resistance testing and plasma HIV-1 RNA measurement results from 
Screening must be available prior to the Baseline visit.
In addition to a full routine medical history and current medical conditions, more detailed 
information will be collected for some disease processes such as:

cardiovascular risk factors (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); 

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);

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
renal (e.g. nephrolithiasis, nephropathy, renal failure); and,

neurologic disorders (e.g. history of seizures).
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).
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 in Adults (see Section 12.4).  
7.4.
Safety
7.4.1.
Clinical evaluations
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).  Additional time points for safety tests (such as vital signs, physical exams 
and laboratory safety tests) may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring.
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 first day 
of the Induction Phase 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.

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
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 resting for about 5 minutes.  At the first day of the Induction Phase, 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.  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.  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.

Regular monitoring of hematology, blood chemistry, urinalysis and fasting glucose 
and lipids (parameters to be tested listed below).  

Periodic assessment of glucose, and bone and renal markers.

Pregnancy testing.  A negative urine pregnancy test is required prior to initiation of 
IP at the beginning of the Induction Phase, prior to the first 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 Phase 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 7.4.6).
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 Table 5), must be performed by the central laboratory.  Laboratory assessments must 

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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 labelled 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 participant 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”).
For fasting laboratory assessments, an overnight fast is preferred; however, a minimum of 
a 6 hour fast is acceptable.
Following are the lab parameters to be assessed as per the Time and Events Schedule (see 
Section 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 (inorganic 
phosphorus)
Creatinine clearanceb
Fasting Lipid Paneld
Total cholesterol
HDL cholesterol
LDL cholesterol
Triglycerides

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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
Follicle stimulating hormone (FSH) and estradiol (only in instances when postmenopausal status is 
questionable)
Urinalysis, urine albumin/creatinine ratio, and urine protein/creatinine ratio, urine phosphate
Genetic 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
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.  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.
f.
CD8+ cells will only be reported at Baseline (Week [-20]), Week (-4), Day 1, Week 4b, Week 24, Week 48, 
Week 96, and Withdrawal.  Additionally, participants transitioning from the ABC/DTG/3TC arm to CAB LA + RPV 
LA will have CD8+ at Week 104b.
g.
HBV DNA will only be performed for participants with a positive anti-HBc, 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 (Table 5). 
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.

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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. 
The definitions of an AE or SAE can be found in Section 12.6, Appendix 6.
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 ViiV/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 7.4.3.3), 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.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Section 12.6.

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.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Section 12.6, Appendix 6.
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?” 
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 7.4.5) will be followed until resolution, until the condition 

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stabilizes, until the event is otherwise explained, or until the participant is lost to follow-
up (as defined in Section 5.4).  Further information on follow-up procedures is given in 
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 5.4.1.  
Additional information for reporting cardiovascular and death events is included in 
Section 7.4.3.7 and Section 7.4.3.8, respectively.
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 reported 
“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 
reported
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”
Seizure or suspected 
seizure
24 hours
eCRF
24 hours
eCRF
Suspected ABC HSR in 
participants 
randomized to the STR 
arm or receiving an oral 
ABC-containing 
regimen during the 
Long-Term Follow-Up 
Phasea
1 week
ABC HSR eCRF
1 week
Updated ABC HSR 
eCRF

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Initial Reports
Follow-up Information on a Previous
Report
Type of Event
Time Frame
Documents
Time Frame
Documents
ALT3×ULN and
bilirubin2×ULN (>35% 
direct) (or ALT3×ULN)
24 hoursb
“SAE” data 
collection tool. 
“Liver Event eCRF” 
and “Liver Imaging” 
and/or “Liver 
Biopsy” eCRFs, if 
applicablec
24 hours
Updated “SAE” data 
collection tool/“Liver 
Event” documentsc
ALT≥5×ULN that 
persists ≥2 weeks 
24 hoursb
Liver Event eCRFc
24 hours 
Updated Liver Event 
eCRFc
ALT ≥8×ULN 
24 hoursb
Liver Event eCRFc
24 hours 
Updated Liver Event 
eCRFc
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 hoursb
Liver Event eCRFc
24 hours 
Updated Liver Event 
eCRFc
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.
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.

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.

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.

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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.
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 (Section 12.4) 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, unless the following conditions apply:

The investigator determines that the event or outcome qualifies as an SAE under part 
‘f’ of the SAE definition (see Section 12.6.2), or

The event or outcome 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

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.

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An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.4.3.7.
Cardiovascular Events
Investigators will be required to fill out event specific data collection tools for the 
following AEs and SAEs:  

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular (CV) events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularisation
This information should be recorded in the specific cardiovascular eCRF within one week 
of when the AE/SAE(s) are first reported.  The CV CRFs are presented as queries in 
response to reporting of certain CV MedDRA terms.
7.4.3.8.
Death Events
In addition, all deaths will require a specific death data collection tool to be completed.  
The death data collection tool includes questions regarding cardiovascular (including 
sudden cardiac death) and noncardiovascular death.
This information should be recorded in the specific death eCRF within one week of when 
the death is first reported.
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
7.4.4.
Toxicity Management
Adverse events that occur during the trial should be evaluated by the Investigator and 
graded according to the Division of AIDS (DAIDS) toxicity scales (See Section 12.2
“Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events”).  Additional information regarding detecting, documenting and reporting AEs 
and SAEs are available in Section 7.4.3 and Section 12.6.

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7.4.4.1.
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 antiretroviral medications is held due to toxicity or adverse 
events, all antiretroviral medications must be held to reduce the risk of development of 
resistance taking into account both the length of the planned interruption and the 
pharmacokinetic half-life of each antiretroviral of the regimen, in a way to minimize the 
risk of development of resistance.
No toxicity-related dose reductions of IP will be allowed.  IP 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 date of the first injection visit [Week 4b]).  An additional (+ or -) 
7 day window, from the projected visit date, is allowable from the third injections 
forward for IM dosing but not preferred.  Any interruption outside of this guidance 
MUST be discussed with the Medical Monitor prior to reinitiating IM IP (see 
Section 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.
7.4.4.2.
Grade 1 or Grade 2 Toxicity/Adverse Event
Participants who develop a Grade 1 or Grade 2 AE or toxicity may continue IP at the 
discretion of the Investigator. (NOTE: See Section 7.4.5 “Specific Toxicities/Adverse 
Event Management” for exceptions to this guideline).  Participants who choose to 
withdraw from 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 and RPV LA.

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7.4.4.3.
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 
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 7.4.5.1).  Isolated Grade 3 lipid abnormalities do 
not require withdrawal of IP.
7.4.4.4.
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 7.4.5.1).  An in-clinic follow-up 
visit will be performed approximately 4 weeks after the last dose of study 

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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.
7.4.5.
Specific Toxicities / Adverse Event Management
General guidelines for the management of specific toxicities that are considered to be 
associated with treatment of HIV infected participants are provided below. 
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.
7.4.5.1.
Liver Chemistry Stopping Criteria
Liver chemistry threshold stopping criteria have been designed to assure participant 
safety and to evaluate liver event etiology during administration of IP and the follow-up
period. 
For a complete listing of stopping and follow-up criteria refer to Section 5.4.1.  
Additional guidance on restart/rechallenge can be found in Section 5.4.1.3 and 
Section 12.3, Appendix 3.
7.4.5.2.
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.

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7.4.5.3.
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.
7.4.5.4.
Seizures
Seizures that occur on study should be managed according to the local guidelines on 
emergency seizure management which may include treatment with benzodiazepines, 
general supportive treatment, exclusion of metabolic and toxicological abnormalities 
using laboratory tests, and septic workup and excluding underlying structural 
abnormalities with neuroimaging.
Where seizures occur, the Sponsor would like to better characterize these occurrences to 
enable systematic analyses.
Investigators are requested to document and report seizure or possible seizure events 
promptly (within 24 hours of learning of the event) to the Sponsor for evaluation and 
onward reporting.  Data should be documented on the appropriate eCRF page.
7.4.5.5.
Creatine Phosphokinase (CPK) Elevation
A Grade 3 or higher elevation in CPK should result in a repeat assessment within 2 to 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 will initiate treatment with HAART enter 
the Long-Term Follow-Up Phase for 52 weeks of follow up.
7.4.5.6.
Lipase Elevations and Pancreatitis
Participants with asymptomatic Grade 1 or 2 elevations in lipase may be followed closely 
for the development of symptoms.

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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, 
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.
7.4.5.7.
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 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 
[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 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.  
7.4.5.7.1.
Proximal Renal Tubule Dysfunction
Proximal Renal Tubule Dysfunction (PRTD) is defined as:

Confirmed rise in serum creatinine of ≥0.5 mg/dL from Baseline AND serum 
phosphate <2.0 mg/dL

Either of the above accompanied by any two of the following:

Glycosuria (≥250 mg/dL) in a non-diabetic

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
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 Medical Monitor to discuss the rationale 
for restarting study drugs (if appropriate).  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. 
7.4.5.8.
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 to 4 weeks.  If confirmed, then consideration should be made for 
additional evaluation after consultation with the Medical Monitor. Additional evaluation 
may include a 24 hr 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 Mol/L (or 0.5 mg/dL) should have confirmation of both results within 2 
weeks.  If confirmed, the Medical Monitor should be immediately contacted.  Further 
management should be agreed between the investigator and Medical Monitor.
7.4.5.9.
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. 
7.4.5.10.
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 persist beyond 2 weeks.  Dermatology will be 

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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.
7.4.5.11.
Allergic Reaction
Participants may continue IP 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 IP should permanently discontinue the IP regimen and the 
participant should be withdrawn from the study.  Participants should be treated as 
clinically appropriate and followed until resolution of the AE.
Participants in the ABC/DTG/3TC 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.
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.
7.4.5.12.
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 TRIUMEQ.  
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 participants, significantly reduced 

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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., TRIUMEQ, 
ZIAGEN, EPZICOM/KIVEXA or TRIZIVIR) if a HSR cannot be ruled out on 
clinical grounds, due to the potential for a severe or even fatal reaction.
7.4.5.12.1. Essential Participant 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.

Participants who are hypersensitive to abacavir should be reminded that they must 
never take any abacavir containing medicinal products (e.g. TRIUMEQ, ZIAGEN, 
EPZICOM / KIVEXA or TRIZIVIR) 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 TRIUMEQ, 
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 TRIUMEQ, 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 
TRIUMEQ, 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. 
7.4.5.12.2. Reporting of Hypersensitivity Reactions
If a clinically suspected case of HSR to ABC meets one of the International Conference 
on Harmonization (ICH), 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 

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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.
7.4.5.13.
Rash Without ABC HSR Symptoms
Rash 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 participants taking ABC-containing 
products.  These participants 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., 
TRIUMEQ, ZIAGEN, TRIZIVIR, EPZICOM or KIVEXA).
As many products other than abacavir also cause rash and/or serious skin reactions, all 
other medicinal products that the 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.
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 DTG IB [GlaxoSmithKline 
Document Number RM2007/00683/11] or local prescribing information.
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.

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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.
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 ABC/DTG/3TC 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 
Week 4b, 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.
7.4.6.
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 

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history of depression or psychiatric illness) in some participants being treated with INIs, 
including ABC/DTG/3TC.  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 behavioral 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 participant completed questionnaire specified in the Time and Events 
Table (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 risk of and possible suicide 
related events.
7.4.7.
Pregnancy
7.4.7.1.
Pregnancy testing
Women of childbearing potential must have a negative pregnancy test at Screening, 
Baseline (Week [-20]), the first Induction Phase visit (Day 1), and Week 100 (if no oral 
lead-in is used) or Week 104b (if using CAB and RPV oral lead-in) for women 
transitioning into the Extension Phase from the ABC/DTG/3TC arm (prior to 
administration of first CAB LA and / or RPV LA injections).  Pregnancy testing will also 
be conducted as per the Time and Events Table (Table 5) and at anytime during the trial 
when pregnancy is suspected.

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Additionally, the Medical Monitor may request that a urine pregnancy test be performed 
in the event of a treatment interruption greater than 7 days.
7.4.7.2.
Time Period for Collecting Pregnancy Information
Pregnancy information will be collected after the start of the Induction Phase 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.
7.4.7.3.
Action to be Taken if Pregnancy Occurs
Any female who becomes pregnant (intrauterine) while participating in this study must be 
withdrawn from the study and must immediately discontinue 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 4.2.6), after discussion with the Medical Monitor.  
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form.  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 may 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.  The 
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.

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7.4.8.
Physical Exams

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. 

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 7.4.5.10 for additional information.

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
7.4.9.
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 heart rate.  These 
will be recorded as per the Time and Events Table in Section 7.1.
7.4.10.
Electrocardiogram (ECG)

A 12-lead ECG will be performed in a semi-supine position.  At the first day of 
the Induction Phase, 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 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.  Refer to 
the Time and Events Table for collection timepoints (Table 5).  Refer to 
Section 5.4.2 for [QTc] withdrawal criteria and additional [QTc] readings that 
may be necessary.
7.5.
Pharmacokinetics
Plasma samples for determination of CAB and RPV concentrations will be collected 
throughout the Maintenance Phase and for the participants transitioning from the 
ABC/DTG/3TC arm in the Extension Phase of the study as noted in Table 8.  Additional 
samples will be collected for storage during the Long-Term Follow Up Phase.  Samples 
(blood and plasma) for determination of RPV concentrations will be protected from light 
at all times, from sampling collection through analysis.

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7.5.1.
PK Sample Collection
Blood samples for evaluation of CAB (2 mL each) and RPV (2 mL each) plasma 
concentrations will be collected from all participants randomized to receive CAB + RPV 
as described in Table 8.  
At Week 4b (and Week 104b for participants using the oral CAB + RPV lead-in and 
transitioning into the Extension Phase from the ABC/DTG/3TC arm), PK samples must 
be collected within the window of 20 to 28 hours after the oral dose of CAB + RPV was 
taken the day prior to the clinic visit.  
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 104b if transitioning into Extension Phase from ABC/DTG/3TC).  The information 
from the diary card 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 on the eCRF.  Participants will take their final dose of oral CAB + RPV in the 
clinic at Week 4b (or Week 104b) after the pre-dose PK sample collection.
PK concentrations will be summarized, sources of variability examined, and used to 
explore 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.  
Table 8
CAB and RPV Plasma Pharmacokinetic Sample Schedule
Group
Analytea
Sample Times Relative to Dose
IM
CAB
Pre-Dose:  Week 4b, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 
48, 52, 56, 60, 96, 100, 108, Withdrawal
2 Hours Post Dose:  Week 4b, Week 48, Week 96
1 Week Post Doseb:  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, 56, 60, 96, 100, 108, Withdrawal
2 Hours Post Dose:  Week 4b, Week 48, Week 96
1 Week Post Doseb:  Week 5 and Week 41
PK samples for storage only:
Pre-dose: Week 64, 72, 80, and 88

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Group
Analytea
Sample Times Relative to Dose
Long-term follow-up Period (off-drug; storage sample)
Months 1, 3, 6, 9, and 12
ABC/DTG/3TC Arm 
Transitioning to 
CAB LA + RPV LA 
at Week 100 
(participants using 
CAB + RPV oral 
lead-in)
CAB
Pre-Dose:  Week 104b, Week 108 (for storage), Withdrawal
2 Hours Post Dose:  Week 104b
Long-term follow-up Period (off-drug; storage sample)
Months 1, 3, 6, 9, and 12
RPV
Pre-Dose:  Week 104b, Week 108 (for storage), Withdrawal
2 Hours Post Dose:  Week 104b
Long-term follow-up Period (off-drug; storage sample)
Months 1, 3, 6, 9, and 12
ABC/DTG/3TC Arm 
Transitioning to 
CAB LA + RPV LA 
at Week 100 (Direct 
to Inject -
participants not
using CAB + RPV 
oral lead-in)
CAB
Pre-Dose:  Week 104a, Week 108 (for storage), Withdrawal
2 Hours Post Dose:  Week 100
1 Week Post Doseb:  Week 101
Long-term follow-up Period (off-drug; storage sample)
Months 1, 3, 6, 9, and 12
RPV
Pre-Dose:  Week 104a, Week 108 (for storage), Withdrawal
2 Hours Post Dose:  Week 100
1 Week Post Doseb:  Week 101
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7 days (4th and all subsequent injections); Sample Collection:  Pre-dose at Week 4b 
(and Week 104b for participants transitioning from ABC/DTG/3TC Arm using oral lead-in):  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.
a.
Each analyte in individual collection tube.
b.
Samples taken at Week 5, Week 41, and Week 101 may be collected from 3 to 10 days after Week 4b, Week 40, 
and Week 100, respectively.  These samples may be collected at anytime during those visits.  
If a participant withdraws from the study, a PK sample should be collected as early as 
practically possible (i.e. at the withdrawal visit or on the day the withdrawal decision was 
made).
Samples for determination of RPV will be protected from light until analyzed. 
Additional details concerning handling of PK samples, labeling and shipping directions 
will be supplied in the central laboratory manual.

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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 Table 8 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 analysis for CAB concentration determination will be performed under the 
control of Platform Technology and Science (PTS), GlaxoSmithKline, the details of 
which will be included in the SPM. 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 SPM).
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 PTS, 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 analysed for RPV any remaining plasma may be used by the 
sponsor for further exploratory work on pharmacokinetics, metabolites, plasma protein 
binding, protein analysis, and biochemistry.  No human DNA analysis will be performed 
on these samples.
7.6.
Biomarker(s)
Blood and urine are being collected to perform renal and bone biomarker assessments as 
outlined in the Time and Events Table (Table 5).  Renal biomarkers include Cystatin C 
(blood), and Retinol Binding Protein (RBP, blood/urine), urine albumin/creatinine ratio, 
urine protein/creatinine ratio, urine 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.  Since 
the intention is to utilize these biomarkers for research purposes, the Sponsor will not be 
reporting the results of these assessments to the investigator except for 25 hydroxy-
vitamin D. 
7.6.1.
Biomarker Endpoints (Exploratory)

Change from Baseline in renal and bone biomarkers at Week 48 and Week 96.

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
Change from Baseline over time in eGFR using cystatin C and other renal 
biomarkers during the Maintenance Phase.
7.7.
Genetics
Information regarding genetic research is included in Appendix 5.
7.8.
Viral Genotyping and Phenotyping
Whole venous blood samples will be obtained from each participant to provide “plasma 
for storage samples” and PBMCs according to the Time and Events Schedule in 
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) and reverse transcriptase (RT), or with their GeneSeq 
Integrase and PhenoSense Integrase assays.
For Screening virologic evaluations, only viral genotype will be analyzed and this will be 
performed through the central laboratory.
7.8.1.
HIV-1 pol Viral Genotyping and Phenotyping
At Screening, samples will be collected for HIV-1 RT and PRO genotype using a 
genotype assay and results will be provided to the Investigator to assist in the 
determination of participant eligibility.
Participants experiencing confirmed virologic failure will have plasma samples tested for 
HIV-1 PRO and RT genotype and phenotype and HIV-1 integrase genotype and 
phenotype from both Baseline samples and from samples collected at the time of 
suspected virologic failure; these results will be reported to the Investigator as soon as 
available to provide guidance for election of a switch regimen.
7.8.2.
HIV-1 Exploratory Analysis
Additional exploratory analyses for HIV-1 pol resistance may include viral genotyping 
and/or phenotyping on a representative subset of Baseline samples or virologic analysis 
on stored plasma samples from other time points.  Analyses for HIV-1 resistance may, be 
carried out on peripheral blood mononuclear cell (PBMC) samples collected at Day 1 and 
Week 96 (or Withdrawal visit if prior to Week 96) and/or on stored plasma samples from 
other relevant time points.  These analyses may also include but are not limited to 
additional viral genotyping and/or phenotyping, as well as other virologic evaluations 
such as linkage and minority species analyses, super low HIV-1 RNA quantitation and 
measurement of viral replicative capacity.  HIV-1 integrase genotype and phenotype will 
also be determined on the last on-treatment isolates from all participants who have HIV-1 
RNA 200 c/mL regardless of confirmatory HIV-1 RNA.

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7.9.
Value Evidence and Outcomes
Health outcomes assessments will be conducted according to the Time and Events Table 
(Table 5).  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).  
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 
items and it is derived from the Medical Outcomes Study 36-Item Short Form Health 
Survey. 
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 participants 
in five European countries.  The adaptation of the HIVTSQ included two additional items 
related to the mode of administration (ie: 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 HIVTSQ 12).  
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 subjects) 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 participants 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 

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always equated with the most favorable perception of the injection, and 5 the most 
unfavorable.
The ACCEPT questionnaire is a generic medication acceptance measure assessing how 
participants weigh advantages and disadvantages of long-term medications (Marant, 
2012).  ACCEPT may be a predictor of participants' future adherence to and/or 
persistence with their treatment.  While the ACCEPT questionnaire consists of 25 items 
that capture six dimensions, only the three questions that focus on general acceptance of 
study medication will be used in this study.
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, a shorter version adapted from the 
original version will be used.  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 to 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 “Preference” question will contain a single item exploring whether participants 
prefer the CAB LA + RPV LA injectable treatment or the current oral ART regimen.
Qualitative interviews may also be conducted regarding the subject’s experience on the 
injection regimen. This would be conducted under a separate IRB/IEC approved consent.  
Participation in the interviews would be voluntary.
7.9.1.
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 Week 4b, Week 24, Week 44, Week 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 Weeks 24, 48, 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 the tolerability of injections (using the NRS) at Weeks 5, 
40, 41, 96.
7.9.2.
Value Evidence and Outcomes Endpoints (Exploratory)

The “Preference” question will be assessed at Week 48 (primary analysis) in 
participants randomized to the “CAB LA and RPV LA” arm to explore participant 
preference between CAB LA + RPV LA injectable regimen and ARV 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 MedDRA 
(Medical Dictionary for Regulatory Activities) 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.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
This study is designed to show that the antiviral effect of oral ABC/DTG/3TC followed 
by intramuscular CAB LA + RPV LA regimen is non-inferior to continuation of 
ABC/DTG/3TC at Week 48 of maintenance treatment.  Non-inferiority in the proportion 
of participants with virologic failure at Week 48 (per FDA’s snapshot algorithm for 
assessing HIV-1 RNA 50 c/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 – ABC/DTG/3TC) is less than 6%.

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If fla is the failure rate on CAB LA + RPV LA and fc is the failure rate on comparator arm 
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 the 
continuation of ABC/DTG/3TC 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 c/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 ABC/DTG/3TC arm 
were 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, 201585, 
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.
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 (Center for Drug Evaluation and Research, Human Immunodeficiency Virus-1 
Infection: Developing Antiretroviral Drugs for Treatment, 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 neighborhood 
of 4% are clinically tolerable, with typical observed rates of virological failure ranging 
from 1 to 3%.

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As this study (201584) and study 201585 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 Snapshot response and failure rates observed in five recent stable switch studies are 
displayed in Table 9, all of which enrolled participants with at least 6 months of prior 
therapy.  To inform the failure rates for early switch studies with INI-based regimens, for 
which no known relevant studies exist, the difference in snapshot failure rates between 
Week 48 and Week 96 observed in recent treatment naive studies with INI- based 
regimens are displayed in Table 10.  These differences provide approximate predictions 
of the failure rates that may be observed for early switch studies enrolling participants 
with 48 weeks of prior initial therapy.  Taken together, these data suggest that a 
reasonable assumption for the true failure rate for the ABC/DTG/3TC control arm is 2%, 
with no clear signal of differential failure rates between early and stable switch studies.

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Table 9
Snapshot Analysis Outcomes in Recent Stable Switch Studies
Week 48
Study
Treatment Arm
HIV-1 RNA
<50 c/mL
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.
[Martinez, 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 2b 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 Phase) of participants previously suppressed at Week 20 to Week 24 

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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 overtime, 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 though there is no clinical 
rationale to suggest that the failure rate is truly higher for the CAB LA + RPV LA 
regimen compared to the control regimen.
Table 11
Snapshot Analysis Outcomes for Phase 2b CAB Studies (Intent-to-
Treat Maintenance Exposed Population)
Week 48
Study
Maintenance Treatment 
Arm
HIV-1 RNA
<50 c/mL
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 + 2 NRTIs (N=56)
89% 
1/56 (2%)
Pooled LA
92%
6/230 (4%)
Week 72 
LATTE (ITT-ME) b
Oral CAB 30 mg + RPV 
(n=53)
83%
9%c
a.
Participants had HIV-1 RNA <50 c/mL at Week (-4) and received oral CAB 30 mg + 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 30 mg + 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 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 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 shows 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

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9.2.3.
Sample Size Re-estimation or Adjustment
No sample-size re-estimation based on response data is planned for this study.
9.2.4.
Sample Size Considerations for Week 124 Extension Switch 
Analysis
For the Week 124 Extension Switch population analysis (Section 9.3.1.6), the primary 
efficacy endpoint of interest is the proportion of participants without oral lead-in who 
have HIV-1 RNA ≥50 c/mL at Week 124 (i.e., 24 weeks from initiation of CAB LA + 
RPV LA, 6-week analysis window, using the FDA Snapshot algorithm).  The endpoint 
will be evaluated descriptively, with no formal statistical comparison to data generated in 
participants receiving oral lead-in by to initiation of CAB LA + RPV LA. 
Table 14 presents the precision in estimation according to sample size and observed 
proportion with HIV-1 RNA 50 c/mL.  For example, if the observed rate is 3% and 250 
Extension switch participants do not receive oral lead-in, then the upper bound of the 
95% CI would be 5.1%.   
Table 14
Precision (Upper Limit of 95% CI) for Single Arm Proportion 
Sample Size 
without Oral Lead-In
Observed Proportion
HIV-1 RNA 50 c/mL
Upper limit of 95% 
Confidence Interval†
175
2%
4.1%
200
2%
3.9%
225
2%
3.8%
250
2%
3.7%
175
3%
5.5%
200
3%
5.4%
225
3%
5.2%
250
3%
5.1%
175
4%
6.9%
200
4%
6.7%
225
4%
6.6%
250
4%
6.4%
† Two-sided confidence Interval calculated using the Wald normal approximation method.
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
9.3.1.1.
All Participants Enrolled
The All Participants Enrolled population will consist of all enrolled participants who 
receive at least one dose of study drug in the Induction Phase.  The All Participants 
Enrolled population will be the secondary population for some analyses. 
9.3.1.2.
Intent-to-Treat Exposed Population (ITT-E)
The ITT-E population consists of all randomized participants who receive at least one 
dose of IP during the Maintenance Phase of the study (on or after Day 1 visit).  

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Participants will be analyzed according to the randomized treatment regardless of what 
treatment was actually received.  Unless stated otherwise, the population used in the 
primary efficacy analysis will be the ITT-E population.
9.3.1.3.
Per-Protocol Exposed 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.
9.3.1.4.
Safety Population
The Safety Population will consist of all randomized participants who receive at least one 
dose of IP during the Maintenance Phase of the study (on or after Day 1 visit).  
Participants will be assessed according to actual treatment received.  Unless otherwise 
stated, the Safety Population will be used for safety analyses.
9.3.1.5.
PK Population
The PK Population will include all participants who receive CAB and / or RPV and 
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.
9.3.1.6.
Extension Switch Population (ES)
The Extension Switch population will include all participants randomized to the 
Maintenance Phase ABC/DTC/3TC arm who switch to and receive at least one dose of 
CAB and/or RPV during the Extension Phase of the study.  The ES population will be 
used to evaluate safety and efficacy of switching to CAB LA + RPV LA, with and 
without oral lead-in. Participants will be assessed according to actual treatment received 
during the Extension Phase.
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 LA + RPV LA – 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 comparisons 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 over time.
9.3.3.
Planned Analyses
At least three analyses will be conducted to evaluate the objectives of the protocol: after 
all randomized participants have completed their visits at Week 48 and Week 96, 
respectively, and after all Extension switch participants (Section 9.3.1.6) have completed 
the Week 124 visit.  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 and study 201585.  An ad-hoc review of 
data by the IDMC will be triggered whenever the number of CVFs (Section 5.4.4) in the 
CAB LA + RPV LA arm 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 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.
201584 is conducted in parallel with study 201585 with the aim to pool data generated 
from the current study with study 201585, 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-1 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 after randomization into the Maintenance Phase.  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 will be made at a one-sided 2.5% level of significance. 
Treatment with CAB LA + RPV LA will be declared non-inferior to continued 
ABC/DTG/3TC if the upper end of a two-sided 95% confidence interval for the 
difference between the two groups (CAB LA + RPV LA – ABC/DTG/3TC) 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 CMH weights.  All CIs will be two-sided and the analysis will be stratified 
according to the Baseline HIV-1 RNA (<100,000, 100,000 c/mL) 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 HIV-1 RNA 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 LA + RPV LA treated participants, mk is the number 
of ABC/DTG/3TC 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

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where
k
k
k
k
N
m
n
W 
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 
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.
Proportion of participants with plasma HIV-1 RNA <200 c/mL and <50 c/mL, and HIV-1 
RNA 200 c/mL and 50 c/mL, respectively, over time will be summarized using the 
Snapshot algorithm.  
Proportion of participants with confirmed virologic failure will also be summarized over 
time. 

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Secondary analyses of efficacy data will include a repeat of the primary snapshot analysis 
of virologic failure and virologic success, as detailed above, at Week 96. 
Absolute values and change from Baseline in plasma HIV-1 RNA and CD4+ cell count 
will be summarized over time.
The incidence of HIV-1 disease progression (AIDS and death) will be presented.
The observed case dataset will be the primary dataset used for analysis of safety 
endpoints.
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
Changes from Baseline in laboratory (including fasting lipids) and vital signs data will be 
summarized.  Vital signs at Day 1 will be summarized.  In addition, the number and 
percentage of participants with graded laboratory toxicities (based on DAIDS categories) 
will be summarized by treatment group.
Change from Baseline in renal and bone biomarkers will be summarized by treatment and 
visit. 
9.4.2.1.
Week 124 Extension Switch Analysis
For the Week 124 Extension Switch population analysis (Section 9.3.1.6), antiviral 
response will be assessed according to the proportion of participants with and without 
oral lead-in, respectively, who have HIV-1 RNA ≥50 c/mL at Week 124 (i.e., 24 weeks 
from initiation of CAB LA + RPV LA, 6 week analysis window, using the FDA 
Snapshot algorithm), with corresponding 95% confidence interval.  The primary efficacy 
endpoint of interest for this analysis is the proportion of participants without oral lead-in 
who have HIV-1 RNA ≥50 c/mL at Week 124. No formal statistical comparison with 
respect to safety and efficacy outcomes will be performed.
Proportion of participants with plasma HIV-1 RNA <200 c/mL and <50 c/mL and 
confirmed virologic failure, respectively, over time will be summarized.
Absolute values and change from Extension Baseline CD4+ cell count will be 
summarized over time.
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

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
Incidence and severity of AEs leading to withdrawal

Incidence of SAEs
Changes from Extension Baseline in laboratory (including fasting lipids) and vital signs 
data will be summarized.  In addition, the number and percentage of participants with 
Extension emergent graded laboratory toxicities (based on DAIDS categories) will be 
summarized by treatment group.
Further details for secondary efficacy, 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).
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 
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.
9.4.4.
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.  

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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.
9.4.5.
Viral Genotyping/Phenotyping Analyses

The incidence of treatment emergent genotypic and phenotypic resistance will be 
summarized by treatment arm for subjects meeting confirmed virologic failure criteria 
(Section 5.4.4).  Details of the analyses to be performed will be specified in the 
reporting and analysis plan (RAP).
9.4.6.
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). 
9.4.7.
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 including Week 48 
and Week 96 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 and Week 96 
will also be summarized by subgroups.  Additional details on subgroup analyses will be 
provided 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 in the 
Maintenance Phase.  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.

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10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, ViiV Healthcare/GSK will obtain favourable opinion/approval 
from the appropriate regulatory agency to conduct the study in accordance with ICH 
Good Clinical Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable 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:

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 any under a 
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.

Signed informed consent must be obtained for each participant prior to 
participation in the study

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to IRB/IEC)

ViiV Healthcare/GSK will provide full details of the above procedures, either 
verbally, in writing, or both.
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.

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
Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
10.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and 
the regulatory agencies may conduct a regulatory inspection at any time during or 
after completion of the study. 

In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss 
the conduct of the study, any findings/relevant issues and to implement any 
corrective and/or preventative actions to address any findings/issues identified.
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor 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 

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those required by local regulations to be maintained elsewhere), in a safe and 
secure location.  

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review 
in conjunction with assessment of the facility, supporting systems, and relevant 
site staff.  

Where permitted by local laws/regulations or institutional policy, some or all of 
these records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.  

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, 
including re-generating a hard copy, if required.  Furthermore, the investigator 
must ensure there is an acceptable back-up of these reproductions and that an 
acceptable quality control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by 
any institutional requirements or local laws or regulations, GSK 
standards/procedures, and/or institutional requirements.  

The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of 
ownership of the records in the event the investigator is no longer associated with 
the site.
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.

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10.8.
Review Committee
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 4.2.8 and the IDMC charter, which is available upon request.

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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
3TC
Lamivudine, EPIVIR
201584
FLAIR (First Long-Acting Injectable Regimen
ABC
Abacavir, ZIAGEN
ABC/3TC
Abacavir/lamivudine, EPZICOM, KIVEXA
ACCEPT
Chronic Treatment Acceptance questionnaire
ABC/DTG/3TC
Abacavir/dolutegravir/lamivudine, TRIUMEQ
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
Acetaminophen
API
Active pharmaceutical ingredient
ARV
Antiretroviral
ART
Antiretroviral therapy
ATV
Atazanavir
AST
Aspartate aminotransferase
AUC
Area under the curve
AUC(0-)
Area under the curve (Area under the plasma drug 
concentration-time curve from pre-dose to the end of the 
dosing interval at steady state)
BP
Blood pressure
BUN
Blood urea nitrogen
CAB
Cabotegravir
CAB LA
Cabotegravir long-acting
CABG
Coronary artery bypass grafting
c/mL
Copies/milliliter
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
CV
Cardiovascular

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CVF
Confirmed virologic failure
CYP3A
Cytochrome P450 3A
DAIDS
Division of Acquired Immunodeficiency Syndrome
DDI
Drug-drug interaction
DILI
Drug induced liver injury
DHHS
Department of Health and Human Services
DNA
Deoxyribonucleic acid
DRE
Disease-Related Events
DRESS
Drug Reaction with Eosinophilia and Systemic Symptoms
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
ETR
Etravirine
EU
European Union
EVG
Elvitegravir
FC
Fold change
FDA
Food and Drug Administration
FDC
Fixed-dose combination
FSH
Follicle Stimulating Hormone
FTC
Emtricitabine
GCP
Good Clinical Practice
GSK
GlaxoSmithKline
HAART
Highly active antiretroviral therapy
HAT-QoL
HIV/AIDS-targeted quality of life
HBc
Hepatitis B core antibody
HbsAg
Hepatitis B surface Antigen
HBV
Hepatitis B virus
hCG
Human chorionic gonadotrophin
HCV
Hepatitis C virus
HDL
High density lipoprotein
HDPE
High density polyethylene
HIV
Human immunodeficiency virus
HIVTSQ
HIV treatment satisfaction questionnaire
HIVTSQc
HIV treatment satisfaction questionnaire (change version)
HIVTSQs
HIV treatment satisfaction questionnaire (status version)
HLA
Human leukocyte antigen
HLA-B
Major Histocompatibility Complex, Class I, B
HR
Heart Rate
HRQL
Health-related quality of life
HSR
Hypersensitivity reaction

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HRT
Hormonal replacement therapy
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IDMC
Independent data monitoring committee
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IM
Intramuscular
IN
Integrase
INI
Integrase inhibitor
INR
International normalized ratio
IP
Investigational Product
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISR
Injection Site Reactions
ITT-E
Intent-to-treat Exposed
ITT-ME
Intent-to-treat Maintenance Exposed
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IV
Intravenous
LA
Long acting
LDH
Lactate Dehydrogenase
LDL 
Low density lipoprotein
LLOD
Lower Limit Of Detection
LPV
Lopinavir
LPV/r
Lopinavir/ritonavir
MAA
Marketing Application Authorization
MCV
Mean corpuscular volume
MedDRA
Medical dictionary for regulatory activities
mg
Milligram
mg/dL
Milligram per deciliter
MHRA
Medicines and Healthcare products Regulatory Agency
m-ITT
modified Intent to Treat
MSD=F
Missing, switch, or discontinuation equals failure
MSDS
Master Safety Data Sheet
ng/mL
Nanogram per millileter
NNRTI
Non-nucleoside reverse transcriptase inhibitor
NRS
Numeric Rating Scale
NRTI
Nucleoside reverse transcriptase inhibitor
OC
Observed case
OLE
Study Name for: Dual treatment with lopinavir-ritonavir 
plus lamivudine versus triple treatment with lopinavir-
ritonavir plus lamivudine or emtricitabine and a second 
nucleos(t)ide reverse transcriptase inhibitor for maintenance 
of HIV-1 viral suppression
PA IC90
Protein adjusted 90% inhibitory concentration

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PBMC
Peripheral Blood Mononuclear Cell
PI
Protease inhibitor
PI
Prediction interval
PIN
Perception of iNjection questionnaire
PI/r
Ritonavir-Boosted Protease Inhibitor
PK
Pharmacokinetic
PP
Per-protocol
PrEP
Pre-Exposure Prophylaxis
PRO
Protease
PRTD
Proximal renal tubule dysfunction
PSRAE
Possible suicidality-related adverse event
PT
Prothrombin Time
PTCA
Percutaneous transluminal coronary angioplasty
PTI
Partial Thromboplastin Time
Q4W
Every 4 weeks
Q8W
Every 8 weeks
QTc
Corrected QT interval 
RAL
Raltegravir
RAMOS NG
Randomization and Medication Ordering System Next 
Generation
RAP
Reporting and Analysis Plan
RBC
Red blood cell
RBP
Retinol binding protein
RNA
Ribonucleic acid
RPR
Rapid plasma reagin
RPV
Rilpivirine, Edurant
RPV LA
Rilpivirine long-acting
RT
Reverse transcriptase
RTV, r
Ritonavir
SAE
Serious adverse event
SF
Short form survey
SJS
Stevens-Johnson syndrome
SOC
Standard of care
SPM
Study Procedures Manual
STR
Single tablet regimen
TAF
Tenofovir alafenamide
TB
Tuberculosis
TDF
Tenofovir disoproxil fumarate
TEN
Toxic epidermal necrolysis
Tmax
Time to maximum concentration
TMC278
Tibotec Medicinal Compound 278
TSQ
Treatment Satisfaction Questionnaire
ULN
Upper limit of normal
UGT
Glucuronosyltransferase
US
United States
USP
United States pharmacopeia

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VAPI 
Vaccines' Perception of Injection
VAS
Visual Analog Scale
VSLC
ViiV Safety and Labeling Committee
WBC
White blood cell
WOCBP
Woman of Childbearing Potential
Trademark Information
Trademarks of ViiV Healthcare
Trademarks not owned by the ViiV 
Healthcare
EPIVIR
Edurant
EPZICOM/KIVEXA
GenoSure
TIVICAY
Genvoya
TRIUMEQ
Monogram Biosciences
TRIZIVIR
PhenoSense
ZIAGEN
Stribild

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12.2.
Appendix 2: Division Of AIDS Table For Grading The Severity 
Of Adult And Pediatric Averse Events 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.
PARAMETERGRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
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 
hospitalizatio
n 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
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
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

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Blood Pressure
Abnormalities1
Hypertension
(with the 
lowest reading
taken after 
repeat testing 
during a visit)
≥ 18 years of
age
140 to < 160
mmHg 
systolic
OR
90 to < 100
mmHg 
diastolic
≥ 160 to < 
180 
mmHg
systolic 
OR
≥ 100 to < 
110
mmHg
diastolic
≥ 180 mmHg
systolic
OR
≥ 110 mmHg
diastolic
Life-threatening 
consequences in a 
participant not 
previously
diagnosed with
hypertension (e.g., 
malignant
hypertension) OR
Hospitalization 
indicated
< 18 years of
age
> 120/80
mmHg
≥ 95th to < 99th
percentile + 5
mmHg 
adjusted for
age, height,
and gender 
(systolic 
and/or 
diastolic)
≥ 99th
percentile + 5
mmHg
adjusted for
age, height,
and gender
(systolic 
and/or
diastolic)
Life-threatening 
consequences in a 
participant not 
previously
diagnosed with
hypertension (e.g., 
malignant
hypertension) OR
Hospitalization 
indicated
Hypotension
No symptoms Symptoms 
corrected with
oral fluid 
replacement
Symptoms
AND IV fluids 
indicated
Shock requiring
use of 
vasopressors or 
mechanical
assistance to 
maintain blood
pressure
Cardiac 
Ischemia or
Infarction
Report only one
NA
NA
New
symptoms
with ischemia 
(stable
angina) OR
New testing
consistent
with ischemia
Unstable 
angina OR
Acute
myocardial 
infarction

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Heart Failure
No
symptoms
AND
Laboratory
or cardiac 
imaging 
abnormalitie
s
Symptoms
with mild to
moderate 
activity or
exertion
Symptoms at
rest or with
minimal
activity or
exertion (e.g., 
hypoxemia) 
OR
Intervention
indicated 
(e.g., oxygen)
Life-threatening 
consequences OR
Urgent intervention
indicated (e.g.,
vasoactive 
medications,
ventricular assist
device, heart 
transplant)
Hemorrhage
(with significant
acute
blood loss)
NA
Symptoms
AND No 
transfusion
indicated
Symptoms
AND
Transfusion
of ≤2 units
packed
RBCs 
indicated
Life-threatening 
hypotension OR
Transfusion of > 2
units packed RBCs 
(for children,
packed RBCs > 10
cc/kg) indicated
Prolonged PR 
Interval or AV
Block
Report only one
> 16 years of
age
PR interval
0.21 to <
0.25 seconds
PR interval ≥ 
0.25
seconds OR
Type I
2nd degree AV
block
Type II 2nd
degree AV 
block OR
Ventricular 
pause ≥ 3.0
seconds
Complete AV block
≤ 16 years of
age
1st degree AV
block
(PR interval
> normal for
age and rate)
Type I 2nd
degree AV
block
Type II 2nd
degree AV 
block OR
Ventricular 
pause ≥ 3.0
seconds
Complete AV block
Prolonged QTc
Interval 2
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)

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
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
Pruritus3
(without skin
lesions)
Itching
causing no or
minimal 
interference
with usual
social & 
functional
activities
Itching
causing
greater than
minimal 
interference
with usual
social & 
functional
activities
Itching
causing 
inability
to
perform 
usual
social & 
functional
activities
NA

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
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. 
Endocrine and Metabolic
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Diabetes Mellitus
Controlle
d without 
medicatio
n
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)

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
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 
consequence
s (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 
consequence
s (e.g., 
myxedema 
coma)

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Lipoatrophy4
Detectable 
by study 
participant
, caregiver,
or 
physician
AND
Causing
no or
minimal
interference 
with usual
social & 
functional
activities
Obvious on
visual 
inspection
AND Causing
greater than 
minimal
interference 
with usual
social & 
functional
activities
Disfiguring
changes
NA
Lipohypertrophy5 Detectable 
by study 
participant
, caregiver,
or 
physician
AND
Causing
no or
minimal
interference 
with usual
social &
functional
activities
Obvious on
visual 
inspection
AND Causing
greater than 
minimal
interference 
with usual
social & 
functional
activities
Disfiguring
changes
NA
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.

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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 
consequenc
es
Bloating or 
Distension
Report only one
Symptoms 
causing no
or minimal 
interferenc
e with 
usual
social & 
functional
activities
Symptoms 
causing greater
than minimal 
interference
with usual
social &
functional
activities
Symptoms 
causing 
inability to
perform usual
social & 
functional
activities
NA
Cholecystitis
NA
Symptoms
AND Medical
intervention 
indicated
Radiologic, 
endoscopic, or 
operative 
intervention 
indicated
Life-
threatening 
consequences 
(e.g., sepsis,
perforation)
Constipation
NA
Persistent
constipation
requiring regular
use of dietary 
modifications, 
laxatives, or
enemas
Obstipation
with manual
evacuation 
indicated
Life-
threatening 
consequences 
(e.g., 
obstruction)

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
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 
interventi
on other 
than iron 
suppleme
nt
Endoscopic 
intervention
indicated
Transfusion
indicated
Life-
threatening 
consequences 
(e.g., 
hypotensive 
shock)

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Mucositis or 
Stomatitis
Report only 
one and specify 
location
Mucosal 
erythema
Patchy 
pseudomembran
es or ulcerations
Confluent 
pseudomembran
es 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 
intermitt
ent AND 
No or 
minimal 
interfere
nce with 
oral 
intake
Persistent nausea 
resulting in 
decreased oral 
intake for 24 to 
48 hours
Persistent nausea 
resulting in 
minimal oral 
intake for > 48 
hours OR 
Rehydration 
indicated (e.g., 
IV fluids)
Life-
threatening 
consequences 
(e.g., 
hypotensive 
shock)
Pancreatitis
NA
Symptoms with 
hospitalization 
not indicated
Symptoms with 
hospitalization 
indicated
Life-
threatening 
consequences 
(e.g., 
circulatory 
failure, 
hemorrhage, 
sepsis)
Perforation
(colon or 
rectum)
NA
NA
Intervention 
indicated
Life-
threatening 
consequences
Proctitis
Rectal 
discomfo
rt with 
no 
interventi
on 
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)

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Rectal 
Discharge
Visible 
discharge
Discharge 
requiring the use 
of pads
NA
NA
Vomiting
Transient 
or 
intermitt
ent AND 
No or 
minimal 
interfere
nce 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

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Myalgia
(generalized)
Muscle pain
causing no or
minimal 
interference
with usual
social & 
functional
activities
Muscle pain
causing greater
than minimal 
interference
with usual
social & 
functional
activities
Muscle 
pain
causing 
inability to
perform 
usual social
& 
functional
activities
Disabling muscle 
pain causing
inability to 
perform basic 
self-care 
functions
Osteonecrosis
NA
No symptoms 
but with
radiographic 
findings AND
No operative 
intervention 
indicated
Bone pain
with 
radiographic 
findings OR
Operative 
intervention
indicated
Disabling bone
pain with 
radiographic 
findings causing
inability to perform
basic self-care 
functions
Osteopenia6
≥ 30 years of
age
BMD t-score
-2.5 to -1
NA
NA
NA
< 30 years of
age
BMD z-score
-2 to -1
NA
NA
NA
Osteoporosis6
≥ 30 years of
age
NA
BMD t-score < -
2.5
Pathologic 
fracture 
(e.g.,
compressio
n fracture 
causing
loss of
vertebral
height)
Pathologic 
fracture causing
life-threatening 
consequences

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
< 30 years of
age
NA
BMD z-score < -
2
Pathologic 
fracture 
(e.g.,
compressio
n 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 Cognitive,
Behavioral, or 
Attentional
Disturbance 
below)
Changes 
causing no 
or minimal 
interference
with usual
social & 
functional
activities
Mild
lethargy or 
somnolence 
causing
greater than
minimal 
interference
with usual
social & 
functional
activities
Confusion,
memory 
impairment,
lethargy, or 
somnolence 
causing
inability to 
perform usual
social & 
functional
activities
Delirium OR
Obtundation
OR Coma

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Ataxia
Symptoms 
causing no
or minimal 
interferenc
e with 
usual social
& 
functional
activities 
OR No
symptoms 
with ataxia 
detected on
examinatio
n
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 
interferenc
e 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
Institutionalizati
on indicated

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Developmental
Delay
< 18
years of
age
Specify type, if
applicable
Mild
developme
ntal delay,
either
motor or
cognitive,
as 
determined
by 
comparison
with a 
developme
ntal 
screening
tool 
appropriate 
for the 
setting
Moderate 
development
al delay, 
either motor
or cognitive,
as 
determined
by 
comparison
with a 
development
al 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 
interferenc
e 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 
interferenc
e with 
usual 
social & 
functional 
activities 
OR No 
symptoms 
with
decreased 
strength on 
examinatio
n
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 
interferenc
e with 
usual 
social & 
functional 
activities 
OR No 
symptoms 
with 
sensory 
alteration 
on 
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

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
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 
consciousn
ess (e.g., 
pre-
syncope)
Loss of 
consciousnes
s with no 
intervention 
indicated
Loss of 
consciousness 
AND 
Hospitalizatio
n 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
Delivery7 
(report using
mother’s 
participant ID)
Delivery at 34
to < 37 weeks 
gestational age
Delivery at 28
to < 34 weeks 
gestational age
Delivery at 24
to < 28 weeks 
gestational age
Delivery at < 
24 weeks 
gestational age
Spontaneous 
Abortion or 
Miscarriage8
(report using
mother’s 
participant ID)
Report only one
Chemical
pregnancy
Uncomplicated 
spontaneous 
abortion or
miscarriage
Complicated 
spontaneous 
abortion or
miscarriage
NA
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

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
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 specific 
plan or intent
Thoughts of
killing oneself
with partial or 
complete plans 
but no attempt
to do so OR
Hospitalization 
indicated
Suicide attempted

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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)

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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 
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)

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Tinnitus
Symptoms 
causing no or
minimal 
interference
with usual
social & 
functional
activities with
intervention
not indicated
Symptoms 
causing greater
than minimal 
interference
with usual
social & 
functional
activities with
intervention 
indicated
Symptoms 
causing 
inability to
perform 
usual social
& functional
activities
NA
Uveitis
No symptoms
AND
Detectable on 
examination
Anterior uveitis 
with symptoms 
OR 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 
bronchospas
m
Acute 
anaphylaxis 
OR Life-
threatening 
bronchospasm
OR Laryngeal
edema
Chills
Symptoms 
causing no or
minimal 
interference
with usual 
social & 
functional 
activities
Symptoms 
causing 
greater than 
minimal 
interference
with usual
social & 
functional
activities
Symptoms 
causing 
inability to
perform 
usual social
& 
functional
activities
NA
Cytokine 
Release
Syndrome9
Mild signs and 
symptoms
AND Therapy
(i.e., antibody 
infusion)
interruption not
indicated
Therapy (i.e., 
antibody
infusion) 
interruption 
indicated
AND
Responds
promptly to
symptomatic 
treatment OR
Prophylactic 
medications 
indicated for ≤
24 hours
Prolonged
severe signs 
and symptoms 
OR
Recurrence of 
symptoms
following 
initial
improvement
Life-
threatening 
consequence
s (e.g., 
requiring
pressor or 
ventilator
support)

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Fatigue or 
Malaise
Report only one
Symptoms 
causing no or
minimal 
interference
with usual 
social & 
functional
activities
Symptoms 
causing 
greater than 
minimal 
interference
with usual
social & 
functional
activities
Symptoms 
causing 
inability to
perform 
usual social
& 
functional
activities
Incapacitating
symptoms of
fatigue or
malaise causing
inability to 
perform basic 
self-care 
functions
Fever (non-
axillary 
temperature
s only)
38.0 to < 38.6°C 
or 100.4 to <
101.5°F
≥ 38.6 to <
39.3°C or ≥ 
101.5 to < 
102.7°F
≥ 39.3 to < 
40.0°C or ≥ 
102.7 to <
104.0°F
≥ 40.0°C or ≥ 
104.0°F
Pain10 (not
associated 
with study
agent 
injections and
not specified
elsewhere)
Specify location
Pain causing
no or minimal
interference 
with usual
social & 
functional
activities
Pain causing
greater than
minimal 
interference
with usual
social & 
functional
activities
Pain causing
inability to
perform usual
social & 
functional
activities
Disabling pain
causing inability
to perform basic 
self-care
functions OR
Hospitalization
indicated
Serum
Sickness11
Mild
signs and 
symptom
s
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 
consequence
s (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

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
2 to 5 years of
age
NA
WHO
Weight-for-
height z-score 
< -2 to ≤ -3
WHO
Weight-
for- height
z-score < -
3
WHO Weight-
for-height z-score 
< -3 with life-
threatening
consequences
< 2 years of
age
NA
WHO
Weight-for-
length z-score 
< -2 to ≤ -3
WHO
Weight-
for- length
z-score < -
3
WHO Weight-
for-length z-score 
< -3 with life-
threatening
consequences
Weight Loss 
(excludes 
postpartum
weight
loss)
NA
5 to < 9%
loss in body
weight from 
baseline
≥ 9 to < 
20% loss in 
body weight
from 
baseline
≥ 20% loss in
body weight from
baseline OR
Aggressive 
intervention 
indicated (e.g.,
tube feeding, total
parenteral 
nutrition)
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, 2007 reference tables may be accessed 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
dysfunction
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

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Injection Site 
Erythema or 
Redness 13
Report only one
> 15 years of
age
2.5 to < 5 cm
in diameter
OR 6.25 to < 
25 cm2
surface area
AND
Symptoms 
causing no or
minimal 
interference
with usual
social & 
functional
activities
≥ 5 to < 10 cm
in diameter OR
≥ 25 to < 100
cm2 surface
area OR 
Symptoms 
causing greater
than minimal
interference 
with usual
social & 
functional
activities
≥ 10 cm in
diameter OR ≥ 
100 cm2 surface 
area OR
Ulceration OR
Secondary 
infection OR
Phlebitis OR
Sterile abscess 
OR Drainage 
OR Symptoms 
causing inability
to perform usual
social & 
functional
activities
Potentially
life-
threatening 
consequence
s (e.g., 
abscess,
exfoliative 
dermatitis,
necrosis 
involving
dermis or 
deeper
tissue)
≤ 15 years of
age
≤ 2.5 cm in
diameter
> 2.5 cm in
diameter with < 
50% surface 
area of the 
extremity 
segment
involved (e.g.,
upper arm or 
thigh)
≥ 50% surface 
area of the
extremity
segment 
involved (e.g.,
upper arm or
thigh) OR
Ulceration OR
Secondary
infection OR
Phlebitis OR
Sterile abscess 
OR Drainage
Potentially
life-
threatening 
consequence
s (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

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
≤15 years of
age
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15
years of age
Same as for
Injection Site 
Erythema or 
Redness, ≤ 15
years of age
Same as for
Injection Site 
Erythema or 
Redness, ≤ 15
years of age
Same as for
Injection Site 
Erythema or 
Redness, ≤ 15
years of age
Injection Site 
Pruritus
Itching
localized to the 
injection site 
that is relieved 
spontaneously
or in < 48
hours of 
treatment
Itching beyond
the injection
site that is not
generalized OR
Itching
localized to the 
injection site 
requiring ≥ 48
hours treatment
Generalized 
itching causing
inability to 
perform usual
social & 
functional
activities
NA
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
Albumin,
Low
(g/dL;
g/L)
3.0 to < LLN
30  to < LLN
≥ 2.0 to < 3.0
≥ 20  to < 30
< 2.0
< 20
NA

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Alkaline 
Phosphatase, 
High
1.25 to
< 2.5 x
ULN
2.5  to < 5.0 x
ULN
5.0 to < 10.0 x
ULN
≥ 10.0 x ULN
Alkalosis
NA
pH > ULN to ≤ 
7.5
pH > 7.5
without life-
threatening 
consequences
pH > 7.5 with
life-
threatening 
consequences
ALT or SGPT,
High
Report only one
1.25 to
< 2.5 x
ULN
2.5 to < 5.0 x
ULN
5.0  to < 10.0 x
ULN
≥ 10.0 x ULN
Amylase 
(Pancreatic) or
Amylase (Total),
High
Report only one
1.1  to < 1.5 x
ULN
1.5  to < 3.0 x
ULN
3.0  to < 5.0 x
ULN
≥ 5.0 x ULN
AST or SGOT,
High
Report only one
1.25 to
< 2.5 x
ULN
2.5  to < 5.0 x
ULN
5.0  to < 10.0 x
ULN
≥ 10.0 x ULN
Bicarbonate, Low
(mEq/L;
mmol/L)
16.0 to <  LLN
16.0 to <  LLN
11.0 to < 16.0
11.0 to < 16.0
8.0  to < 11.0
8.0  to < 11.0
< 8.0
< 8.0
Bilirubin
Direct
Bilirubin14,
High
> 28 days of
age
NA
NA
> ULN
> ULN with
life-
threatening
consequences (e.g.,
signs
and symptoms of
liver failure)
≤ 28 days of
age
ULN to ≤ 1
mg/dL
> 1 to ≤ 1.5
mg/dL
> 1.5 to ≤2
mg/dL
> 2 mg/dL
Total
Bilirubin,
High
> 28 days 
of age
1.1 to < 1.6 x
ULN
1.6 to < 2.6 x
ULN
2.6 to < 5.0 x
ULN
≥ 5.0 x ULN
≤ 28 days of
age
NA
NA
NA
NA

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
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)
≥ 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

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
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

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
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 CKD-EPI and Schwatrz in 
mL/min/1.73m2).
16. To convert a magnesium value from mg/dL to mmol/L, laboratories should multiply by 0.4114.

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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/mm
3;
cells/L)
> 5 years
of age
(not HIV
infected)
600  to < 650
0.600 x 109 to
< 0.650 x 109
500  to < 600
0.500 x 109 to
< 0.600 x 109
350 to < 500
0.350 x 109 to
< 0.500 x 109
< 350
< 0.350 x 109
Absolute 
Neutrophil
Count 
(ANC), Low
(cells/mm3;
cells/L)
> 7 days
of age
800 to 1,000
0.800 x 109
to 1.000 x 
109
600 to 799
0.600 x 109 to
0.799 x
109
400 to 599
0.400 x 109 to
0.599 x
109
< 400
< 0.400 x 109
2 to 7 days of
age
1,250 to 1,500
1.250 x 109
to 1.500 x 
109
1,000 to 1,249
1.000 x 109 to
1.249 x
109
750 to 999
0.750 x 109 to
0.999 x
109
< 750
< 0.750 x 109
≤ 1 day of age
4,000 to 5,000
4.000 x 109 to
5.000 x 109
3,000 to 3,999
3.000 x 109 to
3.999 x
109
1,500 to 2,999
1.500 x 109 to
2.999 x
109
< 1,500
< 1.500 x 109

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Fibrinogen,
Decreased
(mg/dL; g/L)
100  to < 200
1.00 to < 2.00
OR
0.75 to < 
1.00 x
LLN
75  to < 100
0.75 to < 1.00
OR
≥ 0.50 to < 0.75
x LLN
50  to < 75
0.50 to < 0.75
OR
0.25 to
< 0.50 x
LLN
< 50
< 0.50
OR
< 0.25 x LLN
OR
Associated
with gross 
bleeding
Hemoglobin17,
Low
(g/dL;
mmol/L)18
≥ 13 years of age
(male only)
10.0 to 10.9
6.19 to 6.76
9.0 to < 10.0
5.57 to < 6.19
7.0 to < 9.0
4.34 to < 5.57
< 7.0
< 4.34
≥ 13 years of age
(female only)
9.5 to 10.4
5.88 to 6.48
8.5 to < 9.5
5.25 to < 5.88
6.5 to < 8.5
4.03 to < 5.25
< 6.5
< 4.03
57 days of age to 
< 13 years of age
(male and female)
9.5 to 10.4
5.88 to 6.48
8.5 to < 9.5
5.25 to < 5.88
6.5 to < 8.5
4.03 to < 5.25
< 6.5
< 4.03
36 to 56 days of 
age
(male and female)
8.5 to 9.6
5.26 to 5.99
7.0 to < 8.5
4.32 to < 5.26
6.0 to < 7.0
3.72 to < 4.32
< 6.0
< 3.72
22 to 35 days of 
age
(male and female)
9.5 to 11.0
5.88 to 6.86
8.0 to < 9.5
4.94 to < 5.88
6.7 to < 8.0
4.15 to < 4.94
< 6.7
< 4.15
8 to ≤ 21 days of 
age
(male and female)
11.0 to 13.0
6.81 to 8.10
9.0 to < 11.0
5.57 to < 6.81
8.0 to < 9.0
4.96 to < 5.57
< 8.0
< 4.96
≤ 7 days of age
(male and female)
13.0 to 14.0
8.05 to 8.72
10.0 to < 13.0
6.19 to < 8.05
9.0 to < 10.0
5.59 to < 6.19
< 9.0
< 5.59

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
INR, High
(not on 
anticoagulation 
therapy)
1.1  to < 1.5 x 
ULN
1.5  to < 2.0 x 
ULN
2.0  to < 3.0 x 
ULN
≥  3.0 x ULN
Methemoglobin
(% hemoglobin)
5.0  to < 
10.0%
10.0  to < 
15.0%
15.0  to < 
20.0%
≥  20.0%
PTT, High
(not on 
anticoagulation 
therapy)
1.1  to < 1.66 
x ULN
1.66 to < 2.33 
x ULN
2.33 to < 3.00 x
ULN
≥  3.00 x ULN
Platelets, 
Decreased
(cells/mm3; 
cells/L)
100,000  to
< 124,999
100.000 x 109  
to
< 124.999 x 
109
50,000  to
< 100,000
50.000 x 109  to
< 100.000 x 
109
25,000  to
< 50,000
25.000 x 109  to
< 50.000 x 109
< 25,000
< 25.000 x 109
PT, High
(not on 
anticoagulation
therapy)
1.1  to < 1.25 
x ULN
1.25  to < 1.50 
x ULN
1.50  to < 3.00 
x ULN
≥  3.00 x ULN
WBC, Decreased
(cells/mm3; cells/L)
> 7 days of age
2,000 to 2,499
2.000 x 109 to 
2.499 x 109
1,500 to 1,999
1.500 x 109 to 
1.999 x
109
1,000 to 1,499
1.000 x 109 to 
1.499 x
109
< 1,000
< 1.000 x 109
≤ 7 days of age
5,500 to 6,999
5.500 x 109 to 
6.999 x 109
4,000 to 5,499
4.000 x 109 to 
5.499 x 109
2,500 to 3,999
2.500 x 109 to 
3.999 x
109
< 2,500
< 2.500 x 109

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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
17. Male and female sex are defined as sex at birth.
18. The conversion factor used to convert g/dL to mmol/L is 0.6206 and is the most commonly 
used conversion factor.  For grading hemoglobin results obtained by an analytic method with a 
conversion factor other than 0.6206, the result must be converted to g/dL using the appropriate 
conversion factor for the particular laboratory.
Urinalysis
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Glycosuria
(random 
collection
tested by 
dipstick)
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
indicated
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.tech-
res.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 subject 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 
15, 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 16, 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.
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)

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
subject 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 (Table 15, Figure 9): 

Principal Investigator (PI) requests consideration of drug rechallenge for a subject 
receiving compelling benefit from a critical or life-saving drug, who exhibits 
liver chemistry elevation meeting subject stopping criteria 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 subject’s rechallenge risk factors (consultation with the 
Hepatotoxicity Panel is available) and complete checklist (Table 15).

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 subject and no 
alternative therapy 
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)

Subject currently exhibits severe liver injury defined by: ALT 
>3xULN, bilirubin >2xULN (direct bilirubin >35% of total, if 
available), or INR>1.5

SAE or fatality has earlier been observed with IP rechallenge

IP 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:  

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
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.
Table 15
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 subject and no alternative 
therapy.  Provide brief explanation:
Relative benefit-risk favorable for drug rechallenge, after 
considering the following high risk factors:
Initial liver injury event included:
fever, rash, eosinophilia, or hypersensitivity
bilirubin2xULN (direct bilirubin >35% of total)
Subject 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
Subject 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 subject 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
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.

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VSLC DECISION PROCESS FOR DRUG RESTART APPROVAL OR 
DISAPPROVAL 

Principal Investigator (PI) requests consideration of drug re-initiation for a 
subject stable or improving on IP, who exhibits liver chemistry elevation 
meeting subject stopping criteria, which is transient, non-drug-related, and 
liver chemistries have improved to normal or are within 1.5x baseline and 
ALT< 5xULN. 

GSK Medical Monitor and GCSP Physician to review the subject’s diagnosis 
restart risk factors (Hepatotoxicity Panel consultation is available) and complete 
checklist (Table 16).
–
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.
Table 16
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 subject 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

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Figure 10
VSLC process for drug restart approval or disapproval
Subject 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 subject 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 subject 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#
Subject#
Rechallenge or Restart?
Safety outcome*
Drug benefit
Rechallenge/restart safety outcomes:

0 = no liver chemistry elevation

1 = recurrent liver chemistry elevation not meeting subject stopping criteria

2 = recurrent liver chemistry elevation meeting subject stopping criteria

3 = serious adverse event

4 = fatality

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12.4.
Appendix 4: CDC Classification System for HIV-1 Infections 
(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 

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
Cryptococcosis, extrapulmonary 

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 the relationship between genetic 
variants and: 

Response to medicine, including CAB + RPV, ABC/DTG/3TC, or any 
concomitant medicines;

HIV-1 infection susceptibility, severity, and progression and related conditions
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic 
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research.  Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.  

A 6 mL blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. 
A blood sample is collected at the baseline visit, after the subject has been 
enrolled 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 subject by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number). 
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study, or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form.  Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product.
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.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA 
sample is retained

Discontinue participation in the genetic research and destroy the genetic DNA 
sample 
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis. 

If a subject withdraws consent for genetic research and genotype data has not been 
analyzed, it will not be analyzed or used for future research.  

Genetic data that has been analyzed at the time of withdrawn consent will 
continue to be stored and used, as appropriate. 
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 

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

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

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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:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event.  It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires 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.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity
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 

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significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption
e.
Is a congenital anomaly/birth defect
f.
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
g.
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.

Refer to Appendix 3 for the required liver chemistry follow-up instructions

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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 
the scale’s developer.

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
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.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

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
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 eCRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
12.6.6.
Reporting of SAEs to ViiV Healthcare / GSK
SAE reporting to ViiV Healthcare / GSK via electronic data collection tool

Primary mechanism for reporting SAEs to ViiV Healthcare / 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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12.7.
Appendix 7: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below).
Women in the following categories are not considered WOCBP
a. Premenarchal
b. Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
c. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment.
12.7.1.
Contraception Guidance
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in 
Table 17. 

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Table 17
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulationb

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.) 
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the participant.)
NOTES: 
a.
Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for participants in clinical 
studies. 
b.
Two highly effective methods of contraception should be utilized from 30 days prior to the first dose of study 
medication, throughout the study, and for at least 52 weeks after discontinuation of CAB LA and RPV LA .
Pregnancy Testing
o
WOCBP should only be included after a confirmed menstrual period and a 
negative highly sensitive serum pregnancy test.
o
Additional pregnancy testing should be performed as per the study Time and 
Events Table.

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o
Pregnancy testing will be performed whenever a menstrual cycle is missed or 
when pregnancy is otherwise suspected.
o
Pregnancy testing will be performed and assayed in the central laboratory OR 
using the test kit provided by the central laboratory / provided by the sponsor 
/approved by the sponsor and in accordance with instructions provided in its 
package insert.
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.  Generally, follow-up will not be required for longer than 6 to 
8 weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in Appendix 6. 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 participant who becomes pregnant while participating will discontinue study 
medication and be withdrawn from the study.  If the participant is receiving CAB 
LA + RPV LA, they will be followed for 52 weeks in the Long-Term Follow-Up 
Phase.

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12.8.
Appendix 8: Country Specific Requirements
12.8.1.
United Kingdom (UK)
This requirement has been included based on requests from the Medicines and Healthcare 
products Regulatory Agency (MHRA) to include information on the specific duration of 
the Extension or Continuation Phase/Study Treatment for similar Phase 3 trials.
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. For participants in the UK, estimating a 6 
month recruitment period, Marketing Application Authorisation (MAA) submission in 
1-2Q2019, and 14 to 15 months approval time for the MAA, the Extension Phase is 
anticipated to conclude by approximately 2-3Q2020. During this time, participants will 
be monitored every 4 weeks to ensure they continue to derive clinical benefit from CAB 
LA + RPV LA.
12.8.2.
Japan
Pharmacokinetics
For Japanese participants in the study, blood samples for CAB will be taken at the visit 
shown in the following table in addition to the visits scheduled in Table 5 of Section 7.1
(Time and Event Table) in the protocol.
Table 18
Additional PK Visit and Sample Times for Japanese Participants
Day
Time (Related to Dosing of Study agent)
Oral Cabotegravir
Day 1 (following first oral dose 
during lead-in phase)
Pre-dose, 1, 2, 3, 4, 8, and 24 hours post-dose
The total, maximum, amount of blood drawn for PK during this entire study is 
approximately 146 mL for Japanese participants.
Plasma concentration-time data on Day 1 and Week 4b in Japanese participants will be 
analyzed by non-compartmental methods with WinNonlin.  Calculations will be based on 
the actual sampling times recorded during the study.  From the plasma concentration-time 
data, pharmacokinetic parameters (e.g. Cmax, AUC, tmax, etc) will be determined, as
data permit. Pharmacokinetic data will be presented in graphical and/or tabular form and
will be summarized descriptively as appropriate. Plasma concentration levels of the drug
from this study will be also evaluated using a population pharmacokinetics model.
Full details of all summaries and analyses will be included in the RAP.

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12.9.
Appendix 9:  Protocol Amendments
12.9.1.
Amendment 01 (All Countries)
PROTOCOL AMENDMENT RATIONALE
The rationale for this amendment includes changes to the following:  added new primary 
Medical Monitor contact information; added lipid objective and endpoint back in to the 
table within the Synopsis section; added clarification of text for patient reported outcome 
endpoints; added additional clarification regarding provision of CAB LA and RPV LA 
until available through public/government health sectors; new text added to allow use of 
local labs to determine eligibility in exceptional circumstances; updated Time and Events 
Table to provide more clarity around assessments conducted during the Extension Phase, 
added ‘X’ to include collection of cardiovascular risk information at Screening, added 
temperature to Vital Signs row, added row for randomization, and clarified timings for 
completion of patient reported questionnaires relative to other clinical assessments in the 
table footnotes; clarified timing of dosing for abacavir/dolutegravir/lamivudine 
(ABC/DTG/3TC, Triumeq) for the Day 1 visit; added additional clarification that 
participants of child bearing potential must continue contraception for at least 52 weeks 
after the last injection; revised text to say that Investigators may provide ‘bridging’ 
supply after consultation with Medical Monitor (vs Medical Monitor authorizing bridging 
supply); provided clarification that cabotegravir and rilpivirine exposure may persist for 
more than one year in some participants after intramuscular administration (with added 
references); minor edits to prohibited medication information; added statement that drugs 
that cause Torsade de Pointes should be used with caution when taking rilpivirine; 
additional clarification that background NRTI therapy is not considered Investigational 
Product and accountability will not be done for NRTI background; changed film coat 
color for Tivicay (dolutegravir) from white (clinical trial material supply) to yellow 
(commercial supply) and removed statement to “protect from light” (for both Triumeq 
and Tivicay); sentence added for collection of additional details for the injection device 
used for IM administration; additional information included regarding randomization 
schedule; added text stating the investigator must discuss long-term commitment for the 
study with potential participants; added statement regarding serofast RPR results; allowed 
serum pregnancy testing where required locally (e.g. when urine testing is not available);  
removed duplicate text regarding monitoring for suicidal related events; added option for 
patient reported outcomes to be collected on paper instrument if needed; removed 
information in Appendix requiring collection of pregnancy information for female 
partners of male study participants; definition of ACCEPT, HIVTSQc, and HIVTSQs 
added to abbreviations table, duplication of ICH abbreviation removed; other minor 
corrections (e.g., updated references, adding cross reference to sections, correction of 
hyperlink to one table).
New text is bolded below (Table headings and bolded text within the existing document 
may also appear in bold font).  Deleted text has strikethrough in original text field, or is 
noted as ‘deleted text’.

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PROTOCOL CHANGES / CLARIFICATIONS
Medical Monitor/Sponsor Information Page
Rationale:  Updated Medical Monitor information page to include contact information 
for new Medical Monitor:
Original Text:
Primary Medical Monitor/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:  
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: 
Revised Text:
Primary Medical Monitor/SAE Contact Information: 
 DO, MSc
ViiV Healthcare
Research Triangle Park
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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Five Moore Drive, Research Triangle Park, NC 27709 (USA)
Mobile: 
Office Telephone: 
Fax: 
e-mail:  
Secondary Medical Monitor:
 MD, MPH
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:
 DO, MSc
ViiV Healthcare
Research Triangle Park
Five Moore Drive, Research Triangle Park, NC 27709 (USA)
Mobile: 
Office Telephone: 
Fax: 
e-mail: 
Section 1 Protocol Synopsis; Objective/Endpoints:
Rationale:  Secondary lipid endpoint and objective inadvertently left out of synopsis 
table (included in Section 3.  Objective and Endpoints)
Added Text:
Objectives
Endpoints
To evaluate the effects of CAB LA + RPV 
LA every 4 weeks on fasting lipids over 
time compared to continuation of 
ABC/DTG/3TC over time.

Change from Baseline in fasting lipids 
over time including Week 48 and 
Week 96.
Section 1 Protocol Synopsis; Objective/Endpoints AND Section 3 Objectives and 
Endpoints:
Rationale:  Clarification provided for Health Outcomes Endpoints
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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Original Text:
Objectives
Endpoints
To assess the acceptance of pain and 
injection site reactions following injections.

Dimension scores (e.g., “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). 

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 treatment satisfaction of CAB LA + 
RPV LA compared to continuation of 
ABC/DTG/3TC.

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 degree of health-related quality of 
life (HR QoL) 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 HR QoL from Day 1 and
Week 24, Week 48, Week 96 (or 
Withdrawal).
To assess the health status using the 12-item 
Short Form Survey (SF-12).

Summary statistics and between and 
within treatment group comparisons of 
change in health status from Day 1 and
Week 24, Week 48, and Week 96 (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 (using 
the ACCEPT) from Day 1 and Week 8, 
Week 24, Week 48, Week 96 (or 
Withdrawal).

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Objectives
Endpoints
To assess tolerability of injections using the 
Numeric Rating Scale (NRS) for participants 
randomized to the CAB + RPV LA arm.

Summary statistics and within treatment 
group comparisons and change in 
tolerability of injection from Week 4b,
Week 5, Week 40, Week 41, and 
Week 96.
Revised Text:
Objectives
Endpoints
To assess the acceptance of pain and 
injection site reactions following injections.

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).
To assess treatment satisfaction of CAB LA + 
RPV LA compared to continuation of 
ABC/DTG/3TC.

Change from baseline in total “treatment 
satisfaction” score, and individual item 
scores of the HIV Treatment 
Satisfaction Questionnaire (status 
version) (HIVTSQs) at Week 4b, 
Week 24, Week 44, Week 96 (or 
Withdrawal).

Change in treatment satisfaction over 
time (using the HIVTSQ change version 
[HIVTSQc]) at Week 48 (or Withdrawal).
To assess degree of health-related quality of 
life (HR QoL).

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 health status.

Change from Baseline in health status at 
Week 24, Week 48, and Week 96 (or 

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Objectives
Endpoints
Withdrawal) using the 12-item Short 
Form Survey (SF-12).
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 
injections at Week 5, Week 40, Week 41, 
and Week 96 using the Numeric Rating 
Scale (NRS) within the CAB LA + RPV 
LA arm.
Section 1 Protocol Synopsis: Overall Design; 
Section 1 Treatment Arms and Duration (both Induction and Maintenance Phase 
Sections); 
Section 4.1 Overall Design; 
Section 4.2.2 Induction Phase; 
Section 4.2.3, Maintenance Phase (Day 1 to Week 100); and 
Section 6.3 Dose and Administration:
Rationale:  New text added providing clarification of timing of Day 1 dose relative to 
randomization.
New Text Added:
ABC/DTG/3TC dosing on Day 1 should 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 ABC/DTG/3TC prior to coming 
into the clinic, randomization and initiation of oral CAB and RPV should continue 
as planned for Day 1.
Section 1 Protocol Synopsis, Long-Term Follow-Up Phase – IM Regimen Only and
Section 4.2.6.  Long-Term Follow-Up Phase – IM Regimen Only
Rationale:  Clarification added that adequate contraception must be used for at least 52 
weeks (rather than stating throughout the entire year of follow-up):
Original Text:
Female participants of child bearing potential must continue to use adequate 
contraception methods for the entire year of follow-up.

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Revised Text:
Female participants of child bearing potential must continue to use adequate 
contraception methods for at least 52 weeks after the last injection.
Section 1 Protocol Synopsis, Protocol Permitted Substitutions, and
Section 6.8.1 Oral Bridging
Rationale:  Text revised to state Investigators may provide bridging supply following 
consultation with the Medical Monitor (vs Medical Monitor authorizing bridging supply)
Original Text:
Following the Induction Phase, 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.
Revised Text:
Following the Induction Phase, in exceptional circumstances, and in consultation with 
the Medical Monitor, Investigators may provide oral CAB and RPV as a short-term 
“bridging” strategy for participants who have begun CAB LA + RPV LA and who will 
miss a subsequent scheduled LA injection.  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 4.2.1. Screening Phase
Rationale:  New text added to allow use of local labs to determine eligibility in 
exceptional circumstances.
New Text Added:  
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.  Similarly, if a central 
laboratory result cannot be generated for genotype/phenotype, a local result can be 
considered following review and approval by the study virologist.

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Section 4.2.3.  Eligibility for the Maintenance Phase – Text Slightly Revised and 
Moved to Section 4.2.4.  Maintenance Phase (Day 1 to Week 100)
Rationale:  Text is referring to potential safety issues while a participant is taking oral 
CAB and RPV, which will not be administered until Day 1 of the Maintenance Phase.
Original Text:
In addition to the viral load criteria above, if in the opinion of the Investigator, a 
participant experiences a significant safety event while taking either CAB or RPV, 
Maintenance eligibility will be determined ONLY in consultation with the Medical 
Monitor.  Any rash that is possibly related to study drug, and is present between Day 1 
and Week 4b, must be discussed with the Medical Monitor prior to initiation of CAB LA 
or RPV LA (See Section 7.4.5.13).
Revised Text:
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 between Day 1 and Week 4b, must be discussed with the 
Medical Monitor prior to initiation of CAB LA or RPV LA (See Section 7.4.5.13).
Section 4.2.5.1.  Participants Entering from the CAB LA + RPV LA Arm
Rationale:  Added additional clarification regarding provision of CAB LA and RPV LA 
until available through public/government health sectors.
Original Text:
All participants who successfully complete 100 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 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.  
Revised Text:
All participants who successfully complete 100 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 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.  

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Section 4.2.5.2.  Participants Entering from the ABC/DTG/3TC Arm
Rationale:  Clarification that labs must be reviewed before the Week 104b visit.
Original Text:
In addition, central lab results and safety parameters from the Week 104a visit must be 
available and reviewed.
Revised Text:
In addition, central lab results and safety parameters from the Week 104a visit must be 
available and reviewed before the Week 104b visit.
Section 4.6.1.  Risk Assessment
Rationale:  Clarification that CAB and RPV can have residual concentrations beyond 1 
year.
Original CAB Text:
Development of Resistance 
following discontinuation 
of CAB LA
Residual concentrations of CAB would remain in the 
systemic circulation of participants for prolonged periods 
(up to 1 year) despite stopping treatment (e.g. for 
tolerability issues or treatment failure). 
Participants discontinuing CAB LA regimen may be at 
risk for developing HIV-1 resistance to CAB many weeks 
after discontinuing injectable therapy. 
Revised CAB Text:
Development of 
Resistance following 
discontinuation of 
CAB LA
Residual concentrations of CAB would remain in the systemic 
circulation of participants for prolonged periods (more than 1 
year in some participants; GlaxoSmithKline Document 
Number 2016N269422_00; Study 201120) 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. 

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Original RPV Text:
Development of 
Resistance
Residual concentrations of 
RPV would remain in the 
systemic circulation of 
participants who stopped 
treatment (e.g. for 
tolerability issues or 
treatment failure) for 
prolonged periods 
(months).
Participants discontinuing 
a LA regimen may be at 
risk for developing 
resistance to RPV many 
weeks after discontinuing 
injectable therapy.

Alternative oral 
HAART regimens will 
be prescribed within 
four weeks after 
participants stop RPV 
LA.  This would be 
anticipated to result in 
rapid resuppression of 
HIV-1 RNA thus 
minimizing of 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.
Revised RPV Text:
Development of 
Resistance
Residual concentrations of 
RPV can remain in the 
systemic circulation of 
participants who stopped 
treatment (e.g. for 
tolerability issues or 
treatment failure) for 
more than one year in 
some participants 
[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 
four weeks after 
participants stop RPV 
LA.  This would be 
anticipated to result in 
rapid resuppression of 
HIV-1 RNA thus 
minimizing of 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.

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Section 4.6.1.  Risk Assessment, CAB Table
Rationale:  allowance of short term glucocorticoids use changed from 14 days to 21 days 
within CAB table.
Original Text:
Drug-Drug 
Interactions 
(DDIs)
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. 
Revised Text:
Drug-Drug 
Interactions 
(DDIs)
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 5.1. Inclusion Criteria:
Rationale:  New text added to allow use of local labs to determine eligibility in 
exceptional circumstances.
New Text Added:  
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.  Similarly, if a central 
laboratory result cannot be generated for genotype/phenotype, a local result can be 
considered following review and approval by the study virologist.
Section 5.2. Exclusion Criteria #21:
Rationale:  Short term corticosteriod use modified to 21 days, further clarified this 
exemption is related to chronic (vs short term use).
Original Text:
Immunomodulators that alter immune responses (such as systemic corticosteroids, 
interleukins, or interferons).  Note: Participants using short-term (e.g. 14 day) systemic 
corticosteroid treatment, topical, inhaled or intranasal corticosteroids, are eligible for 
enrollment.

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Revised Text:
Immunomodulators that alter immune responses (such as chronic systemic 
corticosteroids, interleukins, or interferons).  Note: Participants using short-term (e.g. 21
day) systemic corticosteroid treatment; topical, inhaled or intranasal corticosteroids, are 
eligible for enrolment.
Section 6.1.  Investigational Product and Other Study Treatment
Rationale:  Provided clarification that dual NRTI to be taken with single entity DTG is 
not considered IP.
Original Text:
In this study, investigational product (IP) refers to oral ABC/DTG/3TC (or alternate DTG 
+ NRTI background therapy), oral CAB, and CAB LA, which will be supplied by 
GlaxoSmithKline and oral RPV and RPV LA which will be supplied by Janssen 
Pharmaceuticals.  
Revised Text:
In this study, investigational product (IP) refers to oral ABC/DTG/3TC single tablet 
regimen (or alternately DTG), oral CAB, and CAB LA, which will be supplied by 
GlaxoSmithKline and oral RPV and RPV LA which will be supplied by Janssen 
Pharmaceuticals.  The dual NRTI background therapy that is administered with single 
entity DTG is not considered IP.
Section 6.1.5.  ABC/DTG/3TC STR – Tablet
Rationale:  Removed statement to ‘protect from light’ as this is not a storage requirement 
for ABC/DTG/3TC.
Original Text:
ABC/DTG/3TC tablets are to be stored at 25°C [77°F] (excursions permitted to 15°-30°C 
[59°-86°F]) and protected from light.
Revised Text:
ABC/DTG/3TC tablets are to be stored at 25°C [77°F] (excursions permitted to 15°-30°C 
[59°-86°F]).
Section 6.1.6.  Dolutegravir – Tablet
Rationale:  Film coat color changed from white (clinical trial material [CTM] color) to 
yellow (commercial supply color), sentence removed that the film coat was the only 
difference between CTM and commercial supply, and statement removed to ‘protect from 
light’.

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Original Text:
Dolutegravir is manufactured by GlaxoSmithKline and will be provided to participants 
who are HLA-B*5701 positive (to be used in combination with 2 NRTIs). DTG 50 mg 
tablets are white, round, biconvex, film-coated tablets. The tablets contain 52.62 mg 
dolutegravir sodium salt, which is equivalent to 50 mg dolutegravir free acid. Each tablet 
is debossed with “SV 572” on one side and “50” on the other side. The tablets are the 
same formulation as the commercial material with the exception of the film coat color.
The tablets are packaged into high density polyethylene (HDPE) bottles with induction 
seals and child-resistant closures. Each bottle contains 30 tablets and a desiccant. DTG 
tablets are to be stored at 25°C [77°F] (excursions permitted to 15°-30°C [59°-86°F]) and 
protected from light.
Revised Text:
Dolutegravir is manufactured by GlaxoSmithKline and will be provided to participants 
who are HLA-B*5701 positive (to be used in combination with 2 NRTIs). DTG 50 mg 
tablets are yellow, round, biconvex, film-coated tablets. The tablets contain 52.62 mg 
dolutegravir sodium salt, which is equivalent to 50 mg dolutegravir free acid. Each tablet 
is debossed with “SV 572” on one side and “50” on the other side.  The tablets are 
packaged into high density polyethylene (HDPE) bottles with induction seals and child-
resistant closures. Each bottle contains 30 tablets and a desiccant. DTG tablets are to be 
stored at 25°C [77°F] (excursions permitted to 15°-30°C [59°-86°F]).
Section 6.2. Treatment Assignment:
Rationale:  Text added to describe the randomization schedule and the benefit of central 
randomization to eliminate selection bias.
New Text:
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 
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.
Section 6.3.  Dose and Administration (in addition to text noted above regarding 
changes to Day 1 ABC/DTG/3TC dosing)
Rationale:  Clarification to dosing table regarding timing of Day 1 ABC/DTG/3TC 
dosing and that Induction Phase is Week [-20] to (vs through) Day 1.

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Original Text:
Induction Phase (Week [-20] through Day 1) – All Subjects
Week (-20) to Day 1
(1 tablet once daily)
Take 1 tablet ABC 600 mg / DTG 50 mg / 3TC 300 mg once daily 
with or without food
And
ABC/DTG/3TC Once Daily Arm*
Day 1 to Week 100
(1 tablet once daily)
Take 1 tablet ABC 600 mg / DTG 50 mg / 3TC 300 mg once daily 
with or without food
Revised Text:
Induction Phase (Week [-20] to Day 1) – All Subjects
Week (-20) to Day 1
(1 tablet once daily)
Take 1 tablet ABC 600 mg / DTG 50 mg / 3TC 300 mg once daily 
with or without food
*Take Day 1 dose after randomization.
And 
ABC/DTG/3TC Once Daily Arm*
Day 1 to Week 100
(1 tablet once daily)
Take 1 tablet ABC 600 mg / DTG 50 mg / 3TC 300 mg once daily 
with or without food
*Take Day 1 dose after randomization.
Section 6.3. Dose and Administration
Rationale: deleted text regarding how often IP was taken (with a meal) on average, as 
this is not recorded in the eCRF.
Deleted Text:
The participant will be asked how often the IP was taken (with a meal) on average, 
since the last visit, and this information will be recorded in the eCRF.

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Section 6.6.  Preparation/Handling/Storage/Accountability
Rationale:  clarification added that accountability will not be done for NRTI background 
therapy taken with single entity DTG.
Original Text:
IP accountability will be evaluated using pill counts of unused IP for participants 
receiving oral treatment (ABC/DTG/3TC [or alternate DTG + NRTIs], oral CAB, oral 
RPV).  This assessment will be conducted each time the participant receives a new/refill 
supply of IP, when the participant completes oral CAB and RPV (including oral bridging 
supply), and through the Withdrawal visit, study completion, or Week 104b of the 
Extension Phase.  
Revised Text:
IP accountability will be evaluated using pill counts of unused IP for participants 
receiving oral treatment (ABC/DTG/3TC [or alternate DTG], oral CAB, oral RPV).  Pill 
counts will not be done for the dual NRTIs taken with DTG, as these will not be 
provided centrally.  IP accountability will be conducted each time the participant 
receives a new/refill supply of IP, when the participant completes oral CAB and RPV 
(including oral bridging supply), and through the Withdrawal visit, study completion, or 
Week 104b of the Extension Phase.  
Section 6.6.1.  Dosing Considerations for CAB LA + RPV LA
Rationale:  Added statement to allow collection of more information on injection 
device..
New Text:  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
Rationale:  Provided clarification that pill counts will not be done for NRTIs taken 
with single entity DTG, that start and stop dates will be recorded in the eCRF, and 
that Investigators should discuss the long-term commitment for the study with the 
participants and have counselling plans in place for both treatment arms.
Original Text:
IP accountability will be evaluated using pill counts of unused IP (CAB and RPV tablets 
at the end of oral dosing [including bridging supply], and ABC/DTG/3TC [or alternate 
DTG + NRTIs]).  This assessment will be conducted each time the participant receives a 
supply of oral study medication.  These data will be recorded in the participant’s eCRF.
When participants are dosed with CAB LA and RPV LA at the site, they will receive IM 
injections directly from the investigator or designee, under medical supervision.  The date 

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and time of each injection of CAB LA and RPV LA administered in the clinic will be 
recorded in the source documents.  These data 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.  
IP accountability will not be assessed during the Long-Term Follow-Up Phase.
Due to the long acting nature of the CAB LA and RPV LA, it will be imperative that the 
participant is compliant with dosing visits.  
Investigators must have plans in place for adherence counselling.  
Revised Text:
IP accountability will be evaluated using pill counts of unused IP (CAB and RPV tablets 
at the end of oral dosing [including bridging supply], and ABC/DTG/3TC [or alternate 
DTG]).  This assessment will be conducted each time the participant receives a supply of 
oral study medication.  These data will be recorded in the participant’s eCRF.  
Treatment start and stop dates will also be recorded in the eCRF.
When participants are dosed with CAB LA and RPV LA at the site, they will receive IM 
injections directly from the investigator or designee, under medical supervision.  The date 
and time of each injection of CAB LA and RPV LA administered in the clinic will be 
recorded in the source documents.  These data 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.  
IP accountability (e.g. pill counts) will not be assessed for alternate NRTIs taken with 
single entity DTG, or during the Long-Term Follow-Up Phase.
Due to the long acting nature of the CAB LA and RPV LA, it will be imperative that the 
participant is compliant with dosing visits.  As part of the screening and participant 
selection process, Investigators must discuss with potential participants the long-
term commitments for the study, and the importance of adhering to treatment 
regimens.
Investigators must have plans in place for adherence counselling for both treatment 
arms.  
Section 6.9.1.  IM Dosing
Rationale:  clarification that both LA drugs may have measurable plasma concentrations 
beyond 1 year, and reiterated the need for HAART as concentrations decline over time.

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Original Text:
Participants receiving CAB LA and/or RPV LA are anticipated to be at high risk for 
development of virologic resistance if ART is interrupted.  The time period during which 
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 drugs may be measurable for approximately 52 weeks
following IM injections.
Revised Text:
Participants receiving CAB LA and RPV LA are anticipated to be at high 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 in 
some participants 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 (e.g. in the Long-Term Follow-Up 
Phase) to minimize the risk of developing resistance as concentrations of CAB and 
RPV decline over time.
Section 6.13.  Concomitant Medications and Non-Drug Therapies;  Oral RPV 
administration Only
Rationale:  Added drugs that may cause TdP should be used with caution during the 
study when taking rilpivirine.
New Text:
Drugs that cause Torsade de Pointes (TdP) should be used with caution when taking 
rilpivirine (see SPM for list of drugs associated with TdP).
Section 6.13.1.  Prohibited Medications and Non-Drug Therapies
Rationale:  Removed restricted duration for topical imiquimod as minimal systemic 
exposure is expected (other than maintaining [‘short term use’], changed duration for 
glucorticoid use to 21 days to allow, e.g., for treatment of pneumocystis pneumonia, 
clarified HCV treatment is also prohibited during Induction.  Corrected typo in 
glucocorticoids.
Original Text:  

Systemically administered immunomodulators (such as interleukin and interferon 
agents) are prohibited (a list of examples is provided in the SPM).  This includes 

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topical agents with substantial systemic exposure and systemic effects.  Short term
use (30 days or less) of topical imiquimod is permitted.   

Acetaminophen (paracetamol) cannot be used in participants with acute viral 
hepatitis (James, 2009).

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.  

Hepatitis C infection therapy is prohibited during the Maintenance Phase before 
the Week 48 primary endpoint, and interferon-based HCV therapy is prohibited 
throughout the entire study.  Options for treatment of hepatitis C should be 
discussed with the Medical Monitor prior to initiation of therapy.
Revised Text:

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 participants with acute viral 
hepatitis (James, 2009).

Chronic use of systemic (oral or parenteral) glucocorticoids must be avoided due 
to the 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, but more than a single dose in a treatment 
course may cause a significant decrease in RPV plasma concentration and is 
prohibited.  Topical, inhaled or intranasal use of glucocorticoids will be allowed.  

Hepatitis C infection therapy is prohibited during the Induction and Maintenance 
Phase before the Week 48 primary endpoint, and interferon-based HCV therapy is 
prohibited throughout the entire study.  Options for treatment of hepatitis C 
should be discussed with the Medical Monitor prior to initiation of therapy.
Section 6.13.1.  Prohibited Medications and Non-Drug Therapies:  Concurrent with 
RPV
Rationale:  Clarification added that local prescribing information for oral RPV should be 
reviewed for drugs that ‘are prohibited’ with RPV as the list within the protocol may not 
be as current as local prescribing information.

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Original Text:
Please refer to the local prescribing information for other drugs that should be used with 
caution, require dose adjustment, or increased clinical monitoring if taken with oral RPV.
Revised Text:
Please refer to the local prescribing information for other drugs that are prohibited,
should be used with caution, require dose adjustment, or increased clinical monitoring if 
taken with oral RPV.
Section 7.1.  Time and Events Table
Rationale:  New text added before table to explain visits and assessments during the 
Extension Phase.
New Text Added Before Table:
Beginning at Week 112, the schedule of assessments for participants continuing in 
the Extension Phase from the CAB LA + RPV LA arm will be modified to collect 
clinical chemistries, HIV-1 RNA, and CD4+ cell count every 12 weeks. 
Participants originally randomized to ABC/DTG/3TC at Day 1, who choose to 
continue into the Extension Phase and transition to CAB LA + RPV LA, will have 
all assessments noted in the Time and Events table below performed Q4W from 
Week 108 through Week 124.  Beginning at Week 124, the schedule of assessments 
for these participants transitioning from ABC/DTG/3TC into the Extension Phase 
will be modified to collect clinical chemistries, HIV-1 RNA, and CD4+ cell count 
every 12 weeks as noted in the Time and Events schedule below.
From Week 124 forward, all participants (from both originally randomized 
treatment arms), will have the same schedule of events (same visits, same 
assessments, same time frame).
Changes to Time and Events Table (see Section 7.1 for example):

Row added for randomization at Day 1

Cardiovascular Risk Assessment:  “X” noted at Screening

Temperature added to Vital Signs row

PK row – Clarified S = Storage sample

Study treatment accountability – Corrected footnote in column for Week 104b to 
reflect footnote ‘u’ instead of footnote ‘v’.

Column added for assessments performed Q4W after Week 108 (LA Arm) or after 
Week 124 (Switch Arm)

Column for Q12W assessments in Extension renamed to clarify assessments begin at 
W112 (LA Arm) and W124 (Switch Arm)

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
Footnote ‘i’ regarding eCSSR completion clarifies that this assessment should be the 
last patient reported outcome assessment completed (still completed at the beginning 
of the visit).

Footnote ‘j’ changed to allow serum pregnancy testing if required locally:  “Serum 
pregnancy test can substitute for urine pregnancy test if locally required, but 
must be appropriately timed to confirm pregnancy status prior to e.g 
randomization and first IM administration.”

Footnote ‘s’ symbol removed from Week 104b column and “- LA Arm Only” added 
to column

Footnote ‘z’ deleted reference to “PIN” questionnaire, added that patient reported 
assessments should be completed prior to eCSSRs assessments, and changed to 
include completion of health outcomes questionnaires at withdrawal if prior to 
Week 96 (vs Week 48).  

Footnote aa:  “NRS” questionnaire added to first sentence, e.g. The PIN, Preference, 
and NRS questionnaires are to be administered only to participants receiving CAB 
LA + RPV LA injections. The NRS should be collected 30 to 60 minutes post-
injection (and at Week 5 and Week 41, one week post-injections)
Section 7.2.1. Screening
Rationale:  New text added to allow use of local labs to determine eligibility in 
exceptional circumstances.  Additionally, text deleted regarding Screening labs available 
prior to ‘randomization’ (earlier statement in preceeding paragraph explains that all 
Screening labs must be available prior to ‘enrollment’[e.g., Week -20]).
Original Text:
Laboratory results from the central laboratory services provided by this trial will be used 
to assess study eligibility.  A single repeat of a procedure / lab parameter is allowed to 
determine eligibility (unless otherwise specified).  All Screening labs must be available 
prior to randomization.
Each participant screened will be assigned a participant number.  Participants not meeting 
all inclusion and exclusion criteria at initial screen may be re-screened one time with a 
new participant number.  Participants who are enrolled into the trial and subsequently 
withdrawn from the study for any reason may not be rescreened.
At Screening, samples for HIV-1 genotypic and phenotypic resistance testing and plasma 
HIV-1 RNA measurement will be obtained.
Revised Text:  
Laboratory results from the central laboratory services provided by this trial will be used 
to assess study eligibility.  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 

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participant eligibility.  A repeat central lab will be submitted concurrently or at the 
next planned visit.  
Each participant screened will be assigned a participant number.  Participants not meeting 
all inclusion and exclusion criteria at initial screen may be re-screened one time with a 
new participant number.  Participants who are enrolled into the trial and subsequently 
withdrawn from the study for any reason may not be rescreened.
At Screening, samples for HIV-1 genotypic and phenotypic resistance testing and plasma 
HIV-1 RNA measurement will be obtained.  If a central laboratory result cannot be 
generated for Screening genotype/phenotype, a local result can be considered 
following review and approval by the study virologist.
Section 7.2.1. Screening
Rationale:  Clarification added that HBV DNA will only be performed for participants 
with positive anti-HBc and negative HBsAg and negative anti-HBs.
Original Text:
HBV DNA will only be performed for participants with both anti-HBc and negative 
HBsAg and negative anti-HBs (past and/or current evidence).
Revised Text:
HBV DNA will only be performed for participants with positive anti-HBc and negative 
HBsAg and negative anti-HBs (past and/or current evidence).
Section 7.2.1.  Screening
Rationale:  Additional information included regarding participants with a serofast RPR 
result.
New Text:
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.
Section 7.4.1. Clinical Evaluations
Rationale:  Clarification of temperature collection.
New Text: 
Temperature will also be collected.
Section 7.4.1. Clinical Evaluations
Rationale:  Added allowance for serum pregnancy testing to replace urine testing if 
locally required.

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New Text: 
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).
Section 7.4.2.  Laboratory Assessments
Rationale:  Footnote ‘g’ added to Table to address when HBV DNA will be performed 
(previously stated in Section 7.2.1. Screening).  Footnote letters within the table updated 
to include this addition.
New Text:
g.
HBV DNA will only be performed for participants with a positive anti-HBc, 
negative HBsAg, and negative anti-HBs (past and / or current evidence).
Section 7.4.3.4.  
Rationale:  Link provided to sections for reporting cardiovascular and death events.
New Text:
Additional information for reporting cardiovascular and death events is included in 
Section 7.4.3.7. and Section 7.4.3.8., respectively.
Section 7.4.6. Suicidal Risk Monitoring
Rationale: Duplicate Text Removed
Original Text:
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.
Revised Text:
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 

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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.
Section 7.4.6.  Suicidal Risk Monitoring
Rationale:  Added text to ensure sites have a plan for managing risk of and possible 
suicide related events.
New Text:
All sites should have a plan in place for managing risk of and possible suicide 
related events.
Section 7.5.1. PK Sample Collection
Rationale:  Added clarification regarding visits windows and sample collection 
windows, and added 20 to 28 hour window for pre-dose samples at Week 4b and 
Week 104b.
Original Text:
PK window for sample collection: Pre-dose visits: 3 days (1st injection), minus 7 days 
(2nd and 3rd injection), and7days (4th and all subsequent injections), 2 hours post dose: 
one hour; one week post dose visits: 3 to 10 days post injection.
Revised Text:
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7 days (4th and all 
subsequent injections);  Sample Collection:  Pre-dose at Week 4b (and Week 104b for 
participants transitioning from ABC/DTG/3TC 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
Rationale:  Added option of paper instrument collection if needed, and clarified timing 
of NRS assessment:

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Original Text:
Health outcomes assessments will be conducted according to the Time and Events Table 
(Table 5).  Assessments are recommended to be administered at the beginning of the visit 
prior to collection of blood for analysis and other scheduled assessments.
Revised Text:
Health outcomes assessments will be conducted according to the Time and Events Table 
(Table 5).  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)
Rationale:  Additional clarification provided for patient reported outcome analyses.
Original Text:

Dimension scores (e.g., “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). 

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 “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).

Summary statistics and between and within treatment group comparisons will be 
assessed on change in treatment acceptance from Day 1 (using the ACCEPT) and
Weeks 8, 24, 48, 96 (or Withdrawal from the study).

Summary statistics and between and within treatment group comparisons will be 
assessed in the broader impact on health status (using the SF-12) from Day 1, and 
Weeks 24, 48, 96 (or Withdrawal from the study).

Summary statistics and between and within treatment group comparisons will be 
asses on change in HR QoL (using the HAT-QoL short form) from Day 1, Weeks 24, 
48, 96 (or Withdrawal from the study).

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
Summary statistics and within treatment group comparisons will be assessed on the 
tolerability of injections (using the NRS) at Weeks 4b, 5, 40, 41, 96 on participants 
randomized to the “CAB LA and RPV LA” arm.  Change in tolerability of injection 
will be assessed from Week 4b and Week 48 (primary analysis), and from Week 4b 
and Week 96 (secondary analysis).
Revised Text:

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 Week 4b, Week 24, Week 44, Week 96 (or 
Withdrawal).

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 Weeks 24, 48, 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 the tolerability of injections (using the NRS) at Weeks 5, 
40, 41, 96.
Section 12.7.2.  Collection of Pregnancy Information
Rationale:  Bullets regarding collecting information for female partner (of male study 
participants) who become pregnant while participating in the study were deleted.  CAB is 
characterized as low risk for teratogenicity or genotoxicity on the basis of available non-
clinical data, and therefore, in the 201584 study, there are not plans to monitor 
pregnancies outcomes in female partners of male subjects, consistent with GSK standard 
operating procedures.  There is also a statement within inclusion criteria number two that 
'ALL subjects participating in the study must be counseled on safer sexual practices to 
minimize risk of HIV transmission.'  While there is an expectation that men taking part in 
the study will practice safe sex, it is not being monitored as part of the study. 

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Removed ‘female’ in statement describing follow-up for participants who become 
pregnant while on LA treatment.
Original Text:
Any female 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.

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.
Revised Text:
Any participant who becomes pregnant while participating will discontinue study 
medication and be withdrawn from the study.  If the participant is receiving CAB 
LA + RPV LA, they will be followed for 52 weeks in the Long-Term Follow-Up 
Phase.
ADMINISTRATIVE CORRECTIONS (E.G. TYPOGRAPHICAL 
ERRORS, NEW REFERENCES)
Throughout document:
Rationale:  Corrected typo in “enrolment” (vs “enrollment”)
Section 4.2.8.  Independent Data Monitoring Committee
Rationale:  clarification that IDMC will review 201584 and 201585, and corrected typo 
with “of of”.
Original Text:
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.

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An IDMC will evaluate accumulating efficacy, tolerability / safety, and PK of of 
CAB LA + RPV LA at predetermined times during the study.  
Revised Text:
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 (201584) and study 201585.
An IDMC will evaluate accumulating efficacy, tolerability / safety, and PK of CAB LA + 
RPV LA at predetermined times during the study.  
Section 5.4.1.2.  Liver Event Adjudication Committee
Rationale:  Added “be” to the following statement:
A liver safety panel will be used to evaluate all subjects who meet liver stopping criteria. 
Uniform sets of data and standards for adjudication will be applied across cases to inform 
outcomes.
Section 5.4.5.1.  HIV-1 RNA Blips
Rationale:  Corrected typo in “scheduled”
Original Text:
Following discussion with the Medical Monitor, additional viral load testing may be 
performed between visits to determine the appropriate participant disposition for the next 
secheduled visit (e.g. if additional injections should be administered).
Revised Text:
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 (e.g. if additional injections should be administered).
Section 7.4.2.  Laboratory Assessments – typo corrected for labelled (vs labeled).
Section 9.2.1. Sample Size Assumptions – hyperlink corrected in second paragraph 
from Table 10 to Table 13, e.g.,  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).  
Section 11.  References
Rationale:  Added references for CAB and RPV exposures beyond 1 year in some 
participants.

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New Text:
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).  
Durban, South Africa.  Abstract TUAC0103.
Section 11.  References
Rationale:  Updated Reference for Hunt CM 2010 and added ICH E2 Reference.
Revised (bolded) / New Text:
Hunt CM.  Mitochrondrial and Immunoallergic Injury Increase Risk of Positive 
Drug Rechallenge After Drug-Induced Liver Injury:  A Systematic Review. Hepatol 
2010;52:2216-2222. 
International Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use.  ICH Harmonised Tripartite Guideline; Clinical 
Safety Data Management:  Definitions and Standards for Expedited Reporting E2A.  
27Oct1994.  Available at:  
https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E2A
/Step4/E2A_Guideline.pdf
Section 12.1  Appendix 1: Abbreviations and Trademarks
The following abbreviations were added to the table:
ACCEPT
Chronic Treatment Acceptance questionnaire
HIVTSQc
HIV treatment satisfaction questionnaire (change version)
HIVTSQs
HIV treatment satisfaction questionnaire (status version)
The following row was deleted the from the table (2 rows with ICH abbreviation):
ICH
International Conference on Harmonisation Harmonisation 
Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use

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Section 12.2 Appendix 2:  Division of AIDS Table – the following typo was 
corrected: (Medical intervention vs Medicamylasal intervention)
Uveitis
No
symptoms
AND
Detectable on 
examination
Anterior
uveitis with 
symptoms OR
Medicamylasal 
intervention
indicated
Posterior or
pan- uveitis 
OR Operative 
intervention
indicated
Disabling
visual loss in 
affected eye(s)
Section 12.3  Appendix 3 Liver Safety – Study Treatment Restart or Rechallenge
“Table” was entered twice in the following sentence (first instance of “Table” has 
been deleted:
–
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 subject 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
Table 14, Figure 9).
12.9.2.
Amendment 02 (All Countries)
Protocol changes for Amendment 02 (19-JUL-2017), from amendment 01 (13-DEC-
2016)
PROTOCOL AMENDMENT RATIONALE
The rationale for this amendment includes:  update of contact information for secondary 
Medical Monitor; modify text to allow dose reduction for participants who have a decline 
in creatinine clearance to <50 mL/min; clarify that for participants not eligible to 
continue into the Maintenance Phase, only samples with HIV-1 RNA > 400 c/mL will be 
sent for resistance testing; add mitigation for ECG pad removal; clarify 3 day window 
is for all oral dosing (both Induction and Maintenance Phase); add "LA Arm" back to 
columns for Week 68, 76, 84, 92 on Time and Events Schedule (hidden when column 
was narrowed); clarify Week 104b visit is specific to those participants transitioning from 
oral IP to CAB LA + RPV LA; clarification added to footnote ‘p’ that genetics sample 
can be collected at any visit after signing informed consent, but the Week [-20] visit is 
preferred; correct footnote on Week 5 visit to reflect footnote 't'; add footnote 'y' back to 
Time and Events column for Withdrawal Visit (for Induction Phase); add clarification to 
Time and Events column that ISR assessments are only conducted for subjects receiving 
injections.  Administrative typographical errors corrected (e.g. clarification provided 
regarding genetics sample taken after participants are enrolled into the study [vs when 

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participants are randomized]), and investigator brochure references updated, references 
added.
PROTOCOL CHANGES / CLARIFICATIONS
Medical Monitor/Sponsor Information Page
Rationale:  Updated phone contact information for secondary Medical Monitor:
Original Text:
Secondary Medical Monitor:
 MD, MPH
ViiV Healthcare
Research Triangle Park
Five Moore Drive, Research Triangle Park, NC 27709 (USA)
Mobile: 
Office Telephone: 
Fax: 
e-mail:  
New Text:
Secondary Medical Monitor:
 MD, MPH
ViiV Healthcare
Research Triangle Park
Five Moore Drive, Research Triangle Park, NC 27709 (USA)
Mobile: 
Office Telephone: 
Fax: 
e-mail:  
Section 1:  PROTOCOL SYNOPSIS, Protocol Permitted Substitutions
Rationale:  Clarification provided that dose reduction for lamivudine is allowed for 
participant’s with creatinine clearance <50 mL/min (consistent with prescribing 
information).
Original Text:
…..  Local prescribing information should be consulted for information regarding use of 
these medications.
Following the Induction Phase, in exceptional circumstances, and in consultation with the 
Medical Monitor, Investigators may provide oral CAB and RPV as a short-term 
“bridging” strategy for participants who have begun CAB LA + RPV LA and who will 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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miss a subsequent scheduled LA injection.  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.
No other dose reductions, modifications, or changes in the frequency of any components 
of any regimen will be allowed during the Maintenance and Extension Phases of the 
study.  
Revised Text:
…..  Local prescribing information should be consulted for information regarding use of 
these medications.  
For consistency with prescribing information, dose reductions of lamivudine (or 
emtricitabine if used as alternate NRTI) are permitted as needed for creatinine 
clearance <50 mL/min throughout the study.  No other dose reductions, modifications, 
or changes in the frequency of any components of any regimen will be allowed during the 
Maintenance and Extension Phases of the study.  
Following the Induction Phase, in exceptional circumstances, and in consultation with the 
Medical Monitor, Investigators may provide oral CAB and RPV as a short-term 
“bridging” strategy for participants who have begun CAB LA + RPV LA and who will 
miss a subsequent scheduled LA injection.  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 4.2.3.  Eligibility for the Maintenance Phase
Rationale:  Clarification provided that only samples with HIV-1 RNA >400 c/mL at 
Week -4 will be resent for resistance testing.
Original Text:
If the participant is ineligible for the Maintenance Phase, samples will be sent to a central 
laboratory for resistance testing and results provided to the Investigator once available.
Revised Text:
If the participant is ineligible for the Maintenance Phase, samples with a HIV-1 RNA 
>400 c/mL will be sent to a central laboratory for resistance testing and results provided 
to the Investigator once available.
Section 4.2.7.  Dose Modifications / Permitted Treatment Substitutions
Rationale:  Clarification provided that dose reduction for lamivudine is allowed for 
participant’s with creatinine clearance <50 mL/min (consistent with prescribing 
information).

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Original Text: 
During the Induction Phase, prior to randomization into the Maintenance Phase at Day 1, 
one switch to an alternate approved background NRTI therapy is allowed for toxicity or 
tolerability management.  The date of a decision to switch the NRTI background therapy 
for toxicity or tolerability management must be documented in the eCRF.  Switches of a 
background NRTI for any other reason are not permitted in the study.  Local prescribing 
information should be consulted for information regarding use of these medications.
A short term bridging supply for participants on the CAB LA + RPV LA arm may be 
permitted following discussion with the Medical Monitor (see Section 6.8.1.).  No other 
dose reductions, modifications, or changes in the frequency of any components of any 
regimen will be allowed during the Maintenance and Extension Phases of the study.  
Revised Text:
During the Induction Phase, prior to randomization into the Maintenance Phase at Day 1, 
one switch to an alternate approved background NRTI therapy is allowed for toxicity or 
tolerability management.  The date of a decision to switch the NRTI background therapy 
for toxicity or tolerability management must be documented in the eCRF.  Switches of a 
background NRTI for any other reason are not permitted in the study.  Local prescribing 
information should be consulted for information regarding use of these medications.
A short term bridging supply for participants on the CAB LA + RPV LA arm may be 
permitted following discussion with the Medical Monitor (see Section 6.8.1.).
For consistency with prescribing information, dose reductions of lamivudine (or 
emtricitabine if used as alternate NRTI) are permitted in the context of renal 
insufficiency (throughout the study), e.g. as needed for creatinine clearance 
<50 mL/min.  
If a dose reduction of lamivudine, a component of TRIUMEQ, is required for 
participants with creatinine clearance less than 50 mL/min, the individual entities 
should be used (e.g. DTG tablets, ABC tablets, 3TC tablets as separate medications, 
with dosing consistent with prescribing information).  DTG can be provided 
centrally through the study.  Single entity products will need to be sourced locally 
and can be reimbursed by the Sponsor as needed.  Lamivudine (3TC) dose 
reduction will be allowed throughout the study, and is not considered to be a 
“switch to an alternative approved background NRTI therapy”, but rather an 
alignment with prescribing information to maintain consistent 3TC plasma 
exposure for participants with renal insufficiency.
No other dose reductions, modifications, or changes in the frequency of any components 
of any regimen will be allowed during the Maintenance and Extension Phases of the 
study.

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Section 4.6.1. Risk Assessment; Table, Study Procedures
Rationale:  Added mitigation for ECG pad removal.
Original Text:
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.
Revised Text:
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.

ECGs will be conducted by 
appropriately trained personnel and 
effort made to minimise contact time 
for application of the pads.
Section 5.4.  Withdrawal/Stopping Criteria
Rationale:  Clarification provided that dose reduction for lamivudine is allowed for 
participant’s with creatinine clearance <50 mL/min (consistent with prescribing 
information).
Original Text:

Participant requires a second switch or a dose adjustment of any component of the 
ABC/DTG/3TC.  A substitution for NRTI backbone is allowed at Screening, e.g. 
ABC/3TC to TDF/FTC or TAF/FTC for participants who are HLA-B*5701 positive. 
During the Induction Phase, prior to randomization into the Maintenance Phase at 
Day 1, one switch to an alternate approved background NRTI therapy is allowed for 
toxicity or tolerability management.  
Revised Text:

Participant requires a second switch or a dose adjustment of any component of the 
ABC/DTG/3TC (with exception of dose reduction for renal insufficiency as 
noted in Section 4.2.7.).  A substitution for NRTI backbone is allowed at Screening, 
e.g. ABC/3TC to TDF/FTC or TAF/FTC for participants who are HLA-B*5701
positive. During the Induction Phase, prior to randomization into the Maintenance 

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Phase at Day 1, one switch to an alternate approved background NRTI therapy is 
allowed for toxicity or tolerability management.  
Section 6.8.  Protocol Permitted Substitutions
Rationale:  Clarification provided that dose reduction for lamivudine is allowed for 
participant’s with creatinine clearance <50 mL/min (consistent with prescribing 
information).
New Text Added:
For consistency with prescribing information, dose reductions of lamivudine (or 
emtricitabine if used as alternate NRTI) are permitted throughout the study in the 
context of renal insufficiency, e.g. as needed for creatinine clearance <50 mL/min 
(See Section 4.2.7. for additional information).
Section 6.9.2. Oral Dosing
Rationale:  Clarification that 3 day window applies to all oral dosing in Induction, 
Maintenance, and Extension Phases of the study.
Original Text:
There is a (+ or -) 3 day visit window, from the projected visit date.  
Revised Text:
There is a (+ or -) 3 day visit window, from the projected visit date (for all oral dosing 
in the Induction, Maintenance, and Extension Phases of the study).  
Section 7.1.  Time and Events Table
Rationale:  Columns and Footnotes updated that were accidently deleted with 
Amendment 1.
Corrections made:

‘y’ footnote added back to WD column for Induction Phase.  Also added the word 
‘oral’ to clarify this is a follow-up visit for participants withdrawing from oral IP 
(participants withdrawing from CAB LA + RPV LA will go into Long-Term Follow-
Up).

clarification added to footnote ‘p’ that genetics sample can be collected at any visit 
after signing informed consent, but the Week [-20] visit is preferred;

Week 5 footnote corrected to letter ‘t’ (vs ‘s’).

‘LA Arm’ added back to column for Weeks 68, 76, 84, 92 (hidden when column was 
narrowed).

Week 104b – clarification that this visit is only required for the participants switching 
from oral to LA.

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ADMINISTRATIVE CORRECTIONS (E.G. TYPOGRAPHICAL 
ERRORS, UPDATED REFERENCES)
Section 11.  References (Also updated in Section 4.6 and Section 5.0)
Rationale:  Updated investigator brochure references to include most recent version 
numbers.
Original Text:
GlaxoSmithKline Document Number RH2009/00003/05: GSK1265744 (Cabotegravir) 
Clinical Investigator's Brochure, Version 05, January 2016.
Revised Text:
GlaxoSmithKline Document Number RH2009/00003/06: GSK1265744 (Cabotegravir) 
Clinical Investigator's Brochure, Version 06, December 2016.
Original Text:
Rilpivirine Clinical Investigator Brochure [RPV IB], April 2016.
Revised Text:
Rilpivirine Clinical Investigator Brochure [RPV IB], Edition Number 10, April 2017.
Section 11.0.  References
Rationale:  Added references identified in DAIDS table to Reference Section.
New Text:
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.
New Text:
World Health Organization (WHO) Growth Reference:  Available at 
http://www.who.int/growthref/who2007_bmi_for_age/en/.
Section 12.5.  Appendix 5: Genetic Research, Study Assessments and Procedures
Rationale:  Clarification that samples are collected after participant’s are ‘enrolled’ 
versus ‘randomized.’
Original Text:
A blood sample is collected at the baseline visit, after the subject has been randomized 
and provided informed consent for genetic research. 

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Revised Text:
A blood sample is collected at the baseline visit, after the subject has been enrolled and 
provided informed consent for genetic research. 
Section 12.9.1. Amendment 01 (All Countries)
Rationale:  Correction made to rationale section to be consistent with protocol text 
regarding 52 weeks of contraception required (vs 52 years).
Original Text:
Section 1 Protocol Synopsis, Long-Term Follow-Up Phase – IM Regimen Only and
Section 4.2.6.  Long-Term Follow-Up Phase – IM Regimen Only
Rationale:  Clarification added that adequate contraception must be used for at least 52 
years (rather than stating throughout the entire year of follow-up):
Revised Text:
Section 1 Protocol Synopsis, Long-Term Follow-Up Phase – IM Regimen Only and
Section 4.2.6.  Long-Term Follow-Up Phase – IM Regimen Only
Rationale:  Clarification added that adequate contraception must be used for at least 52 
weeks (rather than stating throughout the entire year of follow-up):
12.9.3.
Amendment 03 (All Countries)
Protocol changes for Amendment 03 (25-JUN-2018), from amendment 02 (19-JUL-
2017)
PROTOCOL AMENDMENT RATIONALE
Changes for Amendment 3 were made to the protocol to manage and mitigate risks 
following identification of a potential safety issue related to neural tube defect in infants 
born to women with exposure to dolutegravir (DTG) at the time of conception.

A Risk Assessment table was added to include language regarding risk and mitigation 
of neural tube defects seen with DTG.

The withdrawal criteria were updated to include a reminder that females of 
reproductive potential who change their minds and desire to be pregnant should also 
be withdrawn from the study.

The Time and Events table was updated to include a reminder for investigators to 
check at every visit that females of reproductive potential are avoiding pregnancy.

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Additionally, clarifications were provided for the following:
the DTG IB should be referenced for additional risks, safety information, drug 
interactions, etc.;
‘suspected’ was added to the text prior to the bulleted definition of suspected 
virologic failure in Section 5.4.5.3.;
specific storage conditions were removed from the protocol for IP, and a 
statement added to store according to product label;
insulin was removed from the section regarding clinical assessments performed 
during the study;
timeframe for pregnancy reporting and follow-up were updated to 24 hours to 
align with current reporting process;
prescribing information and IB references were updated.
PROTOCOL CHANGES / CLARIFICATIONS
Section 4.6 Benefit:Risk Assessment
Rationale:  DTG IB added as reference for benefit/risk profile (and typos corrected)
Original Text:
ABC/DTG/3TC is established regimen that has been in clinical use for several years and 
has well an established benefit/risk profile described in detail in the respective country 
product labels (TRIUMEQ Prescribing Information, 2015).
Revised Text:
ABC/DTG/3TC is an established regimen that has been in clinical use for several years 
and has an established benefit/risk profile described in detail in the DTG IB 
(GlaxoSmithKline Document Number RM2007/00683/11) and respective country 
product labels (TRIUMEQ Prescribing Information, 2018).

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Section 4.6 Benefit:Risk Assessment
Rationale:  New text adding regarding risk of neural tube defects associated with DTG:
New Text:
A potential safety issue related to neural tube defect in infants born to women with 
exposure to dolutegravir (DTG) at the time of conception has been recently 
identified as noted below:
Potential Risk 
of Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [ABC/DTG/3TC, DTG]
Refer to DTG IB and country product labels for additional information
DTG: Neural 
tube defects
In one ongoing birth outcome surveillance 
study in Botswana, early results from an 
unplanned interim analysis show that 
4/426 (0.9%) of women who were taking 
DTG when they became pregnant had 
babies with neural tube defects compared 
to a background rate of 0.1%.
1.
A female subject is eligible to 
participate if she is not 
pregnant, not lactating, and, if 
she is a female of reproductive 
potential, 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) from 30 days 
prior to the first dose of study 
medication 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.
2. Women who are breastfeeding 
or plan to become pregnant or 
breastfeed during the study are 
excluded;
3. Women who become pregnant, 
or who desire to be pregnant 
while in the study will have 
study treatment discontinued 
and withdrawn from the study.
4. Females of reproductive 
potential are reminded re: 
pregnancy avoidance and 
adherence to contraception 
requirements at every study 
visit.
5. Pregnancy status is monitored 
at every study visit.

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Section 5 Selection of Study Population and Withdrawal Criteria
Rationale:  DTG IB added as reference.
Original Text:
Information for ABC/DTG/3TC or DTG is provided in the US or country product label 
(TRIUMEQ Prescribing Information, 2015; TIVICAY Prescribing Information, 2015).
Revised Text:
Information for ABC/DTG/3TC or DTG is provided in the current DTG IB 
(GlaxoSmithKline Document Number: RM2007/00683/11) and US or country product 
label (TRIUMEQ Prescribing Information, 2018; TIVICAY Prescribing Information, 
2017).
Section 5.4. Withdrawal/Stopping Criteria
Rationale:  Reminder added to withdraw participants from the study if they desire to 
become pregnant or who are no longer willing to comply with contraceptive 
requirements.
New Text:
As a reminder, females of reproductive potential who changed their minds and desire 
to be pregnant, or who state they are no longer willing to comply with the approved 
pregnancy avoidance methods, should also be withdrawn from the study.
Section 5.4.5.2. Suspected Virologic Failure
Rationale:  “suspected” added to the paragraph directing investigators to obtain 
confirmation of virologic failure.
Original Text:
Upon notification that a participant’s HIV-1 RNA plasma level meets any of the 
definitions of virologic failure, the Investigator should confirm the definition is met by 
initiating a repeat of the HIV-1 RNA assessment.  
Revised Text:
Upon notification that a participant’s HIV-1 RNA plasma level meets any of the 
definitions of suspected virologic failure, the Investigator should confirm the definition 
is met by initiating a repeat of the HIV-1 RNA assessment.  
Section 6.1.1. Cabotegravir (CAB) – Tablet
Rationale:  Storage conditions removed from text and direction provided to refer to the 
product label.

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Original Text:
CAB tablets are to be stored up to 30°C [86°F] and protected from moisture. 
Revised Text:
CAB tablets are to be stored according to the product label.
Section 6.1.2. Rilpivirine (RPV) – Tablet
Rationale:  Storage conditions removed from text and direction provided to refer to the 
product label.
Original Text:
RPV tablets should be stored at 25°C (excursions permitted to 15°-30°C [59°-86°F]) and 
protected from light. 
Revised Text:
RPV tablets are to be stored according to the product label.
Section 6.1.3. Cabotegravir – Injectable Suspension (CAB LA)
Rationale:  Storage conditions removed from text and direction provided to refer to the 
product label.
Original Text:
CAB LA injectable suspension is to be stored at up to 30°C, do not freeze. 
Revised Text:
CAB LA injectable suspension is to be stored according to the product label.
Section 6.1.4. Rilpivirine – Injectable Suspension (RPV LA)
Rationale:  Storage conditions removed from text and direction provided to refer to the 
product label.
Original Text:
RPV LA injectable suspension should be kept in the outer package and stored at 2-8°C 
(do not freeze).  RPV LA should also be protected from light.
Revised Text:
RPV LA injectable suspension should be stored according to the product label and
should be protected from light.

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Section 6.1.5. ABC/DTG/3TC STR - Tablet
Rationale:  Storage conditions removed from text and direction provided to refer to the 
product label.
Original Text:
ABC/DTG/3TC tablets are to be stored at 25°C [77°F] (excursions permitted to 15°-30°C 
[59°-86°F]).
Revised Text:
ABC/DTG/3TC tablets are to be stored according to the product label.
Section 6.1.6. Dolutegravir (DTG) - Tablet
Rationale:  Storage conditions removed from text and direction provided to refer to the 
product label.
Original Text:
DTG tablets are to be stored at 25°C [77°F] (excursions permitted to 15°-30°C [59°-
86°F]).
Revised Text:
DTG tablets are to be stored according to the product label.
Section 6.13. Concomitant Medications and Non-Drug Therapy
Rationale:  Added use of investigator brochure to evaluate potential drug:drug 
interactions.
Original Text:
The investigator should evaluate any potential drug:drug interactions at every visit, 
including reviewing the most current version of the U.S and/or local prescribing 
information for RPV, and ABC/DTG/3TC (or DTG + NRTIs), especially if any new 
concomitant medications are reported by participants.
Revised Text:
The investigator should evaluate any potential drug:drug interactions at every visit, 
including reviewing the most current version of the investigator brochures, the U.S 
and/or local prescribing information for RPV, and ABC/DTG/3TC (or DTG + NRTIs), 
especially if any new concomitant medications are reported by participants.

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Section 6.13.1. Prohibited Medications and Non-Drug Therapies
Rationale:  Added use of investigator brochure to evaluate potential drug:drug 
interactions.
Original Text:
For additional information on concurrent therapies and interactions suspected to be 
relevant to other antiretroviral therapy used during the study (e.g. ABC/DTG/3TC), 
please consult and local prescribing information.
Revised Text:
For additional information on concurrent therapies and interactions suspected to be 
relevant to other antiretroviral therapy used during the study (e.g. ABC/DTG/3TC), 
please consult the current DTG Investigator brochure and local prescribing 
information.
Original Text (Concurrent with RPV):
Please refer to local prescribing information for other drugs that are prohibited, should 
be used with caution, require dose adjustment, or increased clinical monitoring if taken 
with oral RPV.
Revised Text:
Please refer to the current RPV Investigator brochure and local prescribing information 
for other drugs that are prohibited, should be used with caution, require dose adjustment, 
or increased clinical monitoring if taken with oral RPV.
Original Text (Concurrent with ABC/DTG/3TC):
Please refer to the local prescribing information for other drugs that should be used with 
caution, require dose adjustment, or increased clinical monitoring if taken with 
ABC/DTG/3TC (or DTG with alternate NRTI background therapy).
Revised Text:
Please refer to the current DTG IB and local prescribing information for other drugs 
that should be used with caution, require dose adjustment, or increased clinical 
monitoring if taken with ABC/DTG/3TC (or DTG with alternate NRTI background 
therapy).
Original Text (Concurrent with DTG + 2 NRTIs):
In addition to the prohibited medications noted for DTG above (as a component of 
ABC/DTG/3TC), for participants who are HLA-B*5701 positive and who are receiving 
DTG + alternate NRTI background therapy, refer to local prescribing information for 
details regarding concurrent therapies.

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Revised Text:
In addition to the prohibited medications noted for DTG above (as a component of 
ABC/DTG/3TC), for participants who are HLA-B*5701 positive and who are receiving 
DTG + alternate NRTI background therapy, refer to the current DTG IB and local 
prescribing information for details regarding concurrent therapies.
Section 7.1. Time and Events Table
Rationale:  Reminder added to footnote ‘j’ to avoid pregnancy while on study and to 
adhere to contraceptive requirements.
Original Text:
j.
Conduct pregnancy tests for only women of childbearing potential at every visit throughout the study, including 
Q4W during the Extension Phase.  A negative urine pregnancy test is required prior to beginning the Induction 
Phase (Week [-20]), on Day 1 (preferably prior to randomization), and at Week 4b (or Week 104b for subjects 
transitioning from ABC/DTG/3TC) prior to the first injection. Serum pregnancy test can substitute for urine 
pregnancy test if locally required, but must be appropriately timed to confirm pregnancy status prior to e.g.
randomization and first IM administration. S=Serum/U=Urine.
Revised Text: 
j.
Conduct pregnancy tests for only women of childbearing potential at every visit throughout the study, including 
Q4W during the Extension Phase.  Remind females of reproductive potential of the need to avoid pregnancy 
while in study and adherence to the study’s contraception requirements.  A negative urine pregnancy test is 
required prior to beginning the Induction Phase (Week [-20]), on Day 1 (preferably prior to randomization), and at 
Week 4b (or Week 104b for subjects transitioning from ABC/DTG/3TC) prior to the first injection. Serum 
pregnancy test can substitute for urine pregnancy test if locally required, but must be appropriately timed to 
confirm pregnancy status prior to e.g. randomization and first IM administration. S=Serum/U=Urine.
Section 7.4.1. Clinical Evaluations
Rationale:  Removed insulin as a periodic assessment, as this was not collected for 
201584.
Original Text:

Periodic assessment of glucose, insulin, and bone and renal markers.
Revised Text:

Periodic assessment of glucose, and bone and renal markers.

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Section 7.4.3.4. Prompt Reporting of Serious Adverse Events and Other Event (Text 
and Table 7) – Pregnancy Reporting Row
Rationale:  Updated timeframe for pregnancy reporting and follow-up.
Original Text:
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 2 weeks of learning of the pregnancy and should 
follow the procedures outlined in Appendix 7.
Revised Text:
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form.  The investigator should inform GSK within 24 hours of learning 
of the pregnancy and should follow the procedures outlined in Appendix 7.
Original Table Row:
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
Pregnancy
2 weeks
“Pregnancy 
Notification Form”
2 weeks
“Pregnancy Follow-
up Form”
Revised Table Row:
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
Pregnancy
24 hours
“Pregnancy 
Notification Form”
Within 24 hours of 
investigator 
awareness of 
pregnancy outcome
“Pregnancy Follow-
up Form”

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Section 7.4.7.3. Action to be Taken if Pregnancy Occurs
Rationale:  Updated timeframe for pregnancy reporting.
Original Text:
To ensure participant safety, if a pregnancy is reported then the investigator should 
inform GSK within 2 weeks of learning of the pregnancy and should follow the 
procedures outlined in Appendix 7.
Revised Text:
The investigator should inform GSK within 24 hours of learning of the pregnancy and 
should follow the procedures outlined in Appendix 7.
Section 12.7.2.  Collection of Pregnancy Information
Rationale:  Updated timing for collection of pregnancy information.
Original Text:

Information will be recorded on the appropriate form and submitted to GSK within 
2 weeks of learning of a participant's pregnancy.
Revised Text:

Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy.
ADMINISTRATIVE CORRECTIONS (E.G., UPDATED
REFERENCES)
Section 11:  References
Original Text:
Edurant Prescribing Information, August 2015.
Revised Text:
Edurant Prescribing Information, February 2018.
Original Text:
GlaxoSmithKline Document Number RH2009/00003/06: GSK1265744 (Cabotegravir) 
Clinical Investigator's Brochure, Version 06, December 2016.

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Revised Text:
GlaxoSmithKline Document Number RH2009/00003/07: GSK1265744 (Cabotegravir) 
Clinical Investigator's Brochure, Version 07, December 2017.
Original Text:
GlaxoSmithKline Document Number RM2007/00683/09: GSK1349572 Clinical 
Investigator's Brochure, Version 09, 09 October 2015.
Revised Text:
GlaxoSmithKline Document Number RM2007/00683/11: GSK1349572 Clinical 
Investigator's Brochure, Version 11, 13 October 2017; Supplement 01, 11 Dec 2017; 
Supplement 02, Jun 2018.
Original Text:
TIVICAY Prescribing Information, August 2015.
Revised Text:
TIVICAY Prescribing Information, November 2017.
Original Text:
TRIUMEQ Prescribing Information, September 2015.
Revised Text:
TRIUMEQ Prescribing Information, May 2018.
12.9.4.
Amendment 04 (All Countries)
Protocol changes for Amendment 04 (24-SEP-2018), from Amendment 03 (25-JUN-
2018).  Some of the modifications noted below are not inclusive of full text within a 
section, but rather the edited pieces of the section.

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PROTOCOL AMENDMENT RATIONALE
The primary reason for protocol amendment 04 is to allow an optional (vs mandatory) 
oral lead-in for participants randomized to the ABC/DTG/3TC arm who choose to 
continue into the Extension Phase of the study and receive CAB LA + RPV LA.  The 
Appendix (Appendix 7) for contraceptive guidance and collection of pregnancy 
information was updated to be consistent with current protocol template text.  Other 
minor clarifications were made as needed, e.g., the eCSSRs timing in the footnote for the 
Time and Events Table, updated abbreviations, etc.
PROTOCOL CHANGES / CLARIFICATIONS
Section 1.0 Protocol Synopsis for 201584, Rationale:
Rationale for change:  to highlight direct to injection as an option for participants 
transitioning from ABC/DTG/3TC to CAB LA + RPV LA in the Extension Phase.
Original Text:
Eligible participants (HIV-1 ribonucleic acid [RNA] <50 c/mL at Week 96) would 
transition to LA dosing, beginning with 4 weeks oral CAB + RPV therapy at Week 100, 
and receive the first IM CAB LA + RPV LA injections at Week 104b.
Revised Text:
Eligible participants (HIV-1 ribonucleic acid [RNA] <50 c/mL at Week 96) would 
transition to LA dosing, beginning with the first IM CAB LA + RPV LA injections at
either Week 100 (direct to injection) or Week 104b (following optional oral lead-in 
with CAB 30 mg and RPV 25 mg).
Section 1.0. Protocol Synopsis for 201584, Objectives/Endpoints AND Section 3.0.  
Objectives And Endpoints:
Rationale for change: an objective that was Exploratory in previous versions of the 
protocol has been modified to a Secondary endpoint to provide data for participants 
transitioning from ABC/DTG/3TC to CAB LA + RPV LA in the Extension Phase, with 
or without CAB + RPV oral lead-in. Secondary endpoint also added to support the 
importance of collecting PK data in participants who do not use an oral lead-in.
Original Text:
Exploratory
To evaluate the antiviral and immunologic 
effects, safety and tolerability, and viral 
resistance of CAB LA + RPV LA for all 
participants in the Extension Phase.

Proportion of participants with plasma HIV-1 
RNA <200 c/mL and HIV-1 RNA <50 c/mL 
over time.

Proportion of participants with confirmed 
virologic failure over time.

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Exploratory

Incidence of treatment emergent genotypic 
and phenotypic resistance to CAB and RPV 
in over time.

Absolute values and change from Baseline 
in plasma HIV-1 RNA over time.

Absolute values and changes from Baseline 
in CD4+ cell counts over time.

Incidence of disease progression (HIV-
associated conditions, acquired 
immunodeficiency syndrome [AIDS] and 
death).

Incidence and severity of AEs and 
laboratory abnormalities over time.

Proportion of participants who discontinue 
treatment due to AEs over time.

Absolute values and changes in laboratory 
parameters over time.

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Revised Text:
Secondary
To evaluate the antiviral and immunologic 
effects, safety and tolerability, and 
development of viral resistance to CAB LA + 
RPV LA at Week 124 and over time for 
participants switching from ABC/DTG/3TC in 
the Extension Phase, with and without 
optional oral lead-in.

Proportion of participants with HIV-1 
RNA 50 c/mL at Week 124, with and 
without oral lead-in (FDA Snapshot 
algorithm, Extension Switch population).

Proportion of participants with plasma 
HIV-1 RNA <50 c/mL and HIV-1 RNA 
<200 c/mL over time.

Proportion of participants with 
confirmed virologic failure over time.

Incidence of treatment emergent 
genotypic and phenotypic resistance to 
CAB and RPV over time.

Absolute values and change from 
Baseline in CD4+ cell counts over time.

Incidence and severity of AEs and 
laboratory abnormalities over time.

Proportion of participants who 
discontinue treatment due to AEs over 
time.

Absolute values and change in 
laboratory parameters over time.
To evaluate the pharmacokinetics of CAB 
and RPV in the setting of no oral lead-in for 
participants switching from ABC/DTG/3TC in 
the Extension Phase.

To evaluate plasma CAB and RPV 
concentrations over time (Week 100 
[direct to inject without oral lead-in] and 
Week 104 [both direct to inject and 
optional oral lead-in participants])

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Section 1.0. Protocol Synopsis for 201584, Overall Design AND Section 4.1. Overall 
Design, Study Schematic:
Rationale for change:  to highlight direct to injection as an option for participants 
transitioning from ABC/DTG/3TC to CAB LA + RPV LA in the Extension Phase. Also 
corrected error in schematic entry viral load from >1000 c/mL to 1000 c/mL.
Original Text:
†Optional switch to CAB LA + RPV LA at Wk 100 for subjects randomized to ABC/DTG/3TC.
¥Subjects who withdraw from IM CAB LA + RPV LA treatment must enter the 52 week long term follow up phase. 
Wk 104a
ARV-naïve,  
HIV-1 
RNA>1000
Any CD4
n≈620
Screening 
Phase
Maintenance Phase
Extension Phase†
ABC/DTG/3TC
Oral CAB
+ RPV
CAB LA + RPV LA¥
Oral CAB
+ RPV
Extension¥
Phase
1o Endpoint
2o Endpoint
Day 1
Wk 96
Wk 24
Wk 48
Wk 4b
Wk 100
Wk 104b
ABC/DTG/3TC 
Single Tablet 
Regimen
Induction 
Phase
Wk -20
Wk -4
Randomization 
(1:1)
N=570
Confirm HIV-1 RNA <50 c/mL
Wk 108
Wk 4a
Wk 8
Q4 Weeks
Revised Text:
¥Subjects who withdraw from IM CAB LA + RPV LA must enter the 52 week Long Term Follow-Up Phase.

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Section 1.0. Protocol Synopsis for 201584, Treatment Arms and Duration AND 
Section 4.2.4. Maintenance Phase (Day 1 to Week 100):
Rationale for change:  to highlight patients must remain virologically suppressed 
through Week 96 to continue into the Extension Phase.
Original Text:

Continue on the oral ABC/DTG/3TC initiated during the Induction Phase for at 
least an additional 100 weeks.  Participants who successfully complete Week 100 
(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.
Revised Text:

Continue on the oral ABC/DTG/3TC initiated during the Induction Phase for at 
least an additional 100 weeks.  Participants who successfully complete Week 100 
(without meeting study defined withdrawal criteria and who remain virologically 
suppressed through Week 96:  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.
Section 1.0 Protocol Synopsis for 201584, Treatment Arms and Duration, Extension 
Phase:
Rationale for change:  updated to reflect the two options for participants transitioning 
from ABC/DTG/3TC to CAB LA + RPV LA in the Extension Phase.  Also rearranged 
some text to improve flow of section.
Original Text:
Extension Phase
Participants Entering from the CAB LA + RPV LA Arm
All participants who successfully complete Week 100 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 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.
Participants Entering from the ABC/DTG/3TC Arm
Participants randomized to continue ABC/DTG/3TC 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 100.

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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 
ABC/DTG/3TC while eligibility is being confirmed.  
All participants with an undetectable HIV-1 RNA (<50 c/mL) result from the Week 96 
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 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 with a 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 96 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 with a Week 96 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 100.  Clinical chemistries will also be 
assessed at Week 100.  At Week 104a, following the 4 week CAB + RPV oral lead-in, 
participants will have additional safety assessments including clinical chemistries.  In 
addition, central lab results and safety parameters from the Week 104a visit must be 
available and reviewed.  If a clinical chemistry retest is required based on Week 104a 
labs, the retest should be performed as soon as possible (and preferably no later than 
7 days following Week 104a). Participants will remain on oral CAB 30 mg + RPV 
25 mg until the Week 104b injection visit, and until any required Visit 104a retest results 
are available for review.
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.
Participants not eligible to enter the Extension Phase will end their study participation 
(Week 100 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.
Revised Text:
Extension Phase
All eligible participants who transition into the Extension Phase 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.
Participants not eligible to enter the Extension Phase will end their study 
participation (Week 100 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.

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Participants Entering from the CAB LA + RPV LA Arm
All participants who successfully complete Week 100 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.  
Visits will continue to occur every 4 weeks.
Participants Entering from the ABC/DTG/3TC Arm
Participants randomized to continue ABC/DTG/3TC 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 100.  
The transition from ABC/DTG/3TC to CAB LA + RPV LA within the Extension 
Phase can be completed with or without an oral lead-in prior to commencement of 
injectable treatment.  The oral lead-in decision will be made by the participant in 
consultation with the investigator and must be appropriately documented.  As 
participants approach the Week 100 visit, sites must ensure sufficient CAB and 
RPV supply are available to support the participant’s decision for transition to LA.
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 
ABC/DTG/3TC while eligibility is being confirmed.  
All participants with an undetectable HIV-1 RNA (<50 c/mL) result from the Week 96 
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 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 with a 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 96 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 Transitioning Direct to Injection in the Extension Phase
Central lab results and safety parameters from the Week 96 visit must be available 
and reviewed for participants who choose to transition direct to injection.  
Participants with ongoing safety issues or laboratory abnormalities of clinical 
concern (e.g., Grade 3 or Grade 4 liver enzyme elevations), will require consultation 
and agreement with the Medical Monitor prior to proceeding directly to injections 
in the Extension Phase. 
If a clinical chemistry retest is required based on Week 96 labs, the retest should be 
performed as soon as possible (and preferably no later than 7 days following 
Week 96). Participants will remain on oral ABC/DTG/3TC until the Week 100 
injection visit, and until any required Week 96 retest results are available for 
review.
At Week 100, eligible participants will take the last dose of ABC/DTG/3TC (or DTG 
+ 2 NRTIs), and receive the first injections of CAB LA (600 mg) + RPV LA (900 mg) 

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as initial loading doses.  Clinical chemistries will also be assessed at Week 100.  At 
Week 101, participants will return to the clinic for PK and safety assessments 
including clinical chemistries.  The second and third injections (CAB LA 400 mg + 
RPV LA 600 mg) will be administered at Week 104a and Week 108.  There will be a 
one week dosing window for the second and third IM injections such that the second 
injections occur within the window of Week 103 to Week 104a, but not later than 
Week 104a, and the third injections occur within the window of Week 107 to Week 
108, but no later than Week 108.  Subsequent injections (CAB LA 400 mg + RPV 
LA 600 mg) will occur every 4 weeks thereafter, from the projected visit date, with a 
(+ or -) 7 day dosing window being allowed (but not preferred).  Following the Week 
108 injection, the interval between injection visits should be limited to a maximum 
of 5 weeks.  The Medical Monitor must be contacted if the length of time between 
injections exceeds, or is projected to exceed, 5 weeks.
Participants Receiving Optional Oral Lead-In in the Extension Phase
At Week 100, eligible participants who after discussion with the investigator, choose 
to receive the optional oral lead-in will initiate a 4 week lead-in of oral CAB 30 mg + 
oral RPV 25 mg once daily.  It is not necessary to dose ABC/DTG/3TC on the day the 
participant begins the oral lead-in with CAB + RPV.  However, if the participant 
takes ABC/DTG/3TC prior to coming into the clinic, initiation of oral CAB and 
RPV should continue as planned.  Clinical chemistries will also be assessed at Week 
100.  At Week 104a, following the 4 week CAB + RPV oral lead-in, participants will 
have additional safety assessments including clinical chemistries.  In addition, central lab 
results and safety parameters from the Week 104a visit must be available and reviewed.  
If a clinical chemistry retest is required based on Week 104a labs, the retest should be 
performed as soon as possible (and preferably no later than 7 days following 
Week 104a). Participants will remain on oral CAB 30 mg + RPV 25 mg until the 
Week 104b injection visit, and until any required Visit 104a retest results are available 
for review.  An HIV-1 RNA sample will not be collected at Week 104a for 
participants receiving the optional oral lead in, but will be obtained at the Week 
104b visit to serve as the injection baseline viral load.
Section 1.0 Protocol Synopsis for 201584, Analysis:
Rationale for change:  to describe new Week 124 analysis.
New Text:
In descriptive analyses, antiviral response will be assessed according to the 
proportion of participants with and without oral lead-in who have HIV-1 RNA 
≥50 c/mL at Week 124 (i.e., 24 weeks from initiation of CAB LA + RPV LA at 
Week 100, 6 week analysis window, using the FDA Snapshot algorithm), with 
corresponding 95% confidence interval.  No formal statistical comparison with 
respect to safety and efficacy outcomes will be performed.  

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Section 2.1. Study Rationale:
Rationale for change:  to include information on the reason for assessing no oral lead-in.
Original Text:
Additionally, participants initially randomized to continue ABC/DTG/3TC will have an 
option to switch to CAB LA + RPV LA after completion of the Week 100 visit.  Eligible 
participants (HIV-1 RNA <50 c/mL at Week 96) would transition to LA dosing, 
beginning with 4 weeks oral CAB + RPV therapy at Week 100, and receiving the first IM 
CAB LA + RPV LA injections at Week 104b.
Revised Text:
Additionally, participants initially randomized to continue ABC/DTG/3TC will have an 
option to switch to CAB LA + RPV LA at, or after, completion of the Week 100 visit.  
Amendment 04 of the FLAIR study will provide an opportunity to access an 
optional (vs mandatory) oral lead-in for these participants who transition to LA 
treatment at Week 100.  Eligible participants (HIV-1 RNA <50 c/mL at Week 96) 
would transition to LA dosing, beginning at either Week 100 (direct to injection) or 
Week 104b (optional oral lead-in with CAB 30 mg and RPV 25 mg).
Importantly, the oral lead-in during the early development program for CAB LA 
and RPV LA was instituted to minimize the risk of severe adverse drug reactions 
during LA dosing (e.g. acute hypersensitivity).  The 4 week oral lead-in allowed for 
an evaluation of any untoward adverse events and an assessment of safety labs prior 
to initiation of LA therapy.  To date, the principal safety risk identified with 
cabotegravir, following 3145 exposures to drug (oral and/or LA), is suspected DILI, 
which has occurred in a few individuals, all of whom were receiving oral CAB.  The 
time to onset ranged between 4 weeks and one year and manifested as asymptomatic 
elevations of ALT, without compromise to hepatic function.  Each participant fully 
recovered, with removal of investigational product, without hospitalization or 
intervention.  During the Phase 3 ATLAS and FLAIR studies, no cases of DILI have 
been identified, during the oral lead-in period, or following initiation of LA dosing.  
There has been no evidence to date of a risk for clinically significant hepatotoxicity 
observed with cabotegravir.  Additionally, throughout the development program to 
date, no cases of severe drug hypersensitivity or severe drug allergy have been 
observed.  While the risk of idiosyncratic severe drug reactions cannot be fully 
excluded, the risk of occurrence is felt to be low, on the basis of safety data 
generated to date.
Based on blinded, instream review of ongoing Phase 3 aggregate AE data (from 
FLAIR, and ATLAS) and of individual case reports (SAEs), no new, emerging, drug 
related safety issues have been identified within the four week oral lead-in dosing 
period (e.g., hypersensitivity, Drug Reaction with Eosinophilia and Systemic 
Symptoms [DRESS], severe drug induced liver injury [DILI]) that would have 
precluded participants from proceeding to CAB LA + RPV LA injections during the 
Maintenance Phase of the studies.  Additionally, review of accumulating data has 

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not identified any new safety issues occurring on CAB LA + RPV LA that were 
otherwise predictable based on oral exposure experience.
As a result of the accumulated safety data, which has been generated over the 
course of the Phase 1, 2 and 3 clinical studies, this amendment has been developed to 
generate safety, efficacy and PK data for the transition from oral ART to CAB LA + 
RPV LA without receiving an oral lead-in.  These data are intended to inform 
regulatory discussions around the safe and effective direct to inject dosing option 
with CAB LA + RPV LA.  The decision to dose with or without an oral-lead-in will 
be optional in this study, as elected by the study participant following informed 
consent discussions with the investigator.
At Week 124, a descriptive analysis will be conducted to assess antiviral response 
(HIV-1 RNA 50 c/mL) for participants who choose no oral lead-in.  No formal 
statistical comparison will be performed with respect to safety and efficacy 
outcomes at Week 124.
Data from this optional oral lead in will provide valuable knowledge/insight into the 
evolution of the ‘direct to injection’ concept.
Section 4.1 Overall Design:
Rationale for change:  to highlight direct to injection as an option for participants 
transitioning from ABC/DTG/3TC to CAB LA + RPV LA in the Extension Phase.
Original Text:
Participants randomized to ABC/DTG/3TC during the Maintenance Phase will continue 
ABC/DTG/3TC for at least an additional 100 weeks.  Participants who successfully 
complete Week 100 (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.
Revised Text:
Participants randomized to ABC/DTG/3TC during the Maintenance Phase will continue 
ABC/DTG/3TC for at least an additional 100 weeks.  Participants who successfully 
complete Week 100 (without meeting study defined withdrawal criteria and who remain 
virologically suppressed through Week 96:  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.  
The transition from ABC/DTG/3TC to CAB LA + RPV LA within the Extension 
Phase can be completed with or without an oral lead-in prior to commencement of 
injectable treatment.  The oral lead-in decision will be made by the participant in 
consultation with the investigator and must be appropriately documented.
Section 4.2.5. Extension Phase:
Rationale for change:  Text moved from the end of Section 4.2.5.2 to under main 
Section 4.2.5. heading as applicable to all participants who go into the Extension Phase:

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Rearranged Text within section (deleted from the end of Section 4.2.5.2.):
All eligible participants who transition into the Extension Phase 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.
Participants not eligible to enter the Extension Phase will end their study 
participation (Week 100 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.
Section 4.2.5.1.  Participants Entering from the CAB LA + RPV LA Arm
Rationale for change:  Simplified text as this information is duplicate text provided in 
multiple sections, including Section 4.2.5.
Original Text:
All participants who successfully complete 100 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 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 4.2.5.2. Protocol Synopsis for 201584, Treatment Arms and Duration, 
Extension Phase (edited pieces included below – not inclusive of entire section):
Rationale for change:  to highlight direct to injection as an option for participants 
transitioning from ABC/DTG/3TC to CAB LA + RPV LA in the Extension Phase.
Original Text:
Participants randomized to continue ABC/DTG/3TC 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 100 (no withdrawal visit needed).
Participants receiving ABC/DTG/3TC with a Week 96 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 100.  
Clinical chemistries will be assessed at Week 100.  At Week 104a, 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 
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reviewed before the Week 104b visit. If a clinical chemistry retest is required based on 
Week 104a labs, the retest should be performed as soon as possible (and preferably no 
later than 7 days following Week 104a). Participants will remain on oral CAB 30 mg + 
RPV 25 mg until the Week 104b injection visit, and until any required Visit 104a retest 
results are available for review.
Revised Text:
Participants randomized to continue ABC/DTG/3TC 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 100 (no withdrawal visit needed).  The 
transition from ABC/DTG/3TC to CAB LA + RPV LA within the Extension Phase 
can be completed with or without an oral lead-in prior to commencement of 
injectable treatment.  The participant’s decision will be taken in consultation with 
the investigator and must be appropriately documented. As participants approach 
the Week 100 visit, sites must ensure sufficient CAB and RPV supply are available 
to support the participant’s decision for transition to LA.
Participants Transitioning Direct to Injection in the Extension Phase:  
Central lab results and safety parameters from the Week 96 visit must be available 
and reviewed for participants who choose to transition directly to injections.  
Participants with ongoing safety issues or laboratory abnormalities of clinical 
concern (e.g. Grade 3 or Grade 4 liver chemistry elevations) will require 
consultation and agreement with the Medical Monitor prior to proceeding directly 
to injections in the Extension Phase.
If a clinical chemistry retest is required based on Week 96 labs, the retest should be 
performed as soon as possible (and preferably no later than 7 days following 
Week 96). Participants will remain on oral ABC/DTG/3TC until the Week 100 
injection visit, and until any required Week 96 retest results are available for 
review.
At Week 100, eligible participants will take the last dose of ABC/DTG/3TC (or DTG 
+ 2 NRTIs), and receive the first injections of CAB LA (600 mg) + RPV LA (900 mg) 
as initial loading doses.  Clinical chemistries will also be assessed at Week 100.  At 
Week 101, participants will return to the clinic for PK and safety assessments 
including clinical chemistries.  The second and third injections (CAB LA 400 mg + 
RPV LA 600 mg) will be administered at Week 104a and Week 108.  There will be a 
one week dosing window for the second and third IM injections such that the second 
injections occur within the window of Week 103 to Week 104a, but not later than 
Week 104a, and the third injections occur within the window of Week 107 to Week 
108, but no later than Week 108.  Subsequent injections (CAB LA 400 mg + RPV 
LA 600 mg) will occur every 4 weeks thereafter, from the projected visit date, with a 
(+ or -) 7 day dosing window being allowed (but not preferred).  Following the Week 
108 injection, the interval between injection visits should be limited to a maximum 
of 5 weeks.  The Medical Monitor must be contacted if the length of time between 
injections exceeds, or is projected to exceed, 5 weeks.

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Participants Receiving Optional Oral Lead-In in the Extension Phase:
As participants approach the Week 100 visit, sites must ensure sufficient oral CAB 
and RPV are available for participants who choose to use the oral lead-in.
At Week 100, eligible participants who after discussion with the investigator, choose 
to receive the optional oral lead-in will initiate a 4 week lead-in of oral CAB 30 mg + 
oral RPV 25 mg once daily. It is not necessary to dose ABC/DTG/3TC on the day the 
participant begins the oral lead-in with CAB + RPV.  However, if the participant 
takes ABC/DTG/3TC prior to coming into the clinic, initiation of oral CAB and 
RPV should continue as planned.
Section 4.5.1.  Dose Justification, Oral Lead-In Phase:
Rationale for change:  to discuss ART coverage for participants who choose no oral 
CAB + RPV lead-in when transitioning from ABC/DTG/3TC to LA.
New Text Added:
The oral lead-in for participants randomized to the ABC/DTG/3TC arm who choose 
to receive CAB LA + RPV LA during the Extension Phase of the study is optional.  
Without oral lead-in dosing, CAB LA and RPV LA achieve concentrations following 
their initial injections similar to induction doses of their respective efficacious oral 
products.  Oral ABC/DTG/3TC administered up to and including the day of the 
initial CAB LA + RPV LA injections will provide additional exposure to active 
antiviral agents during the transition from oral to LA treatment (e.g., exposure that 
would replace oral CAB + RPV exposure).

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Section 4.6.1. Risk Assessment Oral CAB and CAB LA (GSK1265744/ GSK1265744 LA):
Rationale for change:  to update information relating to no oral lead-in.
Original Text:
Potential Risk of 
Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Drug Induced Liver 
Injury
A small proportion of participants in the CAB 
program to date (total exposure approximately 1198 
to 01 April 2016) have developed transaminitis 
(elevated liver transaminases characterised by 
predominant ALT elevation).  In some of these 
participants’ transient transaminitis were explained 
by acute hepatitis C infection and whilst a small 
number of others did not have alternative 
explanations, suggesting a mild form of DILI 
without hepatic dysfunction which resolved upon 
withdrawal of treatment with CAB. 
Of the five participants with possible or probable 
cases of DILI identified in Phase 2 studies, four
participants were receiving oral CAB and one 
participant developed probable DILI following CAB 
LA or Placebo LA administration.  

Exclusion criteria as described in Section 5.2 will 
prohibit participants with significant liver impairment 
based on screening liver chemistry including 
transaminases (ALT and 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 period is being implemented in
this study, where all participants will receive oral 
CAB prior to the administration of CAB LA 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 
7.4.5.1 of this protocol. Participants will be 

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Mitigation Strategy
withdrawn from CAB treatment where no compelling 
alternative cause is identified and DILI is suspected

Participants who develop ALT ≥3 times ULN while 
on study must consult with Medical Monitor prior to 
initiation or continuation of CAB LA.  

All instances of liver transaminase elevations of 
Grade 2 and above will be followed to resolution.  
Participants withdrawn from CAB treatment due to 
meeting liver chemistry stopping criteria will be 
regularly monitored and both clinically and using 
liver chemistries to determine progress towards 
resolution of the liver event.
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 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.

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 will be given 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, 

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Potential Risk of 
Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
None of the ISRs reported to date was serious and 
no clinically significant complications were 
reported.
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.

Specialist dermatology consultation will be sought if 
warranted for individual participants.
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 
CAB LA. The long exposures anticipated after 
CAB LA injection may complicate the management 
of a drug hypersensitivity reaction, were it to occur.

The risk of developing a hypersensitivity reaction 
post administration of CAB LA will be minimized by 
the use of a 4-week oral lead-in of CAB to determine 
individual safety and tolerability prior to the 
introduction of CAB LA. 

Clinical assessments, laboratory tests (including liver 
transaminases) and vital signs will be performed 
throughout this study (refer to Time & Events Table).  
Results from these assessments may aid early 
detection of HSR.

Oral CAB will be withdrawn immediately for cases 
with suspected HSR during the oral lead-in phase.  
During oral and CAB LA treatment, any HSR 
reactions that occur would be managed supportively

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Revised Text:
Potential Risk of 
Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Drug Induced Liver 
Injury
A small proportion of participants in the CAB 
program to date (total exposure >3100 participants) 
have developed transaminitis (elevated liver 
transaminases characterised by predominant ALT 
elevation).  In some of these participants’ transient 
transaminitis were explained by acute hepatitis C 
infection and whilst a small number of others did 
not have alternative explanations, suggesting a mild 
form of DILI without hepatic dysfunction which 
resolved upon withdrawal of treatment with CAB. 
Of the four participants with possible or probable 
cases of DILI identified in Phase 2 studies, all were 
receiving oral CAB. 

Exclusion criteria as described in Section 5.2 will 
prohibit participants with significant liver impairment 
based on screening liver chemistry including 
transaminases (ALT and 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 period was implemented at the 
beginning of this study, where all participants will 
receive oral CAB prior to the administration of CAB 
LA to determine individual safety and tolerability.  
During the Extension Phase of the study, following 
review of available oral lead-in and Maintenance 
Phase safety data, the protocol was amended to 
allow an optional oral lead-in for the participants 
transitioning from ABC/DTG/3TC to CAB 
LA+RPV LA.

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 
7.4.5.1 of this protocol. Participants will be 

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withdrawn from CAB treatment where no compelling 
alternative cause is identified and DILI is suspected.

Participants who develop ALT ≥3 times ULN while 
on study must consult with Medical Monitor prior to 
initiation or continuation of CAB LA.  

All instances of liver transaminase elevations of 
Grade 2 and above will be followed to resolution.  
Participants withdrawn from CAB treatment due to 
meeting liver chemistry stopping criteria will be 
regularly monitored both clinically and using liver 
chemistries to determine progress towards resolution 
of the liver event.
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 receiving multiple injections. 
Although some Grade 3 ISRs were reported, the 
majority of ISRs have not, to date, been associated 
with an excess of participants’ withdrawal.
None of the ISRs reported to date was serious and 

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 will be given 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, 

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no clinically significant complications were 
reported.
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.

Specialist dermatology consultation will be sought if 
warranted for individual participants.
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 
CAB LA. The long exposures anticipated after 
CAB LA injection may complicate the management 
of a drug hypersensitivity reaction, were it to occur.

The risk of developing a hypersensitivity reaction 
post administration of CAB LA was minimized at 
the start of the study by the use of a mandatory 4-
week oral lead-in of CAB to determine individual 
safety and tolerability prior to the introduction of 
CAB LA.  During the Extension Phase of the 
study, following review of available oral lead-in 
and Maintenance Phase safety data, the protocol 
was amended to allow an optional oral lead-in for 
the participants transitioning from 
ABC/DTG/3TC to CAB LA+RPV LA.

Clinical assessments, laboratory tests (including liver 
transaminases) and vital signs will be performed 
throughout this study (refer to Time & Events Table).  
Results from these assessments may aid early 
detection of HSR.

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
Oral CAB will be withdrawn immediately for cases 
with suspected HSR during the oral lead-in phase.  
During oral and CAB LA treatment, any HSR 
reactions that occur would be managed supportively
Section 4.6.1. Risk Assessment Oral RPV and RPV LA:
Rationale for change:  to update information relating to no oral lead-in.
Original Text:
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’ 

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 

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withdrawal due to ISRs.
None of the ISRs was serious and no 
clinical significant complications were 
reported.
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.

Specialist dermatology consultation 
will be sought if warranted for 
individual participants.
Rash
Some observations of rash with oral RPV 
have been reported in clinical studies 
executed to date (the majority are Grade 1 
or Grade 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 

In this study, RPV LA 
administration will be preceded by a 
four week 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.

Participants experiencing a grade 3 
or 4 rash should discontinue their 
ART medication and will be 

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serum biochemistries.
withdrawn from the study.

All rash events should be assessed 
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.
Revised Text:
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 

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 

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individual participant receiving multiple 
injections. Although some Grade 3 ISRs 
were reported, the majority of ISRs have 
not, to date, been associated with an excess 
of participants’ withdrawal due to ISRs.
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.

Specialist dermatology consultation 
will be sought if warranted for 
individual participants.
Rash
Some observations of rash with oral RPV 
have been reported in clinical studies 
executed to date (the majority are Grade 1 
or Grade 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 

At the beginning of this study, RPV 
LA administration was preceded by 
a four week oral RPV lead-in to 
evaluate safety and tolerability in 
individual participants.  During the 
Extension Phase of the study, 
following review of available oral 
lead-in and Maintenance Phase 
safety data, the protocol was 
amended to allow an optional oral 

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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.
lead-in for the participants 
transitioning from ABC/DTG/3TC 
to CAB LA+RPV LA.

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.

Participants experiencing a grade 3 
or 4 rash should discontinue their 
ART medication and will be 
withdrawn from the study.

All rash events should be assessed 
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.

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Section 5.  Selection of Study Population and Withdrawal Criteria
Rationale for change:  Similar text duplicated in Section 5.1. and Section 5.2.
Text Deleted:
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.
Section 6.3. Dose and Administration
Rationale for change:  Table revised to explain direct to inject dosing option during the 
Extension Phase.
Original Text:
Extension Phase (Week 100 through End of Study) 
CAB LA + RPV LA Arm – continue IM dosing Every 4 Weeks+
ABC/DTG/3TC Arm (Transition to CAB LA + RPV LA)*
Oral Lead-In
Week 100 to Week 104a
(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 Injection (Loading Dose) – Week104b^
Week 104b^
(two 3 mL injections once)
Receive last dose of oral CAB + RPV
Receive CAB LA 600 mg given as 1 X 3 mL IM injection
Receive RPV LA 900 mg given as 1 X 3 mL IM injection 

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Maintenance Injections – Every 4 Weeks following Week 104b
Week 108 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
Revised Text:
Extension Phase (Week 100 through End of Study) 
CAB LA + RPV LA Arm – continue IM dosing Every 4 Weeks+
ABC/DTG/3TC Arm (Transition to CAB LA + RPV LA)* - Optional Oral Lead-In
Dosing If Using Optional Oral Lead-In
Week 100 to Week 104b
(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 Injection (Loading Dose) – Week104b^ - Optional Oral Lead-In
Week 104b^
(two 3 mL injections once)
Receive last dose of oral CAB + RPV
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 following Week 104b – Optional Oral Lead-In
Week 108 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
ABC/DTG/3TC Arm (Transition to CAB LA + RPV LA)*
Direct to Inject Dosing - if Not Using Oral Lead-In
First Injection (Loading Dose) – Week100^ - No Oral Lead-In
Week 100^
(two 3 mL injections once)
Receive last dose of oral ABC/DTG/3TC
Receive CAB LA 600 mg given as 1 X 3 mL IM injection
Receive RPV LA 900 mg given as 1 X 3 mL IM injection

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Maintenance Injections – Every 4 Weeks following Week 100 – No Oral Lead-In
Week 104a 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
Section 6.9.1. IM Dosing
Rationale for change:  Text moved to before Extension Phase dosing transition for 
participants beginning LA dosing in the Extension Phase 
Rearranged text within Section 6.9.1. and addition of Week 101 to one week post dose 
visits:
At one-week post dose visits (Week 5, Week 41, and Week 101), 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.
Section 6.9.1. IM Dosing
Rationale for change:  To explain dosing transition into the Extension Phase using 
optional oral lead-in.
Original Text:
Participants who were randomized to the ABC/DTG/3TC arm and are 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 100.  

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New Text Added:
Transition from ABC/DTG/3TC to IM Dosing into the Extension Phase:
Participants who were randomized to ABC/DTG/3TC and are eligible to enter the 
Extension Phase will transition to IM dosing at, or after, Week 100.  The transition 
from ABC/DTG/3TC to CAB LA + RPV LA can be completed with or without an 
oral lead-in prior to commencement of injectable treatment.  The participant 
decision will be taken in consultation with the investigator and appropriately 
documented.  In order to ensure no interruption in study treatment, the transition 
into Extension should be performed as follows:
Participants Transitioning Directly to Injections in the Extension Phase:  
Central lab results and safety parameters from the Week 96 visit must be available 
and reviewed for participants who choose to transition direct to injection.  If a 
clinical chemistry retest is required based on Week 96 labs, the retest should be 
performed as soon as possible (and preferably no later than 7 days following 
Week 96). Participants will remain on oral ABC/DTG/3TC until the Week 100 
injection visit, and until any required Week 96 retest results are available for 
review.
At Week 100, eligible participants will take the last dose of ABC/DTG/3TC (or DTG 
+ 2 NRTIs), and receive the first injections of CAB LA (600 mg) + RPV LA (900 mg) 
as initial loading doses.  Clinical chemistries will also be assessed at Week 100.  At 
Week 101, participants will return to the clinic for PK and safety assessments 
including clinical chemistries.  The second and third injections (CAB LA 400 mg + 
RPV LA 600 mg) will be administered at Week 104a and Week 108.  There will be a 
one week dosing window for the second and third IM injections such that the second 
injections occur within the window of Week 103 to Week 104a, but not later than 
Week 104a, and the third injections occur within the window of Week 107 to Week 
108, but no later than Week 108.  Subsequent injections (CAB LA 400 mg + RPV 
LA 600 mg) will occur every 4 weeks thereafter, from the projected visit date, with a 
(+ or -) 7 day dosing window being allowed (but not preferred).  Following the Week 
108 injection, the interval between injection visits should be limited to a maximum 
of 5 weeks.  The Medical Monitor must be contacted if the length of time between 
injections exceeds, or is projected to exceed, 5 weeks.
Participants Receiving Optional Oral Lead-In in the Extension Phase:
At Week 100, eligible participants who after discussion with the investigator, choose 
to receive the optional oral lead-in will begin a 4 week lead-in of oral CAB 30 mg + 
oral RPV 25 mg once daily.  It is not necessary to dose ABC/DTG/3TC on the day 
the participant begins the oral lead-in with CAB + RPV.  However, if the 
participant takes ABC/DTG/3TC prior to coming into the clinic, initiation of oral 
CAB and RPV should continue as planned.

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Section 7.1. Time and Events Table:
Rationale for change:  Updated to reflect changes for transition into the Extension Phase 
based on Oral Lead-In Design.
Original Text:
Participants originally randomized to ABC/DTG/3TC at Day 1, who choose to continue 
into the Extension Phase and transition to CAB LA + RPV LA, will have all assessments 
noted in the Time and Events table below performed Q4W from Week 108 through 
Week 124.  
Revised Text:
Participants originally randomized to ABC/DTG/3TC at Day 1, who choose to continue 
into the Extension Phase and transition to CAB LA + RPV LA, will have all assessments 
noted in the Time and Events table below performed Q4W through Week 124.  
Section 7.1. Time and Events Table:
Rationale for change: Updated to reflect changes for transition into the Extension Phase 
based on Oral Lead-In Design.

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Changes made to Table: New columns added to describe assessments for Direct to 
Inject Arm (changes to table noted in teal)
Symptom Directed 
Physical Exam 
and Medical 
Assessment d
X
X
X
X
X
X
HIV Associated 
Conditions
X
X
X
X
X
X
AE and SAE 
Assessment, Con 
Meds
X
X
X
X
X
X
Clinical Chemistry
Pregnancy 
Testingj
UjS
S
S
U
S
HIV-1 RNA and 
sample for 
storagek 
Sk 
X
X
X
PK Sample
IM Study 
Treatment 
Administration – 
Q4W throughout 
Maintenance and 
Extension Phase
X
X
X
Xs
X
Procedures
Maintenance 
Phase by Week
Extension Phase
by Week
104b – Oral 
Lead-InSwitch 
Arm
108
100
101 – Direct to 
Inject Arm
104a – Direct to 
Inject Arm
104a LA and 
Oral Lead-In 
Arm
ISR Assessment 
(LA Arm Only)
X
X
X
X
X
X
X
X
X
X
Xv w
S
X
Xv
Xv

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Also clarified Oral Lead-In Dispensing and Accountability for participants using 
optional oral lead-in only.
Table Footer and Footnotes Amended (only edited footnotes included below):
Note: Footnote i clarifies differences in eCSSRs for participants receiving 
ABC/DTG/3TC after Week 48 (based on every 8 week visits compared to continued 
Q4W visits for participants on LA).
i.  On Day 1, the eC-SSRS is to be administered prior to randomization.  During the 
Maintenance Phase, the eC-SSRS will be administered at each Q4W visit through the 
Week 48 primary endpoint, and then followed by Q12W assessments for CAB LA + 
RPV LA arm, thereafter through Week 96 (LA:  Week 60, 72, 84, 96).  The 
ABC/DTG/3TC arm will have assessments at Week 72 and Week 96.  Preferably 
completed at the beginning of the visit following administration of other patient reported 
questionnaires required prior to injections
v.  Take PK samples pre-dose.  At Week 4b (and Week 104b for participants 
transitioning to LA from ABC/DTG/3TC using the optional oral lead-in), the pre-dose
PK sample should be taken after review of the PK diary and prior to the final oral CAB + 
RPV dose.  A sample will be also be taken at Week 4b, Week 48, and Week 96 (and 
Week 100 [direct to inject] or Week 104b [using CAB + RPV oral lead-in]), 
approximately 2 hours post-injections.  The Week 5, Week 41, and Week 101 visit can 
be performed at any time from 3 to 10 days after the Week 4b, Week 40, and Week 100
Procedures
Week 100
Week 104a
Week 104b
Oral CAB and 
Oral RPV 
Dispensation 
Xx
OLI Only
Xx
OLI Only
ABC/DTG/3TC 
Dispensation (or 
DTG alternate)
Study Treatment 
Accountability 
(pill counts)
X
OLI Only
X
OLI Only
Xu
OLI Only
Follow Up Visit:  Conduct ~4 weeks after the last dose of oral IP.  Required only if the participant has ongoing AEs / lab 
abnormalities at the last on-study visit.  This visit may be conducted by telephone.
Direct to Inject:  Participants transitioning into the Extension Phase who do not use the optional CAB + RPV 
oral lead-in beginning at Week 100.
Oral Lead-In:  Participants transitioning into the Extension Phase who do use the optional CAB + RPV oral 
lead-in beginning at Week 100.
LA Arm:  Participants who were originally randomized to CAB LA + RPV LA at Day 1.
Switch Arm:  All participants who transition into the Extension Phase from ABC/DTG/3TC (or DTG + 2 NRTI’s) 
at Week 100 – e.g., both direct to inject and oral lead-in participants.

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injection, respectively. PK samples at Week 5, Week 41, and Week 101 can be taken at 
any time during the visit.
w.  Participants should take the last dose of oral CAB+RPV at Week 4b (and Week 104b 
for participants transitioning to LA from ABC/DTG/3TC if using the optional oral lead-
in) in the clinic after PK sampling.  Participants should take the last dose of 
ABC/DTG/3TC at Week 100 if transitioning directly to injections at Week 100.  
Injections should be administered within 2 hours of the last oral dose where possible.
Section 7.4.3.1. Adverse Events and Serious Adverse Events (SAEs)
Rationale for change:  Bullet removed as all AEs will be collected during Extension and 
Long-Term Follow-Up Phase (not just AEs leading to Withdrawal):
Deleted Text:

During the Extension Phase and Long-Term Follow-Up Phase, AEs leading to 
Withdrawal and all SAEs will be recorded.
Section 7.4.3.4. Prompt Reporting of Serious Adverse Events and Other Events
Rationale for change:  clarification that ABC HSR will be collected for participants 
receiving ABC in the Long-Term Follow-Up Phase.
Original Text:
Suspected ABC HSR in 
participants 
randomized to the STR 
arm 
1 week
ABC HSR eCRF
1 week
Updated ABC HSR 
eCRF
Revised Text:
Suspected ABC HSR in 
participants 
randomized to the STR 
arm or receiving an 
oral ABC-containing 
regimen during the 
Long-Term Follow-Up 
Phasea
1 week
ABC HSR eCRF
1 week
Updated ABC HSR 
eCRF

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Section 7.4.7.1. Pregnancy Testing
Rationale for change: Clarification added for negative pregnancy test at Week 100 if 
particpants choose no oral CAB + RPV lead-in.
Original Text:
Women of childbearing potential must have a negative pregnancy test at Screening, 
Baseline (Week [-20]), the first Induction Phase visit (Day 1), and Week 104b for women 
transitioning into the Extension Phase from the ABC/DTG/3TC arm (prior to 
administration of first CAB LA and / or RPV LA injections).  
Revised Text:
Women of childbearing potential must have a negative pregnancy test at Screening, 
Baseline (Week [-20]), the first Induction Phase visit (Day 1), and Week 100 (if no oral 
lead-in is used) or Week 104b (if using CAB and RPV oral lead-in) for women 
transitioning into the Extension Phase from the ABC/DTG/3TC arm (prior to 
administration of first CAB LA and / or RPV LA injections).  
Section 7.5.1. PK Sample Collection
Rationale for change:  Clarification of text for optional oral lead-in.
Original Text:
At Week 4b (and Week 104b for participants transitioning into the Extension Phase from 
the ABC/DTG/3TC arm), PK samples must be collected within the window of 20 to 28 
hours after the oral dose of CAB + RPV was taken the day prior to the clinic visit.  
Revised Text:
At Week 4b (and Week 104b for participants using the oral CAB + RPV lead-in and
transitioning into the Extension Phase from the ABC/DTG/3TC arm), PK samples must 
be collected within the window of 20 to 28 hours after the oral dose of CAB + RPV was 
taken the day prior to the clinic visit.  
Section 7.5.1. PK Sample Collection
Rationale for change:  Updated sampling schedule based on optional oral CAB + 
RPV lead-in during the Extension Phase.

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Original Text (Table 8):
ABC/DTG/3TC Arm 
Transitioning to 
CAB LA + RPV LA 
at Week 100
CAB
Pre-Dose:  Week 104b, Week 108, Withdrawal
2 Hours Post Dose:  Week 104b
Long-term follow-up Period (off-drug; storage sample)
Months 1, 3, 6, 9, and 12
RPV
Pre-Dose:  Week 104b, Week 108, Withdrawal
2 Hours Post Dose:  Week 104b
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7 days (4th and all subsequent injections); Sample Collection:  Pre-dose at Week 4b 
(and Week 104b for participants transitioning from ABC/DTG/3TC 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.
a.
Each analyte in individual collection tube.
b.
Samples taken at Week 5, Week 41, may be collected from 3 to 10 days after Week 4b, Week 40, respectively.  
These samples may be collected at anytime during those visits.  

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Revised Text:
ABC/DTG/3TC Arm 
Transitioning to CAB 
LA + RPV LA at 
Week 100
(participants using 
CAB + RPV oral 
lead-in)
CAB
Pre-Dose:  Week 104b, Week 108 (for storage), Withdrawal
2 Hours Post Dose:  Week 104b
Long-term follow-up Period (off-drug; storage sample)
Months 1, 3, 6, 9, and 12
RPV
Pre-Dose:  Week 104b, Week 108 (for storage), Withdrawal
2 Hours Post Dose:  Week 104b
Long-term follow-up Period (off-drug; storage sample)
Months 1, 3, 6, 9, and 12
ABC/DTG/3TC Arm 
Transitioning to 
CAB LA + RPV LA 
at Week 100 (Direct 
to Inject -
participants not
using CAB + RPV 
oral lead-in)
CAB
Pre-Dose:  Week 104a, Week 108 (for storage), 
Withdrawal
2 Hours Post Dose:  Week 100
1 Week Post Doseb:  Week 101
Long-term follow-up Period (off-drug; storage sample)
Months 1, 3, 6, 9, and 12
RPV
Pre-Dose:  Week 104a, Week 108 (for storage), 
Withdrawal
2 Hours Post Dose:  Week 100
1 Week Post Doseb:  Week 101
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7 days (4th and all subsequent injections); Sample Collection:  Pre-dose at Week 4b 
(and Week 104b for participants transitioning from ABC/DTG/3TC Arm using oral lead-in):  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.
a.
Each analyte in individual collection tube.
b.
Samples taken at Week 5, Week 41, and Week 101 may be collected from 3 to 10 days after Week 4b, Week 40, 
and Week 100, respectively.  These samples may be collected at anytime during those visits.  

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Section 9.2.4.  Sample Size Considerations for Week 124 Extension Switch Analysis
– New Section
Rationale for change:  Text added regarding sample size for endpoint for Extension 
Phase endpoint.
New Text Added:
For the Week 124 Extension Switch population analysis (Section 9.3.1.6), the primary 
efficacy endpoint of interest is the proportion of participants without oral lead-in who 
have HIV-1 RNA ≥50 c/mL at Week 124 (i.e., 24 weeks from initiation of CAB LA + 
RPV LA, 6-week analysis window, using the FDA Snapshot algorithm).  The endpoint 
will be evaluated descriptively, with no formal statistical comparison to data generated in 
participants receiving oral lead-in by to initiation of CAB LA + RPV LA. 
Table 14 presents the precision in estimation according to sample size and observed 
proportion with HIV-1 RNA 50 c/mL.  For example, if the observed rate is 3% and 250 
Extension switch participants do not receive oral lead-in, then the upper bound of the 
95% CI would be 5.1%.   
Table 14
Precision (Upper Limit of 95% CI) for Single Arm Proportion 
Sample Size 
without Oral Lead-In
Observed Proportion
HIV-1 RNA 50 c/mL
Upper limit of 95% 
Confidence Interval†
175
2%
4.1%
200
2%
3.9%
225
2%
3.8%
250
2%
3.7%
175
3%
5.5%
200
3%
5.4%
225
3%
5.2%
250
3%
5.1%
175
4%
6.9%
200
4%
6.7%
225
4%
6.6%
250
4%
6.4%
† Two-sided confidence Interval calculated using the Wald normal approximation method
Section 9.3.1.6.  Extension Switch Population (ES) – New Section
Rationale for change:  Explanation of population for participants switching from 
ABC/DTG/3TC to CAB LA + RPV LA in the Extension Phase.
New Text Added:
The Extension Switch population will include all participants randomized to the 
Maintenance Phase ABC/DTC/3TC arm who switch to and receive at least one dose 
of CAB and/or RPV during the Extension Phase of the study.  The ES population
will be used to evaluate safety and efficacy of switching to CAB LA + RPV LA, with 

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and without oral lead-in. Participants will be assessed according to actual treatment 
received during the Extension Phase.
Section 9.3.3.  Planned Analyses
Rationale for change:  To describe new Week 124 analysis for participants switching to 
LA during the Extension Phase.
Original Text:
At least two analyses will be conducted to evaluate primary and secondary objectives of 
the protocol, one after all subjects have completed their visit at Week 48 and one after 
Week 96.  
Revised Text:
At least three analyses will be conducted to evaluate the objectives of the protocol: after 
all randomized participants have completed their visits at Week 48 and Week 96, 
respectively, and after all Extension switch participants (Section 9.3.1.6) have 
completed the Week 124 visit.  
Section 9.4.2.  Secondary Analyses
Rationale for change:  Clarification of planned analyses.
Original Text:
Proportion of participants with plasma HIV-1 RNA <200 c/mL and <50 c/mL and 
confirmed virologic failure, respectively, over time will be summarized using the 
Snapshot algorithm.  
Revised Text:
Proportion of participants with plasma HIV-1 RNA <200 c/mL and <50 c/mL, and HIV-
1 RNA 200 c/mL and 50 c/mL, respectively, over time will be summarized using the 
Snapshot algorithm.  
Section 9.4.2.1. Week 124 Extension Switch Analysis (New Section Added)
Rational for change:  To describe new Week 124 planned analysis.
New Text Added”
Section 9.4.2.1.  Week 124 Extension Switch Analysis
For the Week 124 Extension Switch population analysis (Section 9.3.1.6), antiviral 
response will be assessed according to the proportion of participants with and 
without oral lead-in, respectively, who have HIV-1 RNA ≥50 c/mL at Week 124 (i.e., 
24 weeks from initiation of CAB LA + RPV LA, 6 week analysis window, using the 
FDA Snapshot algorithm), with corresponding 95% confidence interval.  The 

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primary efficacy endpoint of interest for this analysis is the proportion of 
participants without oral lead-in who have HIV-1 RNA ≥50 c/mL at Week 124. No 
formal statistical comparison with respect to safety and efficacy outcomes will be 
performed.
Proportion of participants with plasma HIV-1 RNA <200 c/mL and <50 c/mL and 
confirmed virologic failure, respectively, over time will be summarized.
Absolute values and change from Extension Baseline CD4+ cell count will be 
summarized over time.
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
Changes from Extension Baseline in laboratory (including fasting lipids) and vital 
signs data will be summarized.  In addition, the number and percentage of 
participants with Extension emergent graded laboratory toxicities (based on DAIDS 
categories) will be summarized by treatment group.
Further details for secondary efficacy, safety and exploratory analyses will be 
included in the RAP.  
Section 12.7 Appendix 7:  Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) and Collection of Pregnancy 
Information
Rationale for change:  Text updated to be consistent with current template language.
Original Text:
Section 12.7. Appendix 7:  Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (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.
1. Contraceptive subdermal implantntrauterine device or intrauterine system
2. Combined estrogen and progestogen oral contraceptive [Hatcher, 2011])
3. Injectable progestogen [Hatcher, 2011]

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4. Contraceptive vaginal ring [Hatcher, 2011]
5. Percutaneous contraceptive patches [Hatcher, 2011]
6. Male partner sterilization 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.
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that participants understand how to properly use these methods of contraception.
Revised Text:
Section 12.7.  Appendix 7:  Contraceptive Guidance and Collection of Pregnancy 
Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below).
Women in the following categories are not considered WOCBP
a. Premenarchal
b. Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
c. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 

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to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment.
Section 12.7.1.  Contraception Guidance
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in 
Table 17. 
Table 17
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulationb

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.) 
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the participant.)
NOTES: 
a.
Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for participants in clinical 
studies. 
b.
Two highly effective methods of contraception should be utilized from 30 days prior to the first dose of study 
medication, throughout the study, and for at least 52 weeks after discontinuation of CAB LA and RPV LA .

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Pregnancy Testing
o
WOCBP should only be included after a confirmed menstrual period and a 
negative highly sensitive serum pregnancy test.
o
Additional pregnancy testing should be performed as per the study Time and 
Events Table.
o
Pregnancy testing will be performed whenever a menstrual cycle is missed or 
when pregnancy is otherwise suspected.
o
Pregnancy testing will be performed and assayed in the central laboratory OR 
using the test kit provided by the central laboratory / provided by the sponsor /
approved by the sponsor and in accordance with instructions provided in its 
package insert.