An Amendment to the FLAIR Study to Evaluate the Pharmacokinetics, Safety, Tolerability, Maintenance of Virological Suppression and Patient Reported Outcomes for Participants Receiving Cabotegravir (CAB 200 mg/mL) and Rilpivirine (300 mg/mL) Long-Acting Injections Following Sub-cutaneous (SC) Administration in the Anterior Abdominal Wall SC Tissue Compared With Intramuscular (IM) Administration in the Gluteus Medius Muscle in Adult Participants Living With HIV-1 Infection in the FLAIR Study
Phase: PHASE3
Conditions: Human Immunodeficiency Virus Type 1 (HIV-1)
Sponsor: ViiV Healthcare

Protocol
Main Study ID:  201584
Main Study Official 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
NCT ID for Main Study: NCT02938520
Sub-Study ID:  201584-001
Sub-Study Official Title:  An Amendment to the FLAIR Study to Evaluate the 
Pharmacokinetics, Safety, Tolerability, Maintenance of Virological Suppression 
and Patient Reported Outcomes for Participants Receiving Cabotegravir (CAB 200 
mg/mL) and Rilpivirine (300 mg/mL) Long-Acting Injections Following Sub-
cutaneous (SC) Administration in the Anterior Abdominal Wall SC Tissue 
Compared With Intramuscular (IM) Administration in the Gluteus Medius Muscle 
in Adult Participants Living With HIV-1 Infection in the FLAIR Study
NCT ID for Sub-Study: NCT05896748
Date of Document of Sub-Study: 28-Aug-2023 

TMF-16441767 
CONFIDENTIAL 
201584 
ViiV Healthcare group of companies 
 
Protocol Amendment 09 
 
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TITLE PAGE    
Protocol 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 
 
Protocol Number: 201584 / Amendment 09 
Compound Number: GSK1265744 
Study Phase: Phase 3 
Sponsor Name and Legal Registered Address:  
This study is sponsored by ViiV Healthcare UK Limited. GlaxoSmithKline is supporting 
ViiV Healthcare in the conduct of this study.  
 
Sponsor Legal Registered Address (excluding US):  
ViiV Healthcare UK Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
 
US IND Sponsor Legal Registered Address: 
ViiV Healthcare Company 
410 Blackwell Street,  
Durham, NC 27701 
Telephone: +1 877 844 8872 
Fax number: + 1 919 237 9294 
 
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 Research and Medical Strategy. 
 
Medical Monitor Name and Contact Information can be found in the Study 
Reference Manual. 
 
Sponsor Signatory: 
Name:  
Sherene Min, MD, MPH 
Title:  
Vice President, Head of Clinical Development 
 
 
ViiV Healthcare  
 
Approval Date: 28 Aug 2023 
 

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ViiV Healthcare group of companies 
 
Protocol Amendment 09 
 
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Copyright 2022 ViiV Healthcare group of companies.  All rights reserved.  Unauthorized 
copying or use of this information is prohibited. 
 
 
Regulatory Agency Identifying Number(s):  
US IND: 109,678 
EudraCT #:  2016-001646-25 
 

TMF-16441767 
CONFIDENTIAL 
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ViiV Healthcare group of companies 
 
Protocol Amendment 09 
 
3 
 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Document Identifier 
Amendment 09 
28 Aug 2023 
TMF-16441767 
Amendment 08 
21 October 2022 
TMF-15038148 
Amendment 07 
17-Jun-2022 
TMF-14728112 
Amendment 06 
05-Aug-2021 
TMF-13030701 
Amendment 05 
20-May-2020 
2015N248866_05 
Amendment 04 
24-Sep-2018 
2015N248866_04 
Amendment 03 
25-Jun-2018 
2015N248866_03 
Amendment 02 
19-Jul-2017 
2015N248866_02 
Amendment 01 
13-Dec-2016 
2015N248866_01 
Original Protocol (00) 
26-May-2016 
2015N248866_00 
 
Amendment 09 28 Aug 2023 
This amendment is considered to be substantial based on the criteria defined in EU 
Clinical Trial Regulation No 536/2014 of the European Parliament and the Council of the 
European Union.  
Overall Rationale for the Amendment 09:  
The primary purposes of this amendment are: 
• To update the Potential Risk of Clinical Significance of HSR when using 
integrase inhibitors, such as CAB. 
Section # and Name 
Description of Change 
Brief Rationale 
Section 4.6.1 Risk 
Assessment  
Updated the Summary of Data/Rationale for 
Risk for HSR that have been reported in 
association with integrase inhibitors.  
 
Updated the description of the cases reported 
to be associated with CAB. 
• 
Updated safety 
information 
from CAB IB 
v13 
supplement 2  
 
 
 
 
 

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TABLE OF CONTENTS 
PAGE 
1. 
PROTOCOL SYNOPSIS FOR STUDY 201584 ........................................................ 9 
1.1. 
Rationale ...................................................................................................... 9 
1.2. 
Objectives/Endpoints .................................................................................... 9 
1.3. 
Overall Design ............................................................................................ 13 
1.3.1. 
201584 (FLAIR) Study Schematic ................................................ 15 
1.4. 
Treatment Arms and Duration ..................................................................... 15 
1.5. 
Type and Number of Participants ................................................................ 22 
1.6. 
Analysis ...................................................................................................... 22 
2. 
INTRODUCTION .................................................................................................... 23 
2.1. 
Study Rationale .......................................................................................... 25 
2.2. 
Brief Background ........................................................................................ 26 
3. 
OBJECTIVES AND ENDPOINTS ........................................................................... 29 
4. 
STUDY DESIGN .................................................................................................... 33 
4.1. 
Overall Design ............................................................................................ 33 
4.2. 
Treatment Arms and Duration ..................................................................... 36 
4.2.1. 
Screening Phase (Up to 35 days) ................................................ 36 
4.2.2. 
Induction Phase ........................................................................... 37 
4.2.3. 
Eligibility for the Maintenance Phase ........................................... 37 
4.2.4. 
Maintenance Phase (Day 1 to Week 100) .................................... 38 
4.2.5. 
Extension Phase .......................................................................... 39 
4.2.6. 
Long-Term Follow-Up Phase – IM Regimen only ......................... 42 
4.2.7. 
Dose Modifications / Permitted Treatment Substitutions .............. 43 
4.2.8. 
Independent Data Monitoring Committee ..................................... 44 
4.3. 
Type and Number of Participants ................................................................ 45 
4.4. 
Design Justification ..................................................................................... 45 
4.5. 
Dose Justification ........................................................................................ 47 
4.5.1. 
Oral Lead-In Phase ...................................................................... 47 
4.5.2. 
Long Acting Injectable for Maintenance Phase ............................ 49 
4.5.3. 
Modeling and Dose Simulations for CAB LA and RPV LA ............ 54 
4.6. 
Benefit:Risk Assessment ............................................................................ 58 
4.6.1. 
Risk Assessment ......................................................................... 61 
4.6.2. 
Other Clinically Relevant Information ........................................... 77 
4.6.3. 
Benefit Assessment ..................................................................... 77 
4.6.4. 
Overall Benefit:Risk Conclusion ................................................... 77 
5. 
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA ............. 77 
5.1. 
Inclusion Criteria ......................................................................................... 78 
5.2. 
Exclusion Criteria ........................................................................................ 80 
5.3. 
Screening/Baseline/Run-in Failures ............................................................ 83 
5.4. 
Withdrawal/Stopping Criteria....................................................................... 83 
5.4.1. 
Liver Chemistry Stopping Criteria ................................................ 86 
5.4.2. 
QTc Stopping Criteria .................................................................. 91 
5.4.3. 
Virologic Failure ........................................................................... 92 
5.4.4. 
Definition of Virologic Failure ....................................................... 92 
5.4.5. 
Managing Virologic Failure .......................................................... 92 

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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 ........................................................ 95 
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 
6.14. 
Medical Devices ........................................................................................ 113 
7. 
STUDY ASSESSMENTS AND PROCEDURES ................................................... 113 
7.1. 
Time and Events Table ............................................................................. 113 
7.2. 
Screening and Critical Baseline Assessments .......................................... 126 
7.2.1. 
Screening .................................................................................. 126 
7.2.2. 
Baseline Assessments ............................................................... 127 
7.3. 
Efficacy ..................................................................................................... 128 
7.3.1. 
Plasma HIV-1 RNA .................................................................... 128 
7.3.2. 
Lymphocyte Subsets, CD4+ and CD8+ ..................................... 128 
7.3.3. 
HIV Associated Conditions ........................................................ 128 
7.4. 
Safety ....................................................................................................... 128 
7.4.1. 
Clinical evaluations .................................................................... 128 
7.4.2. 
Laboratory Assessments ........................................................... 130 
7.4.3. 
Adverse Events (AEs) and Serious Adverse Events 
(SAEs) ....................................................................................... 132 
7.4.4. 
Medical Device Deficiencies ...................................................... 137 
7.4.5. 
Time Period for Detecting Medical Device Deficiencies ............. 137 
7.4.6. 
Follow-Up of Medical Device Deficiencies.................................. 137 
7.4.7. 
Prompt Reporting of Medical Device Deficiencies to 
Sponsor ..................................................................................... 137 
7.4.8. 
Regulatory Reporting Requirements for Medical Device 
Deficiencies ............................................................................... 138 

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7.4.9. 
Toxicity Management ................................................................. 138 
7.4.10. 
Specific Toxicities / Adverse Event Management ....................... 140 
7.4.11. 
Suicidal Risk Monitoring ............................................................. 148 
7.4.12. 
Pregnancy ................................................................................. 149 
7.4.13. 
Physical Exams ......................................................................... 151 
7.4.14. 
Vital Signs .................................................................................. 152 
7.4.15. 
Electrocardiogram (ECG) ........................................................... 152 
7.5. 
Pharmacokinetics ..................................................................................... 152 
7.5.1. 
PK Sample Collection ................................................................ 152 
7.5.2. 
Rationale of PK Sampling Strategy ............................................ 154 
7.5.3. 
Sample Analysis ........................................................................ 155 
7.6. 
Biomarker(s) ............................................................................................. 155 
7.6.1. 
Biomarker Endpoints (Exploratory) ............................................ 155 
7.7. 
Genetics ................................................................................................... 155 
7.8. 
Viral Genotyping and Phenotyping ............................................................ 156 
7.8.1. 
HIV-1 pol Viral Genotyping and Phenotyping ............................. 156 
7.8.2. 
HIV-1 Exploratory Analysis ........................................................ 156 
7.9. 
Value Evidence and Outcomes ................................................................. 156 
7.9.1. 
Value Evidence and Outcomes Endpoints (Secondary) ............. 158 
7.9.2. 
Value Evidence and Outcomes Endpoints (Exploratory) ............ 159 
8. 
DATA MANAGEMENT ......................................................................................... 159 
9. 
STATISTICAL CONSIDERATIONS AND DATA ANALYSES ............................... 159 
9.1. 
Hypotheses ............................................................................................... 159 
9.2. 
Sample Size Considerations ..................................................................... 160 
9.2.1. 
Sample Size Assumptions ......................................................... 160 
9.2.2. 
Sample Size Sensitivity .............................................................. 163 
9.2.3. 
Sample Size Re-estimation or Adjustment ................................. 165 
9.2.4. 
Sample Size Considerations for Week 124 Extension 
Switch Analysis .......................................................................... 165 
9.3. 
Data Analysis Considerations ................................................................... 166 
9.3.1. 
Analysis Populations .................................................................. 166 
9.3.2. 
Treatment Comparisons ............................................................ 167 
9.3.3. 
Planned Analyses ...................................................................... 167 
9.4. 
Key Elements of Analysis Plan ................................................................. 168 
9.4.1. 
Primary Analyses ....................................................................... 168 
9.4.2. 
Secondary Analyses .................................................................. 170 
9.4.3. 
Pharmacokinetic Analyses ......................................................... 171 
9.4.4. 
Pharmacokinetic/Pharmacodynamic Analyses ........................... 172 
9.4.5. 
Viral Genotyping/Phenotyping Analyses .................................... 172 
9.4.6. 
Health Outcomes Analyses ........................................................ 172 
9.4.7. 
Other Analyses .......................................................................... 173 
10. STUDY GOVERNANCE CONSIDERATIONS ...................................................... 173 
10.1. 
Posting of Information on Publicly Available Clinical Trial Registers .......... 173 
10.2. 
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ...................................................................................... 173 
10.3. 
Quality Control (Study Monitoring) ............................................................ 174 
10.4. 
Quality Assurance ..................................................................................... 174 
10.5. 
Study and Site Closure ............................................................................. 175 
10.6. 
Records Retention .................................................................................... 175 

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10.7. 
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication ............... 176 
10.8. 
Review Committee .................................................................................... 176 
10.8.1. 
Independent Data Monitoring Committee ................................... 176 
11. REFERENCES ..................................................................................................... 177 
12. APPENDICES ...................................................................................................... 181 
12.1. 
Appendix 1: Abbreviations and Trademarks .............................................. 181 
12.2. 
Appendix 2: Division Of AIDS Table For Grading The Severity Of 
Adult And Pediatric Averse Events Version 2.0, November 2014 .............. 186 
12.2.1. 
Reference .................................................................................. 223 
12.3. 
Appendix 3:  Liver Safety – Required Actions, Follow Up 
Assessments and Study Treatment Restart Guidelines ............................ 224 
12.4. 
Appendix 4: CDC Classification System for HIV-1 Infections (2014) ......... 228 
12.4.1. 
Reference .................................................................................. 229 
12.5. 
Appendix 5: Genetic Research ................................................................. 230 
12.6. 
Appendix 6: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events ............................................. 232 
12.6.1. 
Definition of Adverse Events ...................................................... 232 
12.6.2. 
Definition of Serious Adverse Events ......................................... 233 
12.6.3. 
Definition of Cardiovascular Events ........................................... 235 
12.6.4. 
Recording of AEs and SAEs ...................................................... 235 
12.6.5. 
Evaluating AEs and SAEs .......................................................... 236 
12.6.6. 
Reporting of SAEs to ViiV Healthcare / GSK .............................. 237 
12.7. 
Appendix 7:  Contraceptive Guidance and Collection of Pregnancy 
Information ................................................................................................ 238 
12.7.1. 
Contraception Guidance ............................................................ 239 
12.7.2. 
Collection of Pregnancy Information .......................................... 240 
12.8. 
Appendix 8: Country Specific Requirements ............................................. 241 
12.8.1. 
United Kingdom (UK) ................................................................. 241 
12.8.2. 
Japan ......................................................................................... 241 
12.8.3. 
Russia ....................................................................................... 242 
12.9. 
Appendix 9:  COVID-19 Pandemic and Clinical Trial Continuity ................ 242 
12.9.1. 
Changes to Study Visits and Study Procedures ......................... 243 
12.9.2. 
Changes to Informed Consent ................................................... 243 
12.9.3. 
Permissible Use of Antiretroviral Therapy .................................. 244 
12.9.4. 
Direct-To-Patient (DTP) Shipment of Oral Study IP ................... 245 
12.9.5. 
COVID-19 Experimental Agents ................................................ 246 
12.9.6. 
COVID-19 Specific Data Capture ............................................... 246 
12.10. Appendix 10: Information and Guidance for Managing Pregnant 
Participants ............................................................................................... 248 
12.10.1. Collection of Pregnancy Information .......................................... 249 
12.10.2. Introduction ................................................................................ 249 
12.10.3. Benefit/Risk Assessment ........................................................... 250 
12.10.4. Clinical Considerations .............................................................. 253 
12.10.5. Study Assessments and Procedures: specific 
assessments for pregnant participants ....................................... 256 
12.10.6. References ................................................................................ 257 
12.11. Appendix 11: Device Deficiencies: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting in Medical Device 
Studies ..................................................................................................... 258 

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12.11.1. Definition of Device Deficiency ................................................... 258 
12.11.2. Recording and Follow-Up of Device Deficiencies ....................... 258 
12.11.3. Reporting of Medical Device Deficiencies for Participants .......... 259 
12.11.4. Reporting of Medical Device Deficiencies for Associated 
Person ....................................................................................... 260 
12.12. Appendix 12: Sub-Cutaneous Administration PK Sub-Study 
Amendment .............................................................................................. 260 
12.12.1. Sub-Study Amendment Background .......................................... 261 
12.12.2. Sub-Study Amendment Rationale .............................................. 269 
12.12.3. Sub-Study Objectives and Endpoints ......................................... 274 
12.12.4. Sub-Study FLAIR Amendment Design ....................................... 277 
12.12.5. Sub-Study Time and Events Table............................................. 289 
12.12.6. Sub-Study Health Outcomes Questionnaires ............................. 294 
12.12.7. Sub-Study Treatment ................................................................. 295 
12.12.8. Sub-Study Data Management .................................................... 296 
12.12.9. Sub-Study Statistical Considerations and Data Analyses ........... 296 
12.12.10. Sub-Study Pharmacokinetics ..................................................... 299 
12.12.11. References ................................................................................ 300 
12.13. Appendix 13: Mitigation for Geopolitical Situation in Russia/Ukraine ......... 301 
12.13.1. Changes to Study Visits and Study Procedures ......................... 301 
12.13.2. Changes to Informed Consent ................................................... 302 
12.13.3. Permissible Use of Antiretroviral Therapy .................................. 302 
12.13.4. Direct To Patient (DTP) Shipments of Oral Study IP .................. 303 
12.14. Appendix 14:  Protocol Amendments ........................................................ 304 
12.14.1. Amendment 01 (All Countries) ................................................... 304 
12.14.2. Amendment 02 (All Countries) ................................................... 332 
12.14.3. Amendment 03 (All Countries) ................................................... 339 
12.14.4. Amendment 04 (All Countries) ................................................... 348 
12.14.5. Amendment 05 (All Countries) ................................................... 387 
12.14.6. Amendment 06 (All Countries) ................................................... 394 
12.14.7. Amendment 07 (All Countries) ................................................... 403 
12.14.8. Amendment 08 (All Countries) ................................................... 406 
12.14.9. Amendment 09 (All Countries) ................................................... 411 
 

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1. 
PROTOCOL SYNOPSIS FOR STUDY 201584 
1.1. 
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. 
1.2. 
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 

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Objectives 
Endpoints 
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 (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 

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Objectives 
Endpoints 
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 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 

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Objectives 
Endpoints 
(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 
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) 

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Objectives 
Endpoints 
(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. 
1.3. 
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 

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(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.   
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 must enter the 52-week 
Long-Term Follow-Up Phase (please refer to the Long Term Follow-up Phase – IM 
Regimen Only section of the synopsis for additional details).  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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1.3.1. 
201584 (FLAIR) Study Schematic 
 
1.  
 
¥Subjects who withdraw from IM CAB LA + RPV LA must enter the 52 week Long Term Follow-Up 
Phase if the marketed product is not locally available.  
 
1.4. 
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 

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withdrawn from the study.  Note:  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. 
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 
Grade 4 liver enzyme elevations), will require consultation and agreement with the 

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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 
occur within the window of Week 107 to Week 108, but not later than Week 108, and the 

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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 
• Where the CAB LA + RPV LA marketed product is not locally available, 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 enter the LTFU 
Phase. The participant 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 LTFU Phase will begin the 
day of the last CAB LA and/or RPV LA dose and continue for 52 weeks. These 
participants will not complete a Withdrawal visit but will instead move directly into 
the LTFU Phase.  
 
• Where the CAB LA + RPV LA marketed product is locally available, only 
participants that discontinue the CAB LA + RPV LA regimen for safety-related 
reasons only. must enter the LTFU Phase. Participants must remain on suppressive 
HAART for at least 52 weeks after the last dose of LA and/or RPV LA in order to 
prevent selective pressure on HIV and the potential for selection of resistant mutants. 
Investigators must discuss the choice of the follow-up HAART regimen with the 
Medical Monitor prior to initiating the new regimen with the participant. 
HAART therapy should be initiated within four weeks of the last injection. The 
LTFU Phase will begin the day of the last CAB LA and/or RPV LA dose and 
continue for 52 weeks. These participants will not complete a Withdrawal visit but 
will instead move directly into the LTFU Phase. In addition, for participants who 
withdraw during the LTFU, the final visit will be considered the study withdrawal 
visit.  
 
• NOTE: Participants transitioning to CAB LA + RPV LA marketed product or 
alternative HAART (except due to safety-related reasons) do not need to enter the 
LTFU Phase. 
 
 
 
 

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Long-Term Follow-Up Phase requirement 
Marketed product 
locally available 
Subject WD due to safety-
related reasons 
LTFU Phase required? 
No 
Yes 
Yes 
No 
Yes 
Yes 
Yes 
No 
No, but Safety FU visit required to 
assess potential safety issues 
occurred after the last injection 
 
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.  
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 

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<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 
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 

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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. 
1.5. 
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. 
1.6. 
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 

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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. 
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.  

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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 
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. 

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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 
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 

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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 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.  

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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%]).   
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 

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(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 
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 

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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. 
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 

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Objectives 
Endpoints 
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. 
• 
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 

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Objectives 
Endpoints 
(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 + 
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 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 
• Proportion of participants with HIV-1 RNA 
≥ 50 c/mL at Week 124, with and without 
oral lead-in (FDA Snapshot algorithm, 

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Objectives 
Endpoints 
ABC/DTG/3TC in the Extension Phase, with 
and without oral lead-in. 
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 
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 
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Objectives 
Endpoints 
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 
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.  

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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. 
Where the CAB LA + RPV LA marketed product is not locally available, 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 enter the 52-week Long-Term Follow-Up 
Phase. Where CAB LA + RPV LA marketed product is locally available, only 
participants that discontinue the CAB LA + RPV LA regimen for safety-related reasons 
should enter the LTFU Phase. All 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 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 

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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 
 
1.  
 
¥Subjects who withdraw from IM CAB LA + RPV LA must enter the 52 week Long Term Follow-Up 
Phase if the marketed product is not locally available.  
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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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. 
If, in the opinion of the Investigator, a participant experiences a significant safety event 

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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 7.4.10.13). 
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. 

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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 
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 

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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: 
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 

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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 
• Where the CAB LA + RPV LA marketed product is not locally available, 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 enter the LTFU 
Phase. The patient 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. The 
LTFU Phase will begin the day of the last CAB LA + RPV LA dose and continue for 
52 weeks. These participants will not complete a Withdrawal visit but will instead 
move directly into the LTFU Phase as per the Time and Events Table (Section 7.1). 
 
• Where CAB LA + RPV LA marketed product is locally available, only participants 
that discontinue the CAB LA + RPV LA regimen for safety-related reasons 
included in Section 5.4 must enter the LTFU Phase. Participants must remain on 
suppressive HAART for at least 52 weeks after the last dose of CAB LA and/or RPV 
LA in order to prevent selective pressure on HIV and the potential for selection of 
resistant mutants. Investigators must discuss the choice of the follow-up HAART 
regimen with the Medical Monitor prior to initiating the new regimen with the 
patient. HAART therapy should be initiated within four weeks of the last 
injection. The LTFU Phase will begin the day of the last CAB LA and/or RPV LA 
dose and continue for 52 weeks. These participants will not complete a Withdrawal 
visit but will instead move directly into the LTFU Phase. In addition, for participants 
who withdraw during the LTFU, the final visit will be considered the study 
withdrawal visit.  
 
• NOTE: Participants transitioning to CAB LA + RPV LA marketed product or 
alternative HAART (except due to safety-related reasons) do not need to enter the 
LTFU Phase. 
Long-Term Follow-Up Phase requirement 
Marketed product 
locally available 
Subject WD due to safety-
related reasons 
LTFU Phase required? 
No 
Yes 
Yes 
No 
Yes 
Yes 
Yes 

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Marketed product 
locally available 
Subject WD due to safety-
related reasons 
LTFU Phase required? 
No 
No, but Safety FU visit required to 
assess potential safety issues 
occurred after the last injection 
 
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 

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(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. 
Please refer to Appendix 9 in Section 12.9. for study management information during the 
COVID-19 pandemic. 
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. 
 

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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 
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.  

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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 
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 

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acceptability and patient reported preferences to this novel injectable regimen, relative to 
daily oral standard of care (SOC) ART.  An unblinded study design supports collection of 
participant preference data in a way that would not be possible if a double-blind, double-
dummy design were implemented. 
Due to the complexities, limitations and risks of blinding each switch study, both Phase 3 
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 a Phase 2b, dose-ranging study (randomized 1:1:1 to CAB 10 mg, 30 mg, or 
60 mg) which evaluated 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) 
a. 
CAB was administered with two NRTIs during the 24 week Induction Period. 
b. 
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. 
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 
6 (5) 
1 (<1) 
7 (3) 
0 

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Outcome 
Q8W IM 
N=115 
n (%) 
Q4W IM 
N=115 
n (%) 
Q8W+Q4W 
N=230 
n (%) 
CAB 30 
mg 
N=56 
n (%) 
threshold 
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). 
 
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-τ)b 
(µg.h/mL) 
Cmaxc 
(µg/mL) 
Individual  
Average C0d 
(µg/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, 
3027  
(2762, 
3.55 
(3.2, 
3.33 
(3.1, 
1.43 
(1.3, 
1.49 
(1.4, 
6.9  
(0 – 59) 
7.0  
(0 –  

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Cohort 
Plasma CAB PK Parametera 
AUC(0-τ)b 
(µg.h/mL) 
Cmaxc 
(µg/mL) 
Individual  
Average C0d 
(µg/mL) 
tmaxe 
(d) 
Week 24 
Week 40 
Week 
24 
Week 
40 
Week 
24 
Week 
40 
Week 
24 
Week 
40 
3310) 
[42] 
3322) 
[47] 
3.9) 
[56] 
3.6) 
[47] 
1.6) 
[54] 
1.6) 
[42] 
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-τ) = 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. 

T M F -1 6 4 4 1 7 6 7  
C O N FI D E N TI A L  
2 0 1 5 8 4  
 
 
Pr ot o c ol A m e n d m e nt 0 9  
 
5 2  
 
Fi g ur e 2 
M e a n ( S D) O b s er v e d C o n c e ntr ati o n -Ti m e D at a f oll o wi n g C A B L A 
Q 8 W a n d Q 4 W a n d C τ (f oll o wi n g C A B 3 0 m g Or al O n c e D ail y a ) 
t hr o u g h W e e k 4 8 ( L A T T E-2)  
 
a.  
Or al C A B 3 0 m g o nc e d aily a d mi nist er e d f or f o ur w e eks pri or t o first i nj ecti o n.  
T a bl e 4 
S u m m ar y of O b s er v e d R P V P K P ar a m et er s f oll o wi n g R e p e at D o s e 
A d mi ni str ati o n of R P V L A t o HI V -i nf e ct e d S u bj e ct s ( L A T T E-2)  
C o h ort  
Pl a s ma R P V P K Par a met er a 
A U C( 0 -τ)b 
( n g. h/ m L) 
C m a x c 
( n g/ m L) 
I n di vi d u al 
A v er a g e C 0 d 
( n g/ m L) 
t m a xe 
( d) 
W e e k 24  
W e e k 40  
W e e k 
2 4  
W e e k 
4 0  
W e e k 
2 4  
W e e k 
4 0  
W e e k 
2 4  
W e e k 
4 0  
Q 4 W  
( n = 1 1 5) 
6 1 30 9  
( 5 6 7 24, 
6 6 26 4) 
[ 3 7] 
7 1 10 6  
( 6 5 3 54, 
7 7 36 6) 
[ 3 9] 
1 0 3  
( 9 4, 
1 1 4) 
[ 4 9] 
1 2 7  
( 1 1 8, 
1 3 6) 
[ 3 6] 
7 7. 2  
( 7 2, 
8 3)  
[ 3 5] 
9 2. 1  
( 8 7, 
9 8)  
[ 3 2] 
6. 9 9  
( 0-
2 9)  
6 0. 
( 0-
2 8)  
Q 8 W 
( n = 1 1 5) 
9 6 19 6  
( 8 7 2 86, 
1 0 60 1 5) 
[ 4 8] 
1 1 61 6 0  
( 1 0 8 18 9, 
1 2 47 1 9) 
[ 3 5] 
1 0 4  
( 9 5, 
1 1 4) 
[ 4 7] 
1 2 1  
( 1 1 1, 
1 3 1)  
[ 4 2] 
4 9. 3  
( 4 6, 
5 3)  
[ 4 1] 
6 3. 2  
( 5 9, 
6 8)  
[ 3 5] 
7. 0 0  
( 0-
5 7)  
6 0. 
( 0-
5 9)  
a.  
G e o m etric m e a n ( 9 5 % CI) [ Cv b %]  
b.  
A U C( 0 -τ) = A U C( W e ek 2 4 t o W e ek 2 8) f or Q 4 W r e gi m e n ( n = 8 4), a n d A U C( W e ek 2 4 t o W e ek 3 2) f or Q 8 W 
r e gi m e n ( n = 8 6) or A U C( W e ek 4 0 t o W e ek 4 4) f or Q 4 W  ( n = 8 0) a n d A U C( W e ek 4 0 t o W e ek 4 8) f or Q 8 W r e gi m e n 
( n = 9 2) vi a n o n-c o m p art m e nt al P K a n alysis 
c. 
C m ax:  Q 4 W: b et w e e n W e ek 2 4 a n d W e ek 2 8 ( n = 9 6) or W e ek 4 0 a n d W e ek 4 4 ( n = 9 4); Q 8 W: b et w e e n W e ek 2 4 
t o W e ek 3 2 ( n = 9 7) or W e ek 4 0 a n d W e ek 4 8 ( n = 1 0 4) 
d.  
I n divi d u al Av er a g e C 0 W e ek 2 4 o bs erv e d usi n g tr o u g hs at W e ek 2 4, W e ek 2 8 a n d W e ek 3 2 f or t h e Q 4 W ar m 
 
W e e k
0 1 
4 
8
1 2 
1 6 
2 0 
2 42 5 
2 8 
3 2
3 2 
3 6 
4 04 1 
4 4 
4 8
4 8
Pl a s m a C A B ( g/ m L)
0. 1
1
1 0
8 0 0 m g I M L D, 6 0 0 m g I M W 4, W 8 a n d Q 8 W
8 0 0 m g I M L D, 4 0 0 m g I M Q 4 W
3 0 m g P O Q D
P A-I C 9 0 ( 0. 1 6 6 g/ m L)
1 0 m g P O Q D C  ( L A T T E, 1. 3 5g/ m L)

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(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) 
Figure 3 
Mean (SD) Observed Concentration-Time Data following RPV LA 
Q8W and Q4W and Cτ (following RPV 25 mg Oral Once Dailya) 
through Week 48 (LATTE-2) 
 
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, 
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)

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respectively.  
 
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 µg/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^) 
 
a. 
* Note: current simulations based on interim plasma concentration dataset 
b. 
^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) 
c. 
Medium dashed line at 1.35 µg/mL corresponds to the geometric mean Ctrough concentration following oral CAB 
10 mg once daily (LATTE) and is equivalent to 8x PA-IC90  
d. 
Dotted line at 0.664 µg/mL corresponds to 4x PA-IC90  
e. 
Long dashed line at 0.166 µg/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^) 
 
a. 
* Note: current simulations based on interim plasma concentration dataset 
b. 
^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 µg/mL corresponds to the geometric mean Cτ following oral CAB 10 mg once daily  
(LATTE) and is equivalent to 8x PA-IC90  
Dotted line at 0.664 µg/mL corresponds to 4x PA-IC90  
Long dashed line at 0.166 µg/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 Cτ 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 Cτ 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^) 
 
a. 
* Note: current simulations based on interim plasma concentration dataset 
b. 
^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)  
c. 
Horizontal line at 72 ng/mL corresponds to median Cτ following oral RPV 25mg once daily in LATTE-2 (oral lead-
in) and is similar to median RPV Cτ 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 Cτ 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^) 
 
a. 
*Note: current simulations based on interim plasma concentration dataset 
b. 
^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) 
c. 
Horizontal line at 72 ng/mL corresponds to median Cτ following oral RPV 25 mg once daily in LATTE-2 (oral lead-
in) and is similar to median RPV Cτ 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 
A preliminary analysis of an ongoing birth 
outcome surveillance study in Botswana 
involving women exposed to dolutegravir 
(DTG) identified four cases (as of May 
2018) of neural tube defects in 426 infants 
born to mothers who were exposed to 
DTG-containing regimens from the time of 
conception. In the same study, no infant 
born to a women who started DTG during 
pregnancy had a neural tube defect, out of 
2,824 women. A causal relationship of 
these events to the use of DTG has not 
been established. The incident rate of 
neural tube defects in the general 
population ranges from 0.5-1 cases per 
1,000 live births. As neural tube defects 
occur within the first 4 weeks of fetal 
development (at which time the neural 
tubes are sealed) this potential risk would 
concern women exposed to DTG at the 
time of conception and in early pregnancy. 
Recently updated data (April 2020) for this 
birth outcome study showed that among 
women who were on DTG when they 
became pregnant, 7/3,591 neural tube 
defects (NTD) occurred (0.19%). In 
comparison, NTDs were identified in 
21/19,361 (0.11%) women delivering on 
any non-DTG antiretrovirals. There was 
not a significant difference in the number 
of neural tube defects between births to 
women taking DTG and those taking other 
non-DTG antiretroviral treatments (0.09% 
difference).  
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 12.7.1.) 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. Females of reproductive 
potential are reminded re: 
pregnancy avoidance and 
adherence to contraception 
requirements at every study 
visit. 
4. Pregnancy status is monitored 
at every study visit 
5. In Russia, women who become 
pregnant or who desire to 
become pregnant while in the 
study will have study treatment 
discontinued and will be 
withdrawn from the study.  
 

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The most significant toxicity associated with ABC is the well-characterized drug-related 
hypersensitivity reaction (HSR).  Studies have shown that carriage of the HLA-B*5701 
allele is associated with a significantly increased risk of a HSR to ABC.  In the 
prospective study CNA106030 (PREDICT-1), the use of pre-therapy screening for the 
presence of HLA-B*5701 and subsequently avoiding ABC in HLA-B*5701 positive 
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 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 
(DILI) 
Less than 1% of participants in the CAB program to 
date 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.  
 
• 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 

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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 7.4.10.1 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 in 
association with integrase inhibitors. These reactions 
were characterized by rash, constitutional findings, 
and sometimes, organ dysfunction, including liver 
• 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 

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Summary of Data/Rationale for Risk  
Mitigation Strategy 
 
injury.  
The cases which have been reported in association 
with CAB have predominantly presented with 
angioedema and urticaria. While a causal association 
with more severe or systemic hypersensitivity 
reactions has not been identified with CAB to date, 
there remains a theoretical risk of such reactions 
with or without hepatic symptoms. The long 
exposures anticipated after CAB LA injection may 
complicate the management of a drug 
hypersensitivity reaction, were it to occur. 
 
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. 
• 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 
Effects in pregnancy 
seen in non-clinical 
studies 
In animal reproduction studies, CAB when 
administered to rats at >30 times the systemic 
exposure at the maximum recommended oral human 
dose (MRHD) of 30 mg during organogenesis 
through delivery, had adverse effects on labor and 
delivery that may be related to a delay in the onset of 
parturition, resulting in increased fetal mortality 
• Pregnant females are excluded from 
enrolment in this study and women of 
childbearing potential (WOCBP) are required 
to adopt highly reliable means of 
contraception during participation and 
throughout the long term follow up phase of 

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(stillbirths) and neonatal deaths immediately after 
birth. 
A delay in the onset of parturition, increased 
stillbirths and neonatal deaths were observed in a rat 
pre- and postnatal development study at greater than 
30 times the exposure at the recommended human 
dose (RHD). No evidence of adverse developmental 
outcomes was observed with oral cabotegravir in rats 
or rabbits (greater than 30 times or similar to 
(approximately 0.7 times) the exposure at the RHD, 
respectively) given during organogenesis.  
The clinical significance of these findings in humans 
is unknown. 
For pregnant participants remaining in the study, 
refer to Appendix 10 for additional data regarding 
CAB and pregnancy. Not applicable in Russia. 
this study following exposure to CAB LA. 
• WOCBP are also required to undergo regular 
pregnancy testing throughout study conduct. 
Pregnant participants who remain in the 
study do not need pregnancy testing for the 
duration of the pregnancy.  
• Participants who become pregnant during the 
study may remain in the study provided all 
protocol defined pregnancy related 
assessments, procedures and documentation 
are completed, and a pregnancy specific ICF 
addendum is signed by the participant. Not 
applicable in Russia. Details regarding 
management of pregnant participants are 
found in Appendix 10.  
• In Russia, women who become pregnant or 
who desire to become pregnant while in the 
study will have study treatment discontinued 
and will be withdrawn from the study. 
Potential effects in 
females exposed to 
dolutegravir during 
conception and early 
pregnancy 
A preliminary analysis of an ongoing birth outcome 
surveillance study in Botswana involving women 
exposed to dolutegravir (DTG), a different molecule 
in the same integrase class of medications as CAB, 
identified four cases (as of May 2018) of neural tube 
defects in 426 infants born to mothers who were 
• Pregnant females are excluded from 
enrolment in clinical trials of CAB at this 
time and women of childbearing potential 
(WOCMP) are required to adopt highly 
reliable means of contraception during 
participation and throughout the long term 

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exposed to DTG-containing regimens from the time 
of conception. In the same study, no infant born to a 
woman who started DTG during pregnancy had a 
neural tube defect, out of 2,824 women. A causal 
relationship of these events to the use of DTG has 
not been established. The incidence of neural tube 
defects in the general population ranges from 0.5-1 
cases per 1,000 live births. As neural tube defects 
occur within the first 4 weeks of fetal development 
(at which time the neural tubes are sealed) this 
potential risk would concern women exposed to 
DTG at the time of conception and in early 
pregnancy. Recently updated data (April 2020) for 
this birth outcome study showed that among women 
who were on DTG when they became pregnant, 
7/3591 neural tube defects (NTD) occurred (0.19%). 
In comparison, NTDs were identified in 21/19,361 
(0.11%) women delivering on any non-DTG 
antiretrovirals. There was not a significant difference 
in the number of neural tube defects between births 
to women taking DTG and those taking other non-
DTG antiretroviral treatments (0.09% difference).  
The clinical relevance of either of these findings in 
relation to CAB use is unknown.  
follow up phase of the studies after exposure 
to CAB LA.  
• WOCBP also undergo regular pregnancy 
testing throughout study conduct.  
• Pregnant participants who remain in the 
study do not need pregnancy testing for the 
duration of the pregnancy. It should be noted 
that CAB concentration could remain for 
prolonged periods despite discontinuation of 
CAB LA.  
• Participants who become pregnant during the 
study may remain in the study, provided that 
all protocol defined pregnancy related 
assessments, procedures and documentation 
are completed and a pregnancy specific ICF 
addendum is signed by the participant. Not 
applicable in Russia. Details regarding 
management of pregnant participants is found 
in Appendix 10. 
• In Russia, women who become pregnant or 
who desire to become pregnant while in the 
study will have study treatment discontinued 
and will be withdrawn from the study. 

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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 Sponsor will continue to monitor 
participants in this study who discontinue a 
LA regimen for a minimum of 52 weeks 
from the time of the last LA administration. 
Drug-Drug 
Interactions (DDIs) 
For a complete listing of permitted and prohibited 
concurrent medications for 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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- 
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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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.  Systemic reactions following RPV LA injections have been observed in 
clinical trials. These occur infrequently (in less than 0.5% of participants) and typically begin to resolve within minutes of the injection 
however, some participants required supportive care. Where timely PK data was available, high RPV PK plasma concentrations have been 
observed which may have resulted from an accidental partial IV injection of RPV 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, 

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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 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 , depending on the 

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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. 
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].   
 
 
• 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 

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Participants discontinuing a LA regimen may be at risk for 
developing resistance to RPV many weeks after discontinuing 
injectable therapy. 
risk of emergent resistance. 
• The Sponsor will continue to 
monitor participants in this study 
who discontinue a LA regimen for a 
minimum of 52 weeks from the 
time of the last LA administration. 
Drug-Drug Interactions 
(DDIs) 
For a complete listing of permitted and prohibited concurrent 
medications for RPV and RPV LA, refer to Section 6.13. 
RPV 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 
• 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 
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.  
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. 
 
Systemic reactions following RPV LA injections have been 
observed in clinical trials. These occur infrequently (in less 
than 0.5% of participants) and typically begin to resolve 
within minutes of the injection, however, some participants 
required supportive care. Where timely PK data was 
available, high RPV PK plasma concentrations have been 
observed which may have resulted from an accidental partial 
IV injection of RPV. 
• 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 

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Mitigation Strategy 
 
of RPV 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 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 
• HIV-1 RNA will be closely 
monitored throughout the study.  
 
• Plasma samples will be collected 

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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 
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.   
throughout the Maintenance Phase 
for determination of CAB and RPV 
concentration and possible 
pharmacokinetic correlation with 
virologic response.   
 
 

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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: 
A small number of seizure cases have been reported following CAB administration (less 
than 1% of all those receiving CAB in clinical studies). . These cases have had alternative 
explanations for their occurrence.  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 CAB.   Subjects with recent history of, or recent treatment for seizure will be 
excluded from study participation. Report any cases of seizure or seizure like events 
immediately. 
4.6.3. 
Benefit Assessment 
The antiviral activity of CAB against HIV-1 has been well established through Phase 2 
and Phase 3 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 IM agents, has been 
demonstrated through Week 96 of this study and the ongoing 200056 and 201585 studies 
.  .  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. 
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 

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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 
1. 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  
2. HIV-1 infection as documented by Screening plasma HIV-1 RNA ≥1000 c/mL; 
3. 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 
4. 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 
the use and benefit/risk of effective barrier methods (e.g., male condom) and on the 
risk of HIV transmission to an uninfected partner. 

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INFORMED CONSENT 
5. 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 
6. 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  
1. Women who are pregnant, breastfeeding, or plan to become pregnant or breastfeed 
during the study. 
2. 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). 
3. Participants with known moderate to severe hepatic impairment. 
4. Any pre-existing physical or mental condition (including substance abuse disorder) 
which, in the opinion of the Investigator, may interfere with the participant’s ability 
to comply with the dosing schedule and/or protocol evaluations or which may 
compromise the safety of the participant. 
5. 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.  
6. 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. 
7. The participant has a tattoo or other dermatological condition overlying the gluteus 
region which may interfere with interpretation of injection site reactions. 
8. 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: 

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Exclusionary Medical Conditions  
• 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. 
9. 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)) 
10. 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).   
11. History of liver cirrhosis with or without hepatitis viral co-infection. 
12. Ongoing or clinically relevant pancreatitis. 
13. All participants will be screened for syphilis (rapid plasma reagin 
[RPR]).  Participants with untreated syphilis infection, defined as a positive RPR 
without clear documentation of treatment, are excluded.  Participants with a 
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Exclusionary Medical Conditions  
after completion of antibiotic treatment for syphilis. 
14. 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. 
15. 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. 
16. 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. 
17. Current or anticipated need for chronic anti-coagulation. 
18. Alanine aminotransferase (ALT) ≥3 times ULN.   
19. 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 
20. 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. 
21. 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. 
22. Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening. 
23. 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. 
24. Use of medications which are associated with Torsades de Pointes (See SPM for a 
list of relevant medications). 

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Exclusionary Medical Conditions  
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA 
25. 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. 
26. 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). 
27. Any verified Grade 4 laboratory abnormality.  A single repeat test is allowed 
during the Screening Phase to verify a result. 
28. Any acute laboratory abnormality at Screening, which, in the opinion of the 
Investigator, would preclude the participant’s participation in the study of an 
investigational compound. 
29. Participant has estimated creatinine clearance <50 mL/min/1.73m2 via the Chronic 
Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (Levey, 2009). 
30. Participation in other interventional studies is generally not permitted, however for 
eligible subjects in South Africa, co-enrolment in the AIDS Clinical Trial Group 
(ACTG) interventional study (A5392) could be exceptionally permitted after 
review and approval by the Medical Monitor. 
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  the CAB LA 
+ RPV LA marketed product being locally available 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. 
Participants who enter the Extension Phase but permanently discontinue participation in 
the Extension Phase when the CAB LA + RPV LA marketed product is locally available 

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must enter the Long Term Follow-Up Phase if they withdraw from the study due to 
safety-related reasons only. 
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. 
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 

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Phase. 
• 
Confirmed virologic failure. 
• 
In Russia, 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 up in the LTFU phase. 
• 
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.  

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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.    
Where the CAB LA + RPV LA marketed product is not locally available, 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 enter the 52-week Long-Term Follow-Up 
Phase.  
Where CAB LA + RPV LA marketed product is locally available, only participants that 
discontinue the CAB LA + RPV LA regimen for safety-related reasons must enter the 
LTFU Phase.  
All 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. 
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 

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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). 
• 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: 

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• 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; 
• 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 
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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 
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 Restart approved by the VSLC, which is 
maintained as a separate document (See Section 12.3, Appendix 3) must be followed. 
5.4.1.4. 
General Guidance Restart 
• The definition restart is not always clear cut in medical practice. 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.  
• For long-acting agents, a restart may actually be continuation of therapy rather 
than a true re-start due to the timeframe between dose administration relative to 
decision making on allowing a restart. 
• If protocol defined stopping criteria for liver chemistry elevations are met 
(Section 5.4.1), study drug must be stopped. Participants who meet liver 
chemistry stopping criteria should not be retreated with investigational product 
unless an exemption has been approved by the VSLC.  The guideline for Restart 
approved by the VSLC, which is maintained as a separate document must be 
followed. 
• If the restart 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.  
• Ethics Committee or Institutional Review Board approval of drug restart must be 
obtained, as required. 
• The participant must also provide signed informed consent specifically for the IP 
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 restart of 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. Longer durations of close monitoring may be required for long-acting 
IP. 
Drug Restart 
“Drug restart” can be approved by the VSLC for defined non-drug-induced liver injury 
if no evidence of: 
• 
immunoallergic injury /HLA association with injury 
• 
alcoholic hepatitis 

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Study drug must be held while labs and evaluation are completed to assess diagnosis. 
 
If participant meets liver chemistry stopping criteria do not restart the participant with 
study treatment unless: 
• ViiV Healthcare Safety and Labelling Committee (VSLC) approval is granted, 
• Ethics and/or IRB approval is obtained, if required, and 
• Separate consent for treatment restart is signed by the participant. 
Refer to 12.3for full guidance. 
Background 
• 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.  
• For long-acting agents, a restart may actually be continuation of therapy rather 
than a true re-start due to the timeframe between dose administration relative to 
decision making on allowing a restart. 
• If protocol defined stopping criteria for liver chemistry elevations are met 
(Section 12.3), study drug must be stopped. Subjects who meet liver chemistry 
stopping criteria should not be retreated with investigational product unless an 
exemption has been approved by the VSLC.  The algorithm for restart is 
described in Section 12.3 and summarised in Figure 9. 
• If the restart is approved by the VSLC in writing, the subject must be provided 
with a clear description of the possible benefits and risks of drug administration, 
including the possibility of recurrent, more severe liver injury or death.  
• Ethics Committee or Institutional Review Board approval of drug restart must be 
obtained, as required. 
• The subject must also provide signed informed consent specifically for the IP 
restart. Documentation of informed consent must be recorded in the study chart. 
• Study drug must be administered at the dose specified by the VSLC. 
• Subjects approved by the VSLC for restart of 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. Longer durations of close monitoring may be required for long-acting 
IP. 
Refer to Section 12.3for full guidance.  
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: 
• Abnormalities in liver chemistries have a clear underlying cause (e.g., biliary 
obstruction, hypotension, acute viral hepatitis) and liver chemistries have 

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significantly improved. . 
• If definitive non-study drug related diagnosis, restart will be considered once ALT 
<3x ULN (for participants with baseline ALT <1.5x ULN) or <3x baseline ALT 
value (for participants with baseline ALT >1.5x UNL). 
• Ethics Committee or Institutional Review Board approval of drug restart 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.  
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.   
 

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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 
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. 
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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. 
• 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 
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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 
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. 
Safety Follow Up Visit: 
In addition to the 52 week Long-Term Follow-Up Phase required for participants 
randomized to CAB LA + RPV LA, an in-clinic or telephone Follow-Up visit will be 
conducted as described below.  
1. Where marketed CAB LA + RPV LA is locally available: Safety Follow Up 
Visit is required for subjects completing the study (regardless of whether subjects 
are transitioning to CAB LA + RPV LA marketed product or alternative 
HAART). It should be conducted approximately 2-4 weeks after the last dose of 
IP to assess HIV associated conditions, AEs, Concomitant medications, ISR AEs 
after the last injection and the plan to transition to marketed product. This visit 
may be conducted in person or by telephone. Ensure that relevant eCRF forms 
(including the Conclusion Visit) are updated/completed. 
2. Where marketed CAB LA + RPV LA is not yet locally available: 
a. Safety Follow Up Visit should be conducted approximately 2-4 weeks 
after the last dose of IP and may be conducted in person or by telephone. 
Ensure relevant eCRF forms (including the Conclusion Visit) are 
updated/completed. This visit is only required if the subject: 
i. Has ongoing AEs, SAEs related and not related to study drug and 

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also any laboratory abnormalities that are considered to be AEs or 
potentially harmful to the participant, at the last on-study visit 
AND 
ii. Is not planning to attend additional study visits after the last IP 
injection (i.e. Withdrawal visit, Long Term Follow Up visits) 
where the ongoing AEs/SAEs/lab abnormalities can be assessed.  
b. Safety Follow Up Visit is not required if the subject enters the Long Term 
Follow Up Phase. Note: If the first LTFU visit after the last injection is 
scheduled more than 3 months after the last dose of IP, please consult the 
Medical Monitor to advise if the Safety Follow Up Visit is still required. 
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 GSK 
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. 
6.1.1. 
Cabotegravir (CAB) – Tablet 
CAB is manufactured by GSK and is formulated as white to almost white oval shaped 
film coated 30 mg tablets for oral administration, packaged in high density polyethylene 
(HDPE) bottles with desiccant and child-resistant closure that include an induction seal.  

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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 GSK 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 
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 

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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 GSK.  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 GSK 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. 
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 

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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 
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 
 

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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 
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 

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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 
a. 
+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. 
b. 
*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. 
c. 
^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 
in a secure environmentally controlled and monitored (manual or automated) area in 
accordance with the labelled storage conditions with access limited to the investigator 
and authorized site staff. 

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IP accountability will be evaluated using pill counts of unused IP for 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.  
• 
Please refer to Appendix 9 in Section 12.9. for study management information 
during the COVID-19 pandemic. 
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.   
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 

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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.   
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. 

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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.   
Please refer to Appendix 9 in Section 12.9. for study management information during the 
COVID-19 pandemic. 
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.   
Please refer to Appendix 9 in Section 12.9. for study management information during the 

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COVID-19 pandemic. 
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 7.4.10.12). 
6.10.2. 
Discontinuation of CAB LA or RPV LA 
 Where the CAB LA + RPV LA marketed product is not locally available, 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 enter the 52-week Long-Term Follow-Up 
Phase.  
Where CAB LA + RPV LA marketed product is locally available, only participants that 
discontinue the CAB LA + RPV LA regimen for safety-related reasons must enter the 
LTFU Phase.  
All 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. (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.   

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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). 
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: 
1. contact the Medical Monitor immediately. 
2. 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). 
3. obtain a plasma sample for pharmacokinetic (PK) analysis if possible within 2 days 
from the date of the last dose of study treatment if requested by the Medical Monitor 
(determined on a case-by-case basis). 
4. document the quantity of the excess dose as well as the duration of the overdosing in 
the 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. 

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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 
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). 
 

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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. 
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 

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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. 
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). 

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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. 
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 

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DTG + alternate NRTI background therapy, refer to the current DTG IB and local 
prescribing information for details regarding concurrent therapies. 
6.14. 
Medical Devices 
The medical devices to be used in this study are: vial adaptor, syringe and needle. 
Instructions for medical device use are provided in the Study Reference Manual. 
All device deficiencies, (including malfunction, use error and inadequate labeling) shall 
be documented, and reported by the investigator throughout the clinical investigation (see 
12.11) and appropriately managed by the sponsor. 
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 
Please refer to Appendix 9 in Section 12.9. for study management information during the 
COVID-19 pandemic. 

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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. 
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 
Withdrawal 
Safety Follow-Up Y 
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 S it h A
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 
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 
Withdrawal 
Safety Follow-Up Y 
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 S it h A
Q4W after 108 (LA Arm) or 
after 124 (Switch Arm)
Q12W beginning 112 (LA 
Arm) or 124 (Switch Arm)j
Physical Exam 
and Medical 
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 
Withdrawal 
Safety Follow-Up Y 
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 S it h A
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 
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 
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 
X  
If 
appli-
cable 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

TMF-16441767 
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Procedures 
Screening a 
Induction Phase 
by Week 
Maintenance Phase by Week 
Extension Phase  
by Week 
Withdrawal 
Safety Follow-Up Y 
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 S it h A
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 
S
k 
 
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
O 
 
 

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Procedures 
Screening a 
Induction Phase 
by Week 
Maintenance Phase by Week 
Extension Phase  
by Week 
Withdrawal 
Safety Follow-Up Y 
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 S it h A
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 
Withdrawal 
Safety Follow-Up Y 
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 S it h A
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X
x 
O
LI 
O
nl
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 
O
LI 
O
 
 
X 
OLI 
Onl
y 
X
u 
 
 
 
 
 
 
 

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Procedures 
Screening a 
Induction Phase 
by Week 
Maintenance Phase by Week 
Extension Phase  
by Week 
Withdrawal 
Safety Follow-Up Y 
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 S it h A
Q4W after 108 (LA Arm) or 
after 124 (Switch Arm)
Q12W beginning 112 (LA 
Arm) or 124 (Switch Arm)j
nl
y 
IM Study 
Treatment 
Administration – 
Q4W throughout 
Maintenance and 
Extension Phase 
 
 
 
 
 
 
 
 
X  
X X X X 
 
X X X X 
X 
X 
X 
X 
 
X 
X 
X
s 
X X 
X – 
co
nt 
do
s-
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
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 

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Procedures 
Screening a 
Induction Phase 
by Week 
Maintenance Phase by Week 
Extension Phase  
by Week 
Withdrawal 
Safety Follow-Up Y 
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 S it h A
Q4W after 108 (LA Arm) or 
after 124 (Switch Arm)
Q12W beginning 112 (LA 
Arm) or 124 (Switch Arm)j
4
4 
HIVTSQ(c) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
PIN (LA Arm 
Only)aa 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
NRS (LA Arm 
Only) 
 
 
 
 
 
 
 
 
X X 
 
 
 
W
4
0 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Preference (LA 
Arm Only) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Follow Up Visit (for subjects completing the study, whether transitioning to CAB LA + RPV LA marketed product or alternative HAART) and Safety Follow Up Visit (for subjects 
withdrawing from the study) are required as described in Section 5.5 
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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Procedures 
Screening a 
Induction Phase 
by Week 
Maintenance Phase by Week 
Extension Phase  
by Week 
Withdrawal 
Safety Follow-Up Y 
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 S it h A
Q4W after 108 (LA Arm) or 
after 124 (Switch Arm)
Q12W beginning 112 (LA 
Arm) or 124 (Switch Arm)j
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 ), eligibility to enter the Extension Phase (Section ). 
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. 
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 

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Procedures 
Screening a 
Induction Phase 
by Week 
Maintenance Phase by Week 
Extension Phase  
by Week 
Withdrawal 
Safety Follow-Up Y 
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 S it h A
Q4W after 108 (LA Arm) or 
after 124 (Switch Arm)
Q12W beginning 112 (LA 
Arm) or 124 (Switch Arm)j
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 .  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. 
x. 
For participants transitioning to CAB LA + RPV LA from ABC/DTG/3TC only. 
y. 
Safety Follow Up Visit (for subjects completing the study, whether transitioning to CAB LA + RPV LA marketed product or alternative HAART) and Safety Follow Up Visit (for 

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Procedures 
Screening a 
Induction Phase 
by Week 
Maintenance Phase by Week 
Extension Phase  
by Week 
Withdrawal 
Safety Follow-Up Y 
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 S it h A
Q4W after 108 (LA Arm) or 
after 124 (Switch Arm)
Q12W beginning 112 (LA 
Arm) or 124 (Switch Arm)j
subjects withdrawing from the study) are required as described in Section 5.5 
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 
7.4.11) 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). 
• 
Participants who are enrolled in the study and have a positive pregnancy test 
during the course of the study will be allowed to remain in the study, provided a 
pregnancy specific ICF addendum is signed by the participant. No IP can be 
continued (oral or LA) in any pregnant participant until the benefit/risk 
assessment is discussed with the participant and the pregnancy specific ICF 
addendum has been signed. See details in Appendix 10. Not applicable in 
Russia. 
• 
Pregnant participants who remain in the study do not need pregnancy testing during 
the study, for the duration of their pregnancy. Not applicable in Russia. 
• 
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 

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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 7.4.11). 
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 
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 

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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 
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 
1. 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 (AEs) 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. 
Please refer to Appendix 9 in Section 12.9. for study management information during the 
COVID-19 pandemic. 
Reporting of medical device deficiencies are covered in Appendix 11.  
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). 
• 
All AEs and SAEs associated with medical device deficiencies for associated 
persons (i.e. healthcare professionals) will be collected.  The associated person 
will be provided with a safety reporting information and an authorisation letter, as 
indicated in Section 7.4.4. 
• 
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?”  

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• 
“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 7.4.10) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the participant is lost to follow-
up (as defined in Section 5.4).  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 

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Initial Reports 
Follow-up Information on a Previous 
Report 
Type of Event 
Time Frame 
Documents 
Time Frame 
Documents 
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 
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 

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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 and in the Study Reference 
Manual. 
• 
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. 
The method of recording, evaluating, and follow-up of AEs and SAEs plus procedures 
for completing and transmitting SAE reports to the Medical Monitor are provided in the 
SPM.  Procedures for post study AEs/SAEs are provided in the SPM. Primary and 
secondary Medical Monitor/SAE contact information is provided at the beginning of this 
protocol on the Sponsor/Medical Monitor Contact Information Page and in the Study 
Reference Manual. 
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 
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clinical investigation are met.  
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators. 
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary. 
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements. 
7.4.3.7. 
Cardiovascular 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. 
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reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported. 
7.4.4. 
Medical Device Deficiencies 
The vial adaptor, syringe and needles used in the study are classed as medical devices by 
the US Food and Drug Administration (FDA). To fulfil regulatory reporting obligations 
worldwide, the investigator is responsible for the detecting and documentation of events 
meeting the definitions of device deficiency that occur during the study with such 
devices. 
The definition of a medical device deficiency can be found in Appendix 11. 
NOTE: Medical device deficiencies associated with an SAE will be reported together 
with an SAE form. AEs associated with a medical device deficiency must be documented 
in the eCRF.  
7.4.5. 
Time Period for Detecting Medical Device Deficiencies 
• Medical device deficiencies that result in an incident will be detected, 
documented and reported during all periods of the study in which the medical 
device is used. 
• If the investigator learns of any device deficiency at any time after a participant 
has been discharged from the study, and such device deficiency is considered 
reasonably related to a medical device provided for the study, the investigator will 
notify the sponsor within 24 hours. 
• Medical device deficiencies and any associated AE/SAEs for associated persons 
(i.e. healthcare professionals) will be collected.  The associated person will be 
provided with a safety reporting information and authorization letter. 
• The method of documenting Medical Device Incidents is provided in Appendix 
11. 
7.4.6. 
Follow-Up of Medical Device Deficiencies 
• Follow-up applies to all participants, including those participants who discontinue 
study treatment or the study, and associated persons. 
• The investigator is responsible for ensuring that follow-up includes any 
supplemental investigations as indicated to elucidate the nature and/or causality of 
the deficiency. 
• New or updated information will be recorded on the original completed form with 
all changes signed and dated by the investigator. 
7.4.7. 
Prompt Reporting of Medical Device Deficiencies to Sponsor 
• Device deficiencies will be reported to the sponsor within 24 hours after the 
investigator determines that the event meets the protocol definition of a device 
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• The medical device deficiency report form will be sent to the sponsor by email. 
• The sponsor will be the contact for the receipt of device deficiency reports. 
7.4.8. 
Regulatory Reporting Requirements for Medical Device 
Deficiencies 
The investigator will promptly report all deficiencies occurring with any medical device 
used for CAB + RPV in the study, as described in 12.11in order for the sponsor to fulfil 
the legal responsibility to notify appropriate regulatory authorities and other entities 
about certain safety information relating to medical devices being used in clinical studies.  
The investigator, or responsible person according to local requirements (e.g., the head of 
the medical institution), will comply with the applicable local regulatory requirements 
relating to the reporting of device deficiencies to the IRB/IEC. 
7.4.9. 
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. 
7.4.9.1. 
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 

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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. 
7.4.9.2. 
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 7.4.10 “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. 
7.4.9.3. 
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 2-4 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 

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evidence that the toxicity is not related to IP, with the exception of liver chemistry 
stopping criteria (See Section 7.4.10.1).  Isolated Grade 3 lipid abnormalities do 
not require withdrawal of IP. 
7.4.9.4. 
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 7.4.10.1).  An in-clinic follow-up 
visit will be performed approximately 2-4 weeks after the last dose of study 
medication if AEs, SAEs, or laboratory abnormalities considered potentially 
harmful to the participant are ongoing at the last on-study visit.  Isolated Grade 4 
lipid abnormalities do not require withdrawal of IP. 
7.4.10. 
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. 
7.4.10.1. 
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 can be found in Section 5.4.1.3 and Section 12.3, 
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7.4.10.2. 
Diarrhea 
Participants with Grade 1 or 2 diarrhea may continue study treatment without 
interruption. Participants with diarrhea of any toxicity grade may be treated 
symptomatically with anti-motility agents; however, the recommended daily dose of the 
chosen anti-motility agent must not be exceeded.  If symptoms persist or get worse on the 
recommended daily dose of the chosen anti-motility agent then the anti-motility agent 
must be discontinued and consultation made with the Medical Monitor. 
For participants with Grade ≥3 diarrhea that is unresponsive to the recommended dose of 
the anti-motility agents and for which an alternative etiology (e.g., infectious diarrhea) is 
not established, the treatment with the anti-motility agent and IP must be interrupted until 
resolution of diarrhea to Grade ≤2 or Baseline, after which IP and background ART may 
be resumed after discussion and agreement with the Medical Monitor.  If Grade ≥3 
diarrhea recurs within 28 days upon the resumption of IP, the IP should be permanently 
discontinued and the participant withdrawn from the study.  Any participant receiving at 
least one dose of CAB LA and /or RPV LA who discontinue IP / Withdraw will initiate 
treatment with HAART and enter the Long-Term Follow-Up Phase for 52 weeks of 
follow up. 
If loperamide is used for treatment of diarrhea, local prescribing information should be 
followed with respect to dose and frequency of administration.  Loperamide dosing 
should not exceed local prescribing information. 
7.4.10.3. 
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. 
7.4.10.4. 
Seizures 
A small number of seizure cases have been reported following CAB administration (less 
than 1% of all those receiving CAB in clinical studies). These cases have had alternative 
explanations for their occurrence. 
ViiV Healthcare has reviewed these cases in detail and does not believe they constitute a 
reasonable likelihood of causation associated with CAB. This assessment is supported by 
the lack of preclinical signal, class effect or known CNS mechanism, the relatively low 
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participants and clinical cofounders in each case. The Sponsor considers the risk of 
developing seizures on the study as being no higher than that of the rest of the HIV-1 
infected population.  
Seizures that occur on study should be managed according to the local guidelines on 
emergency seizure management which may include treatment with benzodiazepines, 
general supportive treatment, exclusion of metabolic and toxicological abnormalities 
using laboratory tests, 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. 
7.4.10.5. 
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. 
7.4.10.6. 
Lipase Elevations and Pancreatitis 
Participants with asymptomatic Grade 1 or 2 elevations in lipase may be followed closely 
for the development of symptoms. 
Participants with asymptomatic Grade ≥3 elevations in lipase that are considered possibly 
or probably related to IP should have IP interrupted until serum lipase returns to 
Grade ≤2.  The lipase assay should be repeated within 2 weeks of any Grade ≥3 result.  
Participants with persistence of Grade ≥3 lipase in the absence of other diagnoses or 
reoccurrence of lipase elevation (at Grade ≥2) following reintroduction of IP should 
permanently discontinue IP. 
Participants with a confirmed diagnosis of clinical pancreatitis that is considered possibly 
or probably related to IP should have IP held.  After complete resolution of the episode, 
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 

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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. 
7.4.10.7. 
Decline in Renal Function 
Participants who experience an increase in serum creatinine from Baseline of 
45 micromoles/liter (µMol/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.   
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 
• 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.  

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7.4.10.8. 
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 µMol/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. 
7.4.10.9. 
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.  
7.4.10.10. 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 
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 
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7.4.10.11. 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. 
7.4.10.12. 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 
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. 
 

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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.  
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 
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. 
7.4.10.13. 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 

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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. 
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 
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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. 
7.4.11. 
Suicidal Risk Monitoring 
Participants with HIV infection may occasionally present with symptoms of depression 
and/or suicidal ideation or behavior.  In addition, there have been some reports of 
depression, suicidal ideation and behavior (particularly in participants with a pre-existing 
history of depression or psychiatric illness) in some 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. 

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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. 
7.4.12. 
Pregnancy 
7.4.12.1. 
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. 
If pregnancy is confirmed, a discussion with the pregnant study participant assessing the 
benefit/risk assessment of continuing in the study will be undertaken. If, after this 
discussion, the participant would like to continue in the study, this will be allowed, 
provided the pregnant participant signs the pregnancy specific ICF addendum. See 
Appendix 10 for details.  
Pregnant participants who remain in the study do not need pregnancy testing during the 
study, for the duration of their pregnancy. 
Additionally, the Medical Monitor may request that a urine pregnancy test be performed 
in the event of a treatment interruption greater than 7 days.  
Not applicable in Russia. In Russia, women who become pregnant or who desire to 
become pregnant while in the study will have study treatment discontinued and will enter 

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the LTFU phase. 
7.4.12.2. 
Rationale for Continued Use in Pregnancy 
Additional data regarding the use of CAB + RPV LA during pregnancy and management 
of pregnant participants remaining in the study are found in Appendix 10.  
The use of CAB + RPV LA during pregnancy may offer unique benefits. It is well 
documented that treatment adherence challenges to oral therapy exists both in the peri-
partum and post-partum periods with LA dosing offering a unique opportunity to 
overcome such adherence challenges. LA therapy may also help with nausea (50% mild 
to moderate) or hyperemesis (2%) that is frequently see, especially during the first 
trimester of gestation.  
Participants on LA dosing who become pregnant will have exposures throughout 
pregnancy due to the long half-life and PK tail of CAB/RPV. Prior to this protocol 
amendment, pregnant participants would have been withdrawn from the study, and 
initiated on an alternative oral ART regimen. Alternative regimens consist of either 2 or 3 
antiretrovirals to protect the life of the mother and for the prevention of MTCT. This 
regimen, combined with the long half-life and PK tail of CAB/RPV would potentially 
expose the fetus to additional ARVs during gestation (in some cases upwards of 5 
antiretrovirals). 
Given the risk/benefit ratio for CAB + RPV LA dosing in WOCBP coupled with 
concerns of increasing fetal exposure to several additional antiretrovirals upon participant 
withdrawal, this amendment to the protocol will allow pregnant participants to remain in 
the study after a pregnancy specific ICF addendum is signed by the participant.  
Not applicable in Russia. In Russia, women who become pregnant or who desire to 
become pregnant while in the study will have study treatment discontinued and will enter 
the LTFU phase. 
7.4.12.3. 
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. 
Pregnant study participants who consent to remain in the study while pregnant will 
continue to have all clinical assessments (with the exception of pregnancy tests) 
performed as per the Time and Events Table (Section 7.1), including the collection of 
additional PK samples for CAB and RPV. See Appendix 10 for details. Not applicable in 
Russia. 
Pregnant participants who have received at least one dose of CAB LA or RPV LA and do 
not continue in the study during pregnancy will enter the Long-Term Follow-Up Phase of 
the study and will be monitored for 52 weeks after the last dose of CAB + RPV LA. 
Moreover, an alternative oral HAART will be initiated, at the discretion of the PI and in 
discussion with the Medical Monitor.   If a participant becomes pregnant within 52 weeks 
of the last dose of study drug, the participant should notify the study site. 

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7.4.12.4. 
Action to be Taken if Pregnancy Occurs 
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. 
Pregnant participants who elect to continue in the study and receive CAB + RPV LA 
must sign a pregnant specific ICF addendum. Cabotegravir and rilpivirine are detected in 
systemic circulation for up to 12 months or longer after discontinuing injections of CAB 
+ RPV LA; therefore, consideration should be given to the potential for fetal exposure 
during pregnancy and should be discussed between the study participant and the study PI.  
Participants who become pregnant during the study and elect to continue in the study and 
receive CAB + RPV LA will have additional PK samples collected to monitor CAB LA 
and RPV LA exposure throughout the pregnancy (see Appendix 10) and at the time of 
delivery.    
Participants in Russia who become pregnant during the study may not elect to continue in 
the study and receive CAB + RPV LA. They must discontinue LA study treatment and 
enter the LTFU phase.  
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. 
7.4.13. 
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 7.4.10.10 for additional information. 

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• 
Investigators should pay special attention to clinical signs related to previous 
serious illnesses. 
7.4.14. 
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. 
7.4.15. 
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. 
Pregnant participants will have additional PK samples collected for the duration of the 
pregnancy. See Appendix 10 for details. Not applicable in Russia. 
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 

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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 
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 

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Group 
Analytea 
Sample Times Relative to Dose 
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 
1. 
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. 
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. 
 

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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), GSK, 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. 
• 
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. 
 

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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. 
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 
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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 
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 

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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). 
• 
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). 

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• 
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. 
• 
The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. Detailed information about study data 
collection and management process including systems used can be found in the 
study Data Management Plan. 
• 
Please refer to Appendix 9 in Section 12.9. for study management information 
during the COVID-19 pandemic. 
 
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 
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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) 
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. 
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] 

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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% 
 
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 
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. 

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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. 
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 

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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 
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 
 
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 

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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).  
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 

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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.   
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, 

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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. 
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 

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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 
 
where 
 
are CMH weights and 
 are estimates of the differences in response rates 
between the two treatment arms, fla-fc, for the kth stratum using the variance 
estimator 
, 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) 
∑
∑
=
k
k
k
cmh
W
d
W
d
ˆ
ˆ
 
 
k
dˆ
 
)
ˆ
r(
aˆ
v
cmh
d

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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.  
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 

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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 
• 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). 

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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.   
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).  

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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. 
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 

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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. 
• 
If follow-up information from a treating physician or other licensed medical 
practitioner is required for a medical device incident with an AE/SAE involving 
an associated person(s), the Associated Person Safety Reporting Information and 
Authorization Letter must be signed by the associated person to obtain consent.  
10.3. 
Quality Control (Study Monitoring) 
• 
In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.   
• 
When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the eCRF 
will serve as the source document. 
GSK will monitor the study and site activity to verify that the: 
• 
Data are authentic, accurate, and complete. 
• 
Safety and rights of participants are being protected. 
• 
Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements. 
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents 
10.4. 
Quality Assurance 
• 
To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and 
the regulatory agencies may conduct a regulatory inspection at any time during or 
after completion of the study.  
• 
In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss 
the conduct of the study, any findings/relevant issues and to implement any 
corrective and/or preventative actions to address any findings/issues identified. 

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

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comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by 
any institutional requirements or local laws or regulations, GSK 
standards/procedures, and/or institutional requirements.   
• 
The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of 
ownership of the records in the event the investigator is no longer associated with 
the site. 
10.7. 
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location. 
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study participants, as 
appropriate. 
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy. 
10.8. 
Review 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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11. 
REFERENCES 
Andrade RJ, Robles M, Lucena MI.  Rechallenge in drug-induced liver injury: the 
attractive hazard.  Expert Opin Drug Saf 2009;8(6):709-714. 
Arribas J, Clumeck N, Nelson M, et al. The MONET trial: week 144 analysis of the 
efficacy of darunavir/ritonavir (DRV/r) monotherapy versus DRV/r plus two nucleoside 
reverse transcriptase inhibitors, for patients with viral load <50 copies/ml at baseline. HIV 
MED, 2012: Aug;13(7):398-405. 
Arribas J, Girard PM, Landman R,et al.  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.  Lancet Infect 
Dis., 2015: 15:785-792. 
Arribas JR, Pialoux G, Gathe J, et al. Simplification to coformulated elvitegravir, 
cobicistat, emtricitabine, and tenofovir versus continuation of ritonavir-boosted protease 
inhibitor with emtricitabine and tenofovir in adults with virologically suppressed HIV 
(STRATEGY-PI): 48 week results of a randomised, open-label, phase 3b, non-inferiority 
trial. Lancet Infect Dis. 2014;14:581-589. 
Bierman WF, van Aqtamael MA, Nijhuis M, et al. HIV monotherapy with ritonavir-
boosted protease inhibitors: a systematic review. AIDS, 2009; 23(3):279-291. 
Centers for Disease Control and Prevention (CDC). Revised Surveillance Case Definition 
for HIV Infection – United States, 2014. MMWR 2014; 63 (RR-03);1-10. 
Chevat C, Viala-Danten M, Dias-Barbosa C, et al. Development and psychometric 
validation of a self-administered questionnaire assessing the acceptance of influenza 
vaccination: the Vaccinees' Perception of Injection (VAPI©) questionnaire.  Health Qual 
Life Outcomes. 2009;7:21. 
Department of Health and Human Services (DHHS). Panel on Antiretroviral Guidelines 
for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-
infected adults and adolescents. Updated April 08, 2015. Available at: 
https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-treatment-guidelines/0 
Department of Health and Human Services, Food and Drug Administration, Center for 
Drug Evaluation and Research (US). Guidance for Industry.  Human Immunodeficiency 
Virus-1 Infection: Developing Antiretroviral Drugs for Treatment, Revision 1, 
November 2015.  Available at:  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/defaul
t.htm 
Dube MP, Stein JH, Aberg JA, et al. Guidelines for the evaluation and management of 
dyslipidemia in human immunodeficiency virus (HIV)-infected adults receiving 
antiretroviral therapy: recommendations of the HIV Medical Association of the Infectious 
Disease Society of America and the Adult AIDS Clinical Trials Group. Clin Infect Dis 
2003; 37(5):613-627. 

TMF-16441767 
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Edurant Prescribing Information, February 2018. 
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. 
Fleiss JL. Statistical Methods for Rates and Proportions. 2nd ed. New York:John Wiley; 
1981. 
GlaxoSmithKline Document Number 2011N112455_03: LAI115428: A Randomized, 
Open Label Study to Investigate the Safety, Tolerability and Pharmacokinetics of Repeat 
Dose Administration of Long-Acting GSK1265744 and Long-Acting TMC278 
Intramuscular and Subcutaneous Injections in Healthy Adult.  Effective Date:  
04Feb2013.   
GlaxoSmithKline Document Number 2011N130484_00:  LAI116181: A Phase 1, Open-
Label, Crossover Study to Evaluate the Pharmacokinetics and Safety of GSK1265744 
and Rilpivirine and Dolutegravir and Rilpivirine in Healthy Adult Subjects.  Effective 
Date:  18Jul2012. 
GlaxoSmithKline Document Number 2014N216014_00: LAI116482:  A Phase IIb, Dose 
Ranging Study of Oral GSK1265744 in Combination with Nucleoside Reverse 
Transcriptase Inhibitors for Induction of HIV-1 Virologic Suppression Followed by an 
Evaluation of Maintenance of Virologic Suppression when Oral GSK1265744 is 
Combined with Oral Rilpivirine in HIV-1 Infected, Antiretroviral Therapy Naive Adult 
Subjects - Week 96 Results.  Effective Date 02Sept2015. 
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. 
GlaxoSmithKline Document Number RH2009/00003/07: GSK1265744 (Cabotegravir) 
Clinical Investigator's Brochure, Version 07, December 2017. 
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. 
Hatcher RA, Trussell J, Nelson AL, et al, Contraceptive Technology. 20th edition. 
Atlanta, Georgia: Ardent Media, Inc., 2011: 50.Table 3-2. 
Holmes WC, Shea JA. A new HIV/AIDS-targeted quality of life (HAT-QoL) instrument: 
development, reliability, and validity. Med Care. 1998 Feb;36(2):138-154. 
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.  

TMF-16441767 
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International Antiviral Society ( IAS)–USA ART Treatment of Adult HIV Infection: 
2015 Recommendations of the International Antiviral Society-USA Panel. Wensing AM 
et al. 2015 update of the drug resistance mutations in HIV-1. Topics in Antiviral 
Medicine October/November 2015: 23(4). Available at: 
http://www.iasusa.org/sites/default/files/tam/23-4-132.pdf. date accessed 22Mar2016.] 
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 
James LP, Letzig L, Simpson PM, et al. Pharmacokinetics of acetaminophen-protein 
adducts in adults with acetaminophen overdose and acute liver failure. Drug Metab 
Dispos 2009;37(8):1779-1784.  
Levey AS, Stevens LA, Schmid CH, et.al. A new equation to estimate glomerular 
filtration rate.  Ann Int Med. 2009; 150: 604-612. 
Lui KJ, Kelly C. A revisit on tests for the homogeneity of the risk difference. Biometrics. 
2000; 56: 309-315. 
Marant C, Longin J, Gauchoux R, et al. Long-term treatment acceptance: what is it, and 
how can it be assessed? Patient. 2012;5(4):239-249. 
Martinez E, Larrousse M, Llibre JM, et al. Substitution of raltegravir for ritonavir-
boosted protease inhibitors in HIV-infected patients: the SPIRAL study. 
AIDS 2010;24:1697-1707. 
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. 
Palella F, Tebas P, Gazzard B, et.al. SPIRIT study: switching to 
emtricitabine/rilpivirine/tenofovir df (FTC/RPV/TDF) single-tablet regimen (STR) from 
a ritonavir-boosted protease inhibitor and two nucleoside reverse transcriptase inhibitors 
(NRTIS) maintains HIV suppression and improves seru. 19th International AIDS 
Conference: Abstract no. TUAB0104. 2014. 
Papay JI, Clines D, Rafi R, et al.  Drug-induced liver injury following drug rechallenge.  
Regul Tox Pharm 2009;54:84-90.  
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification 
Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the 
FDA’s pediatric suicidal risk analysis of antidepressants. Am J Psychiatry. 
2007;164:1035–1043. 
Pozniak A, Markowitz M, Mills A, et al. Switching to coformulated elvitegravir, 

TMF-16441767 
CONFIDENTIAL 
201584 
 
 
Protocol Amendment 09 
 
180 
 
cobicistat, emtricitabine, and tenofovir versus continuation of non-nucleoside reverse 
transcriptase inhibitor with emtricitabine and tenofovir in virologically suppressed adults 
with HIV (STRATEGY-NNRTI): 48 week results of a randomised, open-label, phase 3b 
non-inferiority trial. Lancet Infect Dis. 2014;14:590-599. 
Raffi F, Jaeger H, Quiros-Roldan E, et al. Once-daily dolutegravir versus twice-daily 
raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 
week results from a randomised, double-blind, non-inferiority trial.  Lancet Infect Dis. 
2013;13(11):927-935.  
Rilpivirine Clinical Investigator Brochure [RPV IB], Edition Number 10, April 2017. 
Sato T. On the variance estimator for the Mantel-Haenszel risk difference. 
Biometrics.1989;45:1323-1324. 
TIVICAY Prescribing Information, November 2017. 
TRIUMEQ Prescribing Information, May 2018. 
Walmsley S, Baumgarten A, Berenguer J, et al.  Dolutegravir Plus Abacavir/Lamivudine 
for the Treatment of HIV-1 Infection in Antiretroviral Therapy-Naive Patients: Week  96 
and Week 144 Results from the SINGLE Randomized Clinical Trial.  J Acquir Immune 
Defic Syndrome.  2015; 70(5): 515-519. 
Ware JE, Kosinski M, Keller SD. SF-12: How to Score the SF-12 Physical and Mental 
Health Summary Scales. Boston, MA: The Health Institute, New England Medical 
Center, Second Edition, 1995. 
Woodcock A, Bradley C . Validation of the HIV treatment satisfaction questionnaire 
(HIVTSQ). Qual Life Res. 2001;10(6):517-531. 
Woodcock A, Bradley C. Validation of the revised 10-item HIV Treatment Satisfaction 
Questionnaire status version (HIVTSQs) and new change version (HIVTSQc). Value in 
Health. 2006;9(5):320-333. 
World Health Organization (WHO) Growth Reference:  Available at 
http://www.who.int/growthref/who2007_bmi_for_age/en/.

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12. 
APPENDICES 
12.1. 
Appendix 1: Abbreviations and Trademarks 
Abbreviations 
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-τ) 
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 
CVF 
Confirmed virologic failure 
CYP3A 
Cytochrome P450 3A 

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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 
DTP 
Direct to Patient 
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 
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 
HCP 
Healthcare Provider 
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 
HRT 
Hormonal replacement therapy 

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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 
LTFU 
Long-Term Follow Up 
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 
SVF 
Suspected Virological Failure 
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 

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USP 
United States pharmacopeia 
VAPI  
Vaccines' Perception of Injection 
VAS 
Visual Analog Scale 
VSLC 
ViiV Safety and Labeling Committee 
WBC 
White blood cell 
WOCBP 
Woman of Childbearing Potential 
EQ-5D-5L 
European Quality of Life-5 Dimensions 
3TC 
Lamivudine, EPIVIR 
201584 
FLAIR (First Long-Acting Injectable Regimen 
 
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 
Abnormalities 1 
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., 
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 
Transfusio
n 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 
Pruritus 3 
(without skin 
lesions) 
Itching 
causing no or 
minimal 
interference 
with usual 
social & 
functional 
activities 
Itching 
causing 
greater than 
minimal 
interference 
with usual 
social & 
functional 
activities 
Itching 
causing 
inability 
to 
perform 
usual 
social & 
functional 
activities 
NA 

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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 
Modificatio
n 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 
interferenc
e 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 
Lipoatrophy 4 
Detectable 
by study 
participant
, caregiver, 
or 
physician 
AND 
Causing 
no or 
minimal 
interferenc
e with 
usual social 
& 
functional 
activities 
Obvious on 
visual 
inspection 
AND Causing 
greater than 
minimal 
interference 
with usual 
social & 
functional 
activities 
Disfiguring 
changes 
NA 
Lipohypertrophy 5 Detectable 
by study 
participant
, caregiver, 
or 
physician 
AND 
Causing 
no or 
minimal 
interferenc
e 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 
decrease
d 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 
Symptom
s 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 
intervent
ion other 
than iron 
supplem
ent 
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 
intervent
ion 
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 
discharg
e 
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 
Osteopenia 6 
≥ 30 years of 
age 
BMD t-score 
-2.5 to -1 
NA 
NA 
NA 
< 30 years of 
age 
BMD z-score 
-2 to -1 
NA 
NA 
NA 
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 
interferenc
e 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 
consciousne
ss 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 
Delivery 7 
(report using 
mother’s 
participant ID) 
Delivery at 34 
to < 37 weeks 
gestational age 
Delivery at 28 
to < 34 weeks 
gestational age 
Delivery at 24 
to < 28 weeks 
gestational age 
Delivery at < 
24 weeks 
gestational age 
Spontaneous 
Abortion or 
Miscarriage 8 
(report using 
mother’s 
participant ID) 
Report only one 
Chemical 
pregnancy 
Uncomplicated 
spontaneous 
abortion or 
miscarriage 
Complicated 
spontaneous 
abortion or 
miscarriage 
NA 
7. Definition:  A delivery of a live-born neonate occurring at ≥ 20 to < 37 weeks gestational age. 
8. Definition:  A clinically recognized pregnancy occurring at < 20 weeks gestational age. 
Psychiatric 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Insomnia 
Mild 
difficulty 
falling 
asleep, 
staying 
asleep, or 
waking up 
early 
Moderate 
difficulty 
falling asleep, 
staying asleep, 
or waking up 
early 
Severe 
difficulty 
falling asleep, 
staying asleep, 
or waking up 
early 
NA 

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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 
Sickness 11 
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 
12.2.1. 
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 – Required Actions, Follow Up 
Assessments and Study Treatment Restart Guidelines  
VSLC GUIDELINES FOR DRUG RESTART  AFTER STOP FOR LIVER 
CRITERIA 
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. 
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 RESTART 
“Drug restart” can be approved by the VSLC for transient, defined non-drug-induced 
liver injury if no evidence of: 
• 
immunoallergic injury /HLA association with injury 
• 
alcoholic hepatitis 
Study drug must be held while labs and evaluation are completed to assess diagnosis. 
VSLC DECISION PROCESS FOR DRUG RESTART APPROVAL OR 
DISAPPROVAL  
• Principal Investigator (PI) requests consideration of drug re-initiation for a 
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 15). 
– must present source data defining the patient’s current resistance profile 
with documented evidence of extensive drug resistance and previous drug 
history. 
• The local operating company (LOC) medical director should be informed that 
study drug restart is under consideration and of the final decision, whether or 
not to proceed. 
• Relevant physicians (listed below) must review and agree on action to be taken 
regarding request for drug restart:   
• Safety Review Team Leader, Safety Development Leader, or Senior Safety 

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Physician 
• MDL and PPL 
• 
Request is taken to VSLC for final decision. 
 
Table 15 
Checklist for Phase III drug restart after well-explained liver injury 
(e.g. biliary, pancreatic, hypotensive events, congestive heart failure 
(CHF), acute viral hepatitis), and improvement of liver chemistry to 
normal or ≤ 1.5x baseline & ALT<5xULN. 
 
Yes 
No 
Is 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 9 
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 
FOLLOWING VSLC DECISION 
Medical Monitor and GCSP Physician Actions: 
• Medical Monitor must notify PI of VSLC’s restart decision and recommended 
dosing regimen in writing and Medical Monitor must record note in study files. 
• The Safety Review Team must record restart outcomes and the GCSP Physician 
must send these to the VSLC (see template below). 
• All severe reactions (SAEs or fatalities which occur following a drug 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 restart, as required.  
• If VSLC approves drug 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 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 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 restart. 
Drug Restart Outcomes Table Template 
To be completed/updated and provided to VSLC with each event 
recorded across studies and indications 
Drug Restart Outcomes Table – Update with each event 
Protocol# 
Subject# 
Safety outcome* 
Drug benefit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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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 
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/µL, 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/µL, 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/µL, 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/µL 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 

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o No information on presence of AIDS-defining conditions. 
Stage-3-defining opportunistic illnesses in HIV infection 
• 
Candidiasis of bronchi, trachea, or lungs  
• 
Candidiasis of oesophagus  
• 
Cervical cancer, invasive 
• 
Coccidioidomycosis, disseminated or extrapulmonary  
• 
Cryptococcosis, extrapulmonary  
• 
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. 
12.4.1. 
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  
In the event a participant withdraws from the study and requests destruction of their 
samples then the site staff must document this in the site study records, complete form F-
GRD-001 and must inform ViiV/GSK via the CRA within 5 days of notification by the 
participant to trigger sample destruction requests. 
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 
reconciliation process.  In this instance a sample destruction form will not be available to 

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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. 
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-

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Events meeting AE definition include: 
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 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. 

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Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose: 
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 
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 

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Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose: 
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 
 
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 

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AEs and SAE Recording: 
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. 
• 
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. 

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Assessment of Causality 
• 
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. 
• 
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. 

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SAE reporting to ViiV Healthcare / GSK via electronic data collection tool 
• 
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. 
 
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.  
• 
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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 16. 
Table 16 
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 ovulation  
• injectable  
Highly Effective Methods That Are User Independent  
• Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation 
• 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.  

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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. 
o If pregnancy is confirmed, please see Appendix 10 for details regarding allowing 
pregnant participants to remain in the study. Not applicable in Russia. 
 
12.7.2. 
Collection of Pregnancy Information 
• 
The Investigator will collect pregnancy information on any participant who becomes 
pregnant while participating in this study. See Appendix 10 for information to be 
collected for participants who become pregnant while participating in this study. 
• 
Participants who become pregnant while in the study may remain in study and 
continue scheduled dosing with CAB + RPV LA, once a pregnancy specific ICF 
addendum is signed by the participant. See Appendix 10 for additional data and 
information regarding the management of participants who remain in the study while 
pregnant. Not applicable in Russia. 
• 
Participants in Russia who become pregnant while in study may not elect to remain 
in the study. They must discontinue LA study treatment and continue to be followed 
up in the LTFU Phase.  
• 
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.   

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• 
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. 
 
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 17 
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 

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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. 
12.8.3. 
Russia 
In accordance with part 6th of article 43rd of the Russian Federal Law dated by 
12.04.2010 (# 61-FZ "On the Circulation of Medicines"), it is prohibited to conduct a 
clinical trial of investigational medical product (IMP) of pregnant women, including 
women during breastfeeding, except for cases when a clinical trial with IMP is being 
specifically carried out for this population of patients. Therefore study participants in 
Russia who become pregnant while receiving IMP (CAB+RPV LA) must stop IMP, 
begin an approved oral ART and enter the LTFU phase. 
12.9. 
Appendix 9:  COVID-19 Pandemic and Clinical Trial 
Continuity 
Background 
The COVID-19 pandemic presents significant logistical challenges for many clinical sites 
around the world, with variable restrictions being placed on site resources and operations, 
and on an individual participants ability to attend clinic visits.  In some places, medical 
visits are occurring, and in others, research clinics are operating with only emergency 
staff. 
Based on these challenges, it may be necessary to adopt additional measures and 
procedures to protect participant safety, and to ensure that there are no gaps in HIV-1 
treatment for participants enrolled in this clinical study, through continuous access to 
antiretroviral therapy. 
In order to maintain the scientific integrity of the study, and adhere to updated guidance 
from regulators, procedures have also been put into place to ensure that the actions taken 
to mitigate against any impact of COVID-19 are well documented in the trial database. 
A “Memo to Investigators” was issued on March 18th, 2020 and served as a record of 
approved emergency actions being taken within this clinical trial to manage issues related 
to COVID-19.  That memo continues to serve as record of approved actions which can be 
fully implemented by Investigators, in advance of this protocol guidance.  This appendix 
will remain consistent with the guidance provided within the “Memo to Investigators” 
and will also serve to provide additional protocol documentation requirements and 
procedures. 
This appendix outlines the measures which are approved for implementation within this 
clinical trial, to protect patient safety and to ensure the integrity of the clinical trial, as a 

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result of COVID-19 only. These measures may be implemented in accordance with any 
requirements and expectations set out by local Independent Review Boards/Independent 
Ethics Committees and National Competent Authorities, as necessary. 
This appendix does not apply to participant management issues that are unrelated to a 
specific, and documented, impact from COVID-19.  
12.9.1. 
Changes to Study Visits and Study Procedures 
• Where site staff resource is constrained due to COVID-19, IM dosing visits may 
proceed with limited or no other protocol-defined assessments (e.g. lab tests, 
questionnaires, etc.). If lab tests will be missed for more than one consecutive 
visit, the Medical Monitor must be contacted, to provide guidance for safety 
monitoring.  
• For WOCBP, point of care pregnancy testing should be performed, prior to IM 
dosing. 
• If central laboratory testing cannot be performed at a particular visit, and 
monitoring for safety is required, tests may be performed at an appropriately 
authorised/accredited local laboratory (or other relevant clinical facility), if this 
can be done within local restrictions on physical distancing. The site should 
proactively inform the Sponsor about such instances. Local laboratory results may 
be used to inform safety decisions. Results should be retained in source records. 
• When on-site visits are reduced, it is important that the investigator continue 
collecting relevant clinical information, including adverse events, from the 
participant through alternative means, e.g. by telephone contact. 
• There may be cases where the current principal investigator (PI) of a site is 
indisposed for a period and may need to delegate parts of his/her duties 
temporarily, e.g. to a sub-investigator. Any such changes should be documented 
in the site’s source records. Any permanent changes in PI should be 
communicated to the Sponsor. 
• There may also be circumstances where immediate actions are required by the 
Sponsor and/or investigator, outside of what is contemplated in the protocol, in 
order to protect a study participant from immediate hazard. Any such measures 
will be carefully documented and conducted in accordance with the National 
Competent Authority (NCA)/IRB/IEC regulations. 
 
12.9.2. 
Changes to Informed Consent 
Informed consent should continue per normal procedure and as described in the main 
body of the protocol, to the extent possible. However, there may be circumstances where 
re-consent of participants is needed, and a physical signature on site is not possible. In 
these cases, alternative ways of obtaining such re-consent should be considered, such as 
the participant sending a picture of his/her written consent to the investigator, or the 
investigator contacting the participant by telephone or video call and obtaining verbal 
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Any updated informed consent form or other subject-facing materials should be provided 
to participants by e-mail, mail or courier before re-consent is obtained. Any consent 
obtained this way should be documented in source records and confirmed by way of 
normal consent procedure at the earliest opportunity when participants attend their next 
on-site study visit. 
Any alternative informed consent procedure must be undertaken only after site 
IRB/Ethics Committee agreement and approval. 
 
12.9.3. 
Permissible Use of Antiretroviral Therapy 
In order to minimize the risk of gaps in HIV-1 antiretroviral therapy (ART) for 
participants impacted by COVID-19 in the clinical trial, the following options can be 
considered with regards to ART dosing, in order of preference: 
1. Where possible, and safe to do, please continue to prioritize IM dosing visits in 
order to keep the participants on the protocol-defined regimen. 
 
a. Qualified healthcare professionals (HCPs) trained on study procedures can 
administer IM injections outside of the study clinic setting (e.g. home, 
nursing facility, hospital), assuming this can be done safely, without 
compromising investigational product 
preparation/handling/storage/accountability requirements and done in 
accordance with local requirements. Please seek approval by the study 
team on a case-by-case basis. 
 
 
2. If a participant is not able to attend an IM injection visit due to COVID-19 related 
restrictions, the gap in IM dosing should be covered with oral ART, until IM 
dosing can resume. Participants should be reminded of the importance of adhering 
with daily oral dosing. Two options can be approved for oral bridging therapy in 
consultation with the Medical Monitor, listed in order of preference: 
 
a. Oral CAB + RPV  
i. Investigator should request availability of oral CAB + RPV supplies, 
prior to pursuing option b. 
b. Oral standard of care (SOC) commercial ART (prescribed locally); Note:  
For participants who are HLA-B*5701 negative, if the site has 
investigational product, ABC/DTG/3TC, remaining in study stock that is 
within expiry, this can also be used as the SOC bridging therapy. 
 
Oral bridging with CAB + RPV 
The protocol permits oral bridging to cover planned missed injections with oral CAB + 
RPV, only until IM dosing can be resumed. The start date of oral bridging should be 
within the dosing window for the missed IM dosing visit. This recommendation can be 
used to accommodate requests for oral dosing due to COVID-19. Oral bridging 

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recommendations should be followed as per protocol Section 6.8.1. The process and 
required information for requesting oral bridging can be found in your Study 
Reference/Procedure Manual.  Please continue to reach out to your study Medical 
Monitor for approval of oral bridging, in order to document use and to ensure expeditious 
shipment of oral CAB + RPV to your site.  
Participants who use oral CAB + RPV as short-term oral bridging are permitted to return 
to IM dosing, on protocol, once the COVID-19 conditions permit resumption of site 
activities.  
The investigator should reach out to the Medical Monitor to confirm IM restart 
instructions, and to ensure the participant remains appropriate for resumption of IM 
dosing. If oral bridging with CAB/RPV is anticipated to continue for > 2 months, 
additional approval and guidance should be obtained from the Medical Monitor to 
continue with oral bridging therapy. Loading/Re-initiation doses of CAB + RPV IM may 
be required, depending on the length of oral bridging. 
Oral bridging with Standard of Care Antiretroviral Therapy (SOC ART) 
For participants impacted by COVID-19, where the participant is unable to receive IM 
injections, and oral CAB + RPV is not available for use, oral bridging with any 
commercially available, guideline-recommended, SOC ART regimen is permitted. The 
start date of oral bridging should be within the dosing window for the missed IM dosing 
visit.  Please reach out to your study Medical Monitor for approval of SOC ART as oral 
bridging, in order to document the use of commercially available SOC ART within the 
study. 
Participants who use oral SOC ART as short-term oral bridging as a result of COVID-19 
will not be considered formally withdrawn insofar as they wish to continue on the study.  
Individuals who bridge with SOC ART will be permitted to return to IM dosing, on 
study, once the COVID-19 conditions permit resumption of site activities.   
The investigator should reach out to the Medical Monitor to confirm IM restart 
instructions, and to ensure the participant remains appropriate for resumption of IM 
dosing. If oral bridging with SOC ART is anticipated to continue for > 2 months, 
additional approval and guidance should be obtained from the medical monitor to 
continue with oral bridging therapy.  Loading/Re-initiation doses of CAB + RPV IM may 
be required, depending on the length of oral bridging. 
12.9.4. 
Direct-To-Patient (DTP) Shipment of Oral Study IP 
If a participant is unable to travel to the clinic, either to receive IM injections or to be 
dispensed oral bridging, sites are encouraged to consider DTP shipments of drug, from 
the site, to the participant, to ensure access to medicines.  
• If the study site is considering DTP shipment of oral CAB + RPV investigational 
product (IP), the site must first verify if DTP IP dispensing by 
investigators/hospital pharmacies is locally permitted and whether it requires 
regulatory and/or local ethics pre-approval, or post-hoc notification. 

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• The study participant should express his/her agreement for DTP shipment and the 
sharing of their personal information with any third-party couriers (as applicable), 
in accordance with local requirements.  This agreement should be documented in 
source records. 
• Oral CAB + RPV IP can be shipped at ambient temperatures via ground transport 
without a temperature monitoring device, with low risk of temperature excursions. 
Sites are encouraged to use discretion in determining the need for in-transit 
temperature monitoring based on the labelled storage requirements and the 
planned mode of transport and apply this as appropriate.  Shipment of oral CAB + 
RPV via air courier continues to require appropriate temperature monitoring.  For 
shipment conditions of oral medications other than oral CAB + RPV, please 
consult the product labelling. 
• In all cases IP accountability must be maintained, and all DTP dispensing 
documentation should be reflected in source records and dispensing logs per GCP. 
• Please refer to your CRA or local study manager for support with the DTP 
process, ensuring reference to current sponsor guidance and arrangement of a 
courier that can support shipment of IMP directly to participants. 
 
12.9.5. 
COVID-19 Experimental Agents 
If any treatments for COVID-19 are planned for a study participant, please consult with 
the study Medical Monitor to ensure that relevant drug interactions are considered and to 
ensure that continued study participation remains appropriate. 
12.9.6. 
COVID-19 Specific Data Capture 
12.9.6.1. 
Capturing COVID-19 Specific Protocol Deviations 
In order to summarise the impact of COVID-19 in a systematic way and in line with 
regulatory authorities’ recommendations, any study-level impact around COVID-19 will 
be documented as a protocol deviation. This will include the permissible actions 
summarized in this Appendix, which are taken to protect patient safety, including the use 
of CAB + RPV or SOC ART as oral bridging as well as missed visits and assessments as 
a result of logistical challenges resulting from COVID-19. 
Although the conduct of remote visits and the continuity of antiretroviral therapy, via oral 
bridging, are being utilized to protect patient safety, these events fall outside of the intent 
of the original protocol design, may have an impact on data interpretation, and thus will 
be characterized as protocol deviations for the purposes of data summary and analysis. 
 
Any protocol deviations resulting from COVID-19 will be clearly identified as such 
within the protocol deviation description and summarised separately. 
 

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12.9.6.2. 
Capturing COVID-19 Specific AEs and SAEs 
It is important for the study team to describe COVID-19 related adverse events/serious 
adverse and their impact on study data and outcomes. Standardization of case definitions 
will facilitate future data analysis.  
Please use the following guidance:  
1. 
AEs should continue to be evaluated as to whether they meet SAE criteria as 
defined in the protocol, and if so, submitted according to established SAE 
reporting requirements. SAEs and AEs should be submitted following usual 
study procedures and timelines.  
 
2. 
When an in-person clinic visit is not possible, please conduct a remote 
telehealth visit to assess for, and document any AEs/SAEs. 
3. 
Investigators should use the WHO definition to classify COVID-19 cases. The 
definition below, released March 20, 2020, represents a time point for 
standardized collection. We recognize definitions are likely to continue to 
evolve. When reporting both serious and non- serious adverse events (related 
to COVID-19 infection, investigators should use the following Verbatim 
terms:  
a) Suspected COVID-19 infection; or  
b) Probable COVID-19 infection; or  
c) Confirmed COVID-19 infection  
 
4. 
Sites should contact the study Medical Monitor for questions related to 
definitions and reporting, and decisions around impact to study drug 
continuation.  
 
5. 
A new COVID-19 infection Case Report Form will be added to the eCRF to 
collect additional details about the reported COVID-19 AE or SAE data. It is 
important to collect the correct information from each participant reporting a 
COVID-19 AE or SAE.  Therefore, please use the CRF templates to help you 
collect this information, once available. 
 
WHO Case Definition - March 20, 2020 Version (https://www.who.int/publications-
detail/global-surveillance-for-human-infection-with-novel-coronavirus-(2019-ncov)):  
Suspected case:  
A. A patient with acute respiratory illness (fever and at least one sign/symptom of 
respiratory disease, e.g., cough, shortness of breath), AND a history of travel to or 
residence in a location reporting community transmission of COVID-19 disease 
during the 14 days prior to symptom onset;  
OR  
B. A patient with any acute respiratory illness AND in contact (see definition of 
“contact” below) with a confirmed or probable COVID-19 case (see definition of 
contact) in the last 14 days prior to symptom onset;  

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OR  
C. A patient with severe acute respiratory illness (fever and at least one 
sign/symptom of respiratory disease, e.g., cough, shortness of breath; AND 
requiring hospitalization) AND in the absence of an alternative diagnosis that 
fully explains the clinical presentation.  
 
Probable case:  
A. A suspect case for whom testing for the COVID-19 virus is inconclusive 
(Inconclusive being the result of the test reported by the laboratory).  
OR  
B. A suspect case for whom testing could not be performed for any reason.  
 
Confirmed case:  
A person with laboratory confirmation of COVID-19 infection, irrespective of 
clinical signs and symptoms.  
Covid-19 Contact: 
A contact is a person who experienced any one of the following exposures during the 2 
days before and the 14 days after the onset of symptoms of a probable or confirmed case:  
1. 
Face-to-face contact with a probable or confirmed case within 1 meter and for 
more than 15 minutes;  
2. 
Direct physical contact with a probable or confirmed case;  
3. 
Direct care for a patient with probable or confirmed COVID-19 disease 
without using proper personal protective equipment; OR  
4. 
Other situations as indicated by local risk assessments.  
 
Note: for confirmed asymptomatic cases, the period of contact is measured as the 2 days 
before through the 14 days after the date on which the sample was taken which led to 
confirmation. 
12.10. 
Appendix 10: Information and Guidance for Managing 
Pregnant Participants 
Not applicable to participants in Russia. In Russia, women who become pregnant or who 
desire to become pregnant while in the study will have study treatment discontinued and 
will be withdrawn from the study. 

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12.10.1. 
Collection of Pregnancy Information 
The 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 for medical reasons 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 the protocol in Section 12.7.2., Appendix 7.  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. 
• 
Females who become pregnant while in the study may remain in study, and continue 
scheduled dosing with CAB + RPV LA, once a pregnancy ICF addendum is signed 
by the participant. 
12.10.2. 
Introduction 
Pregnancy increases the risk of HIV progression, while HIV increases the risk for 
maternal complications from pregnancy and poses the risk of perinatal HIV transmission 
to the unborn fetus.  Mother to child transmission (MTCT) of HIV can occur during 
pregnancy, labor, delivery or postpartum through breastfeeding.  In the absence of any 
interventions, vertical HIV transmission rates approximate 35%, but fall below 5% with 
effective interventions [WHO, 2010].  In the United States and other developed countries, 
the risk of perinatal infection has decreased from 25% without intervention to less than 
2% with intervention [WHO, 2012].  The HIV-infected mother who breastfeeds her 
infant while taking ARVs herself or giving ARVs to her infant reduces the risk of 
transmission to about 2% after 6 months of breastfeeding, or 4% over 12 months 
[UNAIDS, 2011]. 
The 2013 WHO Guidelines thus recommend (strong recommendation, moderate-quality 
evidence) all pregnant and breastfeeding women with HIV should initiate triple ARVs 
(ART), which should be maintained at least for the duration of mother-to-child 
transmission risk. Women meeting treatment eligibility criteria should continue lifelong 
ART [WHO, 2013]. The global benefits anticipated from ART in pregnant women who 

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are eligible for treatment include treatment of the mother’s underlying HIV disease, 
eliminating pediatric transmission/infection and reducing sexual transmission of HIV. 
Recent recommendation updates to treatment guidelines have included objectives to 
increase HIV screening of patients, including pregnant women (noting the importance of 
adopting HIV screening to be a part of prenatal care). 
The ART recommendation for pregnant females prioritizes the health of women over 
potential risks and increased cost.  For females who are on ARV therapy at the time that 
they become pregnant, the World Health Organization recommends that they continue 
such therapy if they are responding to the ARV. 
In line with this recommendation, this study will allow those females participating in 
201584 who are receiving CAB + RPV LA but become pregnant on study, to continue in 
the study in order to maintain their effective regimen with minimal disruption.  The PK of 
CAB + RPV LA, characterization of the safety of CAB + RPV LA administered during 
pregnancy, and characterization of maternal, birth and infant outcomes following 
treatment with CAB + RPV LA will be examined.  
12.10.3. 
Benefit/Risk Assessment 
Discuss with pregnant participant the benefit-risk of continuing in the study and 
continuing to receive CAB + RPV LA injections, or being withdrawn from study, as a 
result of her pregnancy. All participants who chose to stay in the study during pregnancy, 
and who choose to continue to receive CAB + RPV LA injections will need to sign a 
pregnancy specific ICF addendum. 
There is a pregnancy exposure registry that monitors pregnancy outcomes in women 
exposed to CAB + RPV LA (CABENUVA) during pregnancy. Healthcare providers are 
encouraged to register all pregnant study participants, whether or not they choose to 
remain in the study, by calling the Antiretroviral Pregnancy Registry [Antiretroviral 
Pregnancy Registry (APR) Steering Committee, 2013] at 1-800-258-4263. 
12.10.3.1. Cabotegravir 
Cabotegravir use in pregnant women has not been evaluated and there are insufficient 
human data on the use of during pregnancy to adequately assess a drug-associated risk of 
birth defects and miscarriage.  
The rate of miscarriage is not reported in the APR. The background risk for major birth 
defects and miscarriage for the indicated population is unknown. The background rate for 
major birth defects in a U.S. reference population of the Metropolitan Atlanta Congenital 
Defects Program (MACDP) is 2.7%. The estimated background rate of miscarriage in 
clinically recognized pregnancies in the U.S. general population is 15% to 20%. The APR 
uses the MACDP as the U.S. reference population for birth defects in the general 
population. The MACDP evaluates women and infants from a limited geographic area 
and does not include outcomes for births that occurred at less than 20 weeks’ gestation. 

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Animal Data (pre-clinical)  
Cabotegravir was administered orally to pregnant rats at 0, 0.5, 5, or 1,000 mg/kg/day 
from 15 days before cohabitation, during cohabitation, and from Gestation Days 0 to 17. 
There were no effects on fetal viability when fetuses were delivered by caesarean 
although a minor decrease in fetal body weight was observed at 1,000 mg/kg/day (greater 
than 30 times the exposure in humans at the RHD). No drug-related fetal toxicities were 
observed at 5 mg/kg/day (approximately 13 times the exposure in humans at the RHD) 
and no drug-related fetal malformations were observed at any dose. 
Cabotegravir was administered orally to pregnant rabbits at 0, 30, 500, or 2,000 
mg/kg/day from Gestation Days 7 to 19. No drug-related fetal toxicities were observed at 
2,000 mg/kg/day (approximately 0.7 times the exposure in humans at the RHD). 
In a rat pre- and postnatal development study, cabotegravir was administered orally to 
pregnant rats at 0, 0.5, 5, or 1,000 mg/kg/day from Gestation Day 6 to Lactation Day 21. 
A delay in the onset of parturition and increases in the number of stillbirths and neonatal 
deaths by Lactation Day 4 were observed at 1,000 mg/kg/day (greater than 30 times the 
exposure in humans at the RHD); there were no alterations to growth and development of 
surviving offspring. In a cross-fostering study, similar incidences of stillbirths and early 
postnatal deaths were observed when rat pups born to cabotegravir-treated mothers were 
nursed from birth by control mothers. There was no effect on neonatal survival of control 
pups nursed from birth by cabotegravir-treated mothers. A lower dose of 5 mg/kg/day (13 
times the exposure at the RHD) was not associated with delayed parturition or neonatal 
mortality in rats. Studies in pregnant rats showed that cabotegravir crosses the placenta 
and can be detected in fetal tissue. 
During the pre-clinical development of CAB, there were no positive genotox findings. 
Embryo-fetal studies also showed no adverse findings including neural tube defects.  In a 
pre and postnatal study, there were some test article-related decreases in F1 pup survival 
(87.4% vs 98.9% in control) in the highest dose (1000mg/kg/day) during postnatal days 
1-4.  No findings in the 0, 0.5 and 5 mg/kg/day doses).  
The clinical significance of these finding in humans is unknown. 
Human Data  
Cabotegravir use in pregnant females has not been evaluated and there are insufficient 
human data on the use of CAB + RPV LA during pregnancy to adequately assess a drug-
associated risk of birth defects and miscarriage.  
While there are insufficient human data to assess the risk of neural tube defects (NTDs) 
with exposure to CAB + RPV LA during pregnancy, preliminary findings from an 
unscheduled analysis of a birth outcomes surveillance study conducted in Botswana 
(Tsepamo Study) and presented in May 2018 showed a higher than expected number of 
neural tube defects (NTDs) among newborns whose mothers were exposed to DTG based 
ART at conception.  DTG is a different molecule in the same integrase class of 
medications as CAB. As of May 2018 four cases of neural tube defects were identified in 
426 infants born to mothers who were exposed to DTG-containing regimens from the 

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time of conception. In the same study, no infant born to a woman who started DTG 
during pregnancy had a neural tube defect, out of 2,824 women. Updated analysis of 
interim data from the Tsepamo study became available in 2019 and more recently in 
2020. Subsequently, the study team presented an updated analysis, including data through 
to 30 April 2020, at the 23rd International AIDS Society (IAS) Meeting [Zash, 2020].  
The latest data from the Tsepamo study included additional data accrued between 1 April 
2019 (the cut-off for the last formal analysis) and 30 April 2020. Over this 13-month 
period, 39,200 additional births were recorded, including 1908 additional exposures to 
DTG at conception. Two additional NTDs were detected in 1908 (0.10%) deliveries to 
mothers taking DTG at conception, compared with six NTDs in 4569 (0.13%) deliveries 
in mothers taking non-DTG regimens at conception, of which five NTDs in 2999 (0.17%) 
deliveries were to mothers taking efavirenz at conception. The incidence in HIV negative 
mothers over the 13-month period was 17/30,258 (0.06%).  
As of the Tsepamo April 2020 analysis, seven cases of neural tube defects were reported 
in 3,591 deliveries (0.19%) to mothers taking dolutegravir -containing regimens at the 
time of conception, compared with 21 cases in 19,361 deliveries (0.11%) to mothers 
taking non- dolutegravir containing regimens at the time of conception (Prevalence 
Difference 0.09%; 95% CI -0.03, 0.30).  Since the first analysis the estimated prevalence 
of neural tube defects with DTG exposure at conception has decreased in magnitude from 
0.94% to 0.19%. In the same study, no increased risk of neural tube defects was reported 
in women who started dolutegravir during pregnancy. Two out of 4,448 deliveries 
(0.04%) to mothers who started dolutegravir during pregnancy had a neural tube defect, 
compared with five out of 6,748 deliveries (0.07%) to mothers who started non-
dolutegravir -containing regimens during pregnancy. 
A causal relationship of these events to the use of DTG has not been established.  
The incidence of neural tube defects in the general population ranges from 0.5-1 case per 
1,000 live births. There are insufficient human data on the use of CAB + RPV LA during 
pregnancy to adequately assess a drug-associated risk of miscarriage or birth defects, 
including NTDs. 
12.10.3.2. Rilpivirine 
Animal Data  
Rilpivirine was administered orally to pregnant rats (40, 120, or 400 mg/kg/day) and 
rabbits (5, 10, or 20 mg/kg/day) through organogenesis (on Gestation Days 6 through 17, 
and 6 through 19, respectively). No significant toxicological effects were observed in 
embryo-fetal toxicity studies performed with rilpivirine in rats and rabbits at exposures 
15 (rats) and 70 (rabbits) times the exposure in humans at the RHD. In a pre- and 
postnatal development study, rilpivirine was administered orally up to 400 mg/kg/day 
through lactation. No adverse effects were noted in the offspring at maternal exposures 
up to 63 times the exposure in humans at the RHD 

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Human Data  
Based on prospective reports to the APR of over 390 exposures to oral rilpivirine-
containing regimens during the first trimester of pregnancy and over 170 during 
second/third trimester of pregnancy, the prevalence of birth defects in live births was 
1.3% (95% CI: 0.4% to 3.0%) and 1.1% (95% CI: 0.1% to 4.0%) following first and 
second/third trimester exposures. 
Available data from the APR show no difference in the overall risk of birth defects for 
rilpivirine compared with the background rate for major birth defects of 2.7% in a U.S. 
reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) 
In a clinical trial, total oral rilpivirine exposures were generally lower during pregnancy 
compared with the postpartum period. Refer to Edurant for additional information on 
rilpivirine. 
12.10.4. 
Clinical Considerations 
12.10.4.1. Exposure 
Lower exposures with oral rilpivirine were observed during pregnancy. Cabotegravir and 
rilpivirine are detected in systemic circulation for up to 12 months or longer after 
discontinuing injections of CAB + RPV LA; therefore, consideration should be given to 
the potential for fetal exposure during pregnancy. 
With the change in volume of distribution associated with pregnancy, drug concentrations 
of CAB and RPV during pregnancy will be assessed in pregnant participants who 
contiune to receive LA therapy while on study. For these participants, PK samples will be 
collected at every study visit throughout the duration of the pregnancy and at the first 
postpartum LA injection visit. Additionally, all other scheduled assessments will continue 
as reflected in as described in the protocol in the Time and Events Table (see Section 
7.1.). 

T M F -1 6 4 4 1 7 6 7  
C O N FI D E N TI A L  
2 0 1 5 8 4  
 
 
Pr ot o c ol A m e n d m e nt 0 9  
 
2 5 4  
 
Fi g ur e 1 0  
L T F U P K i n F e m al e a n d Pr e g n a nt P arti ci p a nt s  
( L A T T E-2, A T L A S)  
W e e k s P o st Fi n al I nj e cti o n
0
1 2
2 4
3 6
4 8
6 0
Pl a s m a C A B ( g/ m L)
0. 0 1
0. 1
1
1 0
L 2 5 1 2
A 5 9 1 1
L 2 5 9 2
A 5 4 8 7 ( + H C G)
A 5 4 8 5 (- H C G)
A 7 2 2 4 (- H C G)
A 6 5 9 5 (- H C G)

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12.10.4.2. Use of Supplements with CAB + RPV LA 
During pregnancy, additional supplements including vitamins, minerals and other 
mediations including OTC meds may be prescribed to the pregnant woman. It is 
important for all female participants who remain in the study to be aware of any potential 
DDIs that may occur with study medications and other agents used during pregnancy. 
Oral Cabotegravir 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. 
12.10.4.3. Overall Benefit:Risk Conclusion  
All medications have AE profiles that must be assessed prior to use, allowing for an 
appropriate risk/benefit assessment.  Additional considerations when using CAB + RPV 
LA can be found in the protocol in Section 4.6. 
There is limited data regarding the use of CAB + RPV LA in pregnant females. Based on 
animal data, the use of CAB + RPV LA is not anticipated to increase the risk of adverse 
developmental or reproductive outcomes in humans.  Available data from the APR show 
no difference in the overall risk of birth defects for rilpivirine compared with the 
background rate for major birth defects of 2.7% in a U.S. reference population of the 
Metropolitan Atlanta Congenital Defects Program (MACDP). 
Refer to Section 12.10.4.1. for additional data. 
The use of CAB + RPV LA during pregnancy may offer unique benefits. It is well 
documented that treatment adherence challenges to oral therapy exists both in the peri-
partum and post-partum periods with LA dosing offering an opportunity to overcome 
such adherence challenges. LA therapy may also help with nausea (50 % mild to 
moderate) or hyperemesis (2%). Female participants on LA dosing who become pregnant 
will have exposures throughout pregnancy due to the long half-life and PK tail of 
CAB/RPV. Pregnant participants who are withdrawn from study and are initiated on an 
alternative oral ART regimen consisting of either 2 or 3 antiretrovirals to protect the life 
of the mother and for the prevention of MTCT, potentially expose the fetus to additional 
ARVs during gestation (in some cases upwards of 5 antiretrovirals). 
In summary, taking into account the measures taken to minimize risk to participants 
participating in this study, the potential risks identified in association with CAB + RPV 
LA are justified by the anticipated benefits that may be afforded to pregnant participants 
with HIV infection. 
Given the risk/benefit ratio for CAB + RPV LA dosing in WCBP, coupled with concerns 
of increasing fetal exposure to several additional antiretrovirals upon participant 
withdrawal, pregnant participants will be allowed to remain in the study and continue to 
receive CAB + RPV LA injections, once the new pregnancy ICF addendum is signed by 

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the participant.  
 
12.10.5. 
Study Assessments and Procedures: specific assessments for 
pregnant participants 
Participants who become pregnant while in the study, and who sign the informed consent 
pregnancy addendum may remain in the study and continue to receive CAB + RPV LA.  
Please note: The HIV provider is responsible for HIV care and will collaborate and share 
information with the subject’s obstetric care provider, discuss the subject’s participation 
in this study, the necessary procedures at delivery, to share HIV information, and to 
collect birth and infant outcomes from the subject’s obstetric care provider and/or the 
pediatric health provider for the infant. 
Because obstetric and/or pediatric care will not be specifically provided via this study, the 
subject must also establish appropriate obstetric and pediatric care (including prenatal 
care) per local standard of care (SoC) in parallel.  It will be necessary for the subject to 
provide a release of medical information to facilitate collection of pregnancy and 
pregnancy outcomes by the investigator 
All assessments will be conducted in accordance with the protocol, Section 7, and as 
described in the Time and Events Table (see Section 7.1.). 
12.10.5.1. Safety Assessments 
Pregnancy related complications and diagnoses, and outcomes will be captured as AEs 
and SAEs as outlined in the protocol in Section 7.4.3. 
Pregnancy complications (e.g., preeclampsia or eclampsia, prolonged hospitalization after 
delivery, for wound infections etc, seizures) and elective terminations for medical reasons 
must be reported as an AE or SAE.  Spontaneous abortions must be reported as an SAE. 
In the event of a pregnancy loss, after the loss is confirmed the subject may continue to 
receive CAB + RPV LA unless they meet the criteria for confirmed virologic withdrawal.  
They may continue to CAB + RPV LA until study medications are locally approved and 
commercially available or until they no longer receive benefit.  In this case the subject 
must agree to use contraception to avoid a ‘new’ pregnancy (See Appendix 7 of the 
protocol). 
Any SAE occurring in association with the pregnancy brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
possibly related to the study treatment, must be promptly reported to GSK 
12.10.5.2. Pharmacokinetics 
Refer to Section 7.5. in the protocol. 
All pregnant participants who elect to remain in the study will have the following PK 
samples obtained at each LA injection visit throughout the pregnancy and at the first 

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postpartum LA injection visit: 
• Blood samples for evaluation of total CAB (2mL each) and total RPV (2mL each) 
plasma PK concentrations.  
• Blood sample for evaluation of unbound CAB (9mL each) plasma PK 
concentration. 
All PK samples will be trough levels and will be collected prior to the scheduled LA 
injection. The pre-dose trough PK sample is to be collected within 15 minutes prior to the 
LA dose, on the day of the study visit.  
For participants pregnant during the Long Term Follow Up Phase, plasma concentrations 
of cabotegravir and rilpivirine will be collected as per 7.1 Time and Events table. 
Please refer to the SPM for PK sample collection, processing, and shipping instructions. 
The actual date and time of each PK sample collection will be recorded in the eCRF. 
12.10.6. 
References 
Antiretroviral Pregnancy Registry (APR) Steering Committee. Antiretroviral Pregnancy 
Registry International Interim Report for 1 January 1989 through 31 January 2013. 
Wilmington, NC: Registry Coordinating Center; 2013. Available from URL: 
www.APRegistry.com. 
Edurant Prescribing Information, February 2018 
UNAIDS (2011) Reference Group on Estimates, Modelling and Projections. Working 
Paper on Mother-to-Child HIV Transmission Rates for use in Spectrum, 6 June 2011. 
Available online at http://www.epidem.org/Publications/MTCTratesworkingpaper.pdf. 
World Health Organization (WHO) (2010). Antiretroviral drugs for treating pregnant 
women and preventing HIV infection in infants: Recommendations for a public health 
approach.  Available online at: 
http://whqlibdoc.who.int/publications/2010/9789241599818_eng.pdf, accessed 6 Feb 
2013. 
World Health Organization (WHO) (2012). Antiretroviral Treatment as Prevention 
(TasP) of HIV and TB:  2012 Update.  June 2012, Available online at: 
http://www.who.int/hiv/pub/mtct/programmatic_update_tasp/en/index.html 
World Health Organization (WHO) (2013). Consolidated Guidelines on the Use of 
Antiretroviral Drugs for Treating and Preventing HIV Infection. 30 June 2013.  Available 
online at: http://www.who.int/hiv/pub/guidelines/arv2013/download/en/index.html 
Zash R, Holmes L, Diseko M, Jacobson D, Mayondi G. Update on neural tube defects 
with antiretroviral exposure in the Tsepamo study, Botswana. JAIDS 2020, 23:183 

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12.11. 
Appendix 11: Device Deficiencies: Definition and 
Procedures for Recording, Evaluating, Follow-up, and 
Reporting in Medical Device Studies 
The definitions and procedures detailed in this appendix are in accordance with ISO 
14155, European Medical Device Regulation (MDR) 2017/745 for clinical device 
research, and the US Food and Drug Administration (FDA) combination product 
reporting rule, 21 CFR 4, Subpart B. 
Both the investigator and the sponsor will comply with all local medical device reporting 
requirements for medical devices. 
The detection and documentation procedures described in this protocol apply to all 
medical devices used in the study (see Section 6.14 for the list of medical devices). 
12.11.1. 
Definition of Device Deficiency 
Device Deficiency Definition 
• 
A device deficiency is an inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety, or performance. Device deficiencies 
include malfunctions, use errors, and information supplied by the manufacturer. 
12.11.2. 
Recording and Follow-Up of Device Deficiencies 
Device Deficiency Recording 
• 
When a device deficiency occurs, with or without an associated AE/SAE, it is the 
investigator’s responsibility to review all applicable documentation (e.g., hospital 
progress notes, laboratory reports, and diagnostics reports) related to the event. 
• 
The investigator will then record all relevant device deficiency information on the 
appropriate form. If applicable, any associated AE or SAE will be documented in 
the participant’s medical records, in accordance with the investigator’s standard 
clinical practice. 
• 
There may be instances when copies of medical records for certain cases are 
requested by the sponsor. In this case, all participant identifiers, with the exception 
of the participant number, will be redacted on the copies of the medical records 
before submission to the sponsor. 
• 
The investigator will attempt to fully describe the device deficiency and provide 
details on any treatment provided.  
• 
For device deficiencies, it is very important that the investigator describe any 
corrective or remedial actions taken to prevent the deficiency’s recurrence. 
o A remedial action is any action other than routine maintenance or servicing of 
a medical device where such action is necessary to prevent the recurrence of a 
device deficiency. This includes any amendment to the device design to 
prevent recurrence. 

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Assessment of Intensity of associated AE/SAEs 
• If an AE or SAE is associated with a device deficiency, the investigator will make 
an assessment of intensity for each AE or SAE as outlined in Section 12.6.5. 
Follow-up of device deficiency 
• The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
sponsor to elucidate the nature of the device deficiency and any associated AE or 
SAE as fully as possible 
• New or updated information regarding the device deficiency will be recorded in the 
originally completed medical device deficiency report form. 
• If there is an associated SAE with the device deficiency, the investigator will 
submit any updated SAE data to GSK within 24 hours of receipt of the information. 
12.11.3. 
Reporting of Medical Device Deficiencies for Participants 
• 
Reporting to GSK  
• 
NOTE: There are additional reporting obligations for medical device deficiencies 
that are potentially related to SAEs that must fulfil the legal responsibility to notify 
appropriate regulatory authorities and other entities about certain safety 
information relating to medical devices being used in clinical studies.  
• Medical device deficiencies that are not related to an AE or SAE should be 
reported via email to gsk-rd.complaints@gsk.com, using the medical device 
deficiency report form.  
 
• If the medical device deficiency is related to a non-serious AE and not linked to an 
SAE, please send the medical device deficiency report form via email to gsk-
rd.complaints@gsk.com only. The eCRF for the subject should also be updated 
with AE information, as outlined in Section 7.4.3 
 
• If the device incident is linked to an SAE, please email the medical device 
deficiency report form, within 24 hours, to both uk.gsk-rd-gcsp-ctsm-
admin@gsk.com (or fax +44(0)20 8754 7822) and gsk-rd.complaints@gsk.com. 
The SAE form should also be reported, as outlined in Section 7.4.3. The eCRF for 
the subject should also be updated with the SAE information. 
 
• GSK will review all device deficiencies and determine and document in writing 
whether they could have led to an SAE. These device deficiencies will be reported 
to the regulatory authorities and IRBs/IECs as required by national regulations. 
• Contacts for Medical Device Deficiency reporting can be found in the medical 
device deficiency report form. 

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12.11.4. 
Reporting of Medical Device Deficiencies for Associated Person 
• 
Reporting to GSK  
If an Associated Person (i.e. a healthcare professional) experiences a device 
deficiency, the medical device deficiency information and any associate AE/SAE 
information will be reported to GSK. The associated person will be provided with 
the safety reporting information and authorization to contact physician letter.  
If follow up information is required, authorization to contact physician (or other 
licensed medial practitioner) must be signed to obtain consent.  
• Medical device deficiencies that are not related to an AE or SAE should be 
reported via email to gsk-rd.complaints@gsk.com, using the medical device 
deficiency report form.  
 
• If the medical device deficiency is related to a non-serious AE and not linked to an 
SAE, please send the medical device deficiency report form with details of the 
associated AE via email to gsk-rd.complaints@gsk.com only. 
 
• If the device incident is linked to an SAE, please email the medical device 
deficiency report form, within 24 hours, to both uk.gsk-rd-gcsp-ctsm-
admin@gsk.com (or fax +44(0)20 8754 7822) and gsk-rd.complaints@gsk.com. 
The associated SAE form should also be reported to uk.gsk-rd-gcsp-ctsm-
admin@gsk.com (or fax +44(0)20 8754 7822). 
 
• GSK will review all device deficiencies and determine and document in writing 
whether they could have led to an SAE. These device deficiencies will be reported 
to the regulatory authorities and IRBs/IECs as required by national regulations. 
 
• Contacts for Medical Device Deficiency reporting can be found in the medical 
device deficiency report form. 
 
 
12.12. 
Appendix 12: Sub-Cutaneous Administration PK Sub-Study 
Amendment 
TITLE PAGE  
Parent Study Protocol 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. 
 

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Sub-study Protocol Amendment Title: An Amendment to the FLAIR Study to Evaluate 
the Pharmacokinetics, Safety, Tolerability, Maintenance of Virological Suppression and 
Patient Reported Outcomes for Participants Receiving Cabotegravir (CAB 200 mg/mL) 
and Rilpivirine (300 mg/mL) Long-Acting Injections Following Sub-cutaneous (SC) 
Administration in the Anterior Abdominal Wall SC Tissue  Compared with Intramuscular 
(IM) Administration in the Gluteus Medius Muscle in Adult Participants Living with HIV-
1 infection in the FLAIR Study. 
 
12.12.1. 
Sub-Study Amendment Background 
Cabotegravir/rilpivirine (CAB/RPV) long acting (LA) intramuscular (IM) injection has 
been approved as a two-drug regimen for the treatment of HIV-1 infection in treatment 
experienced adults and adolescents, virologically suppressed on an orally administered 
regimen, who switch to long-acting therapy. CAB/RPV LA is currently administered in the 
clinic as monthly or every two months dosing for intramuscular gluteal injections  by a 
health care provider.   
 
As more HIV-infected individuals opt for LA therapy to control their HIV infection, there 
has been interest in research and development of potential options to allow for at-home-
based therapy administered by the patient via an auto-injector or pre-filled syringe. In 
assessing options for home based self-administration, data needs to be generated evaluating 
pharmacokinetics, safety and tolerability, virologic response and patient report outcomes 
of cabotegravir and rilpivirine LA following sub-cutaneous (SC) administration. Assessing 
the utility of SC injections in an existing study like FLAIR is an efficient pathway to 
evaluate and compare these parameters among study participants with ongoing experience 
receiving CAB and RPV LA via IM administration. To allow for self-administration, the 
sub-cutaneous tissue of the anterior abdomen   is an easily accessible location  and will be 
the subcutaneous site  utilized in the FLAIR SC amendment (sub-study).   
 
While the ultimate aim of self-administration would be via an auto-injector or pre-filled 
syringe (under development), the FLAIR SC amendment (sub-study) will require HCP 
administered injections via a SC approach in the subcutaneous tissue of the anterior 
abdomen)  compared with HCP administered IM gluteal injections in the gluteus medius. 
 
The currently approved IM formulations for CAB (200 mg/mL) and RPV (300 mg/mL), as 
also used in the FLAIR parent study, will be utilized to assess both IM and SC routes of 
administration.  
 
12.12.1.1. Data Utilizing CAB 200/mL Subcutaneously (SC) 
Two phase I studies have reported the tolerability, safety, and pharmacokinetics of 
cabotegravir long-acting injection administered intramuscularly or via a sub-cutaneous 
route [Spreen et al; J Acquir Immune Defic Syndr 2014;67:481–486)]. In a randomized, 
placebo-controlled, double-blinded, single-dose study, 58 HIV-uninfected adults received 
cabotegravir as a gluteal intramuscular injection of 100 mg, 200 mg, 400 mg or 800 mg 
(administered as two equally divided split injections) or as a subcutaneous abdominal 
injection of 100 mg, 200 mg or 400 mg (administered as two equally divided split 

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injections) or as a placebo injection vehicle. Following single intramuscular or 
subcutaneous injection, plasma drug concentrations increased rapidly over the first week, 
with sustained mean plasma concentrations above the PA–IC90 for approximately 24 weeks 
or longer for doses of at least 200 mg, as shown in Figure 11 
Figure 11 
Mean plasma levels of GSK1265744 over time following single-dose 
administration of long-acting formulation. 
 
Figure 11. GSK1265744 (200 mg/ml) was administered as a single IM (gluteal) or SC (abdominal) 
injection or equally divided IM or SC injection. Each cohort comprised eight healthy adult patients (six 
active/two placebo). The dashed line represents the plasma PA-IC90 value for GSK1265744 against wild-
type HIV-1 of 0.166 mg/ml. 
CAB was detected in plasma for up to 48 weeks. Following LA injections, mean 
absorption-limited apparent terminal-phase half-life ranged from 21 to 50 days as 
compared to approximately 40 h following single-dose oral administration. This longer 
apparent half-life following injection is a result of low solubility of the drug particle, 
prompting a slow absorption rate of drug from the injectable formulation with no change 
in the plasma elimination half-life of the dissolved active drug.  
When the injectable formulation was administered as two equally divided, split dose 
injections (Cohort 4, 400 mg x 2 intramuscular and Cohort 7, 200 mg x 2 subcutaneous), 
total drug release was increased so that the maximum observed plasma concentration 
(Cmax) was greater than dose proportional and there was a more pronounced decay in drug 
concentrations over time. However, overall extent of exposure [area under the curve (AUC) 
from time zero to infinity] was dose proportional and did not change (Table 18).  
Additionally, using a power model, PK parameters seemed to increase proportionally to 
dose after unsplit SC administration (100 and 200 mg).  Administration of the dose as 2 

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separate injections (dose splitting)— 400 mg (200 mg x 2) IM and SC as well as 800 mg 
(400 mg x 2) IM—achieved geometric mean Cw4 above the protein-adjusted IC90.  
Table 18 
Plasma CAB PK Parameter Summary 
 
Although no formal statistical analysis of cabotegravir PK parameters by gender was 
performed, there was a general trend of higher plasma exposures in female subjects after 
SC administration of cabotegravir and of higher exposures in males after split IM 
injections. Gender differences in absorption rate after IM injections may reflect greater 
skin-to-muscle depth in females, which would result in an increased likelihood of 
delivering cabotegravir into the SC space. 
Safety and Tolerability 
Thirty-eight (79%) of 48 subjects receiving an IM injection and 22 (92%) of 24 subjects 
receiving a SC injection reported at least 1 AE. A higher percentage of AEs identified as 
ISRs occurred in subjects receiving CAB than placebo. In subjects receiving IM injections, 
33 (83%) of 40 subjects receiving CAB reported an AE compared with 5 (63%) of 8 
subjects receiving placebo, whereas in subjects receiving SC injections, 17 (94%) of 18 
subjects receiving CAB reported an AE compared with 5 (83%) of 6 subjects receiving 
placebo. Most frequent (>2 subjects in any dose cohort) AEs that occurred while on therapy 
by treatment are shown in Table 19. 
The most common adverse events were self-limited injection site reactions (ISR). ISRs 
were generally mild, with pain and erythema at the injection site reported as the most 
common findings for both IM and SC administration. Erythema, however, was more 
commonly reported after SC administration compared with IM. While nodule formation 
was also seen after both IM and SC administrations, it too was more commonly reported 
after SC vs IM dosing. While ISR of pain did not increase in incidence with increasing 
volume after IM administration (from 0.5 to 2.0 mL), pain was more commonly reported 
with increasing volume after SC administration (0.5 to 1.0 mL). There were no systemic 
serious or grade 3 to 4 adverse events (see Table 19). 
Specific to SC-related ISRs, pain was described in 50%, 100%, and 83% of subjects 

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receiving CAB SC 100 mg, 200 mg, or 400 mg split injections, respectively, relative to 
33% of placebo subjects describing pain. The mean duration of pain ranged from 7 to 12 
days. Erythema was described in 33%, 83%, and 67% of subjects receiving CAB SC 
100 mg, 200 mg, or 400 mg split injections, respectively, relative to 17% of subjects 
receiving SC placebo injection. The mean duration of erythema ranged from 2 to 10.7 days.  
Overall, cabotegravir was generally safe and well tolerated when administered as a single 
or separate IM injection from 100 to 800 mg and as a single SC injection from 100 to 400 
mg. ISRs were reported by most subjects; however, they were all mild (grade 1) in severity. 
In addition, ISRs were self-limited, no subjects required symptomatic treatment, and there 
were no withdrawals due to ISRs. The incidence of ISRs seemed to be related to active 
drug as a higher percentage of AEs occurred in subjects who received cabotegravir than 
placebo. There were no substantial differences in reporting of non-ISR AEs between 
cabotegravir and placebo [Spreen et al, 2014]. 
Table 19 
Summary of Most Frequent (≥ 2 subjects in Any Arm) AEs on 
Therapy by treatment (Safety Population) 
 
In a second phase I study, HIV-negative adults received a 14-day lead-in of oral 
cabotegravir 30 mg per day to assess safety and tolerability before administration of the 
long-acting injection [Spreen et al, 2014].  
Patients were randomized into one of four cohorts: all received cabotegravir 800 mg 
intramuscular (as 400 mg x 2) as a loading dose followed by three monthly doses of 200 mg 
subcutaneous (Cohort 1); 200 mg intramuscular (Cohort 2); 400 mg intramuscular (Cohort 
3); or after 3 months, a single further injection of 800 mg intramuscular (Cohort 4). Cohorts 
2 and 3 also received gluteal intramuscular doses of rilpivirine LA at months 3 (1200 mg) 
and 4 (900 or 600 mg, respectively). Forty-seven patients enrolled, with 40 patients 
receiving at least one long-acting injection; 38 completed all planned injections. Seven 
patients discontinued the oral lead-in phase, six for non-drug-related reasons and one for 
an adverse event (dizziness following first 30 mg dose).  

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Mean plasma CAB concentration–time profiles are shown in Figure 12. All regimens 
achieved therapeutically relevant plasma concentrations within 3 days after injection as 
defined by attaining mean plasma concentrations greater than 4-fold the protein binding–
adjusted IC90 for wild-type HIV (0.66 mg/mL) and persisted until the end of the dosing 
interval. Accumulation over 4 monthly doses was observed for the 800 mg/400 mg IM 
dose regimen while the other regimens seemed to be at or near steady state by the third 
month of dosing.  
Figure 12 
Mean plasma concentration-time profiles of 744 following monthly or 
quarterly injections. 
 
Figure 12: Solid arrows indicate 744 LA as injection administer quarterly (every 84 
days); open arrows indicate 744 LA as injection administered monthly (every 28 days). 
PK parameters following the last dose of 744 (CAB) LA and RPV LA in each cohort are 
shown in Table 20. Geometric mean PK parameters for 744 LA were similar between 
groups receiving IM and SC doses of 200 mg. Cmax and AUC0–t were generally linear 
between the 200 mg and 400 mg 744 LA IM doses. Moreover, for cohort 4, geometric 
mean plasma GSK1265744 Ctau was 1.1 µg/mL, 6.7-fold above the PA-IC90.   

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Table 20 
PK Parameters of 744 LA (both IM and SC) and RPV LA (IM data 
only) After the Last Injection 
 
 
CAB LA was generally well tolerated when administered alone or with RPV LA. The 
majority of AEs were mild or moderate in severity.  ISRs were the most commonly 
observed AEs and reported in the majority of subjects. Table 21 describes the incidence of 
ISRs by subject cohort and Table 22 provides data by ISR event and treatment.  
Cabotegravir SC administration was associated with a greater number of ISR events per 
patient than observed after IM administration with either cabotegravir or rilpivirine LA. 
There was no grade 3 or 4 ISRs. Pain was the most common ISR; the majority of ISRs 
were reported to be mild in severity (Table 22). The median duration of pain was less than 
7 days and similar between CAB LA and RPV LA dosing. Erythema, nodules, induration, 
and warmth at the injection site were also reported. The incidence of nodules was higher 
in those receiving SC CAB LA than in subjects with IM injections of either CAB LA or 
RPV LA. 
Table 21 
Most Common ISRs (> Subjects) by Cohort 
 

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Table 22 
Summary of Incidence, Severity, and Duration of ISRs Across 
Treatments by Event 
 
12.12.1.2. Data Utilizing RPV LA Subcutaneously (SC) 
A phase 1 study of rilpivirine LA with a previous 100 mg/ml nanosuspension evaluated the 
pharmacokinetics and safety of single gluteal intramuscular or abdominal subcutaneous 
injections in 51 HIV-negative adult participants at doses of 200, 400 and 600 mg, vehicle 
(placebo) or saline [Verloes R, 2008]. An additional nine patients received a single 400 mg 
IM injection or saline into the deltoid muscle. Consistent with the preclinical experience, 
rilpivirine was slowly released from the injection site into plasma, with drug concentrations 
of more than 10 ng/ml for 12–26 weeks. Dose proportionality and similar plasma 
concentration–time profiles were observed for both subcutaneous and gluteal 
intramuscular injections (see Figure 13 and Table 23). ISRs consisted of redness, bruising, 
pain and to a lesser extent, induration, and were more frequent with active drug injections 
versus placebo. There was a greater frequency of ISRs with subcutaneous as compared to 
intramuscular administration. Among intramuscular injections, gluteal injections were 
better tolerated than deltoid injections. There were no serious adverse events or grade 3 or 
4 adverse events. 
 

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Figure 13 
Single-dose TMC278 LA provided sustained plasma levels for up to 
12 weeks in humans. 
 
Table 23 
Plasma levels and PK profiles following single-dose TMC278 LA 
injections 
 
Preliminary short-term data of an ongoing Phase 1 study in healthy adult participants with 
the 
current 
commercial 
RPV 
LA 
300 mg/mL 
formulation 
(https://clinicaltrials.gov/ct2/show/NCT05112939) 
suggest 
that 
RPV 
plasma 
concentrations in the first month after SC administration of RPV LA may be somewhat 
lower compared to historical data for IM administration. Modelling and simulation was 
used to estimate what the impact could be for HIV-infected patients on monthly CAB+RPV 
at steady-state switching from IM to SC administration, as planned in this sub-study. A 
conservative estimate of 50% lower bioavailability for SC administration compared to IM 
administration was used. Even with an estimated 50% lower bioavailability, it is predicted 
that after 3 RPV LA 600 mg SC injections, administrated a month apart each time, the RPV 
plasma concentrations would still remain above those observed for the every 2 months IM 
dosing regimen, which has been shown to be efficacious. As a cautionary measure for this 
exploratory sub-study, however, the visit window for the SC administrations will be 
reduced to only allow injections to be administered up to one week earlier (as opposed to 
allowing injections one week earlier through one week later) and will not allow injections 
to be administered up to one week later. 
 

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Figure 14 
Modelling and Simulation Data for RPV to Support SC FLAIR Sub-
study 
 
RPV plasma concentrations over time after monthly RPV LA 600 mg (current 
formulation) IM injections (through Week 128), followed by 3 SC injections of RPV LA 
600 mg every month (Week 128, 132, 136) with a conservative assumption of  50% 
lower bioavailability (relF/2), followed by returning to monthly RPV LA 600 mg IM 
injections (as of Week 140). 
12.12.2. 
Sub-Study Amendment Rationale 
Data from several Phase 1, healthy volunteer studies assessing various doses of CAB 
200 mg/mL and RPV 100 mg/mL administered subcutaneously demonstrated similar 
plasma PK parameters to intramuscular dosing with achieved concentrations above the PA-
IC90 for both drugs. For CAB, the geomean Ctau after 200 mg administered SC was 
1.61 µg/mL and was 1.66 µg/mL after 200 mg administered IM suggesting that switching 
400 mg IM with SC dosing will likely result in similar CAB plasma concentrations and 
above those shown to be efficacious for the every 2 months IM dosing regimen.  For the 
300 mg/mL formulation of RPV, prior data suggest that concentrations after SC 
administration could either be similar or somewhat lower compared to IM administration. 
Modelling and simulation showed that even when using a conservative estimation of 50% 
lower bioavailability for SC administration compared to IM administration, it is predicted 
that after 3 monthly RPV LA 600 mg SC injections, the RPV plasma concentrations would 
still remain above those observed for the every 2 months IM dosing regimen, which has 
been shown to be efficacious. 
Co-administration of both CAB and RPV was generally safe and well tolerated, with the 
most reported AEs classified as grade 1. SC administration was overall less well tolerated 
than IM injections with higher frequency of ISRs being reported after SC administration 
compared with IM administration although there were no SAEs or grade 3 or 4 AEs 
reported with SC administration. These data provided an initial assessment of SC 

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administration of LA CAB and RPV in healthy volunteers and allows for further evaluation 
of SC dosing of LA CAB and RPV in HIV-infected individuals.  
 
The FLAIR study is a large, on-going, Phase 3 clinical study that assessed monthly LA IM 
dosing of CAB and RPV compared with an orally administered standard of care regimen 
in treatment naïve subjects, all of whom received 20 weeks of oral induction therapy with 
abacavir/dolutegravir/lamivudine prior to being randomized to either continue with 
abacavir/dolutegravir/lamivudine therapy or to switch to long-acting CAB/RPV. For those 
randomized at baseline to LA therapy, a 4-week oral lead in with CAB (30 mg) and RPV 
(25 mg) was required to assess tolerability prior to proceeding with LA therapy [Orkin, 
NEJM, 2020]. Since participants in the FLAIR study were randomized either at baseline to 
LA therapy or were given the opportunity to transition to LA therapy in the extension phase 
of FLAIR at week 100 (either with or without an OLI), participants enrolling into the 
FLAIR sub-study would have been exposed to LA therapy for a minimum of at least 12 
months (for those starting LA in the extension phase of FLAIR, with LSLV for the Week 
124 endpoint having occurred on 21-FEB-2020) to over three years (those originally 
randomized at the start of FLAIR to the LA arm).  
 
In addition to PK and safety parameters, other important outcome measures to be assessed 
in the FLAIR sub-study include the ability to maintain virologic suppression for 
participants who transition from IM to SC injections as well as several important patient-
reported outcomes including a preference questionnaire that aims to assess participants’ 
preference for SC vs IM injections and reasons for such a preference.  
 
The use of SC injections in the on-going FLAIR study allows an efficient pathway for 
evaluation of the two routes of administration of CAB and RPV LA as alternative 
approaches to injectable HIV treatment. This approach will generate important data to 
inform future development of a patient self-administered option of CAB and RPV LA. 
Therefore, the FLAIR study has been amended to allow an assessment of IM versus SC 
injections for participants who are currently in the extension phase of FLAIR and are 
receiving maintenance dosing of CAB with the 200 mg/mL formulation (2 mL=400 mg) 
along with RPV 300 mg/mL formulation (2 mL=600 mg).    
 
The window period around the administration of SC dosing will be up to 7 days earlier but 
will not allow injections to be given up to one week later.  This is different from what is 
allowed in the FLAIR parent study (-7 to +7 days) and is due to data emerging from an on-
going healthy volunteer study of RPV 300 mg that suggests RPV plasma concentrations in 
the first month after SC administration of RPV LA may be somewhat lower compared to 
historical data for IM administration but still above those observed for the every 2 months 
IM dosing regimen, which has been shown to be efficacious. 
Overall outcomes being measured include PK parameters Ctau, concentrations 1-week post 
dose (~Cmax), and area under the curve [AUC (0-tau)]); safety, tolerability, virologic 
response and various patient reported outcomes including Numerical Rating Scale (NRS); 
HIV Treatment Satisfaction Questionnaire c and s (HIVTSQc and HIVTSQs ); Perception 
of Injection (PIN), a preference questionnaire and various exploratory objectives including  
reasons to switch from IM to SC in HIV-1 infected participants receiving CAB and RPV 
LA administered via SC versus IM injections. 

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12.12.2.1. Data on CAB/RPV Subcutaneous Injection Site Reactions 
The FLAIR SC sub-study will be the first study in HIV-infected individuals and will 
assess the safety, tolerability and various PK parameters after SC administration of 
CAB/RPV for subjects currently enrolled in FLAIR who opt to enroll (after screening in) 
into this sub-study. Several prior Phase 1, healthy volunteer studies have individually 
assessed SC administration of CAB and RPV and have demonstrated overall tolerability 
after SC dosing with the most commonly reported ISRs being pain, erythema and nodular 
formation. These ISRs tended to be self-limited, have been mostly grade 1 and grade 2.  
Specifically, two Phase 1 studies investigated CAB200 mg/mL administered 
subcutaneously, with single and multiple dose studies ranging from 200-400 mL [Spreen 
et al., 2014; Spreen et al., 2014]. A Phase 1 FTIH healthy volunteer study (212482) 
assessed various doses and routes of administration of a 400mg formulation of 
cabotegravir with IM injections administered into the gluteal and thigh muscles and SC 
injections administrated into the anterior abdominal muscle, with up to 1.5 mL of volume 
administered subcutaneously (600mg total dose of CAB 400mg/mL formulation). 
Specific to the SC arm of study 212482, no SAEs were reported with 1/9 participants 
reporting a grade 3 ISR of rednes/erythema leading to withdrawal. Maximum grade ISRs 
for all other SC participants were grade 1 (2/9) and grade 2 (6/9).   
Finally, an ongoing study supported by Janssen (TMC278LAHTX1003) is assessing 3mL 
of the standard RPV formulation (G001 at 300mg/mL) dosed SC. While the study is still 
ongoing, the initial assessment of the ISR data received to date have shown that almost 
all subjects experienced an ISR, although most were grade 1 or 2 with no grade 3 or 
higher ISRs being reported. The majority of these ISRs were classified as erythema, 
induration, pain, swelling or nodules. Given the results from these healthy volunteer 
studies, the sub-study team does not anticipate an ISR profile to be any different in a 
HIV-infected population than what was seen in the healthy volunteer studies detailed 
above. However, since the FLAIR SC sub-study will be the first study to assess SC 
dosing of CAB and RPV in HIV-infected individuals, the study team has developed ISR 
monitoring/pausing criteria (detailed in Section 12.12.4.7) that will be applied in the 
FLAIR sub-study.  
12.12.2.2. ISR Monitoring Criteria Process 
Most ISRs observed in the healthy volunteer studies were either due to erythema, pain, 
induration or nodules.  Therefore, these typical and anticipated ISRs will not be 
considered as part of the criteria that leads to an ISR monitoring/pausing criteria. 
However, the ISR monitoring/pausing criteria will be applied when considering the 
incidence of ISRs of interest following SC dosing of CAB+RPV, detailed in Section 
12.12.4.7.  
After 50% of participants (equating to 25 out of the expected 50) have experienced their 
first SC injection and after the Week 1 follow-up visit an in-stream safety data cut will be 
performed for ISR data including site reports of details of ISRs of interest. The posterior 
probability that the rate of ISRs of interest is > 0.05 will be calculated based on ISRs of 
interest collected through Week 1 for each participant. A target rate of 0.05 was chosen 
as it would be the equivalent of >1 participant out of 25 having an ISR of interest. If the 
Bayesian posterior probability that the true rate of ISRs of interest is >0.05 is low (< 5%), 

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then individual ISRs will undergo standard safety review. However, if the Bayesian 
posterior probability that the true rate of ISRs of interest is >0.05 is high (>5%), then a 
formal review of all ISR safety data will take place by the ViiV Safety and Labeling 
Committee (the VSLC) with the potential consideration to pause SC injections. If 1 or 2 
participants experience an ISR of interest, these individual cases will be assessed and 
discussed with the FLAIR Medical Monitor and the Clinical Development Lead for the 
CAB Treatment Program to determine whether to continue SC dosing for such 
participants. However, if 3 or more participants experience an ISR of interest, this would 
produce a study likelihood rate of 0.12, leading to posterior probability of >5%. Thus, as 
enrollment is staggered by country, if 3 participants experience an ISR of interest prior to 
25 participants reaching the Week 1 visit, VSLC review will automatically be triggered, 
no matter when the ISR of interest occurs. Otherwise, VSLC will only be triggered based 
on the interim posterior probability. An evidence threshold of 5% gives us 95% 
confidence that the true rate of ISRs of interest is not >0.05 should our interim posterior 
probability not trigger a decision to bring forth formal VSLC review.   
Table 24 and Figure 15 below show predictions of our potential to make a decision to 
formally monitor with 95% confidence based on 1000 simulations with 50 participants. 
Likelihood data was simulated based on the binomial distribution with a potential 
response of failure vs non-failure given the various levels of true rate of ISRs of interest. 
A conjugate beta prior with parameters of a=0.001 (# of failures) and b=79 (# of 
successes) was selected based on participant level data from the previous studies 
mentioned and, as no previous ISRs of interest have been noted, a failure count of 0.001 
is being used conservatively for modeling purposes. As seen in Table 24, if the true rate 
of ISRs of interest is 0.05, then we have a 23.3% chance of formal VSLC review while if 
the true rate is 0.08 or higher, we have a >50% chance of formal VSLC review.  

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Figure 15 
Probability of Formal VSLC Review Given the True Rate of ISRs of 
Interest 
 
Note: The vertical reference line indicates the target acceptable rate of ISRs of interest at 
0.05. The horizontal reference line indicates the posterior probability evidence threshold 
of formal VSLC review at 5%.  

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Table 24 
Probability that True Rate of ISRs > 0.05 
 
12.12.3. 
Sub-Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary Endpoint 
Pharmacokinetic  
To evaluate PK of monthly dosing of 
CAB LA (200 mg/mL) with RPV LA 
(300 mg/mL) following SC  
administration in the anterior abdominal 
wall SC tissue  compared with 
intramuscular administration in the 
gluteus medius muscle in HIV-1 infected 
participants currently enrolled in the 
FLAIR Phase 3 study 
Plasma PK parameters for CAB LA 
200 mg/mL and RPV LA 300 mg/mL 
(Ctau, concentrations 1-week post dose 
[~Cmax], and area under the curve [AUC 
(0-tau)]) for SC injections during the SC 
injection phase compared with similar PK 
parameters for gluteal IM injections 
  
Probability that True Rate of ISRs > 0.05 
True Rate of ISRs of 
Interest 
Probability (Rate of ISRs > 0.05) < 5% 
(No VSLC Review) 
Probability (Rate of ISRs > 0.05) > 
5% (VSLC Review) 
0 
100 
0 
0.01 
99.8 
0.2 
0.02 
98.6 
1.4 
0.03 
94.6 
5.4 
0.04 
86.4 
13.6 
0.05 
76.7 
23.3 
0.06 
65.2 
34.8 
0.07 
53.2 
46.8 
0.08 
41.6 
58.4 
0.09 
32.3 
67.7 
0.1 
23 
77 
0.11 
18.7 
81.3 
0.12 
14.2 
85.8 
0.13 
8.1 
91.9 
0.14 
7.1 
92.9 
0.15 
4.4 
95.6 

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Objectives 
Endpoints 
Secondary Endpoints 
Safety and tolerability 
 
To assess safety and tolerability of monthly 
dosing 
of 
CAB 
LA 
(200 mg/mL) 
administered with RPV (300 mg/mL) LA 
following SC administration in the anterior 
abdominal wall SC tissue  compared with 
intramuscular injections in the gluteus 
medius 
muscle 
in 
HIV-1 
infected 
participants currently enrolled in the 
FLAIR Phase 3 study 
 
 
 
To 
assess 
additional 
safety 
events 
including other AEs, SAEs, and safety labs 
of monthly dosing of CAB LA and RPV 
LA following SC injections in the 
abdominal wall SC tissue  in HIV-1 
infected participants currently enrolled in 
the FLAIR sub-study 
Incidence and severity of ISRs and AEs of 
special interest during the SC injection 
phase.  
  
Proportion of participants who discontinue 
treatment due to ISRs and AEs of special 
interest during the SC injection phase. 
 
 
 
Incidence of other AEs not of special 
interest, SAEs and change in laboratory 
parameters from the last IM gluteal 
injection (prior to the SC abdominal 
Injection Phase) to the end of the SC 
injection phase (week 12). 
Virologic Response  
 
To assess the ability to maintain virologic 
suppression (HIV-RNA <50 copies) in 
participants who transition from IM to SC 
administrations of CAB LA (200 mg/mL) 
plus RPV LA (300 mg/mL) in the FLAIR 
sub-study. 
 
 
 
To assess virologic non-response (HIV-
RNA ≥50 c/mL and ≥200 c/mL) in 
participants who transition from IM to SC 
administrations of CAB LA (200 mg/mL) 
Proportion of participants with plasma 
HIV-1 RNA <50 copies at week 12 during 
the SC abdominal injection phase using the 
FDA Snapshot algorithm. 
  
 
 
 
Proportion of participants with plasma 
HIV-RNA ≥50 c/mL as per Food and Drug 
Administration (FDA) Snapshot algorithm 
at week 12 during the SC abdominal 

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Objectives 
Endpoints 
plus RPV LA (300 mg/mL) in the FLAIR 
sub-study. 
 
 
 
injection phase. 
 
  
Proportion of participants with protocol-
defined confirmed virologic failure (CVF) 
of ≥200 c/mL at week 12 during the SC 
injection phase. 
 
To assess viral resistance in participants 
experiencing protocol-defined confirmed 
virologic failure. 
Incidence of treatment emergent genotypic 
and phenotypic resistance to CAB, RPV 
during the SC injection phase. 
 
 
Health Outcomes 
 
To assess patient reported outcomes during 
the SC injection phase by administering the 
following health outcome measurements: 
NRS, HIVTSQ (both s and c versions), and 
PIN. 
Numerical Rating Scale (NRS): To assess 
the tolerability of injections during both the 
SC abdominal and IM Gluteal Injection 
Phases, separate for CAB LA and RPV LA.  
 
HIVTSQ (both s and c versions): To 
measure levels of satisfaction and detect 
change in satisfaction when switching 
from IM gluteal to SC abdominal 
injections in total “treatment satisfaction” 
score, and individual item scores of the 
HIV Treatment Satisfaction Questionnaire 
(HIVTSQ) during the SC Injection Phase 
as well as change from SC during the 
Return to IM Gluteal Phase. 
 
Perception of injection questionnaire 
(PIN): To assess the acceptance of pain 
and injection site reactions following SC 
abdominal and IM gluteal injections 
separate for CAB LA and RPV LA. 

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Objectives 
Endpoints 
 
To assess participant’s preference of SC 
injections during the SC abdominal 
injection phase compared to IM gluteal 
injections. 
Preference Questionnaire: To assess 
patient’s preference, and reasons for 
preference, for injections received during 
the SC Injection Phase compared with 
prior IM gluteal injections as well as for 
injections received during the Return to 
Gluteal phase compared with prior SC 
injections. 
Exploratory 
 
To assess reasons for switch to SC from IM 
injection and interest in a potential option 
for self-administration of SC injections 
Reasons for switch and interest for home 
administration options questions: To assess 
the reasons participants agreed to switch to 
a SC abdominal injection from a IM gluteal 
injection and their interest in a potential 
option for self-administration of SC 
injections. 
 
12.12.4. 
Sub-Study FLAIR Amendment Design 
The FLAIR amendment (sub-study) will consist of three phases including a Screening/IM 
Gluteal injection Phase (T-4 weeks with 1 gluteal injection interval of 4 weeks), a Sub-
Cutaneous Abdominal Injection Phase (12 weeks with 3 injection intervals of 4 weeks 
each) and a Return to Intramuscular Gluteal Injection Phase (8 weeks with 2 injection 
intervals of 4 weeks each). 80 participants will be targeted for enrollment in order to reach 
the 30-50 necessary to assess the primary PK endpoint as well as to achieve a more robust 
safety conclusion. At the conclusion of the sub-study, participants will have the option to 
continue on the FLAIR parent study or if commercial access is available, the participant 
can transition off the sub-study, complete their participation in the FLAIR study and 
proceed directly to commercially sourced CAB/RPV LA treatment.  

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Figure 16 
Sub-Cutaneous Sub-Study Amendment Design (included as part of 
the Parent FLAIR Study) 
 
NOTE: All injection visits during the sub-study should be kept to the same projected visit 
schedule as in the parent study. 
12.12.4.1. Sub-Study Amendment: Inclusion and Exclusion Criteria  
Sub-Study Inclusion Criteria 
7. Capable of giving signed informed consent (Sub-study specific informed consent), 
which includes compliance with the requirements and restrictions listed in the 
consent form and in this protocol.  Eligible participants or their legal guardians (and 
next of kin when locally required), must sign a written Informed Consent Form 
before any protocol-specified assessments are conducted. Enrolment of participants 
who are unable to provide direct informed consent is optional and will be based on 
local legal/regulatory requirements and site feasibility to conduct protocol 
procedures. 
8. Eligible participants must have been on CAB LA + RPV LA regimen for a 
minimum of 12 months while on the FLAIR study. Any disruptions in dosing 
during FLAIR must be discussed with the Medical Monitor for a final 
determination of eligibility into the sub-study.   
9. Plasma HIV-1 RNA <50 c/mL at Sub-Study Screening. 
 
10. History of SARS-COV-2 vaccination (or booster dosing) is allowed prior to sub-
study screening and will be allowed during the conduct of the sub-study as long as 
the vaccine (or boosters) are not administered within 14 days of VL assessments   
 
Sub-Study Exclusion Criteria (at Screening) 
31. More than 1 plasma HIV-1 RNA measurement ≥50 c/mL to <200 c/mL (virologic 
blip) within 24 weeks prior to sub-study Screening visit that was investigated and 
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received within 4 weeks of the viral blip or NOT associated with intercurrent illness 
that developed within 2-4 weeks of the viral blip. 
a. All viral blips that occurred within 24 weeks prior to screening should be 
discussed with the Medical Monitor to assess whether such a participant can 
enrol into the sub-study  
32. Any Suspected Virologic Failure (HIV-RNA ≥200 c/mL) as defined in Section 
5.4.4 during FLAIR study. 
33. Subjects planning to require oral bridging during participation in the FLAIR sub-
study. 
34. The participant has a tattoo or any dermatological condition overlying the 
abdominal or gluteal regions which may interfere with interpretation of injection 
site reactions. 
35. Any condition which, in the opinion of the Investigator, may interfere with the 
absorption, distribution, metabolism or excretion of the study drugs or render the 
participant unable to receive study medication. 
36. Any woman of childbearing potential who is pregnant at screening will be 
excluded from entering the sub-study. 
Additional Exclusion Criteria While on the FLAIR Sub-Study 
37. Any women of childbearing potential who gets pregnant while on the sub-study 
will have to be withdrawn from the sub-study but will be allowed to transition 
back to the parent FLAIR study if a pregnancy specific ICF is signed, and 
commercial access is not available at the time of pregnancy. For more 
information, please refer to Section 12.12.4.10.Additionally, the following entry 
criteria for the FLAIR parent study will also apply to the sub-study:  
The inclusion and exclusion criteria are the same as in the FLAIR parent study but are 
repeated here for data capture considerations. 
 
FLAIR Parent Study – Inclusion Criteria 
AGE 
1. 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  
2. HIV-1 infection as documented by Screening plasma HIV-1 RNA ≥1000 c/mL; 
3. 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. 

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SEX 
4. 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 counselled on safer sexual practices 
including the use and benefit/risk of effective barrier methods (e.g., male condom) and 
on the risk of HIV transmission to an uninfected partner. 
5. INFORMED CONSENT 
5. 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. 
6. OTHER 

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FLAIR Parent Study – Inclusion Criteria 
6. 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. 
 
 
FLAIR Parent Study – Exclusion Criteria 
Exclusionary Medical Conditions  
1. Women who are pregnant, breastfeeding, or plan to become pregnant or breastfeed 
during the study. 
2. 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). 
3. Participants with known moderate to severe hepatic impairment. 
4. Any pre-existing physical or mental condition (including substance abuse disorder) 
which, in the opinion of the Investigator, may interfere with the participant’s ability 
to comply with the dosing schedule and/or protocol evaluations or which may 
compromise the safety of the participant. 
5. 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.  
6. 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. 
7. The participant has a tattoo or other dermatological condition overlying the gluteus 
region which may interfere with interpretation of injection site reactions. 
8. 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. 
9. 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 

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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)) 
10. 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).   
11. History of liver cirrhosis with or without hepatitis viral co-infection. 
12. Ongoing or clinically relevant pancreatitis. 
13. All participants will be screened for syphilis (rapid plasma reagin 
[RPR]).  Participants with untreated syphilis infection, defined as a positive RPR 
without clear documentation of treatment, are excluded.  Participants with a 
positive RPR test who have not been treated may be rescreened at least 30 days 
after completion of antibiotic treatment for syphilis. 
14. 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. 
15. 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. 
16. History or presence of allergy or intolerance to the study drugs or their components 

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FLAIR Parent Study – Exclusion Criteria 
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. 
17. Current or anticipated need for chronic anti-coagulation. 
18. Alanine aminotransferase (ALT) ≥3 times ULN.   
19. 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. 
FLAIR Parent Study – Concomitant Medications  
20. 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. 
21. 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. 
22. Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening. 
23. 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. 
24. Use of medications which are associated with Torsades de Pointes (See SPM for a 
list of relevant medications). 
FLAIR Parent Study – Diagnostic Assessments and Other Criteria 
25. 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. 
26. 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). 
27. Any verified Grade 4 laboratory abnormality.  A single repeat test is allowed 

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during the Screening Phase to verify a result. 
28. Any acute laboratory abnormality at Screening, which, in the opinion of the 
Investigator, would preclude the participant’s participation in the study of an 
investigational compound. 
29. Participant has estimated creatinine clearance <50 mL/min/1.73m2 via the Chronic 
Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (Levey, 2009). 
30. Participation in other interventional studies is generally not permitted, however for 
eligible subjects in South Africa, co-enrolment in the AIDS Clinical Trial Group 
(ACTG) interventional study (A5392) could be exceptionally permitted after 
review and approval by the Medical Monitor. 
 
12.12.4.2. Screening Phase (Gluteal IM) 
During the screening phase for the sub-study, participants will receive an  IM injection 
while being screened for the sub-study. Eligibility criteria must be assessed at the 
Screening Visit and confirmed prior to the first SC injection. Participants who are enrolled 
in the sub-study and subsequently withdraw from the parent FLAIR study for any reason 
may not be re-screened. Screening procedures should occur within 35 days prior to Day 1 
of the first dose in the SC Abdominal Injection Phase.  
After the Screening Visit/Gluteal Injection Visit, participants will need to return to the 
clinic 1 week later to obtain PK sampling as outlined in the Sub-Study Time and Events 
Table in Section 12.12.5. 
12.12.4.3. Sub-Cutaneous Abdominal Injection Phase (12 Weeks) 
After confirming eligibility into the sub-study, participants will enter into the Sub-
Cutaneous Abdominal Injection Phase and receive a sub-cutaneous injection of CAB LA 
(2 mL; 400 mg) and RPV LA (2 mL; 600 mg) at the following visits: 
• Day 1 
• Week 4 
• Week 8 
The window period around the administration of SC dosing will be up to one week earlier 
and will not allow injections to be given up to one week later (-7 days only without the 
allowance of a +7 day dosing window)  
Participants will need to return to the clinic 1 week after each  injection for PK sampling 
as outlined in the Sub-Study Time and Events Table in Section 12.12.5. 
12.12.4.4. Return to Intramuscular Gluteal Injection Phase 
Following 12 weeks of SC injections, participants will return to the clinic to receive an IM 

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gluteal injection of CAB LA (2 mL; 400 mg) and RPV LA (2 mL; 600 mg) at the following 
visits: 
• Week 12 (-7 days) 
• Week 16 (+/-7 days) 
Participants will complete 8 weeks (2 injections cycles) of CAB/RPV LA therapy. After 
the Week 20 pre-dose assessments are obtained (AEs, SAEs and concomitant medications)  
the participant’s participation in the sub-study will have concluded.  
12.12.4.5. Sub-Study Completion 
Participants are considered to have completed the sub-study once the final Week 20 pre-
dose assessments (AEs, SAEs and concomitant medications) are obtained. The IM 
injection and all other assessments will be considered part of the parent study and 
assessments should be completed as per the parent study time and events table in Section 
7.1. 
Depending on the local availability of the marketed product in each country, after the sub-
study is completed, and based on the particular country the participant is enrolled from, 
such participants in:  
• Countries where CAB LA+RPV LA marketed product is not yet locally 
available: Continue in the Extension Phase of the parent study and complete 
study visits as per the Time and Events table in Section 7.1. 
• Countries where CAB LA+RPV LA marketed product is locally available: 
Transition to CAB LA + RPV LA marketed product or an alternative ART as 
indicated below: 
o After the pre-injection assessments are completed at Week 20, the 
participant will receive the last IM gluteal injection as part of the parent  
study. 
o Participant will complete the Safety Follow Up Visit 2-4 weeks after the 
last injections (please refer to Section 5.5 of the protocol) before 
transitioning to a marketed ART.  
Note: If the participant has to withdraw from the study due to safety related reasons once 
CAB LA + RPV LA marketed product is locally available (see Section 5.4) the subjects 
would need to complete a withdrawal visit and enter the Long Term Follow Up Phase (see 
Section 4.2.6.). 
12.12.4.6. Sub-Study Amendment Withdrawal/Stopping Criteria 
Participants meeting Withdrawal/Stopping criteria as per Section 5.4. will discontinue the 
study treatment and be withdrawn from both FLAIR and the sub-study, and will complete 
all assessments per the Time & Events table in Section 7.1. and enter in the Long Term 
Follow-Up Phase. 
Participants who decide to discontinue their participation in the sub-study for non-safety 
reasons (refer to Section 5.5.), including participants who require Oral Bridging during 

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the sub-study or participants who decide to discontinue their participation in the sub-study 
due to injection-site (abdominal) related tolerability reasons:  
• In countries were the marketed products of CAB and RPV LA are not yet locally 
available, such patients will be allowed to transition back to the parent study and 
continue with IM gluteal injections per the randomized dosing schedule. 
• In countries were the marketed products of CAB and RPV LA are locally available: 
patients will be invited to return to gluteal injections in the parent  study and receive 
1 more gluteal injections (additional injections might be required if requested by 
the Medical Monitor) before transitioning to marketed product as described in 
Section 5.5. 
12.12.4.7. Sub-Study Injection Site Reactions 
For IM administrations, injection site reactions (ISRs) should be assessed as per the 
parent study instructions in Section 7.4.1. and Section 7.4.10.10. 
For SC administrations, any participant who experiences an ISR meeting the below 
criteria must be discussed with both the Medical Monitor and the Clinical Development 
Lead for CAB Treatment. These are ISRs of interest and will be included when 
considering the ISR monitoring/pausing criteria, as mentioned in Section 12.12.2.2.: 
• 
A Grade 4 injection site reaction. 
• 
An ISR of at least Grade 3 in severity where the ISR AE includes any of the 
following: 
o Ulceration 
o Secondary infection 
o Phlebitis 
o Sterile abscess 
o Drainage 
 
ISRs that are Grade 3 based upon the size of erythema or induration alone or based upon 
pain or symptoms causing inability to perform usual social & functional activities will be 
not be included for the purpose of the ISR monitoring/pausing criteria but will be 
reviewed and considered when reviewing the ISR data. 
For SC administration, injection site erythema, redness, induration and swelling will be 
assessed by calculating both the length and width of the affected area.  
Any ISR associated with SC administration of CAB/RPV should be followed to 
resolution. 
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 consulted on all participants 

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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. 
 
12.12.4.8. Sub-Study Amendment Specific Virological Failure Guidance 
Refer to Section 5.4.3., Section 5.4.4., and Section 5.4.5. 
12.12.4.9. Sub-Study Amendment HIV-1 RNA Blips Guidance 
Guidance on SVF management can be found in Section 5.4.5.1.  
The Medical Monitor should discuss all cases of viral blips (defined as HIV-1 RNA 
≥50 c/mL and <200 c/mL) with the site PI to assess whether any recent vaccinations were 
administered (within 4 weeks of blip) or any intercurrent illnesses developed (within 2-4 
weeks of the viral blip) that can spuriously elevate viral load. If there are possible 
alternative causes for the viral blip, further guidance will be provided by the Medical 
Monitor in these instances.  
Participants who have an HIV-1 RNA ≥50 c/mL and <200 c/mL during the SC Injection 
Phase of the sub-study, with no alternative cause for the viral blip identified, will need to 
have a repeat viral load assessment 2-4 weeks after the initial viral blip for confirmation.  
If the repeat HIV-1 RNA is confirmed (≥50 c/mL and <200 c/mL) in participants with no 
recent history of vaccinations or intercurrent illnesses, the participant will have to withdraw 
from the SC sub-study and return to IM dosing in the parent study, or, if access is available, 
continue IM dosing via a commercial source.  
If the repeat VL is not confirmed (i.e, HIV-RNA is < 50 c/mL), the participant can continue 
the sub-study.  
If the repeat VL is ≥ 200 c/mL, the participant has achieved a Suspected Virologic Failure 
and see Section 5.4.5.1 for further details 
Participants who have a viral blip (HIV-1 RNA ≥50 c/mL and <200 c/mL) during the IM 
Injection Phase of the sub-study including during the Return to Gluteal Injection Phase, 
see Section 5.4.5.1 of the parent study for further details on the management of HIV-1 
RNA blips.  
12.12.4.10. Sub-Study Amendment Specific Withdrawal Criteria – Pregnancy 
If a subject becomes pregnant during the sub-study, the subject will need to withdraw 
from the sub-study and will have the option to continue with gluteal injections in the 
parent FLAIR study after signing a pregnancy-specific ICF addendum or be withdrawn 
from FLAIR. Please refer to Appendix 10 for additional information.  

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12.12.4.11. Sub-Study Pharmacokinetics Sample Collection 
Table 25 
Sub-study CAB and RPV Plasma Pharmacokinetic Sample Schedule 
Group 
Analytes 
Sample Times Relative to Dose 
Participants 
receiving CAB 
200 mg/mL LA + 
RPV 300 mg/mL 
LA Q4W 
injections 
CAB and RPV 
Pre-Dose: Screening (Week -4), Day 1, Week 
4, Week 8 (SC abdominal injections), Week 
12, Week 16 (IM gluteal injection) 
1 Week Post dose: Week -3, Week 1, Week 5, 
Week 9 (SC abdominal injections), Week 13 
and Week 17 (IM gluteal injections) 
PK window collection: All scheduled PK samples should be collected on the Day of the 
corresponding visit. Pre-dose samples will be taken prior to performing dosing within the 
clinic.   
Additional details concerning handling of PK samples, labelling and shipping directions 
will be supplied in the central laboratory manual. 

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12.12.5. 
Sub-Study Time and Events Table 
Procedures 
Screening Phase d 
SC Abdominal Injection Phase d 
Return to IM Gluteal Injection Phase d  
Screening, 
Week -4 
Week -3 
Day 1 
Week 1 
Week 4 
Week 5 
Week 8 
Week 9 
Week 12 
Week 13 
Week 16 
Week 17 
Week 20 n 
IM Gluteal 
Administration 
X 
 
 
 
 
 
 
 
X k 
 
X  
 
 
SC Abdominal 
Administration k 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
Written 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
Verification  
 
Inclusion / 
Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Symptom 
directed 
physical exam 
and medical 
assessment a 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Height, Weight 
and BMI 
 
 
X 
 
 
 
 
 
X 
 
 
 
 

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Procedures 
Screening Phase d 
SC Abdominal Injection Phase d 
Return to IM Gluteal Injection Phase d  
Screening, 
Week -4 
Week -3 
Day 1 
Week 1 
Week 4 
Week 5 
Week 8 
Week 9 
Week 12 
Week 13 
Week 16 
Week 17 
Week 20 n 
Vital Signs, BP, 
HR, temp b 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12 EKG c 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
HIV associated 
conditions 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AEs, SAEs, 
concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ISR 
assessments 
for IM injections 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
 
ISR 
assessments 
for SC 
injections 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Clinical 
Chemistry and 
Hematology 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Pregnancy 
testing, serum e 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 

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Procedures 
Screening Phase d 
SC Abdominal Injection Phase d 
Return to IM Gluteal Injection Phase d  
Screening, 
Week -4 
Week -3 
Day 1 
Week 1 
Week 4 
Week 5 
Week 8 
Week 9 
Week 12 
Week 13 
Week 16 
Week 17 
Week 20 n 
HIV-1 RNA and 
sample for 
storage (S) 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
CD4+ cell count 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
CD8+ cell count 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Urinalysis f 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
Fasting lab 
assessments: 
glucose, 
cholesterol 
(total, HDL and 
LDL) and 
triglycerides g 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
PK Sample Collection j 
Pre dose PK 
samples for 
CAB and RPV  
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Post dose PK 
sampling 
(~Cmax) 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 

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Procedures 
Screening Phase d 
SC Abdominal Injection Phase d 
Return to IM Gluteal Injection Phase d  
Screening, 
Week -4 
Week -3 
Day 1 
Week 1 
Week 4 
Week 5 
Week 8 
Week 9 
Week 12 
Week 13 
Week 16 
Week 17 
Week 20 n 
PROs m 
HIVTSQC 
 
 
 
 
 
 
 
X 
 
 
 
 
 
HIVTSQS l 
 
X m 
 
 
 
 
 
X 
 
 
 
X 
 
NRS h 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
 
 
 
PIN i 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
Preference SC 
Abdominal 
injection vs IM 
Gluteal injection 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Reason for 
switch 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Interest for 
home 
administration 
 
 
 
 
 
 
 
X 
 
 
 
 
 
a. Physical exams should be conducted as part of normal routine clinical care. 
b. Measure vital signs about 5 minutes of rest in a semi-supine position. 
c. A 12-lead ECG will be performed after resting in a semi-supine position for at least 5 minutes. ECGs will be performed pre-dose. 
d. All injection visits during the sub-study should be kept to the same projected visit schedule as in the parent study. 
e. Women of childbearing potential only. SR = serum, UR = urine. Urine pregnancy test can be performed at study visits where other 

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blood draws are not required in order to limit needle sticks.  
f. A morning specimen is preferred. 
g. An overnight fast is preferred; however, a minimum of a 6-hour fast is acceptable. 
h. Should be collected 30 to 60 minutes post injection. To be assessed separately for CAB LA and RPV LA 
i. To be assessed separately for CAB LA and RPV LA. 
j. PK window allowed for sample collection: For 1-week post dose sample (3 to 10 days post dose). 
k. During the SC phase (and for the first IM injection in the return to IM injection phase), the dosing window can be -7 days, however, it 
cannot be +7 days from the projected visit date. Once SC injections begin, the next SC administration can be 3-4 weeks later, however, 
SC administration may not take place 5 weeks later. See details in Section 12.12.1.2. and Section 12.12.4.3. 
l.  All Patient Reported Outcome Questionnaires/Surveys will be administered via paper instrument (in exception circumstances, the 
questionnaires could be completed via telephonic interview, please refer to the COVID19 appendix for additional details) at the 
beginning of the visit before any other assessments are conducted, with the exception of the NRS. 
m. For HIVTSQS, we want to measure satisfaction with IM gluteal injection prior to switch to sub-cutaneous. This will be assessed at week 
-3 (questionnaire can be administered at any time during the visit). 
n. AEs, SAEs and concomitant medications to be assessed pre-dose. IM administration itself and all other assessments will be 
considered part of the parent study, and should be completed as per the parent study time and events table in Section 7.1. 
 

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12.12.6. 
Sub-Study Health Outcomes Questionnaires 
12.12.6.1. Sub-Study: Value Evidence and Outcomes 
Health outcomes assessments will be conducted according to the Time and Events Table 
(Section 12.12.5.). Assessments are recommended to be administered with a paper 
instrument at the beginning of the visit (except for NRS which is performed after the 
injections) prior to collection of blood for analysis and other scheduled assessments. There 
will be five health outcome measurements that will be administered during the sub-study 
including Numerical Rating Scale (NRS), HIVTSQc, HIVTSQs, PIN, and a Preference 
questionnaire. 
12.12.6.2. Numerical Rating Scale (NRS) 
A numeric rating scale was used to assess the level of pain experienced following SC vs 
IM injections with CAB + RPV. The scale contains one item, and the response scale is 
ranging from 0= “no pain” to 10= “extreme pain”. The NRS was used to assess 
maximum level of pain on the day of the injection as well as maximum level of pain one 
week following injection. NRS questionnaires should be collected 30 to 60 minutes post 
injection. 
12.12.6.3. HIV Treatment Satisfaction Questionnaire (HIVTSQ) 
HIVTSQ is a self-completion measure specifically designed to measure treatment 
satisfaction in PLHIV. It explores multiple aspects of treatment satisfaction including side 
effects, treatment demands, convenience, flexibility and understanding of HIV.  
There are two versions of this questionnaire: HIVTSQs and HIVTSQc.  
HIVTSQs (status version) is needed to measure absolute level of satisfaction while the 
HIVTSQ change version (HIVTSQc) was developed to overcome ceiling effects associated 
with HIVTSQs and enhance sensitivity to change by allowing those who were optimally 
(or close to optimally) satisfied at baseline to express even greater satisfaction at follow 
up. The HIVTSQc (change version) is assessing the change in patients’ satisfaction 
between their previous and their current treatment within the same group.  
Total score for HIVTSQs ranges from 0-66. Higher scores indicate a greater satisfaction 
and a lower score indicate dissatisfaction. Individual scores range from 0-6.  
HIVTSQc total score ranges from -33 to 33. A higher score indicate improvement in 
satisfaction with treatment; lower scores indicate a greater deterioration in satisfaction with 
treatment; a score of 0 represents no change. Individual items scores range from -3 to 3 (-
3= much less satisfied now, 3= much more satisfied now). 
12.12.6.4. Perception of Injection (PIN) 
The Perception of Injection (PIN) questionnaire explores the bother of pain at the injection 
site and ISR, anxiety before and after injection (SC vs IM), 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 

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with receiving injections. The PIN questionnaire was derived from the Vaccines' 
Perception of Injection (VAPI) questionnaire (Chevat, 2009), and adapted for HIV-infected 
patients who will receive the CAB LA and RPV LA regimen. This measure contains 21 
items that measure pain at injection site, local site reactions, impact on functioning and 
willingness to pursue injectable treatment outside of a clinical trial. Scores range from 1 to 
5, and questions are phrased in such a way as to ensure that 1 always equated with the most 
favourable perception of vaccination, and 5 the most unfavourable. 
12.12.6.5. Preference Questionnaire 
A preference question was used to assess patients’ preference, and reasons for preference, 
for the SC abdominal injections compared with IM gluteal injections. The “Preference” 
questionnaire will include a single item question evaluating preference of HIV treatment 
and the attributes supporting this preference. 
12.12.6.6. Reason for switch questionnaire. 
A single item question will be used to assess reasons participants agreed to switch to a SC 
injection from their current IM injection at screening.  
12.12.6.7. Interest in potential self-administration option 
A single item question will be used to assess participants interest in potential upcoming 
option for self-administering the SC injection. Response options will be evaluated using a 
likert scale ranging from: “Not at all interested” to “Extremely interested”. 
12.12.7. 
Sub-Study Treatment 
12.12.7.1. Sub-Study Amendment: Investigational product and Other Study 
Treatment 
Please refer to Section 6.1.3. Cabotegravir Injectable Suspension (CAB LA) and Section 
6.1.4. Rilpivirine Injectable Suspension (RPV LA) included in the main FLAIR protocol. 
12.12.7.2. Sub-Study Dosage and Administration 
NOTE: All injection visits during the sub-study should be kept to the same projected visit 
schedule as in the parent study. 
Participants who enter into the SC Abdominal Injection Phase will receive a SC injection 
of CAB LA (2 mL; 400 mg) and RPV LA (2 mL; 600 mg) on Day 1. Subsequent SC 
injections with CAB LA 400 mg (2 mL) and RPV LA 600 mg (2 mL) will occur every 4 
weeks (-7 days).  Participants who receive SC injections for a total of 12 weeks during the 
SC Abdominal Injection Phase will return to the clinic 4 weeks later (-7 days) to receive 
their first IM gluteal injections (at Week 12) of CAB LA (2 mL; 400 mg) and RPV LA 
(2 mL; 600 mg) during the Return to Gluteal Injection Phase. The subsequent gluteal 
injection with CAB LA 400 mg (2 mL) and RPV LA 600 mg (2 mL) will occur 4 weeks 
later (±-7 days) at Week 16. Gluteal injections and all assessments administered at the 
Week 20 visit will be considered part of the parent study.  

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The interval between injection visits will be limited to a maximum of 4 weeks during the 
SC Abdominal Injection Phase, and 5 weeks during the Return to Gluteal Injection Phase. 
The Medical Monitor must be contacted to discuss individual participant case management 
if the length of time between injections exceeds or is projected to exceed these intervals.  
During both the SC Abdominal Injection Phase and the Return to Gluteal Injection Phase, 
CAB injections should be given on the left side of the body and RPV injections should be 
given on the right side of the body.  
12.12.7.3. Oral Bridging During the Sub-Study 
Oral bridging will not be allowed during the sub-study as it will interfere with data 
interpretation in the SC injection phase. If oral bridging is needed for any reason, the 
participant must be withdrawn from the sub-study and either continue onto the parent 
FLAIR study or transition to commercial drug supply if locally available. 
12.12.8. 
Sub-Study Data Management 
Please refer to Section 8. 
12.12.9. 
Sub-Study Statistical Considerations and Data Analyses 
12.12.9.1. Statistical Hypotheses 
The primary objective of this sub-study is to evaluate the pharmacokinetics of cabotegravir 
LA (200 mg/mL) and rilpivirine (RPV) LA (300 mg/mL) for monthly dosing as a SC 
injection in the anterior abdominal muscle versus an IM injection into the gluteal muscle 
in HIV-1 infected participants currently enrolled in the FLAIR study. 
An estimation approach will be taken and point estimates and confidence intervals will be 
constructed for the ratio of the geometric mean of SC abdominal injection PK parameters 
to the geometric mean of the IM gluteal injection PK parameters. 
12.12.9.2. Sample Size Considerations 
The sample size of 30-50 subjects is deemed sufficient to evaluate the geometric mean ratio 
(SC abdominal injection vs IM gluteal injection) of PK parameters and to assess the safety, 
tolerability, virologic responses and patient reported outcomes during 12 weeks of the SC 
abdominal injection phase.  
Although a larger sample size is not needed solely to assess the various PK parameters, 
the larger sample size of 30-50 will allow a more robust analysis regarding the safety of 
CAB/RPV when administered subcutaneously. Additionally, the larger sample size will 
provide more insight into subgroup analyses for safety, allowing for a higher likelihood 
of having more than a few participants in a certain age or BMI category.   
Sample size calculations assume the treatment ratio is 1 with confidence intervals within 
0.8-1.25 and a steady state concentration coefficient of variation of 0.4. Assuming 40 
participants, a CV of 0.4, and power of at least 80%, and a true ratio of 1 we would expect 
a 90% confidence interval of approximately (0.831, 1.203) on the original scale. 

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Power 
Total N  
Alpha 
0.70668 
30 
0.05 
0.81565 
40 
0.05 
0.82340 
30 
0.1 
0.89981 
40 
0.1 
12.12.9.3. Sub-Study Analysis Populations 
The Enrolled Population will consist of all participants who sign informed consent into the 
sub-study, excluding screen failures.  
The Safety Population will consist of all enrolled participants who receive at least one SC 
injection. This population will be used to summarize safety, virologic response , and health 
outcomes endpoints. 
The Pharmacokinetic Concentration (PC) Population will consist of all participants who 
received at least one CAB and/or RPV SC injection and provide at least one non-missing 
CAB and/or RPV plasma concentration value during the sub-study.  
The Pharmacokinetic Parameter (PP) Population will consist of all participants who 
received at least one CAB and/or RPV SC injection and have at least one evaluable PK 
parameter estimated. PK samples that may be affected by protocol deviations will be 
reviewed by the study team to determine whether or not the sample will be excluded.  
12.12.9.4. Primary Analysis 
The primary analysis is to compare the abdominal SC injection with  gluteal IM injection 
using the ratio of the geometric mean of SC injection to the geometric mean of IM injection 
for a PK parameter within each analyte (CAB, RPV). The primary PK parameters of 
interest include concentrations at the end of the dosing interval [Ctau], concentrations 1-
week post dose [~Cmax], and area under the curve for the dosing interval [AUC (0-tau)] 
(Table 25).  CAB and RPV concentrations and parameters will be summarized 
descriptively.  No formal bioequivalence testing will be performed.  
 
Following log-transformation, Cmax, Ctau and AUC(0-tau) will be separately analyzed by 
analyte using a mixed effects model with fixed effect term for type of injection (SC, gluteal) 
and and BMI (≥30 Kg/m2, <30 Kg/m2) in addition to a random effect term for subject. As 
it is suspected that varying participant BMI may impact the PK concentration distribution, 
BMI is being included in the model as a covariate to control for any potential impact 
beyond the effect of injection type. In each model, only participants with PK parameter 
estimates from corresponding both SC and gluteal injections are included. For example, in 
the model for comparing Cmax between the first CAB SC injection vs gluteal CAB 
injection, only participants with Cmax estimates from both first CAB SC injection and CAB 
gluteal injection are included.  
 

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Point estimates and their associated 90% confidence intervals will be constructed for the 
differences between the SC injection and the gluteal injection. The point estimates and their 
associated 90% confidence intervals from the log-transformed analysis will then be back-
transformed to provide point estimates and 90% confidence intervals for the ratios between 
the SC injection and the gluteal injection on the original scale. This analysis will be 
performed using the PK Parameter (PP) population.  
Slope of the Ctau  following the last IM through 3rd SC injection will also be determined 
in an attempt to assess changes in steady state conditions established previously.   
Table 26 
Parameters and dosing 
Parameters (CAB 
200mg/mL + 
RPV 300mg/mL) 
Q Monthly Dosing  
Cmax (1-week 
post injection), 
Ctau (end of 
dosing interval) 
AUC(0-tau) 
SC Injection 1: 
gluteal injection 
SC Injection 2: 
gluteal injection 
 
SC Injection 3: 
gluteal injection 
 
12.12.9.5. Secondary and Exploratory Analyses 
The proportion of participants with HIV-1 RNA ≥50 c/mL and HIV-1 RNA <50 c/mL at 
Week 12 of the SC injection phase will be summarized using FDA Snapshot algorithm for 
the Safety population in the sub-study. Proportion of participants with protocol-defined 
confirmed virologic failures at Week 12 will also be summarized. 
 
The proportion of participants reporting AEs will be tabulated for each injection type. 
The following summaries of AEs will be provided: 
• Incidence and severity of ISRs and AEs of special interest during the SC injection phase 
• Proportion of participants who discontinue treatment due to ISRs and proportion of AEs 
of special interest during the SC injection phase 
• Incidence and severity of AEs not of special interest 
• Incidence of SAEs 
• Change from baseline (latest non-missing value prior to the first SC injection) 
in laboratory parameters will be summarized by visit through the end of the SC phase. 
• The incidence of observed genotypic and phenotypic resistance to NRTIs and INIs, PIs, 
and NNRTIs will be summarized for subjects meeting confirmed virologic failure criteria. 
 
The health outcomes analyses include analyses of data collected from the following 
questionnaires, HIVTSQ (both s and c versions), NRS, PIN, and Preference between SC 
and gluteal injections. The reasons for switch to SC from IM injections will be assessed, 
as well as the interest in a potential option for self-administration of SC injections. Further 
details will be provided in the RAP. Health Outcomes assessments will be summarized, 

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where applicable, by study drug (CAB and RPV), domain, and item.  
 
12.12.9.6. Sub-Study Interim Analysis 1: ISR Monitoring/Pausing Criteria 
As mentioned in Section 12.12.2.2. an early interim analysis (Interim Analysis 1) will 
take place to assess the rate of ISRs of interest after 50% of participants (equating to 25 
out of the expected 50) have experienced their first SC injection with a follow-up Week 
1. An in-stream safety data cut will be performed for ISR data including site reports of 
details of ISRs of interest. The posterior probability that the rate of ISRs of interest being 
>0.05 will be calculated based on ISRs of interest collected through Week 1 for each 
participant. A target rate of 0.05 was chosen as it would be the equivalent of >1 
participant out of 25 having an ISR of interest. If the Bayesian posterior probability that 
the true rate of ISRs of interest is >0.05 is low (< 5%), then individual ISRs will undergo 
standard safety review. However, if the Bayesian posterior probability that the true rate of 
ISRs of interest is >0.05 is high ( >5%), then a formal review of all ISR safety data will 
take place by the VSLC with the potential consideration to pause SC injections. As 
enrollment will be staggered by country, if 3 participants experience an ISR of interest 
prior to 25 participants reaching the Week 1 visit, VSLC review will automatically be 
triggered as 3 out of 25, or a sub-study rate of 0.12, would lead to the posterior 
probability of the rate of ISRs of interest >0.05 being >5%. Otherwise, VSLC will only 
be triggered based on the interim posterior probability. An evidence threshold of 5% 
gives us 95% confidence that the true rate of ISRs of interest is not >0.05 should our 
interim posterior probability not trigger a decision to bring forth formal VSLC review.  If 
1 or 2 participants experience an ISR of interest, these individual cases will be assessed 
and discussed with the FLAIR Medical Monitor and the Clinical Development Lead for 
the CAB Treatment Program to determine whether to continue SC dosing for such 
participants.  
 
12.12.9.7. Sub-Study Interim Analysis 2: Week 9 Safety and PRO Review 
A second interim analysis (Interim Analysis 2) will focus on safety, tolerability and 
selected PROs and will not include PK related analyses. The interim analysis will allow 
for an early assessment of the main safety parameters (ISR type and rate; AEs/SAEs, 
safety related labs including eGFR, ALT, AST, total bilirubin, haematology, and basic 
chemistry) and PROs (preference and NRS) being assessed in the sub-study. 
Interim Analysis 2 will take place when 50% of enrolled participants have completed 
their sub-study Week 9 visit. The analysis will consist of an internal review of key 
safety/tolerability and preference endpoints in order to assist in compound development. 
No formal stopping decisions will be made. No formal data cleaning activities will occur. 
Data will be processed instream with what is available at the time of the data cut. Queries 
will be issued as needed. 
12.12.10. Sub-Study Pharmacokinetics 
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacology 
Modeling & Simulation Department (CPMS), GSK. Individual Plasma CAB and RPV 

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concentration-time data will be analyzed by non-compartmental methods with WinNonlin 
5.2 or higher. Calculations will be based on the actual sampling times recorded during the 
study.  The following pharmacokinetic parameters will be determined for each interval, as 
data permit: maximum concentration (Cmax), time to Cmax (tmax), area under the plasma 
concentration-time curve through the end of the dosing interval (AUC(0-tau), and 
concentration at the end of the dosing interval (Ct).  
 
Plasma concentration data will be summarized descriptively by analyte and injection type 
and presented in graphical and/or tabular form.  Parameters will be summarized by analyte 
and injection type, Cmax, AUC (0-tau) and Ct treatment comparisons (seeTable 25); tmax 
will not be compared statistically.  All pharmacokinetic data (both CAB and RPV) will be 
stored in the Archives, GSK Pharmaceuticals, R&D.  Additional analyses including 
modelling, simulation and external validation may be performed to assist in the clinical 
interpretation of these data and will be reported separately. 
12.12.11. References 
Chevat C, Viala-Danten M, Dias-Barbosa C, Nguyen VH. Development and 
psychometric validation of a self-administered questionnaire assessing the acceptance of 
influenza vaccination: the Vaccinees' Perception of Injection (VAPI©) questionnaire. 
Health Qual Life Outcomes. 2009;7:21. 
ClinicalTrials.gov Identifier: NCT05112939 (Study CR109089). A Phase 1, Single-blind, 
Randomized, Parallel-group Study in Healthy Participants to Investigate the Single-dose 
Pharmacokinetics, Safety and Tolerability of Rilpivirine After Subcutaneous 
Administration of a Rilpivirine Extended-Release Suspension Alone, and of Rilpivirine 
and Cabotegravir After Co-administration With Cabotegravir Extended-Release 
Suspension. Available at: https://clinicaltrials.gov/ct2/show/NCT05112939. 
Orkin C, Arasteh K, Górgolas Hernández-Mora M, Pokrovsky V, Overton ET, Girard 
PM, et al. Long-acting cabotegravir and rilpivirine after oral induction for HIV-1 
infection. N Engl J Med. 2020;382(12):1124-35. 
Spreen W, PharmD; Ford Susan L, PharmD; Chen Shuguang, PhD; Wilfret DMD; 
Margolis D, MD; Gould E, BS; and Piscitelli Stephen, PharmD. GSK1265744 
Pharmacokinetics in Plasma and Tissue After Single-Dose Long-Acting Injectable 
Administration in Healthy Subjects. J Acquir Immune Defic Syndr 2014;67:481–486 
Spreen W, PharmD; Williams Peter, PhD; Margolis D, MD; Ford Susan L, PharmD; 
Crauwels Herta, PhD; Lou Yu, MS; Gould Elizabeth, BS; Stevens Marita, MD; and 
Piscitelli Stephen, PharmD. Pharmacokinetics, Safety, and Tolerability with Repeat 
Doses of GSK1265744 and Rilpivirine (TMC278) Long-Acting Nanosuspensions in 
Healthy Adults. J Acquir Immune Defic Syndr _ Volume 67, Number 5, December 15, 
2014; 67:487-492 
Verloes, R vanÔt Klooster G; Baert L; van Velsen F; Bouche M-P; Spittaels K; 
Leempoels J;Williams P; Kraus G; Wigerinck, P. TMC278 long acting - a parenteral 
nanosuspension formulation that provides sustained clinically relevant plasma 
concentrations in HIV-negative volunteers. XVII International AIDS Conference, Mexico 

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City, Mexico, 3-8 August 2008 
12.13. 
Appendix 13: Mitigation for Geopolitical Situation in 
Russia/Ukraine 
Background 
Due the geopolitical situation between Russia and Ukraine there is potential for there to 
be significant logistical challenges for many clinical sites within Russia with risk of 
restrictions being placed on site resources, operations, and on an individual participants 
ability to attend clinic visits.  
Based on these challenges, it may be necessary to adopt additional measures and 
procedures to protect participant safety, and to ensure that there are no gaps in HIV-1 
treatment for participants enrolled in this clinical study, through continuous access to 
antiretroviral therapy. 
This appendix outlines the measures which are approved for implementation within this 
clinical trial, to protect patient safety and to ensure the integrity of the clinical trial, as a 
result of the geopolitical crisis. These measures may be implemented in accordance with 
requirements and expectations set out by local Independent Review Boards/Independent 
Ethics Committees (IRB/IEC) and National Competent Authorities (NCA), as necessary. 
12.13.1. Changes to Study Visits and Study Procedures  
• Where site staff resources is constrained due to the geopolitical situation, IM 
dosing visits may proceed with limited or no other protocol defined assessments 
(e.g lab tests, questionnaires, etc.). If lab tests will be missed for more than one 
consecutive visit, the medical monitor must be contacted, to provide guidance for 
safety monitoring.  
• For WOCBP, point of care pregnancy testing should be performed, prior to IM 
dosing. 
• If central laboratory testing cannot be performed at a particular visit, and 
monitoring for safety is required, tests may be performed at an appropriately 
authorised/accredited local laboratory (or other relevant clinical facility). The site 
should proactively inform the sponsor about such instances. Local laboratory 
results may be used to inform safety decisions. Results should be retained in 
source records. Please refer to the Q2 MEMO sent 03 Mar 2022 for additional 
guidance 
• When on-site visits are reduced, it is important that the investigator continue 
collecting relevant clinical information, including adverse events, from the 
participant through alternative means, e.g. by telephone contact. 
• There may also be circumstances where immediate actions are required by the 
sponsor and/or investigator, outside of what is contemplated in the protocol, in 
order to protect a study participant from immediate hazard. Any such measures 
will be carefully documented and conducted in accordance with the National 
Competent Authority (NCA)/IRB/IEC regulations. 

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12.13.2. Changes to Informed Consent  
Informed consent should continue per normal procedure and as described in the main 
body of the protocol, to the extent possible. However, there may be circumstances where 
re-consent of participants is needed, and a physical signature on site is not possible. In 
these cases, alternative ways of obtaining such re-consent should be considered, such as 
the participant sending a picture of his/her written consent to the investigator, or the 
investigator contacting the participant by telephone or video call and obtaining verbal 
consent, supplemented with email confirmation.   
Any updated informed consent form or other subject-facing materials should be provided 
to participants by e-mail, mail or courier before re-consent is obtained. Any consent 
obtained this way should be documented in source records and confirmed by way of 
normal consent procedure at the earliest opportunity when participants attend their next 
on-site study visit. 
Any alternative informed consent procedure must be undertaken only after site 
IRB/Ethics Committee agreement and approval. 
 
12.13.3. 
Permissible Use of Antiretroviral Therapy  
In order to minimize the risk of gaps in HIV-1 antiretroviral therapy (ART) for 
participants impacted by the geopolitical situation in the clinical trial, the following 
options can be considered with regards to ART dosing:  
If a participant is not able to attend an IM injection visit due to geopolitical related 
restrictions, the gap in IM dosing should be covered with oral ART, until IM dosing can 
resume. Participants should be reminded of the importance of adhering with daily oral 
dosing. Two options can be approved for oral bridging therapy in consultation with the 
Medical Monitor.  
 
1. Oral CAB + RPV  
a. Investigator should request availability of oral CAB + RPV supplies OR ,  
2. Oral standard of care (SOC) commercial ART (prescribed locally) 
 
Oral bridging with CAB + RPV 
The protocol permits oral bridging to cover planned missed injections with oral CAB + 
RPV, only until IM dosing can be resumed.  The start date of oral bridging should be 
within the dosing window for the missed IM dosing visit. This recommendation can be 
used to accommodate requests for oral dosing due to the geopolitical situation. Oral 
bridging recommendations should be followed as per protocol Section 6.8.1. The process 
and required information for requesting oral bridging can be found in your Study 
Reference Manual.  Please continue to reach out to your study medical monitor for 
approval of oral bridging, in order to document use and to ensure expeditious shipment of 
oral CAB + RPV to your site.  

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Participants who use oral CAB + RPV as short-term oral bridging are permitted to return 
to IM dosing, on protocol, once the geopolitical situation permits resumption of site 
activities.  
The investigator should reach out to the medical monitor to confirm IM restart 
instructions, and to ensure the participant remains appropriate for resumption of IM 
dosing. If oral bridging with CAB/RPV is anticipated to continue for > 2 months, 
additional approval and guidance should be obtained from the medical monitor to 
continue with oral bridging therapy. Loading/Re-initiation doses of CAB + RPV IM may 
be required, depending on the length of oral bridging. 
Oral bridging with Standard of Care Antiretroviral Therapy (SOC ART) 
For participants impacted by the  logistic issues, where the participant is unable to receive 
IM injections,  oral  bridging with either oral CAB/RPV or SOC ART guideline-
recommended, SOC ART regimen is permitted. The start date of oral bridging should be 
within the dosing window for the missed IM dosing visit.  Please reach out to your study 
medical monitor for approval of SOC ART as oral bridging, in order to document the use 
of commercially available SOC ART within the study.  In order to assure that participants 
have access to SOC ART during short-term oral bridging, GSK may allow for 
reimbursement of SOC ART or copayments as needed. 
Participants who use oral SOC ART as short-term oral bridging as a result of the 
geopolitical situation will not be considered formally withdrawn insofar as they wish to 
continue on the study.  Individuals who bridge with SOC ART will be permitted to return 
to IM dosing, on study, once the geopolitical situation permits resumption of site 
activities.   
The investigator should reach out to the medical monitor to confirm IM restart 
instructions, and to ensure the participant remains appropriate for resumption of IM 
dosing. If oral bridging with SOC ART is anticipated to continue for > 2 months, 
additional approval and guidance should be obtained from the medical monitor to 
continue with oral bridging therapy.  Loading/Re-initiation doses of CAB + RPV IM may 
be required, depending on the length of oral bridging. 
12.13.4. 
Direct To Patient (DTP) Shipments of Oral Study IP  
If a participant is unable to travel to the clinic, either to receive IM injections or to be 
dispensed oral bridging, sites are encouraged to consider DTP shipments of drug, from 
the site, to the participant, to ensure access to medicines.  
• If the study site is considering DTP shipment of oral CAB + RPV investigational 
product (IP), the site must first verify if DTP IP dispensing by 
investigators/hospital pharmacies is locally permitted and whether it requires 
regulatory and/or local ethics pre-approval, or post-hoc notification. 
• The study participant should express his/her agreement for DTP shipment and the 
sharing of their personal information with any third-party couriers (as applicable), 
in accordance with local requirements.  This agreement should be documented in 

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source records. 
• Oral CAB + RPV IP can be shipped at ambient temperatures via ground transport 
without a temperature monitoring device, with low risk of temperature excursions. 
Sites are encouraged to use discretion in determining the need for in-transit 
temperature monitoring based on the labelled storage requirements and the 
planned mode of transport and apply this as appropriate.  Shipment of oral CAB + 
RPV via air courier continues to require appropriate temperature monitoring.  For 
shipment conditions of oral medications other than oral CAB + RPV, please 
consult the product labelling. 
• In all cases IP accountability must be maintained, and all DTP dispensing 
documentation should be reflected in source records and dispensing logs per GCP. 
Please refer to your CRA or local study manager for support with the DTP process, 
ensuring reference to current sponsor guidance and arrangement of a courier that can 
support shipment of IMP directly to participants. 
12.14. 
Appendix 14:  Protocol Amendments 
12.14.1. 
Amendment 01 (All Countries) 
12.14.1.1. 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 

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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’. 
12.14.1.2. 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 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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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 
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) 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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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 
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). 

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Objectives 
Endpoints 
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). 
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 

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Objectives 
Endpoints 
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 
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 

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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. 
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. 

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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 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.   

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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.   
 
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.  
 

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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.  
 
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 
• Alternative oral 
HAART regimens will 
be prescribed within 
four weeks after 
participants stop RPV 
LA.  This would be 
anticipated to result in 
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some participants 
[McGowan, 2016].   
 
 
Participants discontinuing 
a LA regimen may be at 
risk for developing 
resistance to RPV many 
weeks after discontinuing 
injectable therapy. 
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. 
 
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. 

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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. 
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. 

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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’. 
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 
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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. 
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. 
 
 

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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. 
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. 

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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 
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.   

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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. 
 
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, 

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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 
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. 

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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. 
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 

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• 
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) 
• 
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. 

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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 
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 
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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. 
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 

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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 
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: 
d. 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: 
e. 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. 

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Section 7.9 Value Evidence and Outcomes 
Rationale:  Added option of paper instrument collection if needed, and clarified timing 
of NRS assessment: 
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). 

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• 
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). 
• 
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 

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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.  
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”. 

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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. 
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 

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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. 
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). 
12.14.2. 
Amendment 02 (All Countries) 
Protocol changes for Amendment 02 (19-JUL-2017), from amendment 01 (13-DEC-
2016) 
12.14.2.1. 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 
participants are randomized]), and investigator brochure references updated, references 

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added. 
12.14.2.2. 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 
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 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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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. 
Section 4.6.1. Risk Assessment; Table, Study Procedures 
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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 
Phase at Day 1, one switch to an alternate approved background NRTI therapy is 
allowed for toxicity or tolerability management.   

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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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12.14.2.3. 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): 
12.14.3. 
Amendment 03 (All Countries) 
Protocol changes for Amendment 03 (25-JUN-2018), from amendment 02 (19-JUL-
2017) 
12.14.3.1. 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. 
 
Additionally, clarifications were provided for the following: 
• the DTG IB should be referenced for additional risks, safety information, drug 
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• ‘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. 
 
12.14.3.2. 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). 
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 
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 

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tube defects compared to a background 
rate of 0.1%. 
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. 
 
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 
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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. 
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.  

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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. 
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. 

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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. 
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 

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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. 
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. 

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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. 
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” 
 

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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” 
 
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. 
12.14.3.3. Administrative Corrections (e.g., Updated References) 
Section 11:  References 
Original Text: 
Edurant Prescribing Information, August 2015. 

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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. 
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. 
12.14.4. 
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. 
12.14.4.1. 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 

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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. 
12.14.4.2. 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. 
• Incidence of treatment emergent genotypic 
and phenotypic resistance to CAB and 
RPV in over time. 
• Absolute values and change from Baseline 

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Exploratory 
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. 
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. 

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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]) 
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

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Revised Text: 
 
1.  
 
¥Subjects who withdraw from IM CAB LA + RPV LA must enter the 52 week Long Term Follow-Up 
Phase. 
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 

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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. 
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 

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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. 
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 

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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) 
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 

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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.   
 
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, 

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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 
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 

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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: 
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.   

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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 
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. 
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 

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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: 
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 5.2will 
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 5.4.1 of this protocol. Participants will be 
withdrawn from CAB treatment where no 
compelling alternative cause is identified and DILI 

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Potential Risk of 
Clinical 
Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
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. 
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, erythema, swelling, induration, or 

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Potential Risk of 
Clinical 
Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
no clinically significant complications were 
reported. 
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 5.2will 
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 
5.4.1 of this protocol. Participants will be 

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Clinical 
Significance 
Summary of Data/Rationale for Risk  
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 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’ 
• 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 

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Clinical 
Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
withdrawal. 
None of the ISRs reported to date was serious and 
no clinically significant complications were 
reported. 
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, 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 

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Clinical 
Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
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 
 
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 
• 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 

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Summary of Data/Rationale for Risk  
Mitigation Strategy 
tolerated and have not to date been 
associated with an excess of participants’ 
withdrawal due to ISRs. 
None of the ISRs was serious and no 
clinical significant complications were 
reported. 
 
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 
RPV containing regimens.  While some 
skin reactions were accompanied by 
• 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. 

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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
constitutional symptoms such as fever, 
other skin reactions were associated with 
organ dysfunctions, including elevations in 
hepatic serum biochemistries. 
 
• 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. 
 
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 
• Administration advice to minimize 
risk of poor administration 
technique giving rise to injection 
site reactions.  Advice on care, 
monitoring, natural course, and 

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Summary of Data/Rationale for Risk  
Mitigation Strategy 
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. 
 
 
treatment of ISRs given in study 
documentation. 
• Advice to participants on care of 
injection site on day/days 
immediately post administration, 
use of analgesia, compresses where 
appropriate. 
• Participants will be closely 
monitored for ISRs particularly for 
signs of pain, tenderness, infections, 
erythema, swelling, induration, or 
nodules (granulomas or cysts) 
throughout the study.   
• Complications of ISRs such as 
infections (abscess, cellulitis) and 
collections of fluid requiring 
drainage will be monitored. 
• 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).  
• 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 

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Summary of Data/Rationale for Risk  
Mitigation Strategy 
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. 
 
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 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 

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Summary of Data/Rationale for Risk  
Mitigation Strategy 
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  
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: 

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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 
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 
 
 

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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.   
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:   

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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. 
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.   

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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. 
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 
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, 

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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. 
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 
1. 
PK visit window and sample collection: Pre-dose visits (from projected visit date): ±3 days (1st injection), 

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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.   
 
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 
k. 
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 
and without oral lead-in. Participants will be assessed according to actual treatment 

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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 
primary efficacy endpoint of interest for this analysis is the proportion of 

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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].   
7. 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.  
12.14.5. 
Amendment 05 (All Countries) 
Protocol changes for Amendment 05 (20-MAY-2020), from Amendment 04 (24-SEP-
2018).   
12.14.5.1. 
Protocol Amendment Rationale 
The reason for protocol amendment 05 is to include an Appendix with Covid-19 
guidance for clinical trial continuity (participant and study management) during the 
pandemic.  This appendix will replace the previous Appendix 9, and Appendix 9 
“Protocol Amendment History,” will be included as Appendix 10.  
 
12.14.5.2. Protocol Changes/Clarifications 
Section 4.2.7., Section 6.6., Section 6.8., Section 6.8.1., Section 7.0., Section 7.4.3., 
Section 8.0. 
Rationale for change:  Addition of text cross referencing Covid-19 Appendix 9.  
New Text: 
Please refer to Appendix 9 in Section 12.9 for study management information 
during the COVID-19 pandemic. 
Section 12.9. Appendix 9:  COVID-19 Pandemic and Clinical Trial Continuity 
Rationale for change:  To ensure clinical trial continuity added as Appendix 9. 
New Text: 
Background 
The COVID-19 pandemic presents significant logistical challenges for many clinical sites 
around the world, with variable restrictions being placed on site resources and operations, 
and on an individual participants ability to attend clinic visits.  In some places, medical 
visits are occurring, and in others, research clinics are operating with only emergency 

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staff. 
Based on these challenges, it may be necessary to adopt additional measures and 
procedures to protect participant safety, and to ensure that there are no gaps in HIV-1 
treatment for participants enrolled in this clinical study, through continuous access to 
antiretroviral therapy. 
In order to maintain the scientific integrity of the study, and adhere to updated guidance 
from regulators, procedures have also been put into place to ensure that the actions taken 
to mitigate against any impact of COVID-19 are well documented in the trial database. 
A “Memo to Investigators” was issued on March 18th, 2020 and served as a record of 
approved emergency actions being taken within this clinical trial to manage issues related 
to COVID-19.  That memo continues to serve as record of approved actions which can be 
fully implemented by Investigators, in advance of this protocol guidance.  This appendix 
will remain consistent with the guidance provided within the “Memo to Investigators” 
and will also serve to provide additional protocol documentation requirements and 
procedures. 
This appendix outlines the measures which are approved for implementation within this 
clinical trial, to protect patient safety and to ensure the integrity of the clinical trial, as a 
result of COVID-19 only. These measures may be implemented in accordance with any 
requirements and expectations set out by local Independent Review Boards/Independent 
Ethics Committees and National Competent Authorities, as necessary. 
This appendix does not apply to participant management issues that are unrelated to a 
specific, and documented, impact from COVID-19.  
12.9.1 Changes to Study Visits and Study Procedures 
• Where site staff resource is constrained due to COVID-19, IM dosing visits may 
proceed with limited or no other protocol-defined assessments (e.g. lab tests, 
questionnaires, etc.). If lab tests will be missed for more than one consecutive 
visit, the Medical Monitor must be contacted, to provide guidance for safety 
monitoring.  
• For WOCBP, point of care pregnancy testing should be performed, prior to IM 
dosing. 
• If central laboratory testing cannot be performed at a particular visit, and 
monitoring for safety is required, tests may be performed at an appropriately 
authorised/accredited local laboratory (or other relevant clinical facility), if this 
can be done within local restrictions on physical distancing. The site should 
proactively inform the Sponsor about such instances. Local laboratory results may 
be used to inform safety decisions. Results should be retained in source records. 
• When on-site visits are reduced, it is important that the investigator continue 
collecting relevant clinical information, including adverse events, from the 
participant through alternative means, e.g. by telephone contact. 
• There may be cases where the current principal investigator (PI) of a site is 

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indisposed for a period and may need to delegate parts of his/her duties 
temporarily, e.g. to a sub-investigator. Any such changes should be documented 
in the site’s source records. Any permanent changes in PI should be 
communicated to the Sponsor. 
• There may also be circumstances where immediate actions are required by the 
Sponsor and/or investigator, outside of what is contemplated in the protocol, in 
order to protect a study participant from immediate hazard. Any such measures 
will be carefully documented and conducted in accordance with the National 
Competent Authority (NCA)/IRB/IEC regulations. 
 
12.9.2. Changes to Informed Consent 
Informed consent should continue per normal procedure and as described in the main 
body of the protocol, to the extent possible. However, there may be circumstances where 
re-consent of participants is needed, and a physical signature on site is not possible. In 
these cases, alternative ways of obtaining such re-consent should be considered, such as 
the participant sending a picture of his/her written consent to the investigator, or the 
investigator contacting the participant by telephone or video call and obtaining verbal 
consent, supplemented with email confirmation.   
Any updated informed consent form or other subject-facing materials should be provided 
to participants by e-mail, mail or courier before re-consent is obtained. Any consent 
obtained this way should be documented in source records and confirmed by way of 
normal consent procedure at the earliest opportunity when participants attend their next 
on-site study visit. 
Any alternative informed consent procedure must be undertaken only after site 
IRB/Ethics Committee agreement and approval. 
 
12.9.3. Permissible Use of Antiretroviral Therapy 
In order to minimize the risk of gaps in HIV-1 antiretroviral therapy (ART) for 
participants impacted by COVID-19 in the clinical trial, the following options can be 
considered with regards to ART dosing, in order of preference: 
1. Where possible, and safe to do, please continue to prioritize IM dosing visits in 
order to keep the participants on the protocol-defined regimen. 
 
a. Qualified healthcare professionals (HCPs) trained on study procedures can 
administer IM injections outside of the study clinic setting (e.g. home, 
nursing facility, hospital), assuming this can be done safely, without 
compromising investigational product 
preparation/handling/storage/accountability requirements and done in 
accordance with local requirements. Please seek approval by the study 
team on a case-by-case basis. 
 
2. If a participant is not able to attend an IM injection visit due to COVID-19 related 

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restrictions, the gap in IM dosing should be covered with oral ART, until IM 
dosing can resume. Participants should be reminded of the importance of adhering 
with daily oral dosing. Two options can be approved for oral bridging therapy in 
consultation with the Medical Monitor, listed in order of preference: 
 
a. Oral CAB + RPV  
i. Investigator should request availability of oral CAB + RPV supplies, 
prior to pursuing option b. 
b. Oral standard of care (SOC) commercial ART (prescribed locally); Note:  
For participants who are HLA-B*5701 negative, if the site has 
investigational product, ABC/DTG/3TC, remaining in study stock that is 
within expiry, this can also be used as the SOC bridging therapy. 
Oral bridging with CAB + RPV 
The protocol permits oral bridging to cover planned missed injections with oral CAB + 
RPV, only until IM dosing can be resumed. The start date of oral bridging should be 
within the dosing window for the missed IM dosing visit. This recommendation can be 
used to accommodate requests for oral dosing due to COVID-19. Oral bridging 
recommendations should be followed as per protocol Section 6.8.1. The process and 
required information for requesting oral bridging can be found in your Study 
Reference/Procedure Manual.  Please continue to reach out to your study Medical 
Monitor for approval of oral bridging, in order to document use and to ensure expeditious 
shipment of oral CAB + RPV to your site.  
Participants who use oral CAB + RPV as short-term oral bridging are permitted to return 
to IM dosing, on protocol, once the COVID-19 conditions permit resumption of site 
activities.  
The investigator should reach out to the Medical Monitor to confirm IM restart 
instructions, and to ensure the participant remains appropriate for resumption of IM 
dosing. If oral bridging with CAB/RPV is anticipated to continue for > 2 months, 
additional approval and guidance should be obtained from the Medical Monitor to 
continue with oral bridging therapy. Loading/Re-initiation doses of CAB + RPV IM may 
be required, depending on the length of oral bridging. 
Oral bridging with Standard of Care Antiretroviral Therapy (SOC ART) 
For participants impacted by COVID-19, where the participant is unable to receive IM 
injections, and oral CAB + RPV is not available for use, oral bridging with any 
commercially available, guideline-recommended, SOC ART regimen is permitted. The 
start date of oral bridging should be within the dosing window for the missed IM dosing 
visit.  Please reach out to your study Medical Monitor for approval of SOC ART as oral 
bridging, in order to document the use of commercially available SOC ART within the 
study. 
Participants who use oral SOC ART as short-term oral bridging as a result of COVID-19 
will not be considered formally withdrawn insofar as they wish to continue on the study.  
Individuals who bridge with SOC ART will be permitted to return to IM dosing, on 

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study, once the COVID-19 conditions permit resumption of site activities.   
The investigator should reach out to the Medical Monitor to confirm IM restart 
instructions, and to ensure the participant remains appropriate for resumption of IM 
dosing. If oral bridging with SOC ART is anticipated to continue for > 2 months, 
additional approval and guidance should be obtained from the medical monitor to 
continue with oral bridging therapy.  Loading/Re-initiation doses of CAB + RPV IM may 
be required, depending on the length of oral bridging. 
12.9.4. Direct-To-Patient (DTP) Shipment of Oral Study IP 
If a participant is unable to travel to the clinic, either to receive IM injections or to be 
dispensed oral bridging, sites are encouraged to consider DTP shipments of drug, from 
the site, to the participant, to ensure access to medicines.  
• If the study site is considering DTP shipment of oral CAB + RPV investigational 
product (IP), the site must first verify if DTP IP dispensing by 
investigators/hospital pharmacies is locally permitted and whether it requires 
regulatory and/or local ethics pre-approval, or post-hoc notification. 
• The study participant should express his/her agreement for DTP shipment and the 
sharing of their personal information with any third-party couriers (as applicable), 
in accordance with local requirements.  This agreement should be documented in 
source records. 
• Oral CAB + RPV IP can be shipped at ambient temperatures via ground transport 
without a temperature monitoring device, with low risk of temperature excursions. 
Sites are encouraged to use discretion in determining the need for in-transit 
temperature monitoring based on the labelled storage requirements and the 
planned mode of transport and apply this as appropriate.  Shipment of oral CAB + 
RPV via air courier continues to require appropriate temperature monitoring.  For 
shipment conditions of oral medications other than oral CAB + RPV, please 
consult the product labelling. 
• In all cases IP accountability must be maintained, and all DTP dispensing 
documentation should be reflected in source records and dispensing logs per GCP. 
• Please refer to your CRA or local study manager for support with the DTP 
process, ensuring reference to current sponsor guidance and arrangement of a 
courier that can support shipment of IMP directly to participants. 
 
12.9.5. COVID-19 Experimental Agents 
If any treatments for COVID-19 are planned for a study participant, please consult with 
the study Medical Monitor to ensure that relevant drug interactions are considered and to 
ensure that continued study participation remains appropriate. 
12.9.6. COVID-19 Specific Data Capture 
12.9.6.1. 
Capturing COVID-19 Specific Protocol Deviations 
In order to summarise the impact of COVID-19 in a systematic way and in line with 

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regulatory authorities’ recommendations, any study-level impact around COVID-19 will 
be documented as a protocol deviation. This will include the permissible actions 
summarized in this Appendix, which are taken to protect patient safety, including the use 
of CAB + RPV or SOC ART as oral bridging as well as missed visits and assessments as 
a result of logistical challenges resulting from COVID-19. 
Although the conduct of remote visits and the continuity of antiretroviral therapy, via oral 
bridging, are being utilized to protect patient safety, these events fall outside of the intent 
of the original protocol design, may have an impact on data interpretation, and thus will 
be characterized as protocol deviations for the purposes of data summary and analysis. 
 
Any protocol deviations resulting from COVID-19 will be clearly identified as such 
within the protocol deviation description and summarised separately. 
 
Please refer to your study procedure manual for specific details on capturing protocol 
deviations as a result of COVID-19. 
 
12.9.6.2. 
Capturing COVID-19 Specific AEs and SAEs 
It is important for the study team to describe COVID-19 related adverse events/serious 
adverse and their impact on study data and outcomes. Standardization of case definitions 
will facilitate future data analysis.  
Please use the following guidance:  
1. 
AEs should continue to be evaluated as to whether they meet SAE criteria as 
defined in the protocol, and if so, submitted according to established SAE 
reporting requirements. SAEs and AEs should be submitted following usual 
study procedures and timelines.  
 
2. 
When an in-person clinic visit is not possible, please conduct a remote 
telehealth visit to assess for, and document any AEs/SAEs. 
 
3. 
Investigators should use the WHO definition to classify COVID-19 cases. The 
definition below, released March 20, 2020, represents a time point for 
standardized collection. We recognize definitions are likely to continue to 
evolve. When reporting both serious and non- serious adverse events (related 
to COVID-19 infection, investigators should use the following Verbatim 
terms:  
a) Suspected COVID-19 infection; or  
b) Probable COVID-19 infection; or  
c) Confirmed COVID-19 infection  
 
4. 
Sites should contact the study Medical Monitor for questions related to 
definitions and reporting, and decisions around impact to study drug 
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5. 
A new COVID-19 infection Case Report Form will be added to the eCRF to 
collect additional details about the reported COVID-19 AE or SAE data. It is 
important to collect the correct information from each participant reporting a 
COVID-19 AE or SAE.  Therefore, please use the CRF templates to help you 
collect this information, once available. 
 
WHO Case Definition - March 20, 2020 Version (https://www.who.int/publications-
detail/global-surveillance-for-human-infection-with-novel-coronavirus-(2019-ncov)):  
Suspected case:  
A. A patient with acute respiratory illness (fever and at least one sign/symptom of 
respiratory disease, e.g., cough, shortness of breath), AND a history of travel to or 
residence in a location reporting community transmission of COVID-19 disease 
during the 14 days prior to symptom onset;  
OR  
B. A patient with any acute respiratory illness AND in contact (see definition of 
“contact” below) with a confirmed or probable COVID-19 case (see definition of 
contact) in the last 14 days prior to symptom onset;  
OR  
C. A patient with severe acute respiratory illness (fever and at least one 
sign/symptom of respiratory disease, e.g., cough, shortness of breath; AND 
requiring hospitalization) AND in the absence of an alternative diagnosis that 
fully explains the clinical presentation.  
 
Probable case:  
A. A suspect case for whom testing for the COVID-19 virus is inconclusive 
(Inconclusive being the result of the test reported by the laboratory).  
OR  
B. A suspect case for whom testing could not be performed for any reason.  
Confirmed case:  
A person with laboratory confirmation of COVID-19 infection, irrespective of 
clinical signs and symptoms.  
Covid-19 Contact: 
A contact is a person who experienced any one of the following exposures during the 2 
days before and the 14 days after the onset of symptoms of a probable or confirmed case:  
1. 
Face-to-face contact with a probable or confirmed case within 1 meter and for 
more than 15 minutes;  

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2. 
Direct physical contact with a probable or confirmed case;  
3. 
Direct care for a patient with probable or confirmed COVID-19 disease 
without using proper personal protective equipment; OR  
4. 
Other situations as indicated by local risk assessments.  
Note: for confirmed asymptomatic cases, the period of contact is measured as the 2 days 
before through the 14 days after the date on which the sample was taken which led to 
confirmation. 
12.14.6. 
Amendment 06 (All Countries) 
Protocol changes for Amendment 06 (05-AUG-2021), from Amendment 05 (20-
MAY-2020).   
12.14.6.1. Protocol Amendment Rationale 
The primary purposes of this amendment are: 
• To allow participants who become pregnant while in the study to remain in the 
study and not be withdrawn due to pregnancy. Allowing pregnant participants to 
continue in the study will negate any additional and subsequent fetal exposures to 
new antiretroviral agents that would occur if the pregnant participant was 
withdrawn from the study and placed on an oral SOC regimen. An appendix, 
“Information and Guidance for Managing Pregnant Participants” was inserted as 
Appendix 10 and all subsequent appendices were renumbered accordingly. 
• Contraceptive methods have been updated to permit the use of progestogen-only 
implantable and injectable contraceptives without the requirement of a second 
highly effective method. 
• Removal of the optional collection of cord blood and/or breast milk after delivery. 
• Removal of the option for study treatment rechallenge following suspected drug-
induced liver injury (DILI). 
• Clarification of which participants enter the LTFU phase when CAB+RPV LA 
marketed product is locally available. 
• Medical Device reporting requirement added. 
• Co-enrolment (only applicable for eligible female participants in South Africa in 
the ACTG A5392 study). 
• Updates to primary and secondary Medical Monitors. 
Other additional edits were made, for clarity and/or correction. 
12.14.6.2. Protocol Changes/Clarifications 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1. Long 
Term Follow-Up 
Phase 
Section 4.1. Overall 
New text added: 
- 
Where the CAB LA + RPV 
LA marketed product is not 
locally available, any 
Transition to 
marketed product. 

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Design 
Section 4.2.6. LTFU 
Phase- IM Regimen 
Only 
Section 5.4. 
Withdrawal/Stopping 
Criteria 
Section 6.10.2. 
Discontinuation of 
CAB LA or RPV LA 
 
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 enter the 52 
week Long Term Follow-Up 
Phase.  
 
- 
Where CAB LA + RPV LA 
marketed product is locally 
available, only participants 
that discontinue the CAB LA 
+ RPV LA regimen for 
safety-related reasons should 
enter the LTFU Phase. 
Section 4.5. Dose 
Justification 
Text updated to reflect that the 
LATTE study is no longer ongoing. 
For clarification 
purposes. 
Section 4.6. 
Benefit:Risk 
Assessment. 
DTG Data/Rationale for Risk updated. 
Text removed: In one ongoing birth 
outcome surveillance study in 
Botswana, early results from an 
unplanned interim analysis showed 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%. 
Text added: A preliminary analysis of 
an ongoing birth outcome surveillance 
study in Botswana involving women 
exposed to dolutegravir (DTG) 
identified four cases (as of May 2018) 
of neural tube defects in 426 infants 
born to mothers who were exposed to 
DTG-containing regimens from the 
time of conception. In the same study, 
no infant born to a women who started 
DTG during pregnancy had a neural 
tube defect, out of 2,824 women. A 
causal relationship of these events to 
the use of DTG has not been 
established. The incident rate of neural 
tube defects in the general population 
ranges from 0.5-1 cases per 1,000 live 
births. As neural tube defects occur 
within the first 4 weeks of fetal 
Updated safety 
information. 

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development (at which time the neural 
tubes are sealed) this potential risk 
would concern women exposed to DTG 
at the time of conception and in early 
pregnancy. Recently updated data 
(April 2020) for this birth outcome 
study showed that among women who 
were on DTG when they became 
pregnant, 7/3,591 neural tube defects 
(NTD) occurred (0.19%). In 
comparison, NTDs were identified in 
21/19,361 (0.11%) women delivering 
on any non-DTG antiretrovirals. There 
was not a significant difference in the 
number of neural tube defects between 
births to women taking DTG and those 
taking other non-DTG antiretroviral 
treatments (0.09% difference). 
Section 4.6. 
Benefit:Risk 
Assessment 
DTG Mitigation Strategy updated. 
Text removed: Women who become 
pregnant or who desire to be 
pregnant while in the study will 
have study treatment discontinued 
and withdrawn from the study. 
To allow participants 
who become pregnant 
to remain in the 
study. 
Section 4.6.1. Risk 
Assessment 
Updated section Potential Risk of 
Clinical Significance: Drug Induced 
Liver Injury (DILI) 
Summary of Data/Rationale for Risk 
text removed: 
- 
(total exposure >3100 
participants) 
- 
Of the four participants with 
possible or probable cases of 
DILI identified in Phase 2 
studies, all were receiving 
oral CAB. 
Summary of Data/Rationale for Risk 
text added: All participants with 
suspected DILI identified in clinical 
studies to date were receiving oral 
cabotegravir. 
For clarification 
purposes. 
Section 4.6.1 Risk 
Assessment 
Updated section Potential Risk of 
Clinical Significance: Effects in 
pregnancy seen in non-clinical 
To allow participants 
who become pregnant 
to remain in the 

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studies. 
Summary of Data/Rationale for Risk 
Animal reproduction studies data 
updated. 
Mitigation Strategy updated to allow 
participants who become pregnant 
to remain in the study. 
study. 
Section 4.6.1 Risk 
Assessment 
Added new category: Potential 
effects in females exposed to 
dolutegravir during conception and 
early pregnancy.  
Summary of Data/Rationale for Risk 
with data from preliminary analysis 
of an ongoing birth outcome 
surveillance study in Botswana 
involving women exposed to 
dolutegravir (DTG). 
Mitigation Strategy updated to allow 
participants who become pregnant 
to remain in the study. 
To allow participants 
who become pregnant 
to remain in the 
study. 
Section 4.6.1. Risk 
Assessment 
Removed text from RPV risks, Rash 
mitigation strategy: Participants 
with a Grade 1 or 2 rash will be 
allowed to continue treatment or to 
be rechallenged, depending on the 
clinical judgement of the 
investigator. 
Rechallenge option 
removed. 
Section 4.6.2. Other 
Clinically Relevant 
Information 
Seizure information updated. 
For clarification 
purposes. 
Section 4.6.3. 
Benefit Assessment 
Updated list of ongoing studies. 
Addition of Phase 3 studies. 
For clarification 
purposes. 
Section 5.2. 
Diagnostic 
Assessments and 
Other Criteria 
Added text: Participation in other 
interventional studies is generally 
not permitted, however for eligible 
subjects in South Africa co-
enrolment in AIDS Clinical Trial 
Group (ACTG) interventional study 
(A5392) could be exceptionally 
permitted after review and approval 
Co-enrolment in 
study A5392 would 
be permitted in South 
Africa on a case by 
case approval basis. 

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by the Medical Monitor. 
Section 5.4. 
Withdrawal/Stopping 
Criteria 
Removed text: 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 up in the LTFU phase).  
To allow participants 
who become pregnant 
to remain in the 
study. 
Section 5.4.1. Liver 
Chemistry Stopping 
Criteria 
Removed “rechallenge” option 
throughout the sections. 
Rechallenge option 
removed. 
Section 5.4.1.3. 
Liver Chemistry 
Stopping Criteria – 
Restart  
Rechallenge text removed from the 
section title. Rechallenge option 
removed throughout the sections. 
New text updated with the current 
process required in case of restart. 
Rechallenge option 
removed. 
Section 5.4.1.4. 
General Guidance 
Restart 
New section added with the current 
process required in case of restart. 
Rechallenge option 
removed. 
Section 5.4.1.4. 
Liver Chemistry 
Stopping Criteria - 
Restart 
Added text: If definitive non-study 
drug related diagnosis, restart will 
be considered once ALT <3x ULN 
(for participants with baseline ALT 
<1.5x ULN) or <3x baseline ALT 
value (for participants with baseline 
ALT >1.5x UNL). 
For clarification 
purposes. 
Section 5.5. 
Participant and Study 
Completion 
Added Safety Follow-Up visit. 
Transition to 
marketed product. 
Section 6. Study 
Treatment  
New section added: Section 6.14. 
Medical Devices. 
Medical Device 
reporting 
requirement. 
Section 7.1. Time 
and Events Table 
Added new column for Safety 
Follow-Up visit to clarify visit 
requirements. 
Transition to 
marketed product. 
Section 7.4.1. 
Clinical Evaluation 
Added text: Participants who are 
enrolled in the study and have a 
positive pregnancy test during the 
course of the study will be allowed 
To allow participants 
who become pregnant 
to remain in the 

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to remain in the study, provided a 
pregnancy specific ICF addendum is 
signed by the participant. No IP can 
be continued (oral or LA) in any 
pregnant participant until the 
benefit/risk assessment is discussed 
with the participant and the 
pregnancy specific ICF addendum 
has been signed. See details in 
Appendix 10. Pregnant participants 
who remain in the study do not need 
pregnancy testing during the study, 
for the duration of their pregnancy. 
study. 
Section 7.4.3. 
Adverse Events 
(AEs) and Serious 
Adverse Events 
(SAEs) 
Added text throughout Section 7.4.3 
and Section 7.4.3.1. referring to the 
new requirement to report Medical 
Device incidents. 
Added Medical 
Device incident 
reporting 
requirements. 
Section 7.4.3.4. 
Prompt Reporting of 
Serious Adverse 
Events and Other 
Events 
Added text stating that contacts for 
SAE receipt can be found in the 
Study Reference Manual. 
For clarification 
purposes. 
Section 7.4. Safety 
Added new sections detailing the 
medical device deficiencies 
reporting requirements. New 
sections added: 
7.4.4. Medical Device Deficiencies 
7.4.5. Time Period for Detecting 
Medical Device Deficiencies 
7.4.6. Follow-Up of Medical Device 
Deficiencies. 
7.4.7. Prompt Reporting of Medical 
Device Deficiencies to Sponsor 
7.4.8. Regulatory Reporting 
Requirements for Medical Device 
Deficiencies 
Added medical device 
deficiency reporting 
requirements. 
Section 7.4.9.3. 
Grade 3 
Toxicity/Adverse 
Clarification that a follow-up visit 
should occur 2-4 weeks after the last 
For clarification 
purposes. 

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Event 
dose of IP. 
Section 7.4.10.1. 
Liver Chemistry 
Stopping Criteria 
Removal of rechallenge text. 
Rechallenge option 
removed. 
Section 7.4.10.4. 
Seizures 
Added text: Several cases of seizure 
have occurred during the 
cabotegravir program. These cases 
have had alternative explanations 
for their occurrence. 
ViiV Healthcare has reviewed these 
cases in detail and does not believe 
they constitute a reasonable 
likelihood of causation associated 
with CAB. This assessment is 
supported by the lack of preclinical 
signal, class effect or known CNS 
mechanism, the relatively low 
frequency of seizures relative to 
expected rates in both healthy and 
HIV positive participants and 
clinical cofounders in each case. 
The Sponsor considers the risk of 
developing seizures on the study as 
being no higher than that of the rest 
of the HIV-1 infected population. 
For clarification 
purposes. 
Section 7.4.12. 
Pregnancy 
Added text throughout all sections 
below to allow subjects who 
become pregnant to remain in the 
study: 
 
Added text in Section 7.4.12.1. 
Pregnancy Testing 
Added new Section 7.4.12.2. 
Rationale for Continued Use in 
Pregnancy 
Amended Section 7.4.12.3. Time 
Period for Collecting Pregnancy 
Information 
 
To allow subjects 
who become pregnant 
to remain in the 
study. 
Section 7.4.12.4. 
Removed text: Additionally, there 
Removal of optional 

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Actions to be taken if 
Pregnancy occurs 
will be an optional umbilical cord 
blood collection at time of delivery, 
requiring additional parental 
consent. Cord blood and breast milk 
samples would be used to better 
understand the level of PK exposure 
to the neonate, if any. 
umbilical cord blood 
and/or breast milk PK 
testing. 
Section 7.5. 
Pharmacokinetics 
Added text: Pregnant participants 
will have additional PK samples 
collected during the duration of the 
pregnancy. See Appendix 10 for 
details. 
Added PK collection 
during pregnancy. 
Section 8. Data 
Management 
Added text: The sponsor or designee 
is responsible for the data 
management of this study including 
quality checking of the data. 
Detailed information about study 
data collection and management 
process including systems used can 
be found in the study Data 
Management Plan. 
For clarification 
purposes. 
Section 10.2. 
Regulatory and 
Ethical 
Considerations, 
Including the 
Informed Consent 
Process 
Added text: If follow-up 
information from a treating 
physician or other licensed medical 
practitioner is required for a medical 
device incident with an AE/SAE 
involving an associated person(s), 
the Associated Person Safety 
Reporting Information and 
Authorization Letter must be signed 
by the associated person to obtain 
consent.  
Added medical device 
deficiency reporting 
requirements.  
Section 12.3. 
Appendix 3 
Removed Appendix 3: Liver Safety 
– Study Treatment Restart or 
Rechallenge Guidelines. 
Added new Appendix 3: Liver 
Safety – Required Actions, Follow 
Up Assessments and Study 
Treatment Restart Guidelines 
Removal of 
rechallenge option. 
Section 12.5. 
Appendix 5 Genetics 
Text updated: In the event that a 
participant withdraws from the 
study and requests destructions of 
To align with the 
most recent template 

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Research 
their samples then the site staff must 
document this in the site study 
records, complete form F-GRD-001 
and must inform ViiV/GSK via the 
CRA within 5 days of notification 
by the participant to trigger sample 
destruction requests.  
requirements. 
Section 12.7. 
Appendix 7 
Contraceptive 
Guidance and 
Collection of 
Pregnancy 
Information 
Removed footer b of Table 14 
Highly Effective Contraceptive 
Methods: 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. 
Permitted 
contraceptive 
methods updated. 
Section 12.7. 
Appendix 7 
Contraceptive 
Guidance and 
Collection of 
Pregnancy 
Information 
Added text throughout section for 
cases of pregnancy during the study. 
To allow patients who 
become pregnant to 
remain in the study. 
Section 12.9.6.1. 
Capturing COVID-
19 Specific Protocol 
Deviations 
Removed text: Please refer to your 
study procedure manual for specific 
details on capturing protocol 
deviations as a result of COVID-19. 
For clarification 
purposes. 
Section 12.10. 
Appendix 10 
New appendix added: Appendix 10: 
Information and Guidance for 
Managing Pregnant Participants. 
To allow participants 
who become pregnant 
to remain in the 
study. 
Section 12.11. 
Appendix 11 
New appendix added: Appendix 11: 
Device Deficiencies: Definition and 
Procedures for Recording, 
Evaluating, Follow-up, and 
Reporting in Medical Device 
Studies. 
Medical Device 
Reporting 
Requirements. 
Section 12.12. 
Appendix 12 
Appendix 12: Protocol Amendment 
History updated. 
 
 

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12.14.7. 
Amendment 07 (All Countries) 
Protocol changes for Amendment 07 (17 Jun 2022), from Amendment 06 (05-AUG-
2021).   
Amendment 07 17 Jun 2022 
This amendment is considered to be substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
Overall Rationale for the Amendment:  
The primary purposes of this amendment are: 
• To include the Sub-Cutaneous Abdominal Injection Sub-Study appendix (only 
applicable for countries participating in the Sub-Study).  
• Clarification added: In Russia, subjects who become pregnant while on study may 
not elect to remain on study treatment and must withdraw and enter the LTFU 
Phase. 
• Inclusion of Appendix 13: Mitigations for Geopolitical Situation in 
Russia/Ukraine. 
Section # and Name 
Description of Change 
Brief Rationale 
Title Page and 
Protocol Amendment 
Summary of 
Changes Table 
Document updated as per the latest GSK 
template. 
Template update. 
Sponsor Signature 
Page 
Provided as separate document. 
Template Update 
Investigator 
Signature Page 
Provided as separate document 
Template Update 
Medical 
Monitor/Sponsor 
Information page 
Removed. Document updated as per the 
latest GSK template. 
Template Update 
Section 4.6. 
Benefit:Risk 
Assessment 
DTG Mitigation Strategy updated. Text 
added: In Russia, women who become 
pregnant or who desire to be pregnant 
while in the study will have study treatment 
discontinued and will be withdrawn from 
the study. 
Russia country 
specific 
pregnancy 
requirements. 
Section 4.6.1. Risk 
Assessment 
Updated section Potential Risk of Clinical 
Significance: Effects in pregnancy seen in 
Russia country 
specific 

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Section # and Name 
Description of Change 
Brief Rationale 
non-clinical studies. 
Summary of Data/Rationale for Risk text 
added: Not applicable in Russia. 
Mitigation Strategy text added: Not 
applicable in Russia. In Russia, women 
who become pregnant or who desire to 
become pregnant while in the study will 
have study treatment discontinued and will 
be withdrawn from the study. 
pregnancy 
requirements. 
Section 4.6.1. Risk 
Assessment 
Updated section: Potential effects in 
females exposed to dolutegravir during 
conception and early pregnancy.  
Mitigation Strategy text added: Not 
applicable in Russia. In Russia, women 
who become pregnant or who desire to 
become pregnant while in the study will 
have study treatment discontinued and will 
be withdrawn from the study. 
Russia country 
specific 
pregnancy 
requirements. 
Section 5.1. 
Inclusion Criteria 
Informed consent inclusion criteria now 
inclusion criteria number 5 as per 
continuation of numbering format.  
  
French participants informed consent 
criteria now inclusion criteria number 6 as 
per continuation of numbering format. 
Clarification 
purposes.  
Section 5.4. 
Withdrawal/Stopping 
Criteria 
Added text: In Russia, 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 up in the LTFU 
phase). 
Russia country 
specific 
pregnancy 
requirements. 
Section 5.4.1. Liver 
Chemistry Stopping 
Criteria 
Text removed: Figure 10 
Text added: Figure 9 
Correction 
Section 7.4.1. 
Clinical Evaluation 
Added text: Not applicable in Russia. 
Russia country 
specific 
pregnancy 
requirements. 
Section 7.4.12. 
Added text throughout all sections below to 
clarify that subjects who become pregnant 
Russia country 

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Section # and Name 
Description of Change 
Brief Rationale 
Pregnancy 
in Russia must discontinue LA study 
treatment and continue to be followed up in 
the LTFU phase.  
Added text in Section 7.4.12.1. Pregnancy 
Testing 
Added text in Section 7.4.12.2. Rationale 
for Continued Use in Pregnancy 
Added text in Section 7.4.12.3. Time 
Period for Collecting Pregnancy 
Information 
Added text in Section 7.4.12.4. Action to 
be Taken if Pregnancy Occurs  
specific 
pregnancy 
requirements. 
Section 7.5. 
Pharmacokinetics 
Added text: Not applicable in Russia. 
Russia country 
specific 
pregnancy 
requirements.  
Section 12.1. 
Appendix 1: 
Abbreviations and 
Trademarks 
New abbreviations added: 
DTP – Direct to Patient 
HCP – Healthcare Provider 
LTFU – Long-Term Follow Up 
SVF – Suspected Virological Failure 
For clarification 
purposes. 
Section 12.7. 
Appendix 7: 
Contraceptive 
Guidance and 
Collection of 
Pregnancy 
Information 
Text added throughout to clarify that 
subjects who become pregnant in Russia 
must discontinue LA study treatment and 
continue to be followed up in the LTFU 
phase.  
Section 12.7.1. Contraceptive Guidance 
Section 12.7.2. Collection of Pregnancy 
Information 
Russia country 
specific 
pregnancy 
requirements. 
Section 12.7.1. 
Contraceptive 
Guidance 
Table 15 updated to become Table 16. 
For clarification 
purposes. 
Section 12.8.2. Japan Table 16 updated to become Table 17. 
For clarification 
purposes. 
Section 12.8.3. 
Country specific wording added related to 
Russia country 

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Section # and Name 
Description of Change 
Brief Rationale 
Russia 
the discontinuation of study treatment for 
participants who become pregnant during 
the study.  
specific 
pregnancy 
requirements. 
Section 12.10. 
Appendix 10 
New text added: Not applicable to 
participants in Russia. In Russia, women 
who become pregnant or who desire to 
become pregnant while in the study will 
have study treatment discontinued and will 
be withdrawn from the study. 
Russia country 
specific 
pregnancy 
requirements. 
Section 12.10. 
Appendix 10 
Table of contents removed. 
As per GSK 
writing guidance, 
document should 
only have one 
table of contents. 
Section 12.12. 
Appendix 12 
New appendix added: Appendix 12: Sub-
Cutaneous Administration PK Sub-Study 
Amendment 
Sub-Study 
information 
Section 12.13. 
Appendix 13 
New appendix added: Appendix 13: 
Mitigations for Geopolitical Situation in 
Russia/Ukraine 
To provide 
approval of 
necessary 
mitigation 
strategies in 
Russia 
Section 12.14. 
Appendix 14 
Appendix 14: Protocol Amendment History 
updated. 
 
Section 12.11. Appendix 14:  Protocol Amendments 
Rationale for change:  Appendix 12 (previously history of protocol amendments) is 
now Appendix 14 to retain this section at the end of the protocol as the final 
appendix of change. 
12.14.8. 
Amendment 08 (All Countries) 
Protocol changes for Amendment 08 (21 Oct 2022) from Amendment 07 (17-Jun-
2022).   
This amendment is considered to be substantial based on the criteria defined in EU 
Clinical Trial Regulation No 536/2014 of the European Parliament and the Council of the 
European Union.  
Overall Rationale for the Amendment:  
The primary purposes of this amendment are: 

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• To include the Sub-Study Interim Analysis 1: ISR Monitoring Criteria into the 
Sub-Cutaneous Abdominal Injection Sub-Study appendix (only applicable to for 
countries participating in the Sub-Study). 
• To include the Sub-Study Interim Analysis 2: Week 9 Safety and PRO Review 
into the Sub-Cutaneous Abdominal Injection Sub-Study appendix (only 
applicable for countries participating in the Sub-Study).  
 
Section # and Name 
Description of Change 
Brief Rationale 
Section 4.6.1. Risk 
Assessment 
Text removed from Oral CAB and CAB 
LA (GSK1265744 / GSK1265744 LA): "is 
at an early stage of clinical development, 
and" 
For clarification 
purposes. 
Section 4.6.1. Risk 
Assessment 
Text removed from Drug Induced Liver 
Injury (DILI) Summary of Data/Rationale 
for Risk:  
 
"A small proportion". 
 
"All participants with suspected DILI 
identified in clinical studies to date were 
receiving oral cabotegravir" 
 
Text added to Drug Induced Liver Injury 
(DILI) Summary of Data/Rationale for 
Risk: "Less than 1%" 
For clarification 
purposes. 
Section 4.6.1. Risk 
Assessment 
Text removed from RPV LA: "Beyond 
what has already been identified with oral 
RPV, no new systemic adverse reactions to 
RPV LA (same active moiety) have been 
observed." 
 
Text added to RPV LA: "Systemic 
reactions following RPV LA injections 
have been observed in clinical trials. These 
occur infrequently (in less than 0.5% of 
participants) and typically begin to resolve 
within minutes of the injection however, 
some participants required supportive care. 
Where timely PK data was available, high 
RPV PK plasma concentrations have been 
Updated safety 
information. 

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Section # and Name 
Description of Change 
Brief Rationale 
observed which may have resulted from an 
accidental partial IV injection of RPV."   
Section 4.6.1. Risk 
Assessment 
Text added to Inadvertent Intravenous 
Injection (Accidental Maladministration) 
Summary of Data/Rationale for Risk:  
 
"Systemic reactions following RPV LA 
injections have been observed in clinical 
trials. These occur infrequently (in less than 
0.5% of participants) and typically begin to 
resolve within minutes of the injection, 
however, some participants required 
supportive care. Where timely PK data was 
available, high RPV PK plasma 
concentrations have been observed which 
may have resulted from an accidental 
partial IV injection of RPV." 
Updated safety 
information. 
Section 4.6.2. Other 
Clinically Relevant 
Information 
Text removed from Adverse Events of 
Special Interest: Seizure: "Several cases of 
seizure have occurred during the 
cabotegravir program". 
 
Text added to Adverse Events of Special 
Interest: Seizure: "A small number of 
seizure cases have been reported following 
CAB administration (less than 1% of all 
those receiving CAB in clinical studies)". 
For clarification 
purposes. 
Section 5.2. 
Exclusion Criteria 
Correction to the numbering of the 
exclusion criteria. Previously wrong due to 
an error.  
Correction. 
Section 7.4.10.4. 
Seizures 
Text removed: "Several cases of seizure 
have occurred during the cabotegravir 
program".  
 
Text added: "A small number of seizure 
cases have been reported following CAB 
administration (less than 1% of all those 
receiving CAB in clinical studies)". 
For clarification 
purposes. 
Section 12.12.1. 
Sub-Study 
Reference added. 
For clarification 

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Section # and Name 
Description of Change 
Brief Rationale 
Amendment 
Background 
purposes. 
Section 12.12.2.1. 
Data on CAB/RPV 
Subcutaneous 
Injection Site 
Reactions 
New section added. 
Additional safety 
information.  
Section 12.12.2.2. 
ISR Monitoring 
Criteria Process 
New section added. 
Additional safety 
information. 
Section 12.12.4.1. 
Sub-Study 
Amendment: 
Inclusion and 
Exclusion Criteria 
Correction to the numbering of the 
exclusion criteria. Previously wrong due to 
an error. 
Correction.  
Section 12.12.4.4. 
Return to 
Intramuscular 
Gluteal Injection 
Phase 
Text removed: "Participants will complete 
8 weeks (2 injection cycles) of CAB/RPV 
LA therapy after which the participant's 
participation in the sub-study will 
conclude(after the week 17 assessments 
obtained). The Week 20 injection and all 
assessments obtained at Week 20 and 
beyond will be as part of the parent study 
(FLAIR)." 
 
Text added: "Participants will complete 8 
weeks (2 injection cycles) of CAB/RPV LA 
therapy. After the Week 20 assessments are 
obtained (AEs, SAEs and concomitant 
medications) the participant's participation 
in the sub-study will have concluded." 
For clarification 
purposes. 
Section 12.12.4.5. 
Sub-Study 
Completion 
Text removed: "Participants are considered 
to have completed the sub-study if they 
complete pre-dose assessments at sub-study 
Week 20 visit with the action IM injection 
as part of the parent study." 
 
Text added: "Participants are considered to 
have completed the sub-study once the final 
Week 20 pre-dose assessments (AEs, SAEs 
For clarification 
purposes.  

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Section # and Name 
Description of Change 
Brief Rationale 
and concomitant medications) are obtained. 
The IM injection and all other assessments 
will be considered part of the parent study 
and assessments should be completed as 
per the parent study time and events table 
in Section 7.1." 
Section 12.12.4.7. 
Sub-Study Injection 
Site Reactions 
New section added. 
For safety 
purposes. 
Section 12.12.4.9. 
Sub-Study 
Amendment HIV-1 
RNA Blips Guidance 
Text added: "(defined as HIV-1 RNA ≥50 
c/mL and <200 c/mL) " 
For clarification 
purposes.  
Section 12.12.5. 
Sub-Study Time and 
Events Table 
Removed footnote “i” from Week 16 IM 
administration. 
Footnote not 
required for this 
assessment. 
Section 12.12.5. 
Sub-Study Time and 
Events Table 
Removed footnote “i” from Return to IM 
Gluteal Injection Phase. 
Footnote not 
required for this 
assessment.  
Section 12.12.5. 
Sub-Study Time and 
Events Table 
HIVTSQc requirement at Week 17 
removed. 
Not required. 
Section 12.12.5. 
Sub-Study Time and 
Events Table 
Week 20 column added.  
AEs, SAEs concomitant medications to be 
completed at this visit. 
For clarification 
purposes.  
Section 12.12.5. 
Sub-Study Time and 
Events Table 
Removed footnote "n" marker from Pre 
dose PK samples for CAB and RPV. 
Error, there was 
previously no 
footnote n. 
Section 12.12.5. 
Sub-Study Time and 
Events Table 
Footnote "n" added. 
 
"AEs, SAEs and concomitant medications 
to be assessed pre-dose. IM administration 
itself and all other assessments will be 
considered part of the parent study, and 
should be completed as per the parent study 
time and events table in Section 7.1" 
For clarification 
purposes. 
Section 12.12.5. 
Footnote “n” added for Week 20 column 
For clarification 

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Section # and Name 
Description of Change 
Brief Rationale 
Sub-Study Time and 
Events Table 
title.  
purposes. 
Section 12.12.9.6. 
Sub-Study Interim 
Analysis 1: ISR 
Monitoring Criteria 
New section added. 
Sub-Study 
interim analysis 
added. 
Section 12.12.9.7. 
Sub-Study Interim 
Analysis 2: Week 9 
Safety and PRO 
Review 
New section added. 
Sub-Study 
interim analysis 
added. 
Throughout 
Minor editorial and document formatting 
revisions. 
For clarification 
purposes. 
Throughout 
GlaxoSmithKline replaced with GSK due 
to updated branding.  
For clarification 
purposes. 
Section 12.14. 
Appendix 14 
Appendix 14: Protocol Amendment History 
updated.  
For clarification 
purposes. 
 
12.14.9. 
Amendment 09 (All Countries) 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC). 
Protocol changes for Amendment 09 (28 Aug 2023), from Amendment 08 (21 Oct 
2022).   
Amendment 08 (All Countries) Protocol changes for Amendment 08 (21-Oct-2022), from 
Amendment 07 (17-Jun2022).