A Phase IIIb, Randomized, Multicenter, Parallel-group, Non-inferiority, Open-label Study Evaluating the Efficacy, Safety, and Tolerability of Long-acting Cabotegravir Plus Long-acting Rilpivirine Administered Every 8 Weeks or Every 4 Weeks in HIV-1-infected Adults Who Are Virologically Suppressed
Phase: PHASE3
Conditions: HIV Infections
Sponsor: ViiV Healthcare

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ViiV Healthcare group of companies
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TITLE PAGE
Protocol Title: A Phase IIIb, Randomized, Multicenter, Parallel-group, Non-inferiority, 
Open-label Study Evaluating the Efficacy, Safety, and Tolerability of Long-acting 
Cabotegravir Plus Long-acting Rilpivirine Administered Every 8 Weeks or Every 4 
Weeks in HIV-1-infected Adults who are Virologically Suppressed
Protocol Number: 207966/amendment 02
Short Title: Study Evaluating the Efficacy, Safety, and Tolerability of Long-acting 
Cabotegravir Plus Long-acting Rilpivirine administered every 8 weeks in Virologically 
Suppressed HIV-1-infected Adults.
Compound Number:
GSK1265744
Sponsor Name and Legal Registered Address: 
This study is sponsored by ViiV Healthcare. 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
Five Moore Drive
P.O. 13398
Research Triangle Park, NC 27709-3398, USA
Telephone: 
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.
This study is sponsored by ViiV Healthcare. GlaxoSmithKline is supporting ViiV 
Healthcare in the conduct of this study
Copyright 2018 ViiV Healthcare group of companies.  All rights reserved.  Unauthorized 
copying or use of this information is prohibited.
 
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Medical Monitor Name and Contact Information can be found in the Study 
Reference Manual
Regulatory Agency Identifying Number(s):
IND No. 109,678;
EudraCT No. 2017-002946-62
Approval Date: 03-JUL-2018
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 2
03-Jul-2018
Amendment 1
14-Sep-2017
Original Protocol
17-Jul-2017
Amendment 02 03-JUL-2018
Overall Rationale Amendment 2: The primary reasons for amendment #2 are to:

Add the additional interim analysis of data when all subjects have completed the 
Week 24 visit, with the intent of expediting the submission of study results to 
Health Authorities;

Change the objective for assessing the preference for CAB LA + RPV LA every 8 
weeks or CAB LA + RPV LA every 4 weeks LA compared to oral antiretroviral 
(ARV) and the preference for CAB LA+ RPV LA every 8 weeks compared to 
CAB LA + RPV LA every 4 weeks from an exploratory objective to a secondary 
objective.  A change to the supporting version of the Preference questionnaire 
administered to participants at Week 48 (or withdrawal) is also acknowledged;

Add revisions and clarifications for the administration of health outcomes 
questionnaires;

Extend exclusion criterion #28 to also exclude hereditary coagulation and platelet 
disorders such as haemophilia or Von Willebrand Disease;

Update exclusion criterion #11 to indicate that CD4+ counts ˂200 cells/L are not
exclusionary;

Offer clarification that withdrawal assessments will be performed for any 
participant who withdraws prematurely from the Maintenance or Extension Phase.  
Additional guidance for participants withdrawing at Week 52 or Week 100 has 
been added;

Offer guidance to monitor medications that are dependent on OAT1 and OAT3 
transport upon concomitant exposure with CAB;

Specify that 2-hour post-dose ECG should be performed at Day 1 and Week 48 
only for participants receiving CAB LA + RPV LA as it is not required to perform 
2-hour post-dose ECG for those receiving oral CAB + RPV at Day 1;

Exclude language that previously indicated hormonal contraception may be 
susceptible to interaction with the study drugs.  The lack of a demonstrated 
interaction with a representative contraceptive supports use of CAB and RPV 
across a broad range of estrogen and progestin or progestin only hormonal 
contraceptives;
 
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
Add minor clarifications and corrections to typographical errors/formatting to 
protocol text.
Section # and 
Name
Description of Change
Brief Rationale
Synopsis Section 
1.4.2, and Section 
4.2.2, Maintenance 
Phase (Day1 up to 
Week 100), CAB LA 
+ RPV LA Dosing 
Regimens in 
ATLAS-2M 
Clarified for Q8W cohort 
transitioning from Oral Standard 
of Care (SOC) that CAB LA + 
RPV LA is administered at Week 
4b, Week 8, & Q8W thereafter. 
(Week 8 was added)
Week 8 dosing for this group was 
inadvertently omitted in Amendment #1 
of the prior protocol within these 
sections and is now updated for 
consistency with the intended dosing 
administration in other sections of the 
protocol.
Synopsis Section 
1.2, Section 3
Objectives and 
Endpoints;
Select secondary efficacy and 
safety endpoints have been 
updated to include Week 24 
endpoints.
Adds the additional analysis of data 
through Week 24 with the intent of 
expediting the submission of study 
results to Health Authorities
Synopsis Section 
1.2, Section 3
Objectives and 
Endpoints; Section 
7.8, Value Evidence 
and Outcomes; 
Section 7.8.1, Value 
Evidence and 
Outcomes 
Endpoints 
(Secondary); 
Section 9.3.7, 
Health Outcomes 
Analyses.
Assessment of the preference for 
CAB LA + RPV LA every 8 weeks 
or CAB LA + RPV LA every 4 
weeks LA compared to oral 
antiretroviral (ARV) and the 
preference for CAB LA+ RPV LA 
every 8 weeks compared to CAB 
LA + RPV LA every 4 weeks is 
changed from an exploratory 
objective to a secondary 
objective of ATLAS-2M.  The 
description of the Preference 
questionnaire is updated to 
reflect the revised questionnaire. 
The Preference questionnaire will 
be captured at Week 48 or 
Withdrawal if prior to Week 48.
The version of the Preference 
questionnaire has been updated and 
re-purposed as a secondary objective 
for the ATLAS-2M trial.
Section 4.2.4, LTFU 
Phase-IM Regimen
Only
Window for initiating HAART 
therapy during the LTFU Phase 
has been added:
HAART therapy should be 
initiated within 4 weeks (7 
days) after the last Q4W 
injection, or within 8 weeks (7 
days) after the last Q8W 
injection.
Allowable window for the initiation of 
HAART therapy ensures timely start of 
HAART during the LTFU Phase to 
approximate exposure coverage for 
CAB LA + RPV LA.
 
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Section # and 
Name
Description of Change
Brief Rationale
Section 5.2,
Exclusionary Criteria
Exclusion criterion #28 has been 
extended to also exclude 
hereditary coagulation and 
platelet disorders such as 
haemophilia or Von Willebrand 
Disease.
Exclusion criterion #11 has been 
updated to indicate that CD4+ 
counts ˂200 cells/L are not 
exclusionary.
Due to recurring intramuscular 
injections, participants with coagulation 
disorders are excluded.
HIV Stage 3 disease is excluded with 
the exceptions of cutaneous Kaposi’s 
sarcoma not requiring systemic 
therapy, and CD4+ counts ˂200 
cells/L are not exclusionary.
Section 5.5,
Withdrawal/Stopping 
Criteria; Section 
1.4.4, Long-Term 
Follow-Up Phase
Text has been added to provide 
additional instruction regarding 
withdrawal assessments to be 
performed for participants 
withdrawing from the 
Maintenance or Extension Phase 
Clarification has been added on when 
and how to perform withdrawal 
assessments relative to the time of 
individual participant withdrawal.  
Section 5.6 
Participant and 
Study Completion
Text has been added to clarify 
the definition of a study 
completer:
Randomly assigned to either 
treatment group, completed the 
randomized Maintenance Phase 
including Week 100 (with or 
without Week 100 study 
treatment) and did not enter the 
Extension Phase.
Study completers will include those 
subjects who complete Week 100 
protocol procedures and assessments 
without study treatment at Week 100 
should those subjects not enter into the 
study Extension Phase.
Section 6.1 
Investigational 
Product and Other 
Study Treatment
IP Storage requirements have 
been updated to indicated that 
study IP is to be stored according 
to the product labeling.
Specific IP storage and temperature 
requirements have been removed from 
the text as the storage conditions are 
subject to updates during the course of 
the trial which could lead to 
inconsistencies with the approved 
protocol.  Storage requirements will be 
incorporated in product labeling and
supporting trial documentation which
can be referenced separately from the 
protocol.
 
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Section # and 
Name
Description of Change
Brief Rationale
Section 6.13.2,
Prohibited 
Medications and 
Non-Drug Therapies
The following text is added:
Concurrent with CAB
CAB is a potent inhibitor of OAT1 
and OAT3 transport in vitro, 
however, no clinically significant 
interaction risk is expected for 
most drugs that are substrates of 
these transporters.  Monitoring 
may be required for drugs with a 
narrow therapeutic index and 
dependent on OAT1 and OAT3 
transport (e.g. methotrexate) with 
concomitant CAB administration.  
Refer to the current Investigator’s 
Brochure (Section 4.3.6.1 and 
Section 6.4) for additional 
information. 
Additional guidance is offered for 
monitoring of medications dependent 
on OAT1 and OAT3 transport upon 
concomitant exposure with CAB. 
Section 7.1, Time 
and Events Table 
for Q4W and Q8W 
arms.
Footnote c updated to: for Weeks 
4a and 96: Confirmation of 
eligibility to continue enter the 
Maintenance Phase and eligibility 
to enter the Extension Phase
Clarification of text
Section 7.1, Time 
and Events Table 
for Q4W and Q8W 
arms.
Footnote h updated to:  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. For 
participants transitioning from 
ATLAS, the pre-dose Week 48 
ECG can also serve as the 
ATLAS-2M Screening ECG. ECG 
pre-dose will be performed in 
triplicate at Day 1. A 2-hour post-
dose ECG will also be performed 
at Days 1 and Week 48 for 
participants receiving CAB LA + 
RPV LA with an allowable 
window of 30 minutes.
Additional guidance is provided for any 
Screening ECGs overlapping with 
ATLAS Week 48 for ATLAS rollover 
participants. Language added to 
specify that 2-hour post-dose ECG 
should be performed at Day 1 and 
Week 48 only for participants receiving 
CAB LA + RPV LA as it is not required 
to perform 2 hour post-dose ECG for 
those receiving oral CAB + RPV at Day 
1. 
 
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Section # and 
Name
Description of Change
Brief Rationale
Section 7.1, Time 
and Events Table 
for Q4W and Q8W 
arms.
Footnote r updated to:
One blood sample for CAB and 
RPV each to be collected at each 
PK timepoint.  PK samples are to 
be collected pre-dose relative to 
IM administration. At Week 4b,
Pre-dose samples are to be 
collected after review of PK diary 
provided at Day 1 and prior to the 
final oral dose of CAB + RPV for 
participants randomized from 
SOC.  PK window allowed for 
sample collection is 3 to 10 days 
for 1 wk post dose sample (Visits 
9 and 41).
Clarification of timing for pre-dose PK 
sample collection at Week 4b for 
participants randomized from oral 
SOC.
Section 7.1, Time 
and Events Table 
for Q4W and Q8W 
arms.
Footnote u updated to: All Patient 
Report Questionnaires/Surveys 
will be administered via paper 
instrument at the beginning of the 
visit before any other 
assessments are conducted and 
prior to administration of the eC-
SSRS.  Conduct 
questionnaires/surveys upon 
Withdrawal only if occurring at or 
prior to Week 48.
Clarification that all patient reported 
questionnaires are to be administered 
together at the beginning of the visit 
prior to all other assessments.  
Section 7.1, Time 
and Events Table 
for Q4W and Q8W 
arms.
Footnote v updated to: 
Clarification that versions of the 
HIV-TSQc are to be administered 
to all participants transitioning 
from ATLAS and new participants 
transitioning from oral SOC. For 
participants transitioning from 
ATLAS, the version of the HIV-
TSQc instrument to be 
administered will be based on the 
initial randomization arm at 
ATLAS Day 1
Distinct versions of the HIVTSQc have 
been developed for all participants 
including those transitioning from 
ATLAS and new participants 
transitioning from oral SOC
 
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Section # and 
Name
Description of Change
Brief Rationale
Section 7.1, Time 
and Events Table 
for Q4W and Q8W 
arms.
Footnote w updated to:
For patients randomized to oral 
SOC at Day 1 in ATLAS or new 
patients on SOC, the reasons for 
willingness to switch ART will be 
assessed at Day 1.  For patients 
randomized to CAB LA + RPV LA 
Q4W in ATLAS, the reasons for 
willingness to continue long-
acting ART in ATLAS-2M will be 
assessed at Day 1.
Additional clarification on 
administration of Reason for Switch 
and Reason for Continuation for patient 
groups.
Section 7.1, Time 
and Events Table 
for Q4W and Q8W 
arms.
Footnote X updated to: 
Preference Questionnaire will be 
administered to all participants. 
The version of the Preference 
questionnaire has been revised under 
Protocol Amendment #2 and will be 
administered to all study participants.
Section 7.1, Time 
and Events Table 
for Q4W and Q8W 
arms.
Footnote Y has been added: Refer 
to Section 5.5 of the protocol for 
additional information on 
performing withdrawal 
assessments.  HIV-1 RNA will be 
collected as Storage sample only 
if withdrawal assessments 
coincide with Week 52 or Week 
100 (as per Section 5.5.)
Reference to Section 5.5. for 
withdrawal assessments has been 
added to ensure appropriate sample 
collections are performed.
Section 7.1, Time 
and Events Table 
for Q4W and Q8W 
arms and 
throughout protocol
Footnote Z and throughout 
protocol, Month 1 of the Long-
Term Follow-Up (LTFU) visit has 
been removed such that 
participants receiving one or more 
injections with CAB LA and/or 
RPV LA will be assessed with 
clinic visits at a withdrawal visit, 
and months, 3, 6, 9 and 12 during 
the Long-Term Follow-Up Phase
Withdrawal assessments conducted 
during withdrawal visit will serve as the 
first set of follow-up assessments for 
the LTFU Phase, followed by planned 
visits at months 3, 6, 9, and 12 
following the last CAB LA + RPV LA 
injections received.
 
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Section # and 
Name
Description of Change
Brief Rationale
Section 
7.4.3.1:.Time period 
and Frequency for 
collecting AE and 
SAE information
The following text has been 
removed:
During the Extension Phase, AEs 
leading to Withdrawal and all 
SAEs will be recorded.
Clarification and to add consistency 
with other text that all AEs will be 
collected from the start of study 
treatment until the final follow-up 
contact
Section 7.4.10, 
Electrocardiogram 
(ECG)
The following text has been 
added: At Day 1 and Week 48 of 
the Maintenance Phase, a 2 hour 
post dose ECG will be performed 
for participants receiving CAB 
LA + RPV LA with an allowable 
window of 30 minutes
Adds clarification that the 2 hour post-
dose ECG is only for those participants 
receiving CAB LA  RPV LA at Day 1, 
and specifies the allowable window for 
conduct of the ECG.
Section 7.8.3 
Guidance for 
administering the 
different versions of 
HIVTSQc, 
Preference and 
Reason for Switch
Questionnaires in 
ATLAS-2M
Section 7.8.3 has been added 
including a table to guide 
administration of Evidence and 
Outcomes instruments
Additional guidance towards Value 
Evidence and Outcomes instruments 
has been added to assist investigative 
staff with administration of different 
versions of these patient 
questionnaires.
Section 9.2.2.1: 
Primary Comparison 
of Interest
Treatment with Q8W will be 
declared non-inferior to Q4W if 
the upper end of a two-sided 95% 
confidence interval for the 
difference between the two 
groups (Q8W – Q4W) in the 
proportion of participants with 
HIV-RNA 50 c/mL at Week 48 
(defined by the US FDA snapshot 
algorithm) lies below 4%.
Section 9.2.2.1 Primary Comparison of 
Interest erroneously referred to a non-
inferiority declaration of the Q8W 
regimen relative to the Q4W regimen if 
the difference in the proportion of 
participants with HIV-RNA 50 c/mL 
between the two groups lies below 5% 
rather than the intended update to 4%.  
Section 9.2.3.1  
Week 24 data 
analyses
Section 9.2.3.1 has been added 
to describe the additional 
analyses of early data through 
Week 24.
Adds the additional analysis of data 
through Week 24 with the intent of 
expediting the submission of study 
results to Health Authorities
 
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Section # and 
Name
Description of Change
Brief Rationale
Appendix 7: 
Contraceptive 
Guidance and 
Collection of 
Pregnancy 
Information
Footnote b from Table 14 has 
been modified to exclude 
language indicating that 
hormonal contraception may be 
susceptible to interaction with the 
study drugs.
Hormonal contraception may be 
susceptible to interaction with the study 
drug, which may reduce the efficacy of 
the contraceptive method. In this case
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.
CAB and RPV have demonstrated no 
impact on the pharmacokinetics of 
commonly used combined estrogen 
and progestin containing oral 
contraceptives. Neither CAB nor RPV 
induce or inhibit UGT or CYP enzymes 
which are the predominant metabolic 
routes of elimination for these products. 
The interaction has only been studied 
with levonorgestrel/ethinyl estradiol for 
CAB and norethindrone/ethinyl 
estradiol for RPV. The lack of a 
demonstrated interaction with a 
representative contraceptive supports 
use of CAB and RPV across a broad 
range of estrogen and progestin or 
progestin only hormonal 
contraceptives.
General Updates
Additional minor clarifications and 
corrections to typographical 
errors/formatting to protocol text 
have been added.
Text clarifications and formatting
 
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TABLE OF CONTENTS
Page
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................4
1.
SYNOPSIS.............................................................................................................18
1.1.
Rationale ....................................................................................................18
1.2.
Objectives and Endpoints ...........................................................................19
1.3.
Overall Design ............................................................................................21
1.3.1.
207966 (ATLAS-2M) Study Design Schematic ............................23
1.3.2.
Number of Participants ................................................................23
1.4.
Treatment Groups and Duration .................................................................24
1.4.1.
Screening Phase (Up to 35 days) ................................................24
1.4.2.
Maintenance Phase (Day 1 up to Week 100)...............................24
1.4.2.1.
Patients randomized to LA dosing from current 
ART SOC therapy:......................................................25
1.4.2.1.1.
IM injections every 4 weeks (Q4W 
from SOC): .............................................26
1.4.2.1.2.
IM injections every 8 weeks (Q8W 
from SOC): .............................................26
1.4.2.2.
Participants transitioning from ATLAS and 
currently receiving CAB LA + RPV LA Q4W ...............27
1.4.2.2.1.
IM injections every 4 weeks (Q4W 
from ATLAS Q4W):.................................27
1.4.2.2.2.
IM injections every 8 weeks (Q8W 
from ATLAS Q4W):.................................28
1.4.3.
Extension Phase..........................................................................28
1.4.4.
Long-Term Follow-Up Phase .......................................................29
1.4.5.
Dose Modifications: .....................................................................30
2.
INTRODUCTION....................................................................................................30
2.1.
Study Rationale ..........................................................................................31
2.2.
Background ................................................................................................31
2.3.
Benefit/Risk Assessment ............................................................................34
2.3.1.
Risk Assessment .........................................................................34
2.3.1.1.
Other Clinically Relevant Information..........................48
2.3.2.
Benefit Assessment.....................................................................48
2.3.3.
Overall Benefit:Risk Conclusion...................................................48
3.
OBJECTIVES AND ENDPOINTS...........................................................................49
4.
STUDY DESIGN ....................................................................................................52
4.1.
Overall Design ............................................................................................52
4.2.
Treatment Groups and Duration .................................................................54
4.2.1.
Screening Phase (Up to 35 days) ................................................54
4.2.2.
Maintenance Phase (Day 1 up to Week 100)...............................55
4.2.2.1.
Patients randomized to LA dosing from current 
ART SOC therapy:......................................................56
4.2.2.1.1.
IM injections every 4 weeks (Q4W 
from SOC): .............................................57
4.2.2.1.2.
IM injections every 8 weeks (Q8W 
from SOC): .............................................57
 
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4.2.2.2.
Participants transitioning from ATLAS and 
currently receiving CAB LA + RPV LA Q4W ...............58
4.2.2.2.1.
IM injections every 4 weeks (Q4W 
from ATLAS Q4W):.................................58
4.2.2.2.2.
IM injections every 8 weeks (Q8W 
from ATLAS Q4W):.................................58
4.2.3.
Extension Phase..........................................................................59
4.2.4.
LTFU Phase – IM Regimen Only .................................................60
4.2.5.
Dose Modifications: .....................................................................60
4.2.6.
Independent Data Monitoring Committee.....................................61
4.3.
Type and Number of Participants................................................................61
4.4.
Scientific Rationale for Study Design ..........................................................62
4.5.
Dose Justification........................................................................................64
4.5.1.
Oral Lead-In Phase......................................................................64
4.5.2.
Long Acting Injectable for Maintenance Phase ............................67
4.5.2.1.
CAB LA Q8W .............................................................70
4.5.2.1.1.
CAB PK Profile Following 
Transition to Q8W Regimen....................70
4.5.2.2.
CAB LA Q4W .............................................................73
4.5.3.
RPV LA........................................................................................75
4.5.3.1.
RPV LA Q8W .............................................................76
4.5.3.1.1.
RPV PK Profile Following 
Transition to Q8W Regimen....................77
4.5.3.2.
RPV LA Q4W .............................................................80
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............82
5.1.
Inclusion Criteria.........................................................................................82
5.2.
Exclusion Criteria........................................................................................85
5.3.
Additional Eligibility Criteria.........................................................................89
5.4.
Screening/Baseline/Run-in Failures............................................................90
5.5.
Withdrawal/Stopping Criteria.......................................................................90
5.5.1.
Liver Chemistry Stopping Criteria ................................................93
5.5.1.1.
Liver Chemistry Stopping Criteria, Participant 
Management and Follow-Up.......................................94
5.5.1.2.
Liver Event Adjudication Committee...........................95
5.5.1.3.
Liver Chemistry Stopping Criteria – Restart / 
Rechallenge ...............................................................95
5.5.1.3.1.
Drug Restart / Rechallenge.  
Following Liver Events that are 
Possibly Related to IP.............................95
5.5.1.3.2.
Drug Restart Following Transient 
Resolving Liver Events Not 
Related to IP...........................................96
5.5.2.
QTc Stopping Criteria ..................................................................96
5.5.3.
Virologic Failure...........................................................................97
5.5.4.
Definition of Protocol-Defined Confirmed Virologic Failure...........97
5.5.5.
Managing Virologic Failure ..........................................................97
5.5.5.1.
HIV-1 RNA Blips.........................................................97
5.5.5.2.
Suspected Virologic Failure........................................98
5.5.5.3.
Confirmed Virologic Failure ........................................99
5.6.
Participant and Study Completion...............................................................99
 
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6.
STUDY TREATMENT ..........................................................................................100
6.1.
Investigational Product and Other Study Treatment..................................100
6.1.1.
Formulations of CAB + RPV ......................................................100
6.1.1.1.
Cabotegravir Tablets (CAB)......................................100
6.1.1.2.
Rilpivirine Tablets (RPV)...........................................101
6.1.1.3.
Cabotegravir Injectable Suspension (CAB LA) .........101
6.1.1.4.
Rilpivirine Injectable Suspension (RPV LA) ..............101
6.2.
Treatment Assignment..............................................................................101
6.3.
Dosage and Administration.......................................................................102
6.4.
Blinding.....................................................................................................104
6.5.
Packaging and Labeling............................................................................104
6.6.
Preparation/Handling/Storage/Accountability............................................104
6.6.1.
Dosing Considerations for CAB LA + RPV LA............................105
6.7.
Compliance with Study Treatment Administration.....................................106
6.8.
Protocol Permitted Substitutions...............................................................107
6.8.1.
Oral Bridging..............................................................................107
6.9.
Interruption of Study Treatment and Visit/Dosing Windows.......................107
6.9.1.
IM Dosing ..................................................................................107
6.9.1.1.
IM injections every 4 weeks (Q4W): .........................108
6.9.1.2.
IM injections every 8 weeks (Q8W): .........................109
6.9.1.3.
IM injections every 4 weeks (Q4W) (Q4W from 
ATLAS Q4W):...........................................................109
6.9.1.4.
IM injections every 8 weeks (Q8W) (Q8W from 
ATLAS Q4W):...........................................................110
6.9.2.
Oral Dosing................................................................................110
6.10.
Discontinuation of Study Treatment ..........................................................111
6.11.
Treatment of Study Treatment Overdose..................................................111
6.12.
Treatment after the End of the Study ........................................................112
6.13.
Concomitant Medications and Non-Drug Therapies..................................112
6.13.1.
Permitted Medications and Non-Drug Therapies........................112
6.13.2.
Prohibited Medications and Non-Drug Therapies.......................113
6.13.2.1.
Concurrent with CAB and/or RPV.............................114
6.13.2.2.
Concurrent with either CAB LA or RPV LA ...............115
6.13.2.3.
Prohibited Medications for Participants 
Receiving HAART during the Long-Term 
Follow-Up Phase ......................................................115
7.
STUDY ASSESSMENTS AND PROCEDURES ...................................................115
7.1.
Time and Events Table.............................................................................116
7.1.1.
Time and Events Table for CAB LA + RPV LA Q4 Weekly 
Administration............................................................................117
7.1.2.
Time and Events Table for CAB LA + RPV LA Q8 Weekly 
Administration............................................................................125
7.2.
Screening and Critical Baseline Assessments ..........................................133
7.2.1.
Screening Assessments ............................................................133
7.2.2.
Baseline Assessments...............................................................134
7.3.
Efficacy.....................................................................................................135
7.3.1.
Plasma HIV-1 RNA....................................................................135
7.3.2.
Lymphocyte Subsets, CD4+ and CD8+ .....................................135
7.3.3.
HIV Associated Conditions ........................................................135
7.4.
Safety .......................................................................................................136
7.4.1.
Clinical Evaluations....................................................................136
 
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7.4.2.
Laboratory Assessments ...........................................................137
7.4.3.
Adverse Events (AE) and Serious Adverse Events (SAEs)........139
7.4.3.1.
Time period and Frequency for collecting AE 
and SAE information.................................................139
7.4.3.2.
Method of Detecting AEs and SAEs .........................140
7.4.3.3.
Follow-up of AEs and SAEs......................................140
7.4.3.4.
Prompt Reporting of Serious Adverse Events 
and Other Events .....................................................140
7.4.3.5.
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ..............142
7.4.3.6.
Regulatory Reporting Requirements for SAEs..........143
7.4.3.7.
Cardiovascular and Death Events ............................143
7.4.3.8.
Death Events............................................................144
7.4.4.
Toxicity Management.................................................................144
7.4.4.1.
Treatment Interruption Due to an Adverse 
Event........................................................................144
7.4.4.2.
Grade 1 or Grade 2 Toxicity/Adverse Event .............145
7.4.4.3.
Grade 3 Toxicity/Adverse Event ...............................145
7.4.4.4.
Grade 4 Toxicity/Adverse Event ...............................146
7.4.5.
Specific Toxicities/Adverse Event Management.........................146
7.4.5.1.
Liver Chemistry Stopping and Follow-up 
Criteria......................................................................146
7.4.5.2.
Diarrhea ...................................................................147
7.4.5.3.
Hypertriglyceridemia/ Hypercholesterolemia.............147
7.4.5.4.
Seizures ...................................................................147
7.4.5.5.
Creatine Phosphokinase (CPK) Elevation ................148
7.4.5.6.
Lipase Elevations and Pancreatitis...........................148
7.4.5.7.
Decline in Renal Function.........................................149
7.4.5.7.1.
Proximal Renal Tubule 
Dysfunctions (PRTD)............................150
7.4.5.8.
Proteinuria................................................................150
7.4.5.9.
QTc Prolongation .....................................................151
7.4.5.10.
Injection Site Reactions (ISRs) .................................151
7.4.5.11.
Allergic reaction........................................................151
7.4.5.12.
Abacavir Hypersensitivity Reaction (ABC HSR)........151
7.4.5.12.1.
Essential Patient Information ................152
7.4.5.12.2.
Reporting of Hypersensitivity 
Reactions .............................................153
7.4.5.13.
Rash Without ABC HSR Symptoms .........................153
7.4.6.
Suicidal Risk Monitoring.............................................................155
7.4.7.
Pregnancy .................................................................................156
7.4.7.1.
Pregnancy testing.....................................................156
7.4.7.2.
Time Period for Collecting Pregnancy 
Information ...............................................................156
7.4.7.3.
Action to be Taken if Pregnancy Occurs...................156
7.4.8.
Physical Exams .........................................................................157
7.4.9.
Vital Signs..................................................................................157
7.4.10.
Electrocardiogram (ECG)...........................................................157
7.5.
Pharmacokinetics .....................................................................................158
7.5.1.
PK Sample Collection ................................................................158
7.5.2.
Rationale of PK Sampling Strategy............................................160
7.5.3.
Sample Analysis ........................................................................160
 
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7.5.3.1.
CAB Sample Analysis...............................................160
7.5.3.2.
RPV Sample Analysis...............................................160
7.6.
Genetics ...................................................................................................160
7.7.
Viral Genotyping and Phenotyping............................................................160
7.7.1.
HIV-1 Polymerase Viral Genotyping and Phenotyping ...............161
7.7.2.
HIV-1 Exploratory Analysis ........................................................161
7.8.
Value Evidence and Outcomes.................................................................161
7.8.1.
Value Evidence and Outcomes Endpoints (Secondary).............163
7.8.2.
Value Evidence and Outcomes Endpoints (Exploratory)............163
7.8.3.
Guidance for administering the different versions of 
HIVTSQc, Preference and Reason for Switch 
Questionnaires in ATLAS-2M.....................................................164
8.
DATA MANAGEMENT .........................................................................................165
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES ...............................165
9.1.
Sample Size Considerations.....................................................................166
9.1.1.
Rationale for non-inferiority margin ............................................166
9.1.2.
Assumption for Snapshot Proportion with HIV-RNA 50 
c/mL at Week 48 (Primary Endpoint) .........................................166
9.1.3.
Assumption for Response Rate at Week 48 (Secondary 
Endpoint) ...................................................................................167
9.1.4.
Sample Size Sensitivity..............................................................167
9.1.5.
Sample Size Re-estimation or Adjustment.................................169
9.2.
Data Analysis Considerations ...................................................................169
9.2.1.
Analysis Populations..................................................................169
9.2.1.1.
Intent-to-Treat Exposed (ITT-E)................................169
9.2.1.2.
Per-Protocol Population (PP)....................................169
9.2.1.3.
PK Population...........................................................170
9.2.1.4.
Safety Population .....................................................170
9.2.2.
Treatment Comparisons ............................................................170
9.2.2.1.
Primary Comparison of Interest ................................170
9.2.2.2.
Other Comparisons of Interest..................................170
9.2.3.
Planned Analyses......................................................................170
9.2.3.1.
Week 24 data analyses ............................................171
9.2.3.2.
IDMC analyses.........................................................171
9.3.
Key Elements of Analysis Plan .................................................................171
9.3.1.
Primary Analyses.......................................................................171
9.3.2.
Secondary Analyses ..................................................................173
9.3.2.1.
Key Secondary Efficacy Analysis..............................173
9.3.2.2.
Other Secondary Endpoint Analyses ........................173
9.3.3.
Pharmacokinetic Analyses.........................................................174
9.3.4.
Population PK Analysis:.............................................................175
9.3.5.
Pharmacokinetic/Pharmacodynamic Analyses...........................175
9.3.6.
Viral Genotyping/Phenotyping Analyses ....................................175
9.3.7.
Health Outcomes Analyses........................................................175
9.3.8.
Genetic Analyses.......................................................................176
9.3.9.
Other Analyses ..........................................................................176
10. REFERENCES.....................................................................................................177
11. APPENDICES......................................................................................................181
 
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11.1.
Appendix 1:  Abbreviations and Trademarks.............................................181
11.2.
Appendix 2:  Division of AIDS Table for Grading the Severity of 
Adult and Pediatric Adverse Events Version 2.1, March 2017...................185
11.3.
Appendix 3:  Liver Safety – Study Treatment Restart or Rechallenge 
Guidelines.................................................................................................209
11.3.1.
VSLC Guidelines for Drug Restart or Rechallenge after 
stop for Liver criteria ..................................................................209
11.3.2.
VSLC Decision Process for Drug Rechallenge Approval or 
Disapproval................................................................................210
11.3.3.
VSLC Decision Process for Drug Restart Approval or 
Disapproval................................................................................213
11.3.4.
Medical monitor, GCSP Physician and PI actions for 
Restart or Rechallenge following VSLC decision .......................214
11.3.4.1.
Medical Monitor and GCSP Physician Actions..........214
11.3.4.2.
PI Actions:................................................................215
11.4.
Appendix 4:  CDC Classification for HIV-1 Infection (2014).......................216
11.5.
Appendix 5:  Genetic Research ................................................................218
11.6.
Appendix 6:  Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events ..........................221
11.6.1.
Definition of Adverse Events......................................................221
11.6.2.
Definition of Serious Adverse Events.........................................222
11.6.3.
Definition of Cardiovascular Events ...........................................224
11.6.4.
Recording of AEs and SAEs ......................................................224
11.6.5.
Evaluating AEs and SAEs..........................................................225
11.6.6.
Reporting of SAEs to GSK.........................................................226
11.7.
Appendix 7:  Contraceptive Guidance and Collection of Pregnancy 
Information................................................................................................228
11.7.1.
Collection of Pregnancy Information ..........................................230
11.8.
Appendix 8: Study governance Considerations.........................................231
11.8.1.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process ........................................................231
11.8.2.
Financial Disclosure...................................................................231
11.8.3.
Informed Consent Process ........................................................232
11.8.4.
Data Protection..........................................................................232
11.8.5.
Independent Data Monitoring Committee...................................233
11.8.6.
Quality Control (Study Monitoring) .............................................233
11.8.7.
Data Quality Assurance .............................................................233
11.8.8.
Source Documents ....................................................................234
11.8.9.
Study and Site Closure ..............................................................234
11.8.10. Records Retention.....................................................................235
11.8.11. Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials 
Registers and Publication ..........................................................235
11.9.
Appendix 9: Country-Specific Requirements.............................................237
11.9.1.
Study Duration...........................................................................237
11.10. Appendix 10: Protocol Amendment History...............................................238
 
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1.
SYNOPSIS
Protocol Title: A Phase IIIb, Randomized, Multicenter, Parallel-group, Non-inferiority, 
Open-label Study Evaluating the Efficacy, Safety, and Tolerability of Long-acting 
Cabotegravir Plus Long-acting Rilpivirine Administered Every 8 Weeks or Every 4 
Weeks in HIV-1-infected Adults who are Virologically Suppressed
Short Title: Study Evaluating the Efficacy, Safety, and Tolerability of Long-acting 
Cabotegravir Plus Long-acting Rilpivirine administered every 8 weeks in Virologically 
Suppressed HIV-1-infected Adults.
1.1.
Rationale
The 207966 (ATLAS-2M) study is being conducted to establish if human 
immunodeficiency virus type 1 (HIV-1) infected adult participants with current viral 
suppression (HIV-1 RNA 50 c/mL) remain suppressed upon administration of a two-
drug intramuscular (IM) long-acting (LA) regimen of cabotegravir (CAB) and rilpivirine 
(RPV) administered every 8 weeks (Q8W; every 2 months).  This study is designed to 
demonstrate the non-inferior antiviral activity of CAB LA 600 mg + RPV LA 900 mg 
administered every 8 weeks compared with CAB LA 400 mg + RPV LA 600 mg 
administered every 4 weeks (Q4W; monthly) over a 48-week treatment period.  ATLAS-
2M will also provide comparative data on antiviral activity, safety, tolerability, and 
patient satisfaction through Week 96.  
Two groups of participants with demonstrated virologic suppression will be enrolled into 
ATLAS-2M including participants who at Screening are 1) receiving oral standard of 
care triple antiretroviral therapy (SOC) or 2) receiving a two drug IM regimen of Q4W 
CAB LA + RPV LA.  The majority of participants in ATLAS-2M will rollover from the 
ongoing 201585 (ATLAS) trial and additional participants on SOC will also be included 
in order to support a targeted total sample size of approximately 1020 participants.  
Participants entering on SOC treatment consisting of a stable antiretroviral (ARV)
regimen containing 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus an
integrase inhibitor (INI), non-nucleoside reverse transcriptase inhibitor (NNRTI), or a
protease inhibitor (PI), will therefore either enter as new study participants or will 
rollover from the ongoing ATLAS trial.  All participants entering on Q4W CAB LA + 
RPV LA will be rolled over from the ATLAS trial.    
ATLAS is a Phase III, randomized, multicenter, parallel-group, non-inferiority, open-
label study evaluating the efficacy, safety, and tolerability of switching to CAB LA + 
RPV LA from current INI- NNRTI-, or PI-based antiretroviral regimen in HIV-1-infected 
adults who are virologically suppressed.  ATLAS participants randomized to the SOC, 
“current antiretroviral” treatment arm, consisting of 2 nucleoside reverse transcriptase 
inhibitors (NRTIs) plus a third agent (INI, NNRTI, or a PI), or the CAB LA + RPV LA 
Q4W arm, who successfully complete Week 52 (at minimum) of ATLAS, and remain 
virologically suppressed (HIV-1 RNA <50 c/mL), will be eligible to enter ATLAS-2M.   
Eligible participants entering ATLAS-2M on oral SOC (either from ATLAS or new 
participants) will be randomized (1:1) to the CAB LA + RPV LA Q4W or Q8W regimen 
 
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beginning with 4 weeks of oral lead-in with CAB + RPV to confirm tolerability prior to 
IM dosing with CAB LA and RPV LA.  Eligible participants entering from ATLAS on 
the CAB LA+ RPV LA Q4W regimen will be randomized (1:1) to either continue Q4W 
injections or transition to Q8W injections in ATLAS-2M (without the oral lead-in). 
All participants who successfully complete Week 100 of CAB LA + RPV LA treatment 
in the Maintenance Phase will continue to have access to their randomized CAB LA +
RPV LA regimen 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 their assigned CAB LA + RPV LA regimen is terminated.  
1.2.
Objectives and Endpoints
Objectives
Endpoints
Primary
To demonstrate the non-inferior antiviral 
activity of CAB LA + RPV LA every 8 
weeks (every two months) compared to 
CAB LA + RPV LA every 4 weeks 
(monthly) over 48 weeks in suppressed 
HIV-1 infected antiretroviral therapy 
(ART)-experienced participants
Proportion of participants with plasma
HIV-RNA greater than or equal to 50 
copies/mL as per Food and Drug 
Administration (FDA) Snapshot algorithm 
at Week 48 (Intent-to-Treat Exposed [ITT-
E] population)
Secondary
To demonstrate the antiviral and 
immunologic activity of CAB LA + RPV 
LA every 8 weeks compared to CAB LA + 
RPV LA every 4 weeks
Proportion of participants with plasma 
HIV-1 RNA <50 c/mL (c/mL) at Week 24,
Week 48 and Week 96 using the FDA 
Snapshot algorithm (Intent-to-Treat 
Exposed [ITT-E] population)
Proportion of participants with protocol-
defined confirmed virologic failure (CVF) 
through Week 24, Week 48 and Week 96
Proportion of participants with HIV-RNA 
greater than or equal to 50 c/mL as per 
FDA Snapshot algorithm at Week 24 and
Week 96
Absolute values and changes from Baseline 
in viral load and CD4+ cell counts over 
time including Week 48 and Week 96
 
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Objectives
Endpoints
To evaluate the safety and tolerability of 
CAB LA + RPV LA every 8 weeks 
compared to CAB LA + RPV LA every 4 
weeks
Incidence and severity of AEs and 
laboratory abnormalities over time 
including Week 24, Week 48 and Week 96
Proportion of participants who discontinue 
treatment due to AEs over time including
Week 24, Week 48 and Week 96
Change from Baseline in laboratory 
parameters over time including Week 48 
and Week 96
To assess viral resistance in participants 
experiencing protocol-defined confirmed 
virologic failure 
Incidence of treatment emergent genotypic 
and phenotypic resistance to CAB, RPV 
through Week 24, 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 preference for CAB LA + RPV 
LA every 8 weeks or CAB LA + RPV LA 
every 4 weeks LA compared to oral 
antiretroviral (ARV) 
To assess preference for CAB LA+ RPV
LA every 8 weeks compared to CAB LA + 
RPV LA every 4 weeks 
Preference for CAB LA + RPV LA every 8 
weeks and CAB LA + RPV LA every 4 
weeks compared to oral ARV and 
preference for CAB LA + RPV LA every 8 
weeks compared to CAB LA + RPV LA 
every 4 weeks will be assessed using a 
preference questionnaire at week 48 (or 
Withdrawal). 
To assess patient reported health-related 
quality of life, treatment satisfaction, 
injection tolerability, and treatment 
acceptance.  
Change from Baseline (Day 1) in HRQoL 
at Week 24, and Week 48 (or Withdrawal)
Change from baseline (Day 1) in total 
“treatment satisfaction” score, and 
individual item scores of the HIV 
Treatment Satisfaction Status 
Questionnaire (HIVTSQs) at Week 24, and 
48, (or Withdrawal)
 
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Objectives
Endpoints
Change in treatment satisfaction over time 
using the HIV Treatment Satisfaction 
Change Questionnaire HIVTSQc at Week 
48 (or Withdrawal).
Change from Week 8 in Dimension scores 
(“Bother of ISRs”, “Leg movement”, 
“Sleep”, and “Injection Acceptance”) and 
individual item scores assessing pain 
during injection, anxiety before and after 
injection, willingness to be injected in the 
future and overall satisfaction with mode of 
administration over time will be assessed 
using the Perception of iNjection 
questionnaire (PIN) at Weeks 8, 24, and 48 
(or Withdrawal) 
Change from Baseline (Day 1) in treatment 
acceptance at Week 24 and Week 48 (or 
Withdrawal) will be assessed using the 
“General acceptance” dimension of the 
Chronic Treatment Acceptance (ACCEPT) 
questionnaire
1.3.
Overall Design
Study 207966 (Antiretroviral Therapy as Long Acting Suppression every 2 Months-
ATLAS-2M) is a Phase III, randomized, open-label, active-controlled, multicenter, 
parallel-group, non-inferiority study designed to assess the antiviral activity and safety of 
CAB LA + RPV LA administered every 4 weeks compared to CAB LA + RPV LA 
administered every 8 weeks in approximately 1020 adult HIV-1 infected participants.  
Two groups of patients who fulfill eligibility requirements will be randomized (1:1) to 
receive CAB LA + RPV LA Q4W, or CAB LA + RPV LA Q8W regimen for at least 100 
weeks: 
Group 1: Patients randomized from current ART SOC therapy
Patients randomized from current ART SOC therapy, including those enrolled to the 
“current ART” arm of the ATLAS study following completion of the Week 52 visit (at 
minimum), will begin oral therapy with CAB 30 mg + RPV 25 mg once daily at Day 1 
for 28 days (3 days) to determine individual safety and tolerability prior to receiving 
CAB LA + RPV LA Q4W, or CAB LA + RPV LA Q8W.  For patients on SOC 
transitioning from the ATLAS trial, eligibility for ATLAS-2M can be determined once 
the final central lab results from ATLAS are available and safety parameters have been 
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Group 2: Patients currently receiving CAB LA + RPV LA Q4W
Patients currently receiving CAB LA + RPV LA Q4W within ATLAS will be 
randomized at Day 1 to either continue Q4W administration or transition to Q8W 
administration of CAB LA + RPV LA.  Eligible patients include those originally 
randomized to Q4W in the Maintenance phase of ATLAS and those who transitioned 
from SOC to the Q4W regimen within the Extension Phase of ATLAS.  The first 
injection visit for ATLAS-2M can be performed once the final central lab results from 
ATLAS are available and safety parameters have been reviewed, and the ATLAS 
Week 52 visit (at minimum) has been completed.  Participants will continue to receive 
CAB LA + RPV LA Q4W injections as scheduled within the ATLAS trial until their 
eligibility for ATLAS-2M can be fully evaluated and the participant is re-randomized 
(Q4W or Q8W).  If determined to be ineligible for ATLAS-2M, those participants can 
elect to continue participation in ATLAS or withdraw from the ATLAS study.
Participants in ATLAS-2M who successfully complete Week 100 (without meeting study 
defined withdrawal criteria) will be given the option to continue to receive their 
randomized treatment (CAB LA + RPV LA administered Q4W or Q8W) in the Extension 
Phase until the randomized  study treatment is either locally approved and commercially 
available within the local sector (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 + 
RPV LA Q4W and/or Q8W is terminated.  Alternatively, participants can choose to 
complete study participation and enter the 52-week Long-Term Follow-Up (LTFU) Phase 
of the study.
Any participant who receives at least one dose of CAB LA and/or RPV LA and 
discontinues the CAB LA + RPV LA regimen for any reason will enter a 52-week LTFU 
Phase.  Those 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 treatment arms, randomization will be stratified by 
prior CAB + RPV Exposure: 0 weeks, 1-24 weeks, >24 weeks.  The primary endpoint for 
the study is the proportion of participants with HIV-RNA greater than or equal to 
50 c/mL (Virologic Failure) at Week 48 as per Food and Drug Administration (FDA) 
Snapshot algorithm using the Intent-to-Treat Exposed (ITT-E) population.  The 
proportion of participants with plasma HIV-1 RNA <50 c/mL at Week 48 using the FDA 
Snapshot algorithm (Missing, Switch or Discontinuation = Failure, ITT-E population) is a 
key secondary endpoint comparison.  
The sample size of 1020 provides 85% power to demonstrate non-inferiority in the 
primary endpoint at Week 48 using a 4% margin, assuming a true 3% failure rate for 
Q8W CAB LA + RPV LA and a 2% failure rate for the Q4W CAB LA + RPV LA arm 
and a 2.5% one-sided alpha level (using unpooled Z test statistic).  
 
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1.3.1.
207966 (ATLAS-2M) Study Design Schematic
1.3.2.
Number of Participants
The target population to be enrolled is HIV-1 infected virologically suppressed (HIV-1 
RNA <50 c/mL) patients on stable antiretroviral therapy (ART) including participants 
who have completed, at minimum, Week 52 of the ATLAS study.
It is anticipated that approximately 1020 participants will be enrolled into ATLAS-2M.  
In addition to participants rolled over from the ATLAS study, additional participants on 
SOC treatment will be screened to supplement enrollment such that the study can be 
appropriately powered.  A 15% screen failure rate, for additional patients randomized 
from SOC treatment is anticipated.  Participants will be enrolled from multiple countries 
which may include those countries actively participating in the ATLAS study including 
Australia, Argentina, Canada, France, Germany, Italy, Mexico, Russia, South Africa, 
South Korea, Spain, Sweden, and the United States. 
Randomization will be stratified by prior CAB + RPV exposure: 0 weeks, 1-24 weeks, 
>24 weeks.  A goal of this study is to enroll populations who are underrepresented in 
clinical studies including approximately 25% women.  To provide sufficient data to 
determine whether either gender is correlated with treatment response, sites are expected 
to take into account gender in their screening strategies. 
N=1020, randomized 1:1 to each arm and stratified by prior CAB + RPV Exposure
# SOC Patients not transitioning from the ATLAS study must be on uninterrupted current
regimen (either the initial or second cART regimen) for at least 6 months prior to Screening. 
Documented evidence of at least two plasma HIV-1 RNA measurements <50 c/mL in the 12 
months prior to Screening: one within the 6 to 12 month window, and one within 6 months prior 
to Screening.  No history of virologic failure.  No evidence of viral resistance based on the 
presence of any resistance-associated major INI, or NNRTI mutation (except K103N) from prior 
genotype assay results. No current or prior history of etravirine use.
†Optional Extension Phase to continue randomized CAB LA + RPV LA Q4W or Q8W at Wk 100
¥Participants who withdraw from IM regimen must go into 52 week long term follow up phase if 
randomized regimen is not yet locally approved and commercially available. 
 
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1.4.
Treatment Groups and Duration
1.4.1.
Screening Phase (Up to 35 days)
Informed consent must be obtained prior to any study procedures, including any 
Screening assessment.
Participants will be involved in a Screening period of up to 35 days and may be re-
screened once.  Participants who are randomized into the trial and subsequently 
withdrawn from the study, for any reason, may not be re-screened.  Participants may be 
randomized as soon as all eligibility requirements have been confirmed at the site.
For participants transitioning from the ATLAS study, eligibility to transition to ATLAS-
2M at Week 52 (at the earliest) will be determined once the final central lab results from 
ATLAS, following (at minimum) completion of the ATLAS Week 48 visit are available 
and safety parameters have been reviewed.  Separate Screening Labs will be utilized to 
inform eligibility for ATLAS-2M; however, in some occasions and upon consultation 
with the Medical Monitor, individual lab results and safety data from the final visit of the 
ATLAS study can be considered towards informing eligibility for the ATLAS-2M study 
as long as all other Screening and eligibility criteria are met.    
1.4.2.
Maintenance Phase (Day 1 up to Week 100)
There are two ways in which study participants may transition to the LA regimen, either 
directly from oral SOC or from Q4W dosing from ATLAS. 
The Table and Figure below describe the CAB LA + RPV LA dosing regimens in 
ATLAS-2M based on the mode of transition.
CAB LA + RPV LA Dosing Regimens in ATLAS-2M
Participants Transitioning from Oral Standard of Care (SOC)
Regimen
CAB LA
RPV LA
Q4W
CAB LA:
Week 4b: 600 mg (Loading Dose)
Week 8 & Q4W thereafter: 400 mg  
RPV LA:
Week 4b: 900 mg (Loading Dose)
Week 8 & Q4W thereafter: 600 mg
Q8W
CAB LA:
Week 4b, Week 8, & Q8W thereafter: 
600 mg
RPV LA:
Week 4b, Week 8, & Q8W thereafter: 
900 mg
Participants Transitioning from ATLAS Q4W
Regimen
CAB LA
RPV LA
Q4W
CAB LA:
Day 1 & Q4W thereafter: 400 mg
RPV LA:
Day 1 & Q4W thereafter: 600 mg
 
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Q8W
CAB LA:
Day 1 & Q8W thereafter: 600 mg  
RPV LA:
Day 1 & Q8W thereafter: 900 mg
All participants entering ATLAS-2M from an oral SOC regimen will receive a 4-week oral lead-in of CAB+RPV prior to 
receiving IM injections, except for ATLAS subjects transitioning from Q4W to Q8W injections.  These participants 
previously established safety and tolerability of CAB + RPV within the ATLAS study.
ATLAS-2M Treatment Schematic
Screening Phase
Maintenance Phase and Extension Phase
From ATLAS 
on Q4W
From ATLAS
on SOC
-or-
new SOC 
patients
(PI, NNRTI, or INI  
Regimen + 2 NRTI)
Q8W
Wk 24
Q4W 
Randomize 
1:1
Q8W 
Oral CAB
+ RPV
Oral CAB
+ RPV
Q4W 
Day 1
Wk 4b
Wk 4a
Randomize 
1:1
Wk 12
Wk 8
Wk 16
CAB 600mg/RPV 900mg
CAB 400mg/RPV 600mg
Wk 20
… continued to 
end of study
treatment
1.4.2.1.
Patients randomized to LA dosing from current ART SOC therapy:
All participants randomized from current ART SOC therapy (including those 
transitioning from SOC in ATLAS and new study participants) will begin oral therapy 
with CAB 30 mg + RPV 25 mg once daily at Day 1 for 4 weeks to determine individual 
safety and tolerability prior to administration of CAB LA + RPV LA.  The oral lead-in 
period is part of the Maintenance Phase and will therefore be included within the 48 and 
96 week analyses. 
The final dosing of current daily oral ART regimen should occur the day prior to 
randomization to avoid overlap of treatment regimens however, if the participant takes 
current ART prior to coming into the clinic, randomization and initiation of oral CAB 
and RPV should continue as planned for Day 1.  At the Week 4a visit, safety assessments 
(including e.g., clinical chemistries) will be performed as per the Time and Events Table 
to determine individual safety and tolerability prior to the initial administration of CAB 
LA + RPV LA.  Dosing of CAB LA + RPV LA Q4W or Q8W will initiate at the Week 
4b visit once safety labs from Week 4a are available and have been reviewed.
 
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Subjects receiving oral SOC treatment and randomized to Q4W injections will receive 
loading doses of CAB LA 600 mg + RPV LA 900 mg on Week 4b followed by 
maintenance injections of CAB LA 400 mg + RPV LA 600 mg every 4 weeks thereafter.  
Subjects receiving oral SOC treatment and randomized to Q8W injections will receive 
doses of CAB LA 600 mg + RPV LA 900 mg on Week 4b and Week 8 followed by 
identical maintenance dose injections every 8 weeks thereafter.
All injections should be planned as single injections per drug.
1.4.2.1.1.
IM injections every 4 weeks (Q4W from SOC):
Week 4b visit only - CAB LA 600 mg + RPV LA 900 mg, each given as 1 X 3 mL IM 
injection
Week 8 visit and Q4W thereafter - CAB LA 400 mg IM + RPV LA 600 mg IM every 4 
weeks for 100 weeks, each given as 1 X 2 mL IM injection
At Week 4b, participants will return to the clinic, take the last oral dose (CAB 30 mg + 
RPV 25 mg), and receive the first CAB LA (600 mg) + RPV LA (900 mg) injections 
(within 2 hours of the final oral dose of CAB + RPV).  The first injection visit with IM 
CAB LA + RPV LA at Week 4b can be performed once central lab results are available 
and safety parameters are reviewed from the Week 4a visit.  
The second and third IM injections with CAB LA 400 mg and RPV LA 600 mg will be
performed at Week 8 and Week 12.  There will be a -7-day dosing window for the second 
and third IM injections such that the second injection occurs within the window of Week 
7 and Week 8 but no later than Week 8 and the third injection occurs within the window 
of Week 11 and Week 12 but no later than Week 12.  Subsequent injections with CAB 
LA 400 mg and RPV LA 600 mg will occur every 4 weeks (7 days) thereafter.  In 
addition, starting after the Week 16 injection, the interval between injection visits will be 
limited to a maximum of 5 weeks.  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 5 weeks.
1.4.2.1.2.
IM injections every 8 weeks (Q8W from SOC):
Week 4b visit – CAB LA 600 mg + RPV LA 900 mg IM, each given as 1 X 3 mL IM 
injection
Week 8 visit- CAB LA 600 mg + RPV LA 900 mg IM, each given as 1 X 3 mL IM 
injection
Week 16 visit and Q8W thereafter - CAB LA 600 mg + RPV LA 900 mg IM, every 8 
weeks for 100 weeks, each given as 1 X 3 mL IM injection
At the Week 4b visit, subjects will return to the clinic, take their last oral dose (CAB 
30 mg + RPV 25 mg), and receive the first CAB LA (600 mg) + RPV LA (900 mg) 
injections (within 2 hours of the final oral dose of CAB + RPV).  The first injection visit 
 
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with IM CAB LA + RPV LA at Week 4b can be performed once central lab results are 
available and safety parameters are reviewed from the Week 4a visit.  
The second loading injection will be administered at Week 8 (CAB LA 600 mg + RPV 
LA 900 mg), with subsequent injections (CAB LA 600 mg + RPV LA 900 mg) occurring 
every 8 weeks thereafter.  There will be a -7-day dosing window for the second and third 
IM injections such that the second injection occurs within the window of Week 7 and 
Week 8 but no later than Week 8 and third injection occurs within the window of Week 
15 and Week 16 but no later than Week 16.  Subsequent injections with CAB LA 600 mg 
and RPV LA 900 mg will occur every 8 weeks (7 days).  Starting after the Week 16 
injection, the interval between injection visits will be limited to a maximum of 9 weeks.  
If the length of time between injections exceeds, or is projected to exceed 9 weeks, the 
Medical Monitor must be contacted to discuss individual participant case management.  
1.4.2.2.
Participants transitioning from ATLAS and currently receiving CAB LA 
+ RPV LA Q4W
Subjects receiving Q4W injections within ATLAS and randomized to receive Q4W 
injections in ATLAS-2M, will continue receiving maintenance injections Q4W as 
scheduled and will not require a loading dose on Day 1.
Subjects receiving Q4W injections within ATLAS and randomized to receive Q8W 
injections in ATLAS-2M will receive doses of CAB LA 600 mg + RPV LA 900 mg on 
Day 1 one month after their last Q4W maintenance dose in order to align with day of 
study randomization.  Subjects will not require an intermediate dose at Week 4 and will 
receive their next Q8W maintenance injections at Week 8 and Q8W thereafter.  
Participants transitioning from the ATLAS study and on CAB LA + RPV LA Q4W 
treatment will be randomized at Day 1 to either continue Q4W administration or 
transition to Q8W administration of CAB LA + RPV LA.  The first injection visit for the 
ATLAS-2M study can be performed once the final central lab results from the ATLAS 
study are available and safety parameters have been reviewed.  Screening labs 
determining eligibility for ATLAS-2M can be collected at Week 48 (at minimum) for 
participants originally randomized to the Q4W arm within ATLAS.  Screening labs for 
participants who recently transitioned from SOC to Q4W injections within the ATLAS 
Extension Phase may be obtained at ATLAS Week 56b (after completion of the CAB + 
RPV Oral lead-in period) or at a subsequent ATLAS visit after receiving one set or a 
short course of Q4W injections.  The transition from the final ATLAS to ATLAS-2M 
Day 1 dosing must occur 4 weeks (7 days) from the final injections received in ATLAS. 
Dosing for participants transitioning from CAB LA + RPV LA Q4W in ATLAS is as 
follows:
1.4.2.2.1.
IM injections every 4 weeks (Q4W from ATLAS Q4W):
Starting at Day 1, all injections will continue with the maintenance dose of CAB LA   
400 mg and RPV LA 600 mg administered every 4 weeks (7 days).  In addition, the 
time between injection visits will be limited to a maximum of 5 weeks.  The Medical 
 
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Monitor must be contacted if the length of time between injections exceeds or is 
projected to exceed 5 weeks.
1.4.2.2.2.
IM injections every 8 weeks (Q8W from ATLAS Q4W):
Participants transitioning from ATLAS and randomized to receive CAB LA + RPV LA 
Q8W injections will initiate Q8W dosing at the Day 1 visit as follows: 
Day 1- CAB LA 600 mg + RPV LA 900 mg IM, each given as 1 X 3 mL IM injection
Week 8 and Q8W thereafter- CAB LA 600 mg + RPV LA 900 mg IM, each given as 1 X 
3 mL IM injection
The second injection will be administered at Week 8 (CAB LA 600 mg + RPV LA 
900 mg, with subsequent injections (CAB LA 600 mg + RPV LA 900 mg) occurring 
every 8 weeks thereafter.  There will be a -7-day dosing window for the second and third 
IM injections such that the second injection occurs within the window of Week 7 and 
Week 8 but no later than Week 8 and third injection occurs within the window of Week 
15 and Week 16 but no later than Week 16.  Subsequent injections with CAB LA 600 mg 
and RPV LA 900 mg will occur every 8 weeks (7 days). Starting after the Week 16 
injection, the interval between injection visits will be limited to a maximum of 9 weeks.  
If the length of time between injections exceeds, or is projected to exceed 9 weeks, the 
Medical Monitor must be contacted to discuss individual participant case management.  
The primary study analysis will consist of data collected through the Week 48 visit.  A 
single repeat of HIV-1 RNA for any participant with a HIV-1 RNA 50 c/mL at Week 48 
or Week 96 must be performed.  The retest should be scheduled as soon as possible (but 
no later than 4 weeks from the Week 48 or Week 96 visits, respectively) and will inform 
the Week 48 or Week 96 virological endpoint, respectively.  
1.4.3.
Extension Phase
Participants who successfully complete 96 Weeks of CAB LA + RPV LA treatment in 
the Maintenance Phase will continue to have access to their randomized treatment Q4W 
or Q8W CAB LA + RPV LA in the Extension Phase until study treatment is either 
locally approved and commercially available within the local sector (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 + RPV LA Q4W and/or Q8W is terminated.  For participants 
randomized to Q4W arm, dosing visits will continue to occur every 4 weeks with CAB 
LA 400mg and RPV LA 600 mg.  For participants randomized to the Q8W arm, dosing 
visits will continue to occur every 8 weeks with CAB LA 600 mg and RPV LA 900 mg.  
Safety and efficacy assessments will be conducted as per the Time and Events Schedule. 
Participants choosing to not enter the Extension phase can complete their study 
participation at the Week 100 visit and enter into the LTFU Phase as required. 
Participants who choose to continue on to the Extension Phase will need to be assessed 
for eligibility and will continue on their current CAB LA + RPV LA regimen while 
 
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eligibility is being confirmed. 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 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 treatment. Eligibility to enter the Extension Phase for any 
participants with a retest HIV-1 RNA > 50 c/mL and <400 c/mL will require approval by 
the study Medical Monitor.  
Participants not eligible to enter the Extension Phase or choosing not to participate in the 
Extension Phase will end their study treatment and enter the LTFU until/unless the 
Follow-Up Phase is no longer required based on local approval of the assigned CAB LA 
+ RPV LA regimen.  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.
1.4.4.
Long-Term Follow-Up Phase
Any participant who receives at least one dose of CAB LA and/or RPV LA and 
discontinues the CAB LA + RPV LA regimen for any reason must remain on suppressive 
HAART for at least 52 weeks after the last dose of CAB LA and/or RPV LA in order to 
prevent selective pressure on HIV and the potential for selection of resistant mutants.  
Investigators must discuss the choice of the follow-up HAART regimen with the 
Medical Monitor prior to initiating the new regimen with the participant.  HAART 
therapy should be initiated within 4 weeks after the last Q4W injection, or within 8 
weeks after the last Q8W injection.  The LTFU will begin the day of the last CAB LA 
and/or RPV LA dose and continue for 52 weeks, or until the assigned CAB LA + RPV 
LA regimen is locally approved and commercially available.  Upon discontinuation from 
the Maintenance or Extension Phase, hese participants will complete Withdrawal 
assessments (see Section 5.5 ) and will  then enter into the LTFU as per the Time and 
Events Schedule (Section 7.1 ).  
Participants will be assessed with clinic visits at months 3, 6, 9, and 12 during the 
Follow-Up Phase.  Female participants of child bearing potential must continue to use 
adequate contraception methods (see Study Procedures Manual for list of accepted forms 
of contraception) for the entire year of follow up.  
In order to assure that participants have access to HAART during the LTFU, GSK may 
supply HAART regionally or reimbursement will be provided as needed during this 
phase.  The LTFU Phase may be modified or terminated 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.  Additional withdrawal assessments are not required for participants 
who do not complete the LTFU Phase.  
 
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1.4.5.
Dose Modifications:
No dose reductions, modifications, or changes in the frequency of any components of 
each regimen will be allowed during the study beyond what is allowed within the 
protocol or directly approved by the study Medical Monitor. Protocol waivers or 
exemptions are not allowed. Therefore, adherence to the study design requirements is 
essential and required for study conduct.
In exceptional circumstances, and in consultation with the Medical Monitor, Investigators 
may provide oral CAB and/or RPV as a short-term “bridging” strategy for participants 
who have begun CAB LA + RPV LA.  Should a participant need “oral bridging”, sites 
must contact the Medical Monitor for guidance on treatment strategies prior to a missed 
CAB LA + RPV LA dose.  Should a participant not notify the site in advance, the 
Medical Monitor must be contacted for further treatment guidance.
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM), which is available on 
the online Study Web Portal.  The SPM will provide the site personnel with 
administrative and detailed technical information.
2.
INTRODUCTION
Current HIV treatment guidelines recommend first-line antiretroviral (ARV) regimens
consisting of two nucleoside/nucleotide analogue reverse transcriptase inhibitors (NRTIs)
as a “backbone” combined with a third agent from the non-nucleoside reverse
transcriptase inhibitor (NNRTI), protease inhibitor (ritonavir-boosted) (PI/RTV), or
integrase strand transfer inhibitor (INSTI) classes [BHIVA, 2016; DHHS, 2016; EACS, 
2017; IAS USA, 2016]. While these regimens are highly efficacious and generally well
tolerated, there is growing concern about long-term toxicities, and great interest from
patients and clinicians in unique regimens that might avoid such toxicities, and to provide
effective long-term antiretroviral therapy ART with the most streamlined and convenient 
regimens possible.
The current paradigm in the treatment of Human Immunodeficiency Virus (HIV)
involves life-long therapy with multiple antiretrovirals. This dependency on medical 
therapy requires additional improvements on the durability, safety and tolerability, and 
convenience of all antiretroviral classes.  Fixed-dose combinations (FDCs) have greatly 
advanced HIV treatment by allowing simplification of dosing and reducing pill burden.  
However, adherence to therapy is essential to achieve viral suppression and prevent 
emergence of resistance mutations.  Among regimens of comparable efficacy, physicians 
and HIV-1-infected patients who receive ART rate total pill burden, dosing frequency, 
and safety concerns among the greatest obstacles to achieving adherence.  Drug resistant 
virus eventually emerges in most patients who struggle with consistent adherence.  
Different HIV treatment modalities are being developed to help improve adherence and 
patient outcomes, and prevent resistance and transmission of the virus. 
There is also an increasing desire to develop nucleoside reverse transcriptase inhibitor 
(NRTI)-sparing regimens for long-term treatment of HIV infection as an approach to 
 
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avoid known NRTI-associated adverse drug reactions and long-term toxicities.  In 
addition, while there are no currently approved two-drug regimens to maintain 
suppression, simplifying treatment has long been a goal to increase treatment compliance 
and improve the quality of life for patients with HIV.  
Cabotegravir (CAB) is a potent integrase inhibitor that possesses attributes that allow 
formulation and delivery as a long-acting (LA) parenteral product.  Rilpivirine (RPV) is a 
diarylpyrimidine derivative and a potent non-nucleoside reverse transcriptase inhibitor 
(NNRTI) with in vitro activity against wild type HIV-1 and select NNRTI-resistant 
mutants.  RPV is a globally marketed product available as oral 25 mg tablets [Edurant
Product Information, 2015], and is also formulated as a LA product.  Intramuscular 
administration of a two-drug combination therapy with CAB LA plus RPV LA may offer 
a better tolerability and resistance profile, as well as improved adherence and treatment 
satisfaction in virologically suppressed patients.
2.1.
Study Rationale
The overall objective of the CAB LA + RPV LA clinical development program is to 
develop a highly effective, well tolerated two drug long-acting injectable regimen which 
has the potential to offer improved treatment convenience, compliance and improved 
quality of life for individuals with HIV compared to current standard of care.  Week 96 
efficacy data from study 200056 (LATTE-2) demonstrated that 94% of patients on the 
CAB LA + RPV LA Q8W dosing arm and 87% of patients on the Q4W dosing arm 
maintained virologic suppression (HIV-1 RNA <50 c/mL), with both regimens being 
well tolerated. LATTE-2 results justify further evaluation of CAB LA + RPV LA dosing 
regimens.  Study 201585 (ATLAS) is an ongoing Phase III study conducted to establish 
if human immunodeficiency virus type 1 (HIV-1) infected adult participants with current 
viral suppression on a regimen with 2 nucleoside reverse transcriptase inhibitors (NRTIs) 
plus a third agent, remain suppressed upon switching to CAB LA + RPV LA Q4W. The 
current study, 207966 (ATLAS-2M) is designed to demonstrate the non-inferior antiviral 
activity of CAB LA 600 mg + RPV LA 900 mg every 8 weeks (Q8W, every 2 months) 
compared to CAB LA 400 mg + RPV LA 600 mg administered every 4 weeks (Q4W, 
monthly) for 48 weeks. This study will also provide important long-term comparative 
antiviral activity, safety, tolerability of these regimens through Week 96 of the 
Maintenance Phase of the study. Additionally, eligible participants (HIV-1 RNA 
<50 c/mL at Week 96) will be given an option to continue their randomized CAB LA + 
RPV LA regimen (Q4W or Q8W) in the Extension Phase of the study.
2.2.
Background
It is estimated that 36.7 million people are currently living with HIV/Acquired 
Immunodeficiency Syndrome (AIDS) and that the worldwide epidemic continues to grow 
at a rate of two million new infections and cause 1.1 million deaths per year [UNAIDS, 
2016]. Chronic HIV infection in adults continues to be characterized by increased 
development of resistant virus, increasing transmission of resistant virus and issues 
associated with long term toxicity of ART.  The current paradigm in the treatment of HIV 
involves life-long therapy with multiple antiretrovirals.  This dependency on medical 
 
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therapy requires a need for continuous improvement on the durability, tolerability and 
convenience of all antiretroviral classes.
A study by the Antiretroviral Therapy Cohort Collaboration [ART-CC, 2013] found that 
of more than 21,000 patients in a European and North American cohort on their first 
combination antiretroviral therapy (cART) regimen (either PI or NNRTI-based), 51% 
modified or interrupted their first cART regimen during a median of 28 months of 
follow-up with one third of interruptions occurring within the first 6 months of starting 
therapy.  Forty percent of all treatment interruptions were due to the secondary side 
effects or toxicities of cART, 17% were due to the desire for simplification of the 
regimen and 14% were due to patient choice. These observations have led to numerous 
“switch” ART studies, designed to understand the efficacy, safety, and tolerability of 
switching patients from one regimen to another.
Previous studies have evaluated switches to ritonavir-boosted PI monotherapy in 
virologically suppressed patients [Bierman, 2009 and Arribas, 2012].  These studies 
suggest that simplifying from a three drug dual class regimen to a single boosted protease 
inhibitor may be a safe and effective option for the majority of participants studied, who 
have effectively maintained viral suppression.  In the OLE study, virologically 
suppressed (HIV-1 RNA <50 c/mL) HIV-1 infected participants receiving a lopinavir-
ritonavir (LPV/r) + lamivudine (3TC) or emtricitabine (FTC) based NRTI regimen 
simplified to a dual regimen of LPV/r + 3TC or FTC.  In a modified Intent-to-Treat (m-
ITT) analysis, dual therapy with LPV/r + 3TC demonstrated non-inferiority efficacy and 
comparable safety to LPV/r + 2 NRTIs [Arribas, 2015].  
The 200056 study (GlaxoSmithKline Document Number 2013N168152_05, Study 
[LATTE-2]) is an ongoing Phase 2b study designed to assess the induction of virologic 
suppression with CAB 30 mg daily + two NRTIs, followed by a maintenance period 
where subjects are randomized (1:2:2) to continue on oral CAB 30 mg + two NRTIs or 
switch to an IM injection of CAB LA + RPV LA administered Q4W or Q8W.  A total of 
309 participants were enrolled and treated.
During the Induction Phase there was a rapid and sustained decline in HIV-1 RNA, with 
91% of participants (282/309) achieving HIV-1 RNA <50 c/mL through 20 weeks of 
therapy.  There was a single participant (with known compliance issues) with confirmed 
virologic failure during the Induction period.  Virologic testing revealed no treatment 
emergent phenotypic or genotypic resistance in this participant.
The primary endpoint for 200056 was the Week 32 proportion of participants with HIV-1 
RNA <50 c/mL (Snapshot, Intent-to-Treat Maintenance Exposed population [ITT-ME]). 
Following virologic suppression on three drug oral therapy in the Induction Phase, 286 
participants qualified to enter randomization at the Day 1 visit, and were subsequently 
randomized 2:2:1 onto once every 4 weeks intramuscular (IM) injections with CAB LA + 
RPV LA every 4 weeks (Q4W), once every 8 weeks (Q8W) IM injections with CAB LA 
+ RPV LA or continuation of oral CAB + NRTIs, respectively.  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 
 
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oral CAB + NRTIs, meeting pre-specified criteria for comparability between the dosing 
arms.
Week 48 was a secondary endpoint for 200056, and permitted the evaluation of the two-
drug long-acting combinations’ ability to maintain the virologic suppression 
demonstrated at Week 32.  At Week 48, 92% (Q8W) and 91% (Q4W) of participants 
receiving injectable dosing had a sustained virologic response (HIV-1 RNA <50 c/mL) 
compared to 89% of participants continuing oral CAB + 2 NRTIs.  Week 96 efficacy data 
from study 200056 (LATTE-2) demonstrated that 94% of patients on the CAB LA + 
RPV LA Q8W dosing arm and 87% of patients on the Q4W dosing arm maintained 
virologic suppression (HIV-1 RNA <50 c/mL), with both regimens being well tolerated. 
At Week 48, 10 subjects met virologic nonresponse criteria (Q8W, n=8; Q4W, n=1; oral 
CAB +2 NRTIs, n=1).  For the Q8W IM arm, 4 subjects with virologic nonresponse at 
Week 48 (HIV-1 RNA >50 c/mL) were re-suppressed with HIV-1 RNA <50 c/mL at 
Week 96 without a change in therapy.  Of 5 Q8W subjects with virologic nonresponse at 
Week 96, two had HIV-1 RNA 50 c/mL at Week 96 (one of which had HIV-1 50 c/mL 
at Week 48), one discontinued due to protocol-defined virologic failure at Week 4, one 
withdrew consent due to intolerability of injections at Week 8, and one withdrew due to 
investigator discretion at Week 48 while not suppressed (and subsequently confirmed as a 
protocol-defined virologic failure).  One of the two subjects with HIV-1 RNA >50 c/mL 
at Week 96 remained on the study and had HIV-1 levels <50 c/mL at the next scheduled 
visit.  Through 96 weeks, no subjects in the Q4W arm failed for virologic reasons.  The
Q4W subject with virologic nonresponse at Week 48 (HIV-1 RNA, 59 c/mL) remained 
on the study beyond Week 48 and had subsequent viral re-suppression with HIV-1 
<50 c/mL at Week 96.  CAB LA + RPV LA was well tolerated through Week 96 for both 
the Q8W and Q4W dosing regimens, as demonstrated by a low discontinuation rate due 
to AEs, including injection site reaction (ISR) related AEs in either dosing arm, with no 
significant dose-dependent trends in safety parameters.  Through Week 96, the proportion 
of AEs leading to withdrawal during the study Maintenance Period was low across all 
arms (Q8W IM: n=2, 2%; Q4W IM: n=8, 7%; Oral CAB; n=1, 2%), with only one 
additional AE leading to withdrawal since the Week 48 analysis.  
Long-acting two class therapy consisting of CAB LA + RPV LA as an IM regimen has 
the benefit of being a NRTI-sparing regimen for long-term treatment of HIV infection 
which will avoid known NRTI-associated adverse drug reactions and long-term 
toxicities.  Additionally, a two-drug combination therapy with CAB LA plus RPV LA 
may offer a better tolerability and resistance profile, as well as improved adherence and 
treatment satisfaction in virologically suppressed participants improving the quality of 
life for patients with living with HIV.  
The primary objective of ATLAS-2M is to demonstrate the non-inferior antiviral activity 
of CAB LA 600 mg + RPV LA 900 mg every 8 weeks (Q8W, every 2 months) compared 
to CAB LA 400 mg + RPV LA 600 mg administered every 4 weeks (Q4W, monthly) for 
48 weeks.   ATLAS-2M will also evaluate long-term antiviral and immunologic effects, 
safety and tolerability, and viral resistance of the Q8W and Q4W regimens for a 
minimum of 100 weeks.  In addition, ATLAS-2M will assess patient reported health-
 
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related quality of life, treatment satisfaction, injection tolerability, and treatment 
acceptance of the Q8W and Q4W regimens.  
2.3.
Benefit/Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with oral 
and CAB LA or RPV LA can be found in the Investigator’s Brochures (GlaxoSmithKline 
Document Number RH2009/00003/06, 2016; RPV IB, 2017).
The following section outlines the risk assessment and mitigation strategy for this 
protocol:  
2.3.1.
Risk Assessment
Oral CAB and CAB LA (GSK1265744/GSK1265744 LA)
Since CAB is in clinical development and exposure in humans with or without HIV 
infection is limited, the clinical safety profile in humans has yet to be fully elucidated.  
The following risks have primarily been identified during routine preclinical testing 
and/or from the clinical trial experience to date and are considered of potential relevance 
to clinical usage in the context of this protocol.  Additional information about the clinical 
experience to date and possible risks associated with treatment using CAB can be found 
in the Summary of Data and Guidance for the Investigator section of the IB.
 
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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Drug Induced Liver 
Injury (DILI)
A small proportion of participants in the CAB 
program to date (total exposure approximately 
1644 to 01 April 2017) have developed 
transaminitis (elevated liver transaminases 
characterised by predominant alanine
aminotransferase (ALT) elevation).  In most 
participants, transient transaminitis was explained 
by acute hepatitis C infection (majority) and other 
systemic infections.  In a small number of 
participants, there was not an alternative 
explanation, suggesting a mild form of drug 
induced liver injury (DILI) without hepatic 
dysfunction, which resolved upon withdrawal of 
treatment with CAB. 
All four participants with suspected DILI 
identified in Phase 2 HIV treatment studies, were 
receiving oral CAB.  

Exclusion criteria as described in Section 5.2
will prohibit participants with significant liver 
impairment based on screening liver chemistry 
including transaminases (ALT and Aspartate 
aminotransferase [AST]) as well on prior 
medical history. Participants with a history of 
chronic liver disease with ongoing inflammation 
and/or fibrosis will have additional confirmatory 
assessments to confirm suitability for entry into 
the study. 

A 4-week oral lead- in Phase is being 
implemented in this study, where all participants 
will receive oral CAB prior to the administration 
of IM CAB to assess individual safety and 
tolerability 

Liver transaminases (ALT and AST) will be 
monitored throughout this study (refer to Time & 
Events Table) and the liver chemistry stopping 
criteria will be adopted as described in Section 
5.5.1.1 of this protocol. Participants will be 
withdrawn from CAB treatment where no 
compelling alternative cause is identified and 
DILI is suspected.
 
 
 
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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy

Participants who develop ALT ≥3 times the 
upper limit of normal (ULN) while on study 
must consult with Medical Monitor prior to 
initiation or continuation of CAB LA + RPV LA.  
Injection Site Reactions 
(ISRs)
Clinical, experience to date has demonstrated ISRs 
occur in the majority of exposed participants 
treated with CAB LA but are generally mild 
(Grade 1) or moderate (Grade 2) and include 
events of pain, tenderness, erythema, or nodule 
formation of several days duration (median 
duration for individual events <1 week).
ISRs may occur more than once in an individual 
participant 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 have been 
serious.  

Administration advice will be given to minimize 
risk of poor administration technique giving rise 
to injection site reactions.  Advice on care, 
monitoring, natural course, and treatment of 
ISRs is given in study documentation 

Advice will be given to participants on care of 
injection site on day/days immediately post 
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 
 
 
 
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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy

Significant ISRs may be photographed and 
referred to a dermatologist for specialist advice.
Hypersensitivity 
Reactions (HSR)
Hypersensitivity reactions have been reported as 
uncommon occurrences with integrase inhibitors, 
including the closely related compound 
dolutegravir, and were characterized by rash, 
constitutional findings, and sometimes, organ 
dysfunction, including liver injury. 
While there have been no clinical cases of 
hypersensitivity to CAB to date, there is a 
theoretical risk of systemic or severe 
hypersensitivity reactions with or without hepatic 
symptoms associated with use of IM CAB. The 
long exposures anticipated after IM CAB injection 
may complicate the management of a drug 
hypersensitivity reaction, were it to occur.

The risk of developing a hypersensitivity 
reaction post administration of IM CAB will be 
minimized by the use of a 4-week oral lead-in of 
oral CAB to determine individual safety and 
tolerability prior to the introduction of IM CAB. 

Clinical assessments, laboratory tests (including 
liver transaminases) and vital signs will be 
performed throughout this study (refer to Time 
& Events Table, Section 7.1). Results from these 
assessments may aid early detection of HSR. 

Oral CAB will be withdrawn immediately for 
cases with suspected HSR during the oral CAB 
lead-in phase and would not proceed to the 
injection phase.  Participants in the injection 
phase would not receive further injections.  
During oral and IM CAB treatment, any HSR 
reactions that occur would be managed 
supportively.
Effects in late stage 
pregnancy seen in non-
clinical studies
Non clinical data from rat pre- and postnatal (PPN) 
studies have indicated reduced survival and 
viability rates amongst rat pups during the first 4 
days of life at the maximum tested dose of 1000
mg/kg/day (maternal exposure).  NOAEL was

As a routine precaution, pregnant women are 
excluded from participation in this study at this 
time and females of reproductive potential (FRP) 
are required to adopt highly reliable means of
contraception during participation and 
 
 
 
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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
established at the mid dose 5 mg/kg/day, the 
maternal exposure at this dose calculated using 
systemic exposure from non-pregnant rats is >20 
fold predicted Cmax and AUC exposures for 
anticipated clinical CAB LA exposures for HIV 
treatment
The clinical significance in humans of these 
findings is unknown.
throughout the long term follow up phase of this 
study following exposure to CAB LA.

FRP are also required to undergo regular 
pregnancy testing throughout study conduct to 
enable early discontinuation of CAB LA once 
pregnancy is identified.
Development of 
Resistance following 
discontinuation of CAB 
LA
Residual concentrations of CAB would remain in 
the systemic circulation of participants who stop 
CAB LA treatment for prolonged periods (more 
than 1 year, in some subjects, GlaxoSmithKline 
Document Number 2016N269422_00) after last 
injection (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. 

After participants stop CAB LA, Oral HAART 
regimens will be prescribed within 4 weeks after 
the last Q4W dose or within 8 weeks after the 
last Q8W dose, and following consultation with 
the medical monitor.  This would be anticipated 
to result in continued suppression or rapid 
resuppression of HIV-1 RNA thus minimizing 
the risk of emergent resistance

The participants in this study who discontinue 
IM CAB for any reason will be monitored for a 
minimum of 52 weeks from the time of the last 
IM CAB injection.
 
 
 
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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Drug-Drug Interactions 
(DDIs)
For a complete listing of permitted and prohibited 
concurrent medications for CAB and CAB LA, 
refer to Section 6.13
CAB and CAB LA should not be co-administered 
with the following medicinal products, as 
significant decreases in CAB plasma 
concentrations may occur (due to UGT enzyme 
induction), which may result in loss of therapeutic 
effect of CAB.
- the anticonvulsants carbamazepine, 
oxcarbazepine, phenobarbital, phenytoin
- the antimycobacterials rifampicin, rifapentine, 
rifabutin
- St John’s wort (Hypericum perforatum)
Oral CAB administration only:  Antacid products 
containing divalent cations (e.g., aluminum, 
calcium, and magnesium) must be taken at least 2 
hours before or at least 4 hours after CAB.
Participants discontinuing a LA regimen may be at 
risk for developing DDIs many weeks after 
discontinuing injectable therapy.  

All participants will be informed of prohibited 
medications throughout the study and updates 
provided as needed via the informed consent.
 
 
 
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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Inadvertent 
Intravenous Injection 
(Accidental 
Maladministration)
As with any intramuscular injection, it is possible 
that CAB LA can be inadvertently administered 
intravenously instead of intramuscularly possibly 
resulting in higher than expected concentrations of 
CAB shortly after injection and lower 
concentrations thereafter.  This could be due to 
administrator error, improper injection technique 
and / or improper needle length used based on 
body type.    
The clinical consequences of overdose with CAB 
LA are currently unknown.  HIV-1 viral 
suppression may not be effective following 
accidental maladministration.

Training will be provided to all sites on proper 
injection technique.  

Should IM maladministration be suspected at 
any time (e.g. suspected under or overdose or 
inadvertent IV dosing), a post dose 
electrocardiogram (ECG), vital signs, or any 
other supportive testing may be obtained at the 
discretion of the investigator, and the medical 
monitor will be notified.  

Laboratory samples for safety parameters and 
HIV-1 RNA will be closely monitored in all 
participants.  Additionally, 2 hour post dose PK 
samples will be obtained at a few early 
timepoints for determination of CAB 
concentration and possible pharmacokinetic 
correlation with safety parameters such as ECG 
changes and virologic response.  Additionally, 
an unscheduled PK sample may be drawn 
approximately 2 hours post dosing for future 
evaluation of CAB concentrations.
ORAL RPV
For safety and risk mitigation for oral RPV refer to the RPV local prescribing information [Edurant Product Information, 2015].  
 
 
 
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RPV LA
Information about the clinical experience to date and possible risks associated with treatment using RPV LA can be found in the Summary 
of Data and Guidance for the Investigator section of the IB.  Beyond what has already been identified with oral RPV, no new systemic 
adverse reactions to RPV LA (same active moiety) have been observed.  The following risks are considered to be of specific clinical 
relevance in the context of IM use.
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Injection Site Reactions
Clinical, experience to date has demonstrated ISRs 
occur in the majority of exposed participants 
treated with RPV LA but are generally mild 
(Grade 1) or moderate (Grade 2) and include 
events of pain, tenderness, erythema, or nodule 
formation of several days duration (median 
duration for individual events <1 week).  ISRs 
may occur more than once in an individual 
participant receiving multiple injections.  Although 
some Grade 3 ISRs were reported, overall ISRs 
have been well tolerated and have not to date been 
associated with an excess of participants’ 
withdrawal due to ISRs.
None of the ISRs was serious and no clinical 
significant complications were reported

Administration advice to minimize risk of poor 
administration technique giving rise to injection 
site reactions.  Advice on care, monitoring, 
natural course, and treatment of ISRs given in 
study documentation.

Advice to participants on care of injection site on 
day/days immediately post administration, use of 
analgesia, compresses where appropriate.

Participants will be closely monitored for ISRs 
particularly for signs of pain, tenderness, 
infections, erythema, swelling, induration, or 
nodules (granulomas or cysts) throughout the 
study.

Complications of ISRs such as infections 
(abscess, cellulitis) and collections of fluid 
requiring drainage will be monitored 

Significant ISRs may be photographed and 
referred to a dermatologist for specialist advice.
 
 
 
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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Rash
Some observations of rash with oral RPV have 
been reported in clinical studies executed to date 
(the majority are Grade 1 or 2). 
Severe skin and hypersensitivity reactions have 
been reported during the postmarketing 
experience, including cases of Drug Reaction with 
Eosinophilia and Systemic Symptoms (DRESS), 
with oral RPV containing regimens.  While some 
skin reactions were accompanied by constitutional 
symptoms such as fever, other skin reactions were 
associated with organ dysfunctions, including 
elevations in hepatic serum biochemistries.

In this study, RPV LA administration will be 
preceded by an oral RPV lead in to evaluate 
safety and tolerability in individual participants.

Participants with a Grade 1 or 2 rash will be 
allowed to continue treatment or to be 
rechallenged, depending on the clinical judgment 
of the investigator.

All participants experiencing a Grade 3 or 4 rash 
should discontinue their ARV medication (study 
medication and background regimen) and be 
withdrawn from the study.

All rash events should be assessed with special 
attention to systemic symptoms, laboratory 
abnormalities, or mucosal involvement.  Close 
clinical follow-up, including follow-up of 
laboratory abnormalities, and appropriate 
medical intervention, including referral to 
dermatologist as appropriate, should be instituted 
for these events; daily follow-up is 
recommended for 5 days from the onset of the 
event to monitor for progression of the event.  
See Section 7.4.5.13 for additional guidance on 
management of rash events.
 
 
 
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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Development of 
Resistance
Residual concentrations of RPV LA can remain in 
the systemic circulation of participants who 
stopped treatment (e.g., for tolerability issues or 
treatment failure) for prolonged periods (months to 
more than a year, in some subjects, McGowan, 
2016).
Participants discontinuing a LA regimen may be at 
risk for developing resistance to RPV many weeks 
after discontinuing injectable therapy.

After participants stop RPV LA, Oral HAART 
regimens will be prescribed within 4 weeks after 
the last Q4W dose or within 8 weeks after the 
last Q8W dose, and following consultation with 
the medical monitor. This would be anticipated 
to result in rapid resuppression of HIV-1 RNA 
thus minimizing the risk of emergent resistance

The Sponsor will continue to monitor 
participants in this study who discontinue a LA 
regimen for any reason for a minimum of 52 
weeks from the time of the last LA 
administration.
Drug-Drug Interactions 
(DDIs)
For a complete listing of permitted and prohibited 
concurrent medications for RPV and RPV LA, 
refer to Section 6.13
RPV LA should not be co-administered with the 
following medicinal products, as significant 
decreases in RPV plasma concentrations may 
occur (due to CYP3A enzyme induction), which 
may result in loss of therapeutic effect of RPV LA.
- the anticonvulsants carbamazepine, 
oxcarbazepine, phenobarbital, phenytoin

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
- 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. 
Oral RPV administration only:  
- Antacid products containing divalent cations 
(e.g., aluminum, calcium, and magnesium) 
must be taken at least 2 hours before or at least 
4 hours after RPV.
- H2-antagonists must be taken at least 12 hours 
before or at least 4 hours after taking RPV.
- RPV should not be co-administered with 
proton pump inhibitors, such as esomeprazole, 
lansoprazole, omeprazole, pantoprazole, 
rabeprazole;
 
 
 
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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Participants discontinuing a LA regimen may be at 
risk for developing DDIs many weeks after 
discontinuing injectable therapy.  
Inadvertent 
Intravenous Injection 
(Accidental 
Maladministration)
As with any intramuscular injection, it is possible 
that RPV LA can be inadvertently administered 
intravenously instead of intramuscularly possibly 
resulting in higher than expected concentrations of 
RPV shortly after injection and lower 
concentrations thereafter.  This could be due to 
administrator error, improper injection technique 
and / or improper needle length used based on 
body type.  
In addition, HIV-1 viral suppression may not be 
effective following accidental intravenous 
maladministration.

Training will be provided to all sites on proper 
injection technique.  

Should IM maladministration be suspected at 
any time (e.g., suspected under or overdose or 
inadvertent IV dosing), post dose ECG 
monitoring and vital signs or any other 
supportive testing may be obtained at the 
discretion of the investigator, and the medical 
monitor notified

Laboratory samples for safety parameters and 
HIV-1 RNA will be closely monitored in all 
participants.  Additionally, 2-hour post dose PK 
samples will be obtained at a few early 
timepoints for determination of 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.
 
 
 
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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Other Study Related Risks 
Venipuncture
Participants will be required to have blood samples 
taken.  Risk of bruising, and rarely, infection

Trained personnel will perform 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 minimize contact 
time for application of the pads.
Risk of Treatment Failure
This study employs a novel 2 drug LA ART 
maintenance regimen for the treatment of HIV-1 
infection that remains experimental.  Both IM 
CAB and RPV have demonstrated antiviral 
activity in large clinical studies and the two drug 
combination has demonstrated sustained antiviral 
activity in studies, LAI116482 and 200056, 
however the efficacy of Q8W v Q4W dosing 
remains under evaluation.   
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 and LA formulations.

Viral loads and CD4+ cell counts will be closely 
monitored throughout the study (maintenance 
and extension phases), allowing for early 
detection of failing treatment.  Where confirmed 
virological failure occurs, participants would be 
discontinued from study drugs and transferred to 
an oral HAART regimen.

Plasma samples will be collected throughout the 
Maintenance Phase for determination of CAB 
and RPV concentration and possible 
pharmacokinetic correlation with virologic 
response.
 
 
 
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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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 viral resistance.  
 
 
 
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2.3.1.1.
Other Clinically Relevant Information
Additional details concerning safety observations from clinical studies and for which a 
causal association has not been established or which are of minimal clinical significance 
may be found in the Investigator’s Brochures (GlaxoSmithKline Document Number 
RH2009/00003/06 [CAB IB], RPV IB, 2017).  
Adverse Events of Special Interest:
Seizure
Three cases of seizures have occurred in the cabotegravir programme cumulatively 
through 15 May 2016. Two of the cases occurred in HIV uninfected subjects with a prior 
history of seizure and one case involved a subject in study 200056 with circumstantial 
and anecdotal evidence of illicit drug use. Overall, there is not convincing evidence that 
cabotegravir exposure may be causally associated with seizure or with reduction of 
seizure threshold, due to the low frequency of reports, the confounders present in the 
cases received to date and lack of any pre-clinical signal or identified plausible 
mechanism. However, seizure and seizure-like events are considered as AEs of special 
interest for close monitoring in future studies. Subjects with an unstable or poorly 
controlled seizure disorder will be excluded from study participation. All cases of prior 
seizure history should be discussed with the Medical Monitor prior to enrolment.
2.3.2.
Benefit Assessment
The antiviral activity against HIV-1 of CAB has been well established through Phase 2a 
and Phase 2b studies. RPV is an established antiviral agent against HIV-1 in treatment 
naive patients, with long term durability (>96 weeks in Phase 3 and >240 weeks in Phase 
IIb).
Participants receiving CAB LA + RPV LA are anticipated to benefit from maintenance of 
virological suppression using LA agents. Participants randomized to receive CAB LA+ 
RPV LA Q4W or Q8W weekly dosing will not need to take concomitant daily oral 
therapy.  Adherence in these participants is expected to be improved and will be directly 
observed during IM injections. Efficacy of this two-drug regimen, as IM agents, has been 
demonstrated through Week 96 of the ongoing 200056 study. The reduction in ART, and 
the discontinuation of NRTIs, may offer long term safety and tolerability benefits in these 
participants.
2.3.3.
Overall Benefit:Risk Conclusion
Taking into account the measures taken to minimize risk to participants participating in 
this study, the potential risks identified in association with CAB LA and RPV LA Q4W 
and Q8W regimens, and the study as a whole are justified by the anticipated benefits that 
may be afforded to treatment-experienced patients with HIV-1 infection.
 
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3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
To demonstrate the non-inferior antiviral 
activity of CAB LA + RPV LA every 8 
weeks (every two months) compared to 
CAB LA + RPV LA every 4 weeks 
(monthly) over 48 weeks in suppressed 
HIV-1 infected antiretroviral therapy 
(ART)-experienced participants
Proportion of participants with plasma 
HIV-RNA greater than or equal to 
50 copies/mL as per Food and Drug 
Administration (FDA) Snapshot algorithm 
at Week 48 (Intent-to-Treat Exposed [ITT-
E] population)
Secondary
To demonstrate the antiviral and 
immunologic activity of CAB LA + RPV 
LA every 8 weeks compared to CAB LA + 
RPV LA every 4 weeks
Proportion of participants with plasma 
HIV-1 RNA <50 c/mL (c/mL) at Week 24, 
Week 48 and Week 96 using the FDA 
Snapshot algorithm (Intent-to-Treat 
Exposed [ITT-E] population)
Proportion of participants with protocol-
defined confirmed virologic failure (CVF) 
through Week 24, Week 48 and Week 96
Proportion of participants with HIV-RNA 
greater than or equal to 50 c/mL as per 
FDA Snapshot algorithm at Week 24, and
Week 96
Absolute values and changes from Baseline 
in viral load and CD4+ cell counts over 
time including Week 48 and Week 96
To evaluate the safety and tolerability of 
CAB LA + RPV LA every 8 weeks 
compared to CAB LA + RPV LA every 4 
weeks
Incidence and severity of AEs and 
laboratory abnormalities over time 
including Week 24, Week 48 and Week 96
Proportion of participants who discontinue 
treatment due to AEs over time including 
Week 24, Week 48 and Week 96
Change from Baseline in laboratory 
parameters over time including Week 48 
and Week 96
 
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Objectives
Endpoints
To assess viral resistance in participants 
experiencing protocol-defined confirmed 
virologic failure 
Incidence of treatment emergent genotypic 
and phenotypic resistance to CAB, RPV 
through Week 24, 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 preference for CAB LA + RPV 
LA every 8 weeks or CAB LA + RPV LA 
every 4 weeks LA compared to oral 
antiretroviral (ARV) 
To assess preference for CAB LA+ RPV 
LA every 8 weeks compared to CAB LA + 
RPV LA every 4 weeks
Preference for CAB LA + RPV LA every 8 
weeks or CAB LA + RPV LA every 4 
weeks compared to oral ARV and 
preference for CAB LA + RPV LA every 8 
weeks compared to CAB LA + RPV LA 
every 4 weeks will be assessed using a 
preference questionnaire at week 48 (or 
Withdrawal).
To assess patient reported health-related 
quality of life, treatment satisfaction, 
injection tolerability, and treatment 
acceptance.
Change from Baseline (Day 1) in HRQoL 
at Week 24, and Week 48 (or Withdrawal)
Change from baseline (Day 1) in total 
“treatment satisfaction” score, and 
individual item scores of the HIV 
Treatment Satisfaction Status 
Questionnaire (HIVTSQs) at Week 24, and 
48, (or Withdrawal)
Change in treatment satisfaction over time 
using the HIV Treatment Satisfaction 
Change Questionnaire HIVTSQc at Week 
48 (or Withdrawal).
Change from Week 8 in Dimension scores 
(“Bother of ISRs”, “Leg movement”, 
“Sleep”, and “Injection Acceptance”) and 
individual item scores assessing pain 
during injection, anxiety before and after 
injection, willingness to be injected in the 
future and overall satisfaction with mode of 
 
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Objectives
Endpoints
administration over time will be assessed 
using the Perception of iNjection 
questionnaire (PIN) at Weeks 8, 24, and 48 
(or Withdrawal) 
Change from Baseline (Day 1) in treatment 
acceptance at Week 24 and Week 48 (or 
Withdrawal) will be assessed using the 
“General acceptance” dimension of the 
Chronic Treatment Acceptance (ACCEPT) 
questionnaire
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 <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
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
Incidence of disease progression (HIV-
associated conditions, acquired 
immunodeficiency syndrome [AIDS] and 
death)
To explore the effect of patient 
characteristics on virologic and 
immunologic responses to CAB LA+ RPV 
LA every 8 weeks compared to CAB LA + 
RPV LA every 4 weeks
Proportion of participants by patient 
subgroup(s) (e.g., by age, gender, BMI, 
race, HIV-1 subtype, Baseline CD4+, type 
of oral treatment [NNRTI, PI, or INSTI], 
duration prior CAB LA and RPV LA 
exposure [0 weeks, 1-24 weeks, > 24 
weeks]) with HIV-RNA greater than or 
equal to 50 c/mL, and with protocol-
defined confirmed virologic failure over 
 
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Objectives
Endpoints
time including Week 48 and Week 96 
using the Snapshot algorithm for the ITT-E 
population
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 CAB and 
RPV concentrations and virologic, 
immunologic responses, and/or occurrence 
of adverse events [AEs] over time.
To assess reason for switching using a 
single question. 
To assess reason for continuation using a 
single question
For patients randomized from oral SOC, 
the reasons for willingness to switch ART 
at baseline (Day 1) will be assessed
For patients randomized from CAB LA + 
RPV LA every 4 weeks in ATLAS, the 
reasons for willingness to continue long-
acting ART at baseline (Day 1) will be 
assessed
4.
STUDY DESIGN
4.1.
Overall Design
Study 207966 (Antiretroviral Therapy as Long Acting Suppression every 2 Months-
ATLAS-2M) is a Phase III, randomized, open-label, active-controlled, multicenter, 
parallel-group, non-inferiority study designed to assess the antiviral activity and safety of 
CAB LA + RPV LA administered every 4 weeks compared CAB LA + RPV LA 
administered every 8 weeks in approximately 1020adult HIV-1 infected patients.  
Two groups of patients who fulfill eligibility requirements will be randomized (1:1) at 
Day 1 to receive CAB LA + RPV LA Q4W, or CAB LA + RPV LA Q8W regimen for at 
least 100 weeks: 
Group 1: Patients randomized from current ART Standard of Care (SOC) therapy
Patients randomized from current ART SOC therapy, including those enrolled to the 
“current ART” arm of the ATLAS study following completion of the Week 52 visit (at 
minimum), will begin oral therapy with CAB 30 mg + RPV 25 mg once daily at Day 1 
for 28 days (3 days) to determine individual safety and tolerability prior to receiving 
CAB LA + RPV LA Q4W, or CAB LA + RPV LA Q8W.  For patients on SOC 
transitioning from the ATLAS trial, eligibility for ATLAS-2M can be determined once 
 
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the final central lab results from ATLAS are available and safety parameters have been 
reviewed.
Group 2: Patients currently receiving CAB LA + RPV LA Q4W
At Day 1, patients entering ATLAS-2M from ATLAS and currently receiving CAB LA + 
RPV LA Q4W (including both those who were originally randomized to Q4W in the 
Maintenance phase of ATLAS and those who transitioned from SOC to the Q4W 
regimen within the Extension Phase of ATLAS) will be randomized 1:1 to either 
continue Q4W administration or transition to Q8W administration of CAB LA + RPV 
LA.  The first injection visit for ATLAS-2M can be performed once the final central lab 
results from ATLAS are available and safety parameters have been reviewed, and the 
ATLAS Week 52 visit (at minimum) has been completed.  Participants will continue to 
receive CAB LA + RPV LA Q4W injections as scheduled within the ATLAS trial until 
their eligibility for ATLAS-2M can be fully evaluated and the participant is re-
randomized (Q4W or Q8W).  If determined to be ineligible for ATLAS-2M, those 
participants can elect to continue participation in ATLAS or withdraw from the ATLAS 
study. 
Participants in ATLAS-2M who successfully complete Week 100 (without meeting study 
defined withdrawal criteria) will be given the option to continue to receive their 
randomized treatment (CAB LA + RPV LA administered Q4W or Q8W) in the Extension 
Phase until the randomized study treatment is either locally approved and commercially 
available within the local sector (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 + 
RPV LA Q4W and/or Q8W is terminated.  Alternatively, participants can choose to 
complete study participation and enter the 52-week LTFU Phase of the study.
Any participant who receives at least one dose of CAB LA and/or RPV LA and 
discontinues the CAB LA + RPV LA regimen for any reason will enter a 52-week LTFU
Phase.  Those 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 treatment arms, randomization will be stratified by 
prior CAB + RPV Exposure: 0 weeks, 1-24 weeks, >24 weeks.  The primary endpoint for 
the study is the proportion of participants with HIV-RNA greater than or equal to 
50 c/mL (Virologic Failure) at Week 48 as per Food and Drug Administration (FDA) 
Snapshot algorithm using the Intent-to-Treat Exposed (ITT-E) population.  The 
proportion of participants with plasma HIV-1 RNA <50 c/mL at Week 48 using the FDA 
Snapshot algorithm (Missing, Switch or Discontinuation = Failure, ITT-E population) is a 
key secondary endpoint comparison.  
The sample size of 1020 provides 85% power to demonstrate non-inferiority in the 
primary endpoint at Week 48 using a 4% margin, assuming a true 3% failure rate for 
Q8W CAB LA + RPV LA and a 2% failure rate for the Q4W CAB LA + RPV LA arm 
and a 2.5% one-sided alpha level.  
 
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Figure 1
207966 (ATLAS-2M) Study Design Schematic
N=1020, randomized 1:1 to each arm and stratified by prior CAB + RPV Exposure
# SOC Patients not transitioning from the ATLAS study must be on uninterrupted current regimen 
(either the initial or second cART regimen) for at least 6 months prior to Screening. Documented 
evidence of at least two plasma HIV-1 RNA measurements <50 c/mL in the 12 months prior to 
Screening: one within the 6 to 12 month window, and one within 6 months prior to Screening.  No 
history of virologic failure.  No evidence of viral resistance based on the presence of any 
resistance-associated major INI, or NNRTI mutation (except K103N) from prior genotype assay 
results. No current or prior history of etravirine use.
†Optional Extension Phase to continue randomized CAB LA + RPV LA Q4W or Q8W at Wk 100
¥Participants who withdraw from IM regimen must go into 52 week long term follow up phase if 
randomized regimen is not yet locally approved and commercially available. 
4.2.
Treatment Groups and Duration
4.2.1.
Screening Phase (Up to 35 days)
Informed consent must be obtained prior to any study procedures, including any 
Screening assessment.
Participants will be involved in a Screening period of up to 35 days and may be re-
screened once.  Participants who are randomized into the trial and subsequently 
withdrawn from the study, for any reason, may not be re-screened.  Participants may be 
randomized as soon as all eligibility requirements have been confirmed at the site.
For participants transitioning from the ATLAS study, eligibility to transition to ATLAS-
2M at Week 52 (at the earliest) will be determined once the final central lab results from 
ATLAS, following (at minimum) completion of the ATLAS Week 48 visit are available 
and safety parameters have been reviewed.  Separate Screening Labs will be utilized to 
inform eligibility for ATLAS-2M; however, in some occasions and upon consultation 
with the Medical Monitor, individual lab results and safety data from the final visit of the 
ATLAS study can be considered towards informing eligibility for the ATLAS-2M study 
as long as all other Screening and eligibility criteria are met.    
 
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4.2.2.
Maintenance Phase (Day 1 up to Week 100)
There are two ways in which study participants may transition to the LA regimen, either 
directly from oral SOC or from Q4W dosing from ATLAS. 
Table 1 and Figure 2 describe the CAB LA + RPV LA dosing regimens in ATLAS-2M 
based on the mode of transition.
Table 1
CAB LA + RPV LA Dosing Regimens in ATLAS-2M
Participants Transitioning from Oral Standard of Care (SOC)
Regimen
CAB LA
RPV LA
Q4W
CAB LA:
Week 4b: 600 mg (Loading Dose)
Week 8 & Q4W thereafter: 400 mg  
RPV LA:
Week 4b: 900 mg (Loading Dose)
Week 8 & Q4W thereafter: 600 mg
Q8W
CAB LA:
Week 4b, Week 8, & Q8W thereafter: 
600 mg
RPV LA:
Week 4b, Week 8, & Q8W thereafter: 
900 mg
Participants Transitioning from ATLAS Q4W
Regimen
CAB LA
RPV LA
Q4W
CAB LA:
Day 1 & Q4W thereafter: 400 mg
RPV LA:
Day 1 & Q4W thereafter: 600 mg
Q8W
CAB LA:
Day 1 & Q8W thereafter: 600 mg  
RPV LA:
Day 1 & Q8W thereafter: 900 mg
All participants entering ATLAS-2M from an oral SOC regimen will receive a 4-week oral lead-in of CAB+RPV prior to 
receiving IM injections, except for ATLAS subjects transitioning from Q4W to Q8W injections.  These participants 
previously established safety and tolerability of CAB + RPV within the ATLAS study.
 
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Figure 2
ATLAS-2M Treatment Schematic
Screening Phase
Maintenance Phase and Extension Phase
From ATLAS 
on Q4W
From ATLAS
on SOC
-or-
new SOC 
patients
(PI, NNRTI, or INI  
Regimen + 2 NRTI)
Q8W
Wk 24
Q4W 
Randomize 
1:1
Q8W 
Oral CAB
+ RPV
Oral CAB
+ RPV
Q4W 
Day 1
Wk 4b
Wk 4a
Randomize 
1:1
Wk 12
Wk 8
Wk 16
CAB 600mg/RPV 900mg
CAB 400mg/RPV 600mg
Wk 20
… continued to 
end of study
treatment
4.2.2.1.
Patients randomized to LA dosing from current ART SOC therapy:
All participants randomized from current ART SOC therapy (including those 
transitioning from SOC in ATLAS and new study participants) will begin oral therapy 
with CAB 30 mg + RPV 25 mg once daily at Day 1 for 4 weeks to determine individual 
safety and tolerability prior to administration of CAB LA + RPV LA.  The oral lead-in 
period is part of the Maintenance Phase and will therefore be included within the 48 and 
96 week analyses. 
The final dosing of current daily oral ART regimen should occur the day prior to 
randomization to avoid overlap of treatment regimens however, if the participant takes 
current ART prior to coming into the clinic, randomization and initiation of oral CAB 
and RPV should continue as planned for Day 1.  At the Week 4a visit, safety assessments 
(including e.g., clinical chemistries) will be performed as per the Time and Events Table 
to determine individual safety and tolerability prior to the initial administration of CAB 
LA + RPV LA.  Dosing of CAB LA + RPV LA Q4W or Q8W will initiate at the Week 
4b visit once safety labs from Week 4a are available and have been reviewed.
Subjects receiving oral SOC treatment and randomized to Q4W injections will receive 
loading doses of CAB LA 600 mg + RPV LA 900 mg on Week 4b followed by 
maintenance injections of CAB LA 400 mg + RPV LA 600 mg every 4 weeks thereafter.  
Subjects receiving oral SOC treatment and randomized to Q8W injections will receive 
doses of CAB LA 600 mg + RPV LA 900 mg on Week 4b and Week 8 followed by 
identical maintenance dose injections every 8 weeks thereafter.
 
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All injections should be planned as single injections per drug.
4.2.2.1.1.
IM injections every 4 weeks (Q4W from SOC):
Week 4b visit only - CAB LA 600 mg + RPV LA 900 mg, each given as 1 X 3 mL IM 
injection
Week 8 visit and Q4W thereafter - CAB LA 400 mg IM + RPV LA 600 mg IM every 
4 weeks for 100 weeks, each given as 1 X 2 mL IM injection
At Week 4b, participants will return to the clinic, take the last oral dose (CAB 30 mg + 
RPV 25 mg), and receive the first CAB LA (600 mg) + RPV LA (900 mg) injections 
(within 2 hours of the final oral dose of CAB + RPV).  The first injections with IM CAB 
LA + RPV LA at Week 4b can be performed once central lab results are available and 
safety parameters are reviewed from the Week 4a visit.  
The second and third IM injections with CAB LA 400 mg and RPV LA 600 mg will be 
performed at Week 8 and Week 12.  There will be a -7-day dosing window for the second 
and third IM injections such that the second injection occurs within the window of 
Week 7 and Week 8 but no later than Week 8 and the third injection occurs within the 
window of Week 11 and Week 12 but no later than Week 12.  Subsequent injections with 
CAB LA 400 mg and RPV LA 600 mg will occur every 4 weeks (7 days) thereafter.  In 
addition, starting after the Week 16 injection, the interval between injection visits will be 
limited to a maximum of 5 weeks.  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 5 weeks.
4.2.2.1.2.
IM injections every 8 weeks (Q8W from SOC):
Week 4b visit – CAB LA 600 mg + RPV LA 900 mg IM, each given as 1 X 3 mL IM 
injection
Week 8 visit- CAB LA 600 mg + RPV LA 900 mg IM, each given as 1 X 3 mL IM 
injection
Week 16 visit and Q8W thereafter - CAB LA 600 mg + RPV LA 900 mg IM, every 8 
weeks for 100 weeks, each given as 1 X 3 mL IM injection
At the Week 4b visit, subjects will return to the clinic, take their last oral dose (CAB 
30 mg + RPV 25 mg), and receive the first CAB LA (600 mg) + RPV LA (900 mg) 
injections (within 2 hours of the final oral dose of CAB + RPV).  The first injections with 
IM CAB LA + RPV LA at Week 4b can be performed once central lab results are 
available and safety parameters are reviewed from the Week 4a visit.  
The second loading injection will be administered at Week 8 (CAB LA 600 mg + RPV 
LA 900 mg, with subsequent injections (CAB LA 600 mg + RPV LA 900 mg) occurring 
every 8 weeks thereafter.  There will be a -7-day dosing window for the second and third 
IM injections such that the second injection occurs within the window of Week 7 and 
Week 8 but no later than Week 8 and third injection occurs within the window of Week 
 
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15 and Week 16 but no later than Week 16.  Subsequent injections with CAB LA 600 mg 
and RPV LA 900 mg will occur every 8 weeks (7 days).  Starting after the Week 16 
injection, the interval between injection visits will be limited to a maximum of 9 weeks.  
If the length of time between injections exceeds, or is projected to exceed 9 weeks, the 
Medical Monitor must be contacted to discuss individual participant case management.  
4.2.2.2.
Participants transitioning from ATLAS and currently receiving CAB LA 
+ RPV LA Q4W
Subjects receiving Q4W injections within ATLAS and randomized to receive Q4W 
injections in Study 207966 will continue receiving maintenance injections Q4W as 
scheduled and will not require a loading dose on Day 1.
Subjects receiving Q4W injections within ATLAS and randomized to receive Q8W 
injections in Study 207966 will receive doses of CAB LA 600 mg + RPV LA 900 mg on 
Day 1, one month after their last Q4W maintenance dose, in order to align with Day 1 of 
study randomization.  Subjects will not require an intermediate dose at Week 4 and will 
receive their next Q8W maintenance injections at Week 8 and Q8W thereafter.  
Participants transitioning from the ATLAS study and on CAB LA + RPV LA Q4W 
treatment will be randomized at Day 1 to either continue Q4W administration or 
transition to Q8W administration of CAB LA + RPV LA.  The first injection visit for the 
ATLAS-2M study can be performed once the final central lab results from the ATLAS 
study are available and safety parameters have been reviewed.  Screening labs 
determining eligibility for ATLAS-2M can be collected at Week 48 (at minimum) for 
participants originally randomized to the Q4W arm within ATLAS.  Screening labs for 
participants who transitioned from SOC to Q4W injections within the ATLAS Extension 
Phase may be obtained at ATLAS Week 56b (following the CAB + RPV Oral lead-in 
period) or at subsequent ATLAS visits after receiving one set or a short course of Q4W 
injections.  The transition from the final ATLAS to ATLAS-2M Day 1 dosing must occur 
4 weeks (7 days) from the final injections received in ATLAS 
Dosing for participants transitioning from CAB LA + RPV LA Q4W in ATLAS is as 
follows:
4.2.2.2.1.
IM injections every 4 weeks (Q4W from ATLAS Q4W):
Starting at Day 1, all injections will continue with maintenance doses of CAB LA 400 mg 
and RPV LA 600 mg administered every 4 weeks (7 days).  In addition, the time 
between injection visits will 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.
4.2.2.2.2.
IM injections every 8 weeks (Q8W from ATLAS Q4W):
Participants transitioning from ATLAS and randomized to receive CAB LA + RPV LA 
Q8W injections will initiate Q8W dosing at the Day 1 visit as follows: 
Day 1- CAB LA 600 mg + RPV LA 900 mg IM, each given as 1 X 3 mL IM injection
 
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Week 8 and Q8W thereafter- CAB LA 600 mg + RPV LA 900 mg IM, each given as 1 X 
3 mL IM injection
The second loading injection will be administered at Week 8 (CAB LA 600 mg + RPV 
LA 900 mg), with subsequent injections (CAB LA 600 mg + RPV LA 900 mg) occurring 
every 8 weeks thereafter.  There will be a -7-day dosing window for the second and third 
IM injections such that the second injection occurs within the window of Week 7 and 
Week 8 but no later than Week 8 and third injection occurs within the window of 
Week 15 and Week 16 but no later than Week 16.  Subsequent injections with CAB LA 
600 mg and RPV LA 900 mg will occur every 8 weeks (7 days).  Starting after the 
Week 16 injections, the interval between injection visits will be limited to a maximum of 
9 weeks.  If the length of time between injections exceeds, or is projected to exceed 9 
weeks, the Medical Monitor must be contacted to discuss individual participant case 
management.  
The primary study analysis will consist of data collected through the Week 48 visit.  A 
single repeat of HIV-1 RNA for any participant with a HIV-1 RNA 50 c/mL at Week 48 
or Week 96 must be performed.  The retest should be scheduled as soon as possible (but 
no later than 4 weeks from the Week 48 or Week 96 visits, respectively) and will inform 
the Week 48 or Week 96 virological endpoint, respectively.  
4.2.3.
Extension Phase
Participants who successfully complete 96 Weeks of CAB LA + RPV LA treatment in 
the Maintenance Phase will continue to have access to their randomized treatment Q4W 
or Q8W CAB LA + RPV LA in the Extension Phase until study treatment is either 
locally approved and commercially available within the local sector (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 + RPV LA Q4W and/or Q8W is terminated.  For participants 
randomized to Q4W arm, dosing visits will continue to occur every 4 weeks with CAB 
LA 400 mg and RPV LA 600 mg.  For participants randomized to the Q8W arm, dosing 
visits will continue to occur every 8 weeks with CAB LA 600 mg and RPV LA 900 mg.  
Safety and efficacy assessments will be conducted as per the Time and Events Schedule. 
Participants choosing to not enter the Extension phase can complete their study 
participation at the Week 100 visit and enter into the LTFU Phase as required. 
Participants who choose to continue on to the Extension Phase will need to be assessed 
for eligibility and will continue on their current CAB LA + RPV LA regimen while 
eligibility is being confirmed. 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 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.  Eligibility to enter the Extension Phase for any participants 
 
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with a retest HIV-1 RNA >50 c/mL and <400 c/mL will require approval by the study 
Medical Monitor.  
Participants not eligible to enter the Extension Phase or choosing not to participate in the 
Extension Phase will end their study treatment and enter the LTFU Phase until/unless the 
Follow-Up Phase is no longer required based on local approval of the assigned CAB LA 
+ RPV LA regimen.  Sites may be reimbursed for up to a one-month supply of 
antiretroviral medication to facilitate transition to non-study ART for participants that do 
not qualify for the Extension Phase.
4.2.4.
LTFU Phase – IM Regimen Only
Any participant who receives at least one dose of CAB LA and/or RPV LA and 
discontinues the CAB LA + RPV LA regimen for any reason must remain on suppressive 
HAART for at least 52 weeks after the last dose of CAB LA and/or RPV LA in order to 
prevent selective pressure on HIV and the potential for selection of resistant mutants.  
Investigators must discuss the choice of the follow-up HAART regimen with the 
Medical Monitor prior to initiating the new regimen with the participant.  HAART 
therapy should be initiated within 4 weeks (7 days) after the last Q4W injection, or 
within 8 weeks (7 days) after the last Q8W injection.  The LTFU will begin the day 
of the last CAB LA and/or RPV LA dose and continue for 52 weeks, or until the assigned 
CAB LA + RPV LA regimen is locally approved and commercially available.  These 
participants will complete Withdrawal assessments and will then enter into the LTFU as 
per the Time and Events Schedule.  In addition, for participants who withdraw during the 
LTFU, the final visit will be considered the study withdrawal visit. 
Participants will be assessed with clinic visits at months 3, 6, 9, and 12 during the LTFU 
Phase.  Female participants of child bearing potential must continue to use adequate 
contraception methods (see Study Procedures Manual for list of accepted forms of 
contraception) for the entire year of follow up.  
In order to assure that participants have access to HAART during the LTFU, GSK may 
supply HAART regionally or reimbursement will be provided as needed during this 
phase.  The LTFU Phase may be shortened or terminated 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 LTFU Phase.  The participants’ last on study visit will be considered as their 
withdrawal visit.
4.2.5.
Dose Modifications:
No dose reductions, modifications, or changes in the frequency of any components of 
each regimen will be allowed during the study beyond what is allowed within the 
protocol or directly approved by the study Medical Monitor. Protocol waivers or 
 
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exemptions are not allowed. Therefore, adherence to the study design requirements is 
essential and required for study conduct.
In exceptional circumstances, and in consultation with the Medical Monitor, Investigators 
may provide oral CAB and/or RPV as a short-term “bridging” strategy for participants 
who have begun CAB LA + RPV LA (see Section 6.8.1 for additional details).  Should a 
participant need “oral bridging”, sites must contact the Medical Monitor for guidance on 
treatment strategies prior to a missed CAB LA + RPV LA dose.  Should a participant not 
notify the site in advance, the Medical Monitor must be contacted for further treatment 
guidance.
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM), which is available on 
the online Study Web Portal.  The SPM will provide the site personnel with 
administrative and detailed technical information.
4.2.6.
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. 
The IDMC will evaluate accumulating efficacy, tolerability, safety and PK of CAB LA + 
RPV LA Q8W at predetermined times during the study.  An interim futility analysis will 
be performed for the IDMC to evaluate the efficacy of CAB LA + RPV LA Q8W prior to 
the final analysis.  Full details of the methods, timing, decision criteria, and operating 
characteristics will be pre-specified in the IDMC Charter.
The interim futility analysis will be performed with the intent of having approximately 
50% of participants reaching Week 24 and providing sufficient lead time to allow the 
IDMC to review the data prior to any participants reaching the Week 52 visit.  A futility 
rule based on Bayesian posterior predictive probability approach will be applied to assess 
the probability that the CAB LA + RPV LA Q8W injectable regimen demonstrates non-
inferiority to the CAB LA + RPV LA Q4W regimen, given the partial data set.  The 
sponsor will remain blinded to this analysis.
In addition, the IDMC may also monitor the incidence of participants meeting Confirmed 
Virologic Failure (CVF) criteria through Week 48 to ensure that participants are not 
being sub-optimally treated in the CAB LA + RPV LA Q8W arm.
Full details of the analyses, estimated timing, and the decision criteria that will be used to 
determine regimen performance will be pre-specified in the IDMC Charter.
4.3.
Type and Number of Participants
The target population to be enrolled is HIV-1 infected virologically suppressed (HIV-1 
RNA <50 c/mL) patients on stable antiretroviral therapy (ART) including participants 
who have completed at minimum, Week 52, of the 201585 (ATLAS) study.
 
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It is anticipated that approximately 1020 participants will be enrolled into ATLAS-2M.  
In addition to participants rolled over from the ATLAS study, additional participants on 
SOC treatment will be screened to supplement enrollment such that the study can be 
appropriately powered (See Section 9.1).  A 15% screen failure rate, for additional 
patients randomized from SOC treatment is anticipated.  Participants will be enrolled 
from multiple countries which may include those countries actively participating in the 
ATLAS study including Argentina, Canada, France, Germany, Italy, Mexico, Russia, 
South Africa, South Korea, Spain, Sweden, and the United States. 
Randomization will be stratified by prior CAB + RPV Exposure: 0 weeks, 1-24 weeks, 
>24 weeks.  A goal of this study is to enroll populations who are underrepresented in 
clinical studies, including approximately 25% women.  To provide sufficient data to 
determine whether either gender is correlated with treatment response, sites are expected 
to take into account gender in their screening strategies. 
4.4.
Scientific Rationale for Study Design
The design of this study (1:1 randomized, open-label, active-controlled, multicenter, 
parallel group, non-inferiority study) is well established for confirming the non-
inferiority of an investigational agent compared with an active comparator and is 
generally accepted by regulatory authorities as rigorous proof of antiviral activity. The 
primary endpoint, proportion of participants defined as virologic failures by the FDA 
Snapshot algorithm is recommended in the FDA’s 2015 guidance document (FDA, 2015) 
for assessing efficacy in Switch Trials.  The key secondary endpoints, proportion with 
plasma HIV-1 RNA <50 c/mL at Week 48 and Week 96, is also a well-established 
surrogate endpoint for prognosis of HIV-1 infection and disease progression. The 
Extension Phase will allow for a collection of longer term efficacy, safety and tolerability 
data for CAB LA + RPV LA Q4W and Q8W regimens.
Various approaches to simplify a patient's antiretroviral therapy (ART) regimen, after 
achieving viral suppression, have been studied.  Previous studies have evaluated switches 
to ritonavir-boosted PI monotherapy therapy in virologically suppressed patients 
[Bierman, 2009 and Arribas, 2012].  While the data from these studies have shown both 
long-term non-inferiority and inferiority to continual Highly Active Antiretroviral 
Therapy (HAART), they suggest that simplifying from a three drug dual class regimen to 
a single boosted protease inhibitor may be a safe and effective option for the majority of 
participants studied who have effectively maintained viral suppression. 
The 200056 (LATTE-2) (GlaxoSmithKline Document Number 2013N168152_05) 
clinical trial evaluated a different simplification approach and served as proof of concept 
for ATLAS-2M.  In 200056, HIV-1 RNA suppression was induced with a three drug 
antiretroviral regimen consisting of CAB + ABC/3TC FDC, and then participants 
switched to a two-drug two-class regimen consisting of CAB LA + RPV LA for the 
maintenance of HIV-1 RNA suppression.  Results demonstrate that through 96 weeks on 
two-drug maintenance therapy, 94% (Q8W IM arm) and 87% (Q4W IM) of subjects 
maintained virologic suppression (HIV-1 RNA <50 c/mL) compared to 84% of subjects 
continuing oral CAB + 2 NRTIs. CAB LA + RPV LA was well tolerated through 
Week 96 for both the Q8W and Q4W dosing regimens, as demonstrated by a low 
 
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discontinuation rate due to AEs, including injection site reaction (ISR) related AEs in 
either dosing arm, with no significant dose-dependent trends in safety parameters.  On the 
basis of 200056 Week 48, and Week 96 data, Q4W and Q8W IM dosing are being
progressed into Phase 3 for further clinical development, respectively. The CAB LA + 
RPV LA Q4W regimen is currently under evaluation in the ongoing Phase III ATLAS 
study. 
The open-label design best suits the objectives of this study.  A double-dummy design 
could not be undertaken given the logistical challenges of blinding each regimen.  
Because 2 injections of each investigational product are administered at every visit, a 
double-dummy design would require all subjects to chronically receive 4 injections per
Q4W visit (2 active and 2 placebo), which could be intolerable for patients. In addition,
the volume of CAB LA and RPV LA injections will differ significantly between Q8W 
and Q4W IM injections (3 mL vs 2 mL each), it would not be logistically feasible to 
blind site staff nor patients from the study treatments being administered. 
Participants randomized to receive CAB LA + RPV LA Q8W IM administration will be 
required to participate in clinic visits approximately every 8 weeks while participants 
randomized to receive Q4W IM administration will be required approximately monthly 
clinical visits. Importantly, secondary objectives of this study are to understand the 
acceptability, tolerability, and patient reported preferences to these novel injectable 
regimens.  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. If the Q8W arm were required to receive blinded placebo injections every 
month, the value of comparing safety, tolerability, and convenience of Q8W compared to 
Q4W administrations would be limited and include overly burdensome visit requirements 
for those randomized to Q8W administration.  Additionally, the perceived value for 
participants to transition from the ATLAS study to ATLAS-2M for potential 
randomization to the Q8W regimen would also be limited and may result in loss of 
patients with prior Q4W experience, thereby limiting the ability to compare experience of 
Q4W and Q8W regimens within individual patients.  
Due to the complexities, lack of feasibility and limitations of blinding CAB LA and RPV 
LA injections for Q8W compared to Q4W administration, this Phase 3b study is planned 
as open label.  
To maintain the integrity of the trial, data aggregated by actual treatment group will not 
be made available to members of the Study Team in advance of the first planned sponsor 
analysis when all subjects have completed Week 24 (see Section 9.2.3.1) and will not be 
shared with Investigators until the primary analysis at Week 48. In addition, central 
randomization will be used to ensure that selection bias is avoided (see Section 6.2).  
Lastly, ascertainment bias affecting the primary efficacy analysis is unlikely since the 
primary endpoint is inherently objective, being primarily determined by HIV-1 RNA 
laboratory assessment. The open label design should therefore have no impact on the 
analysis of study endpoints.  
 
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4.5.
Dose Justification
4.5.1.
Oral Lead-In Phase
Participants entering the study from oral SOC will receive oral CAB 30 mg + RPV 25 mg
once daily during the 4-week oral lead-in phase to confirm tolerability prior to receiving 
CAB LA + RPV LA injectable treatment.  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.  Oral RPV 25 mg once daily, the approved oral dose of RPV, has been 
administered in combination with oral CAB to HIV-infected participants in Phase 2b 
studies LAI116482 [(LATTE); GlaxoSmithKline Document Number 2014N216014_00] 
(CAB 10, 30, or 60 mg once daily) and 200056 [LATTE-2] (CAB 30 mg, oral lead-in 
phase).  The CAB 30mg oral dose was selected based on observed safety and efficacy 
from the LATTE-2 study for use during the oral lead phase of Phase 3 studies 201585 
[ATLAS] and 201584 [FLAIR] which are evaluating Q4W dosing of CAB LA + RPV 
LA.  The present study will also use CAB 30 mg once daily with RPV 25 mg once daily 
during the oral lead-in phase.   
CAB demonstrated good short-term safety/tolerability and antiviral activity as 
monotherapy following oral administration of 5 mg and 30 mg once daily.  LAI116482 
(LATTE) is an ongoing Phase IIb, dose-ranging study (randomized 1:1:1: to CAB 10 mg, 
30 mg, or 60 mg) evaluating the long-term efficacy and safety of a two-drug, two-class, 
once daily combination of CAB + RPV in HIV-infected, treatment-naïve adult 
participants.  Following a 24-week phase of induction of virologic suppression using 
CAB + 2 NRTIs, the regimen was simplified to oral CAB + RPV once daily at Week 24 
and continued for an additional 72-weeks (total comparative study duration of 96 weeks; 
Margolis, 2015).  The results of this study also informed the Phase IIb study 200056 
(LATTE-2) with intramuscular CAB LA and RPV LA.  
Comparable efficacy, safety, and tolerability were observed across all three CAB doses at 
the early dose selection and confirmation visits at Week 16 and 24 in LATTE.  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 2).  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 2
Proportion (95% CI) of Participants with Plasma HIV-1 RNA <50 c/mL 
at Key Visits - Snapshot (MSDF) Analysis (ITT-E Population) in 
LATTE
Visit
CAB 10 mg 
N=60
CAB 30 mg 
N=60
CAB 60 mg 
N=61
CAB 
Subtotal 
N=181
EFV 600 mg 
N=47
Week 16
n (%)
54 (90)
50 (83)
53 (87)
157 (87)
46 (74)
95%CI 
Proportion
(82, 98)
(74, 93)
(78, 95)
(82, 92)
(63, 85)
Week 24
n (%)
52 (87)
51 (85)
53 (87)
156 (86)
46 (74)
95%CI 
Proportion
(78, 95)
(76, 94)
(78, 95)
(81, 91)
(63, 85)
Week 48
n (%)
48 (80)
48 (80)
53 (87)
149 (82)
44 (71)
95%CI 
Proportion
(70, 90)
(70, 90)
(78, 95)
(77, 88)
(60, 82)
Week 96
n (%)
41 (68)
45 (75)
51 (84)
137 (76)
39 (63)
95%CI 
Proportion
(57,80)
(64,86)
(74, 93)
(69, 82)
(51, 75)
CAB was administered with 2 NRTIs through Week 24 (Induction Phase) of LATTE.
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, provided further support for CAB 30 mg dose selection in Phase 3 and the 
present study.  In addition, the 30 mg dose achieves CAB plasma trough 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 (Table 3).
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 
 
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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 exposure following 
LA administration, and limited drug-drug interaction potential, support selection of the 
CAB 30 mg dose for once daily administration with the approved dose of RPV 25 mg 
once daily during the oral lead-in phase of this study.  
Table 3
Summary of CAB Pharmacokinetic Parameters Following Repeat 
Oral Administration in HIV-Infected Subjects
Study
Once 
Daily 
Dose
Phase
Plasma CAB PK Parameter
(Geometric mean [95%CI] (CVb%)
AUC(0-)
(g.h/mL)
Cmax
(g/mL)
Cor C0
(g/mL)
Tmaxa
(h)
LAI116482
(LATTE)
10 mg 
tab
(n=14)
Induction 
Phase
+2 NRTIs
45.7
[38.2, 54.6]
(32)
2.77
[2.3, 3.3]
(33)
1.35b
[1.2, 1.5]
(45)
1.0
(0.9 – 8.0)
Maintenance 
Phase
+RPV 25 mg
---
---
1.34c
[1.1, 1.6}
(58)
---
30 mg 
tab
(n=12)
Induction 
Phase
+2 NRTIs
134
[110, 163]
(32)
7.49
[6.3, 8.9]
(28)
4.20d
[3.8, 4.7]
(40)
2.0
(1.0 – 8.0)
Maintenance 
Phase
+RPV 25 mg
---
---
3.93e
[3.5, 4.4]
(44)
---
60 mg 
tab
(2x30 
mg)
(n=9)
Induction 
Phase
+2 NRTIs
195
[138, 277]
(48)
11.5
[8.8, 15.0]
(36)
7.93f
[7.2, 8.8]
(39)
2.0
(1.0 – 8.0)
Maintenance 
Phase
+RPV 25 mg
---
---
8.22g
[7.4, 9.1]
(37)
---
200056
LATTE-2
Day 1, 
predose
30 mg 
tab
(n=246)
Induction 
Phase 
+2NRTIs
---
---
4.22
[4.0, 4.4}
(43)]
---
a.
median (range)
b.
n=57
c.
n=50
d.
n=53
e.
n=51
f.
n=55
g.
n=49
 
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4.5.2.
Long Acting Injectable for Maintenance Phase
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 Phase (16 weeks of oral CAB + 2 
NRTIs, 4 weeks of CAB + 2 NRTIs + oral RPV).  Participants who were eligible to 
continue into the Maintenance Phase were then randomized (2:2:1) to receive IM 
injections of CAB LA every 4 weeks (800 mg Day 1 then 400 mg Q4W) or every 8 
weeks (800 mg Day 1, 600 mg Week 4, 600 mg Week 8, then 600 mg Q8W) in 
combination with IM RPV LA every 4 weeks (600 mg Day 1 then 600 mg Q4W) or 
every 8 weeks (900 mg Day 1, 900 mg Week 8, then 900 mg Q8W), respectively, or to 
continue on their triple ART regimen.
The Q4W dosing strategy was selected for further investigation in Phase 3 based on 
observed efficacy, safety, and tolerability at Week 48.  Both Q4W and Q8W regimens 
were continued throughout the Maintenance Phase as planned, and Week 96 results 
(Table 4) were supportive of further evaluation of the Q8W regimen in the present study.  
Moreover, LATTE-2 was amended to permit subjects to remain on their randomized LA 
regimen (either Q4W or Q8W) during the Extension Phase (post Week 96), and those 
subjects randomized to the oral comparator arm were allowed transition to either LA 
regimen at Week 96.  Forty-four subjects were transitioned from the oral comparator arm 
to LA treatments in the Extension Phase; 34 (77%) opted for the Q8W regimen and 10 
(23%) for the Q4W regimen.  Initial LA injections were administered at Week 100 
following a 4-week oral lead-in where 2 NRTIs were discontinued and RPV 25 mg once 
daily was added to CAB 30 mg once daily.  
Table 4
Summary of Study Outcomes (<50 copies/mL) at Weeks 48 and 96 –
Snapshot (MSDF) Analysis (ITT-ME Population) in LATTE-2
Endpoint 
(Week)
Outcome
Q8W IM
N=115
n (%)
Q4W IM
N=115
n (%)
CAB 30 mg+ 
ABC/3TC
N=56
n (%)
Subtotal IM
N=230
n (%)
W48
Virologic Success, n (%)
106 (92) 
105 (91)
50 (89)
211 (92)
Virologic Failure, n (%)
8 (7) 
1 (<1)
1 (2)
9 (4)
W96
Virologic Success, n (%)
108 (94)
100 (87)
47 (84)
208 (90)
Virologic Failure, n (%)
5 (4)
0
1 (2)
5 (2)
Observed pharmacokinetic data for both CAB LA regimens in LATTE-2 are presented in 
Figure 3 and summarized in Table 5.
 
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Figure 3
Observed Mean (SD) Concentration-Time Data following CAB LA 
Q8W and Q4W and Cfollowing 30 mg PO QD through Week 48 
(200056, LATTE-2)
Week
0 1
4
8
12
16
20
2425
28
32
32
36
4041
44
48
48
Plasma CAB (g/mL)
0.1
1
10
800mg IM LD, 600mg IM W4, W8 and Q8W
800mg IM LD, 400mg IM Q4W
30mg PO QD
PA-IC90 (0.166g/mL)
10mg PO QD C (LATTE, 1.35g/mL)
Both predose and 2h post injection concentrations are shown at Time Zero, Week 32, and 
Week 48.
 
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Table 5
Summary of CAB PK Parameters Following Repeat Dose 
Administration of CAB LA to Healthy and HIV-infected Subjects
Population
Study
CAB LA 
Regimen
Dosing 
Interval
Plasma CAB PK Parameter
(Geometric mean [95%CI] (CVb%)
AUC(0- ) 
(g•h/mL)
Cmax
(g/mL)
C
(g/mL)
Tmaxa
(day post 
last dose)
Healthy 
Subjects
LAI115428
800 mg IM/
400 mg IM 
Q4W
(n=10)
D1-W4
1252
[836, 1873]
(61)
2.74
[1.72 4.35]
(72)
1.78
[1.35, 2.36]
(41)
6
(6 – 28)
W4-W8
2010
[1619, 2494]
(31)
3.79
[2.89, 4.99]
(40)
2.60
[2.20, 3.07]
(24)
6
(2 – 28)
W8-W12
2182
[1798, 2647]
(28)
4.03
[3.05, 5.30]
(40)
2.69
[2.21, 3.27]
(28)
6
(2 – 28)
W12-W16
2473
[2063, 2965]
(26)
4.41
[3.55, 5.48]
(31)
3.27
[2.71, 3.94]
(27)
6
(2 – 13)
HIV 
Infected 
Subjects
200056
LATTE2
800 mg IM/ 
400 mg IM 
Q4W
(n=115)
W24-W28
(n=97)
1858b
[1719, 2007]
(37)
3.50 
[3.2, 3.8]
(39)
2.35c
[2.2, 2.5]
(32)
6.9
(0 – 29)
W40-W44
(n=95)
2017d
[1847, 2203]
(41)
3.50e
[3.3, 3.8]
(37)
2.56f  
[2.4, 2.7]
(32)
6.9 
(0 – 28)
800 mg IM/ 
600 mg IM 
Q8W
(n=115)
W24-W32
(n=98)
3037g
[2786, 3310]
(42)
3.55
[3.2, 3.9]
(56)
1.43h
[1.3, 1.6]
(54)
6.9 
(0 – 59)
W40-W48
(n=104)
3027i
[2762, 3322]
(47)
3.33 
[3.1, 3.6]
(47)
1.49 
[1.4, 1.6]
(42)
7.0 
(0 –  57)
a.
median (range)
b.
n=84
c.
n=108
d.
n=80
e.
n=98
f.
n=86
g.
n=100
h.
n=93 
i.
n=112
The CAB LA population PK model was updated to include data from CAB LA pre-
exposure prophylaxis (PrEP) Study 201120 (ÉCLAIR; GlaxoSmithKline Document 
Number 2016N269422_00) and Study 200056 (LATTE-2), increasing the original model 
from 93 subjects to 416 subjects receiving CAB LA single or repeat IM injections.  
Modeling and simulation was used to enable simplification and alignment of loading dose 
strategy used in LATTE-2 for both Q4W and Q8W CAB LA and RPV LA dosing 
regimens, resulting in selection of optimized Q4W and Q8W LA dosing regimens for use 
in Phase 3 studies (Q4W) and the present study (Q4W and Q8W) as discussed in Section
4.5.2.1 and Section 4.5.2.2.
 
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4.5.2.1.
CAB LA Q8W
The CAB LA 600mg Q8W regimen is predicted to achieve concentrations above 
1.35 g/mL, the geometric mean Cfollowing oral CAB 10 mg once daily which was 
shown to be efficacious in the LATTE study.  The lower bound of the 90% prediction 
interval is approximately 0.166 g/mL, indicating that 95% of subjects on this regimen 
should remain above the PA-IC90 throughout dosing (Figure 4).  The CAB LA Q8W 
regimen consists of identical 600 mg doses administered at Day 1, Week 4, and Q8W 
thereafter.  
Figure 4
Simulated* Median (90% Prediction Interval [PI]) CAB Plasma 
Concentrations versus Time for the Optimized CAB LA Q8W 
Regimen (600 mg IM Day 1, Week 4, Q8W Thereafter)^
*Note: current simulations based on interim plasma concentration dataset
^Study Time and Events include a 4-week oral lead in for subjects transitioning to Q8W from oral SOC.  
Therefore, Day 1 (time zero) = date of first injections in 207966
4.5.2.1.1.
CAB PK Profile Following Transition to Q8W Regimen
There are two ways in which study participants may transition to the Q8W regimen, 
either directly from oral SOC or directly from Q4W dosing from ATLAS.  Figure 4
shows the predicted plasma CAB PK profile for SOC participants directly transitioning to 
Q8W dosing following completion of the oral lead-in phase.  The majority of participants 
receiving Q4W injections will have received injections for more than 1 year and will 
have achieved steady-state CAB concentrations within ATLAS well before transitioning 
to Q8W dosing in ATLAS-2M.  Figure 5 shows the predicted plasma CAB PK profile for 
participants directly transitioning to Q8W dosing from Q4W dosing who have achieved 
 
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steady-state plasma CAB concentrations.  Other participants, however, may have only 
received a short course of Q4W injections in ATLAS and will have not yet achieved 
steady-state plasma CAB concentrations prior to transitioning to Q8W dosing.  Figure 6
shows the predicted plasma CAB PK profile for participants directly transitioning to 
Q8W dosing from a short course of Q4W dosing who have not achieved steady-state 
plasma CAB concentrations.  
Figure 5
Predicted Median (90% PI) CAB Profile following Steady State CAB
LA Q4W Administration in ATLAS prior to Transitioning to Q8W on 
Day 1 of ATLAS-2M assuming 20% of participants are female.
 
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Figure 6
Predicted Median (90% PI) CAB Profile following a Short Course of 
CAB LA Q4W Administration in ATLAS prior to Transitioning to Q8W 
on Day 1 of ATLAS-2M assuming 20% of participants are female.
Figure 7 simultaneously shows the median predicted plasma CAB PK profile following 
transition to Q8W dosing from oral SOC, a short course of Q4W, or long-term Q4W 
dosing.  Regardless of route of transition (oral or IM) or prior length of IM dosing (short 
course or steady-state), plasma CAB concentrations are predicted to be safe and 
efficacious during the transition period and all participants are expected to achieve 
comparable target concentrations at Week 48.  In addition, Figure 7 demonstrates that 
participants transitioning from Q4W dosing (regardless of short course or long-term 
Q4W dosing), do not require an intermediate dose at Week 4 as plasma CAB 
concentrations are above Q8W targets and thus can commence Q8W dosing starting from 
the first Q8W dose at Day 1. 
 
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Figure 7
Predicted CAB Profiles for CAB LA Q8W after Transition from Oral 
Lead In or CAB LA Q4W (assumes 20% female population)
Time (Weeks)
-16 -12
-8
-4
0
4
8
16
24
32
40
48
Predicted Median CAB (ug/mL)
0
1
2
3
4
5
6
7
8
Q8W from oral lead-in (SOC in ATLAS, 600mg IM W4)
Q8W from short course Q4W (SOC to Q4W in ATLAS, 600mg IM D1)
Q8W from steady state Q4W (Q4W in ATLAS, 600mg IM D1)
Geometric mean Ctau 10mg PO (LATTE, 1.35ug/mL, ~8x PA-IC90)
400mg
600mg
A one-week delay in CAB LA dosing for the Q8W regimen at steady state is predicted to 
result in ~92% rather than 95% of subjects achieving trough concentrations above the 
PA-IC90, which is considered acceptable.
4.5.2.2.
CAB LA Q4W
There are two ways in which study participants may transition to the Q4W regimen, 
either directly from oral SOC or directly from Q4W dosing from ATLAS.  Figure 8
shows the predicted plasma CAB PK profile for SOC participants directly transitioning to 
Q4W dosing following completion of the oral lead-in phase.  Former ATLAS participants 
receiving Q4W injections and randomized to the Q4W dosing arm of ATLAS-2M will 
continue receiving Q4W injections as scheduled.
The CAB LA 400 mg Q4W regimen is predicted to achieve trough concentrations above 
4x PA-IC90 in 98% of participants at steady-state and 88% is predicted to achieve trough 
concentrations above the geometric mean trough following the 10 mg oral dose in 
 
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LATTE of 1.35 g/mL (8x PA-IC90).  The lower bound of the PI remains approximately 
at or above 4x PA-IC90 throughout dosing (Figure 8).  The CAB LA Q4W regimen 
consists of a 600 mg loading dose on Day 1 followed by a 400 mg maintenance dose at 
Week 4 and Q4W thereafter.  
Figure 8
Simulated* Median (90% Prediction Interval [PI]) CAB Plasma
Concentrations versus Time for the Optimized CAB LA Q4W 
Regimen (600 mg IM Day 1, then 400 mg IM Q4W thereafter^)
* Note: current simulations based on interim plasma concentration dataset
^Study Time and Events include a 4-week oral lead in.  Therefore, Day 1 (time zero) = date of first 
injections in 207966
Medium dashed line at 1.35 g/mL corresponds to the geometric mean Ctrough concentration following 
oral CAB 10 mg once daily (LATTE) and is equivalent to 8x PA-IC90
Dotted line at 0.664 g/mL corresponds to 4x PA-IC90
Long dashed line at 0.166 g/mL corresponds to the PA-IC90.
At steady state, a one-week delay in dosing of the Q4W regimen results in approximately 
15% reduction in median CAB trough.  With this delay, 95% are predicted to remain 
above 4x PA-IC90, and 79% are predicted to remain above the 10 mg oral trough 
concentrations.  Therefore, a 1-week delay is the maximum allowed per the protocol.  
 
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4.5.3.
RPV LA
Observed PK data for both RPV LA Q4W and Q8W regimens in LATTE-2 are presented 
in Figure 9 and Table 6.  The RPV LA population PK model has been updated to include 
data from LATTE-2 and from Phase 1 studies in healthy volunteers.
Figure 9
Observed Mean (SD) Plasma Concentration-Time Data following 
RPV LA Q8W and Q4W through Week 48 and Day 1 Cfollowing RPV 
25 mg PO QD (LATTE-2)
Week
0 1
4
8
12
16
20
2425
28
32
32
36
4041
44
48
48
Plasma RPV (ng/mL)
10
100
1000
900mg IM Q8W
600mg IM Q4W
25mg PO QD
PA-IC90 (12ng/mL)
25mg PO QD (LATTE, 70ng/mL)
Both predose and 2 hr post injection concentrations are shown at Time Zero, Week 32, 
and Week 48.
 
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Table 6
Summary of RPV PK Parameters following Repeat Dose RPV LA 
Administration with CAB LA in Healthy and HIV-infected Subjects 
Study/
Population
RPV LA 
Regimen
Dosing 
Interval
(from 1st 
RPV IM 
dose)
Plasma RPV PK Parameter
(Geometric mean [95%CI] (CVb%)
AUC(0- ) 
(g•h/mL)
Cmax
(g/mL)
C
(g/mL)
Tmaxa
(day post last 
dose)
LAI115428/ 
Healthy 
Subjects
1200 mg IM/
900 mg IM
(+ CAB LA 
200 mg IM)
(n=9)
D1-W4
52762
[36468, 76335]
(51)
109
[74.2, 159]
(53)
61.6
[39.3, 96.6]
(64)
6
(1.8 – 20)
W4-W8
74420
[57323, 96615]
(35)
168
[128, 222]
(37)
79.1
[57.2, 109]
(44)
6
(2 – 13)
1200 mg IM/
600 mg IM
(+ CAB LA 
400 mg IM)
(n=10)
D1-W4
52703
[42917, 64721]
(29)
108
[87.6, 133]
(30)
64.0
[50.6, 80.9]
(34)
6
(2 – 28)
W4-W8
63656
[50186, 80741]
(34)
126
[101, 158]
(32)
78.9
[60.3,103]
(39)
9.5
(2 – 27)
200056
(LATTE2)/
HIV 
Infected 
Subjects
600 mg IM 
Q4W
(n=115)
W24-W28
(n=96)
61309b
[56724, 66264]
(37)
111 
[103, 120]
(40)
77.2c
[72, 83]
(35)
6.0
(0 – 29)
W40-W44
(n=94)
71106d
[65354, 77366]
(39)]
127
[118, 136]
(36)
92.1e
[87, 98]
(32)
6.0
(0 – 28)
900 mg IM 
Q8W
(n=115)
W24-W32
(n=97)
96196f
[87286, 106015]
(48)
104
[95, 114]
(47)
49.3g
[46, 53]
(41)
7.0
(0 – 57)
W40-W48
(n=104)
116160h
[108189, 124719]
(35)
121
[111, 131]
(42)
63.2i
[59,  68]
(35)
6.0
(0 – 59)
a.
median (range)
b.
n=84
c.
n=104
d.
n=80
e.
n=102
f.
n=86
g.
n=101
h.
n=92
i.
n=100
4.5.3.1.
RPV LA Q8W
The RPV LA Q8W regimen for this study (ATLAS-2M) was selected based on safety 
and efficacy data from study 200056 (LATTE-2) and supported by modeling and 
simulation of pharmacokinetic data obtained following administration RPV LA 
administration in healthy subjects (Phase 1 studies C158, and LAI115428 
[GlaxoSmithKline Document Number 2011N112455_03]) and in HIV-infected subjects 
(Phase 2 study LATTE-2), the majority of the data coming from 200056 (LATTE-2). 
 
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The RPV LA 900 mg Q8W regimen is predicted to achieve median (90% PI) steady-state 
Cof 54 ng/mL (23 – 112 ng/mL) (Figure 10).  With this regimen, 100% of subjects 
remain above the RPV PA-IC90 during the whole dose interval at steady-state.  These 
data are similar to the observed Week 32 median steady-state Cin LATTE-2 for Q8W 
which was also 54 ng/mL and the mean Cwas 58 ng/mL.  The RPV LA Q8W regimen 
consists of identical 900 mg doses administered at Day 1, Week 4, and Q8W thereafter.  
With the second RPV LA dose administered 4 weeks after the first dose, the anticipated 
median RPV Cat Week 4 (prior to second injection) is 40 ng/mL (versus 30 ng/mL 
observed prior to second injection at Week 8 in LATTE-2, where the RPV LA dose at 
Week 4 was not included), with >92% of subjects above the RPV PA-IC90 of 12 ng/mL.
Figure 10
Simulated* Median (90% PI) RPV Plasma Concentrations versus 
Time Profile for the Optimized RPV LA Q8W regimen (900 mg IM Day
* Note: current simulations based on interim plasma concentration dataset
^Study Time and Events include a 4 week oral lead in for subjects transitioning to Q8W from oral SOC.  
Therefore, Day 1 = date of first injections for Study 207966
4.5.3.1.1.
RPV PK Profile Following Transition to Q8W Regimen
As previously described, there are two ways in which study participants may transition to 
the Q8W regimen, either directly from oral SOC or directly from Q4W dosing from 
ATLAS.  Figure 10 shows the predicted plasma RPV PK profile for SOC participants 
directly transitioning to Q8W dosing following completion of the oral lead-in phase.  
 
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Participants may also transition to RPV LA Q8W in ATLAS-2M following RPV LA 
Q4W, treatment for a minimum of 52 weeks in ATLAS or following a shorter duration of 
RPV LA Q4W treatment following transition from oral SOC after Week 52 in ATLAS.  
Figure 11 shows the predicted plasma RPV PK profile for participants directly 
transitioning to Q8W dosing from Q4W dosing who have achieved steady-state plasma 
RPV concentrations.  
Figure 11
Simulated Median (90% PI) RPV Profile following Steady State RPV 
LA Q4W Administration in ATLAS prior to Transitioning to Q8W on 
Day 1 of ATLAS-2M
Figure 12 shows the predicted median (90% PI) profile for subjects switching to RPV LA 
Q8W after having a short course of 4 RPV LA Q4W injections.  In this setting, switching 
immediately to RPV LA 900 mg 8-weekly injections keeps the median Cabove 2x the 
RPV PA-IC90 and 100% of subjects remain above the RPV PA-IC90 during the whole 
dose interval.  Figure 13 shows that (until steady-state is reached), the median predicted 
Cfor those transitioning from Q4W to Q8W is higher than the predicted Cfor those 
transitioning from oral to Q8W, despite not having the extra RPV LA 900 mg IM 
injection 4 weeks after the first injection on the Q8W regimen.  This therefore justifies 
 
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the simplified RPV LA dosing regimen (without injection at Week 4) for those subjects 
that are already on a Q4W regimen.
Therefore, regardless of the length of time that they are already on RPV LA Q4W 
treatment, such subjects transitioning to RPV LA Q8W will receive RPV LA 900 mg IM 
Q8W from Day 1 of ATLAS-2M.
Figure 12
Simulated Median (90% PI) RPV Plasma Concentration versus Time 
Profile for Subjects Switching from a Short Course Q4W Regimen in 
ATLAS to a Q8W regimen (RPV LA on Day 1 and Q8W thereafter^)
 
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Figure 13
Simulated Median RPV Plasma Concentration versus Time Profile 
for Subjects Switching Either from an Oral Regimen or from a Q4W 
Regimen to a Q8W regimen
At steady-state, a one-week delay in dosing for the Q8W regimen is predicted to result in 
a median steady-state Cthat is approximately 11% lower (48 ng/mL) than for dosing 
that is administered on schedule, with >99% of subjects still remaining above the RPV 
PA-IC90.  This supports allowance of some flexibility in the dosing regimen in ATLAS-
2M, similar to what is currently practiced in the LATTE-2 study.
4.5.3.2.
RPV LA Q4W
The RPV LA Q4W regimen for ATLAS-2M was selected based on LATTE-2 safety and 
efficacy data as described above and supported by modeling and simulation of 
pharmacokinetic data as described above.  The Q4W dose regimen consists of a RPV LA 
900 mg dose on Day 1, and RPV LA 600 mg every 4 weeks thereafter.  This regimen is 
also studied in the Phase 3 studies ATLAS and FLAIR. 
There are two ways in which study participants may transition to the Q4W regimen, 
either directly from oral SOC or directly from Q4W dosing from ATLAS.  Figure 14
shows the predicted plasma RPV PK profile for SOC participants directly transitioning to 
 
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Q4W dosing following completion of the oral lead-in phase.  Former ATLAS participants 
receiving Q4W injections and randomized to the Q4W dosing arm of ATLAS-2M will 
continue receiving Q4W injections as scheduled.
The predicted median (90% PI) steady-state Cfor the proposed regimen is 84 ng/mL 
(41 – 161 ng/mL, Figure 14).  With this regimen, >99% of participants remain above the 
5th percentile of steady state trough values following oral RPV 25 mg (corresponding to 
2x the PA-IC90).  With a loading dose of 900 mg RPV LA on Day 1, the anticipated 
median RPV Cat Week 4 is 40 ng/mL, with >92% of participants above the RPV PA-
IC90.
Figure 14
Simulated* Median (90% PI) RPV Plasma Concentrations versus 
Time Profile for the RPV LA Q4W regimen (900 mg IM Day 1, then 
600 mg IM Q4W thereafter^)
* Note: current simulations based on interim plasma concentration dataset
^Study Time and Events include a 4-week oral lead in.  Therefore, Day 1 = day of first injections for Study 207966 
At steady-state, a one-week delay in dosing for the Q4W regimen is predicted to result in 
a median steady-state Cthat remains above the median trough for oral RPV 25 mg once 
daily.  This supports allowance of some flexibility in the dosing regimen, as also 
practiced in LATTE-2 and the Phase 3 studies FLAIR and ATLAS.
 
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5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the investigational regimen or other study treatment 
that may impact participant eligibility is provided in the current Investigator’s Brochures 
(IB) for CAB (GlaxoSmithKline Document Number RH2009/00003/06 and RPV IB,
2017) and Edurant product label.
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
participant safety.  Therefore, adherence to the criteria as specified in the protocol is 
essential.
5.1.
Inclusion Criteria
A participant will be eligible for inclusion in this study only if all of the following criteria 
apply:

Be able to understand and comply with protocol requirements, instructions, and 
restrictions;

Understand the long term commitment to the study and be likely to complete the 
study as planned;

Be considered appropriate candidates for participation in an investigative clinical 
trial with oral and intramuscularly injectable medications (e.g., no active substance 
use disorder, acute major organ disease, or planned long-term work assignments out 
of the country, etc.).  
The following are study specific eligibility criteria unless stated otherwise.  In addition 
to these criteria, Investigators must exercise clinical discretion regarding selection of 
appropriate study participants, taking into consideration any local treatment 
practices or guidelines and good clinical practice (GCP).  All participants must be 
considered appropriate candidates for antiretroviral therapy in accordance with 
local treatment guidelines.
Laboratory results from the central laboratory services provided by this trial will be used 
to assess eligibility.  In exceptional circumstances only, if a repeat lab is required because 
a central lab result cannot be generated, local labs can be reviewed and approved by the 
Medical Monitor for consideration of participant eligibility.  A repeat central lab will be 
submitted concurrently or at the next planned visit.
Source documentation to verify entry criteria must be reviewed by the Principal 
Investigator or designee prior to randomization.  Source documents from other medical 
facilities must be located/received during the 14-day screening phase (or up to 35 days) 
and under no circumstances may the participant be randomized in the absence of source 
documentation. 
 
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All Participants eligible for enrolment in the study must meet all of the following 
criteria:
AGE
1. Aged 18 years or older (or ≥19 where required by local regulatory agencies), at 
the time of signing the informed consent.
SEX
2. A female participant is eligible to participate if she is not pregnant (as confirmed 
by a negative serum human chorionic gonadotropin (hCG) test at screen and a 
negative urine hCG test at Randomization), not lactating, and at least one of the 
following conditions applies:
a. Non-reproductive potential defined as:

Pre-menopausal females with one of the following:

Documented tubal ligation

Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion

Hysterectomy

Documented Bilateral Oophorectomy

Postmenopausal defined as 12 months of spontaneous amenorrhea [in 
questionable cases a blood sample with simultaneous follicle stimulating 
hormone (FSH) and estradiol levels consistent with menopause (refer to 
laboratory reference ranges for confirmatory levels)].  Females on 
hormone replacement therapy (HRT) and whose menopausal status is in 
doubt will be required to use one of the highly effective contraception 
methods if they wish to continue their HRT during the study.  Otherwise, 
they must discontinue HRT to allow confirmation of post-menopausal 
status prior to 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) from 30 days prior to the first dose of study 
medication, throughout the study, for at least 30 days after discontinuation of all 
oral study medications, and for at least 52 weeks after discontinuation of CAB LA 
and RPV LA. 
The investigator is responsible for ensuring that participants understand how to properly 
use these methods of contraception.  
INFORMED CONSENT
3. Capable of giving signed informed consent, which includes compliance with the 
requirements and restrictions listed in the consent form and in this protocol.  
 
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Eligible participants or their legal guardians (and next of kin when locally 
required), must sign a written Informed Consent Form before any protocol-
specified assessments are conducted.  Enrolment of participants who are unable to 
provide direct informed consent is optional and will be based on local 
legal/regulatory requirements and site feasibility to conduct protocol procedures.
OTHER
4. Participants enrolled in France must be affiliated to, or a beneficiary of, a social 
security category.  
Participants receiving oral standard of care (SOC) treatment for HIV-1 (not 
participating in ATLAS Trial)
5. Must be on uninterrupted current regimen (either the initial or second ARV 
regimen) for at least 6 months prior to Screening.  Any prior switch, defined as a 
change of a single drug or multiple drugs simultaneously, must have occurred due 
to tolerability/safety, access to medications, or convenience/simplification, and 
must NOT have been done for treatment failure (HIV-1 RNA ≥400 c/mL). 
Acceptable stable (initial or second) ARV regimens prior to Screening include 2 
NRTIs plus: 

INI (either the initial or second cART regimen) 

NNRTI (either the initial or second cART regimen)

Boosted PI (or atazanavir [ATV] unboosted) (must be either the initial 
cART regimen or one historical within class switch is permitted due to 
safety/tolerability)
The addition, removal, or switch of a drug(s) that has been used to treat HIV 
based on antiretroviral properties of the drug constitutes a change in ART with the 
following limited exceptions: 

Historical changes in formulations of ART drugs or booster drugs will not
constitute a change in ART regimen if the data support similar exposures 
and efficacy, and the change must have been at least 3 months prior to 
Screening.

Historical perinatal use of an NRTI when given in addition to an ongoing 
HAART will not be considered a change in ART regimen.

A change in dosing scheme of the same drug from twice daily to once 
daily will not be considered a change in ART regimen if data support 
similar exposures and efficacy.  
6. Documented evidence of at least two plasma HIV-1 RNA measurements 
<50 c/mL in the 12 months prior to Screening: one within the 6 to 12-month 
window, and one within 6 months prior to Screening; 
7. Plasma HIV-1 RNA <50 c/mL at Screening; 
 
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Participants transitioning from 201585 (ATLAS)
8. Must have been on CAB LA 400 mg + RPV LA 600 mg Q4W or “Current ART” 
regimen through at minimum Week 52 of the ATLAS study as per ATLAS 
protocol dosing requirements and until Day 1 of the ATLAS-2M study.  Any 
disruptions in dosing during ATLAS must be discussed with the Medical Monitor 
for a final determination of eligibility.
9. Plasma HIV-1 RNA <50 c/mL at Screening
All participants participating 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.
5.2.
Exclusion Criteria
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability, or participant 
safety.  Therefore, adherence to the criteria as specified in the protocol is essential.  A 
participant will not be eligible for inclusion in this study if any of the following criteria 
apply:
Exclusionary Criteria prior to Screening or Day 1 for patients not transitioning 
from 201585 (ATLAS)
1. Within 6 months prior to Screening, any plasma HIV-1 RNA measurement 
50 c/mL
2. Within the 6 to 12-month window prior to Screening, any plasma HIV-1 RNA 
measurement >200 c/mL, or 2 or more plasma HIV-1 RNA measurements 
50 c/mL
3. Any drug holiday during the window between initiating first HIV ART and 6 
months prior to Screening, except for brief periods (less than 1 month) where all 
ART was stopped due to tolerability and/or safety concerns
4. Any switch to a second line regimen, defined as change of a single drug or 
multiple drugs simultaneously, due to virologic failure to therapy (defined as a 
confirmed plasma HIV-1 RNA measurement 200 c/mL after initial suppression 
to <50 c/mL while on first line HIV therapy regimen) 
5. A history of use of any regimen consisting of only mono or dual HIV-1 therapy 
(even if only for peri-partum treatment).  
6. Participants who are currently participating in or anticipate to be selected for any 
 
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other interventional study with the exception of the 201585 (ATLAS) study.
Participants transitioning from 201585 (ATLAS)
7. During participation in ATLAS, consecutive (2 or more sequential) plasma HIV-1 
RNA measurements 50 c/mL
8. During participation in ATLAS, any HIV-1 RNA measurement 200 c/mL
9. More than two total measurements of plasma HIV-1 RNA 50 c/mL during 
participation in the ATLAS trial will require direct approval by the ATLAS-2M 
Medical Monitor and Study virologist for study participation.
Exclusionary medical conditions- for all participants
10. Women who are pregnant, breastfeeding or plan to become pregnant or breastfeed 
during the study
11. Any evidence of a current Center for Disease Control and Prevention (CDC) 
Stage 3 disease [CDC, 2014] , except cutaneous Kaposi’s sarcoma not requiring 
systemic therapy, and CD4+ counts <200 cells/L are not exclusionary.
12. Participants with moderate to severe hepatic impairment
13. Any pre-existing physical or mental condition (including substance use disorder) 
which, in the opinion of the Investigator, may interfere with the participant’s 
ability to comply with the dosing schedule and/or protocol evaluations or which 
may compromise the safety of the participant
14. 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
15. All participants will be screened for syphilis. Participants with untreated 
secondary (late latent) or tertiary syphilis infection, defined as a positive RPR and 
a positive treponemal test without clear documentation of treatment, are 
excluded. Participants with a false positive RPR (with negative treponemal test) 
or serofast RPR result (persistence of a reactive nontreponemal syphilis test 
despite history of adequate therapy and no evidence of re-exposure) may enroll
after consultation with the Medical Monitor. Participants with primary syphilis or 
early latent secondary syphilis (acquired within the preceding year) who have a 
positive RPR test and have not been treated may be treated during the screening 
period and if completion of antibiotic treatment occurs during the screening 
period, may be allowed entry after consultation with the Medical Monitor. If 
antibiotic treatment cannot be completed before the screening window ends, 
subjects may be rescreened once following completion of antibiotic therapy for 
primary or early latent secondary syphilis. 
16. Participants who, in the investigator's judgment, pose a significant suicide risk.  
 
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Participant’s recent history of suicidal behavior and/or suicidal ideation should be 
considered when evaluating for suicide risk
17. The participant has a tattoo or other dermatological condition overlying the 
gluteus region which may interfere with interpretation of injection site reactions
18. 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:
a.
•Participants positive for HBsAg are excluded;
b. •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.
19. Asymptomatic individuals with chronic hepatitis C virus (HCV) infection will not 
be excluded, however Investigators must carefully assess if therapy specific for 
HCV infection is required; participants who are anticipated to require HCV 
treatment within 12 months must be excluded.  (HCV treatment on study may be 
permitted post Week 52, following consultation with the medical monitor)
20. Participants with HCV co-infection will be allowed entry into this study if: 
a.
Liver enzymes meet entry criteria
b. HCV Disease has undergone appropriate work-up, and is not advanced, 
and will not require treatment prior to the Week 52 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.
c.
In the event that recent biopsy or imaging data is not available or 
inconclusive, the Fib-4 score will be used to verify eligibility 
i. Fib-4 score >3.25 is exclusionary 
ii. Fib-4 scores 1.45 – 3.25 requires Medical Monitor consultation
Fibrosis 4 Score Formula:
(Age x AST ) / ( Platelets x ( sqr [ ALT ])
21. Unstable liver disease (as defined by any of the following: presence of ascites, 
encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, 
or persistent jaundice or cirrhosis), known biliary abnormalities (with the 
exception of Gilbert's syndrome or asymptomatic gallstones or otherwise stable 
chronic liver disease per investigator assessment)
22. History of liver cirrhosis with or without hepatitis viral co-infection.
23. Ongoing or clinically relevant pancreatitis
24. Clinically significant cardiovascular disease, as defined by history/evidence of 
 
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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
25. Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell 
carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma, or 
cervical intraepithelial neoplasia; other localized malignancies require agreement 
between the investigator and the Study medical monitor for inclusion of the 
participant prior to randomization
26. 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
27. 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
28. Current or anticipated need for chronic anti-coagulation with the exception of the 
use of low dose acetylsalicylic acid (≤325 mg) or hereditary coagulation and 
platelet disorders such as haemophilia or Von Willebrand Disease.
Exclusionary Laboratory Values or Clinical Assessments at Screening (a single repeat to 
determine eligibility is allowed)
29. Any evidence of primary resistance based on the presence of any major known 
INI or NNRTI resistance-associated mutation, except for K103N, (IAS, 2015) by 
any historical resistance test result.
Note: Prior genotypic resistance testing is not required but if available it 
must be provided to GSK, after screening and before randomization 
according to guidance in the SPM, to provide direct evidence of no pre-
existing exclusionary resistance mutations. You must wait for the study 
virologists to confirm the lack of exclusionary resistance mutations, which 
will be provided before the screening window closes. Details regarding 
baseline or prior resistance data must be noted in the source 
documentation
30. Any verified Grade 4 laboratory abnormality. A single repeat test is allowed 
during the Screening phase to verify a result 
31. 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
32. Participant has estimated creatine clearance <50mL/min per 1.73m2 via Chronic 
Kidney Disease-Epidemiology Collaboration (CKD-EPI) Method
33. Alanine aminotransferase (ALT) 3 × ULN
 
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Concomitant Medications
34. Exposure to an experimental drug (with the exception of those in the ATLAS 
study including CAB, CAB LA, and RPV LA) or experimental vaccine within 
either 30 days, 5 half-lives of the test agent, or twice the duration of the biological 
effect of the test agent, whichever is longer, prior to Day 1 of this study;
35. Treatment with any of the following agents within 28 days of Screening:

radiation therapy; 

cytotoxic chemotherapeutic agents; 

tuberculosis therapy with the exception of isoniazid (isonicotinylhydrazid, INH);

anti-coagulation agents;

Immunomodulators that alter immune responses such as chronic systemic 
corticosteroids, interleukins, or interferons. Note: Participants using short-term 
(e.g. ≤21 days) systemic corticosteroid treatment; topical, inhaled and intranasal 
corticosteroids are eligible for enrolment. 
36. Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening
37. Treatment with any agent, except recognized ART as allowed above, with 
documented activity against HIV-1 within 28 days of study Day 1. Treatment 
with acyclovir/valacyclovir is permitted. 
38. Use of medications which are associated with Torsade de Pointes.  (See SPM for 
a list of relevant medications)
39. Current or prior history of etravirine (ETR) use
40. Current use of tipranavir/ritonavir or fosamprenavir/ritonavir
41. Participants receiving any prohibited medication and who are unwilling or unable 
to switch to an alternate medication.  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
5.3.
Additional Eligibility Criteria
To assess any potential impact on participant eligibility with regard to safety, the 
investigator must refer to the IB and supplements, approved product labels, and/or local 
prescribing information for detailed information regarding warnings, precautions, 
contraindications, AEs, drug interactions, and other significant data pertaining to the 
study drugs.
Notwithstanding these minimum inclusion and exclusion criteria, investigators must also 
follow country specific guidelines where they exist when making decisions about 
participants who are eligible for study participation.
 
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5.4.
Screening/Baseline/Run-in Failures
Screen failures are defined as participants who consent to participate in the clinical trial 
but are never subsequently randomized. In order to ensure transparent reporting of screen 
failure participants, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and Serious Adverse Events.
A single repeat of a procedure / lab parameter is allowed to determine eligibility (unless 
otherwise specified).
Participants are allowed to re-screen for this study one time.  This will require a new 
participant number.
5.5.
Withdrawal/Stopping Criteria
Participants permanently discontinuing study treatments prior to the Week 100 visit are 
considered to be withdrawn from the study treatments.  Participants who enter the 
Extension Phase but permanently discontinue participation in the Extension Phase prior 
to commercially available CAB LA + RPV LA are considered to be withdrawn from the 
study treatments but are not considered to be withdrawn from the study because they will 
enter the follow Follow-up Phase.
A participant may withdraw consent and discontinue participation in this study at any 
time at his/her own request. The investigator may also, at his or her discretion, 
discontinue the participant from participating in this study at any time (e.g., safety, 
behavioral or administrative reasons). Participants may have a temporary interruption to 
their study treatment for management of toxicities. If a participant withdraws from the 
study, he/she may request destruction of any samples taken, and the investigator must 
document this in the site study records. Withdrawn participants will not be replaced.  
All participants who discontinue prematurely from the study, irrespective of arm, will be 
asked for additional information to establish the reason for withdrawal.
Participants are not obligated to state the reason for withdrawal.  However, the reasons 
for withdrawal, or failure to provide a reason, must be documented by the Investigator on 
the Completion/Withdrawal section of the electronic case report form (eCRF). Every 
effort should be made by the Investigator to follow-up participants who withdraw from 
the study. 
A in-clinic withdrawal visit will also be used to assess 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.  The withdrawal visit will be distinct from visits conducted during the LTFU 
Phase.
 
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Following completion of withdrawal assessments, all participants who received one or 
more injections of CAB LA+ RPV LA will subsequently enter the LTFU Phase initiating 
with the Month 3 LTFU visit.
Withdrawal decision coincides with a planned clinic visit: 

For any participant who withdraws prematurely from the Maintenance or 
Extension Phase during a planned in-clinic study visit, withdrawal 
assessments and procedures are to be performed (according to the Time 
and Events Table (Section 7.1) instead of the assessments for the active 
planned visit during which the withdrawal decision is made.  
Withdrawal decision occurs between planned clinic visits:

In the event that a decision to withdraw a participant occurs between clinic 
visits, participants will be instructed to return for an unscheduled 
withdrawal visit (within 4 weeks of the last Q4W LA injection or within 8 
weeks of the last Q8W LA injection received) during which withdrawal 
assessments according to the Time and Events Table (Section 7.1) will be 
completed. For participants who received one or more injections of CAB 
LA+ RPV LA withdrawal assessments must occur prior to initiation of 
the next ART regimen. 
If withdrawal coincides with the active planned Week 52 or Week 100 visits, HIV-1 
RNA will only be assessed if the last HIV-RNA measurement from Week 48 or Week 96 
was 50 copies per mL (i.e. retest for viral load blip). This will ensure that only the Week 
48 or Week 96 viral load assessments or required retest will be counted towards the 
primary and secondary efficacy endpoint windows.
The in-clinic visit will be recorded as an unscheduled withdrawal visit with the following 
exception. A withdrawal visit and assessments coinciding with the planned Week 100 
visit will be recorded as the Week 100 visit such that the participant can be considered a 
completer, consistent with the definition of study completer in Section 5.6.
Participants may be prematurely discontinued from the study treatment for any of 
the following reasons:

Adverse event / Serious adverse event

Protocol deviation

Intolerability of injections

Participant lost to follow-up

Participant or Investigator non-compliance;

Termination of the study by the Sponsor

At the request of the participant, Investigator, GSK or ViiV Healthcare;
 
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
The participant requires concurrent prohibited medications during the course of the 
study. The participant may remain in the study if in the opinion of the Investigator 
and the medical monitor; such medication will not interfere with the conduct or 
interpretation of the study or compromise the safety of the participant.
Participants must be discontinued from study treatment for any of the following 
reasons:

Participants who are not eligible to continue into the Maintenance Phase.

Participants who are not eligible, or do not wish to continue on to the Extension 
Phase.

Virologic withdrawal criteria as specified in Section 5.5.4 are met;

Participant requires substitution of ART; 

Participant requires substitution or dose reduction of CAB LA or RPV LA (oral 
bridging supply and potential for a second loading dose may be permissible 
following discussion with the Medical Monitor).

Liver toxicity where stopping criteria are met and no compelling alternate cause is 
identified (see Section 5.5.1);

Renal toxicity are met and no compelling alternate cause is identified;

QT interval (QTc) interval >550 msec from three or more tracings separated by at 
least 5 minutes and considered causally related to IP.  

Grade 4 clinical AE considered causally related to study drug; 

Participant has a Grade 3 or higher rash or Grade 2 rash with evidence of systemic 
involvement and no compelling alternative cause is identified

Pregnancy (intrauterine), regardless of termination status of pregnancy. 

Participant withdrew consent
Efficacy data for participants withdrawing from the study will be considered evaluable up 
to the point at which they are withdrawn using the same criteria for evaluability as for 
participants who complete the study.
Safety data for all participants who receive any amount of study drug, including 
participants who withdraw from the study, will be included in evaluations of safety.
All data from the Withdrawal visit will be recorded, as they comprise an essential 
evaluation that should be done prior to discharging any participant from the study.
The following actions must be taken in relation to a participant who fails to attend the 
clinic for a required study visit:
a.
The site must attempt to contact the participant and re-schedule the missed visit as 
soon as possible. 
 
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b.
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. 
c.
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. 
d.
Should the participant continue to be unreachable, only then will he/she be 
considered to have withdrawn from the study with a primary reason of “Lost to 
Follow-up”. 
A participant may withdraw from study treatment at any time at his/her own request, or 
may be withdrawn at any time at the discretion of the investigator for safety, 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. 
5.5.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology.
IP will be stopped if any of the following liver chemistry criteria are met:

ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin, bilirubin fractionation 
required).

NOTE: serum bilirubin fractionation should be performed if testing is available.  If 
testing is unavailable, sites should evaluate the presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver 
injury.  If testing is unavailable and a participant meets the criterion of total bilirubin 
2xULN, then the event meets liver stopping criteria.

ALT 8xULN.

ALT ≥3xULN (if Baseline ALT is <ULN) with symptoms or worsening of acute
hepatitis or hypersensitivity such as fatigue, nausea, vomiting, right upper quadrant
pain or tenderness, fever, rash, or eosinophilia, OR;

ALT ≥3x Baseline ALT with symptoms or worsening of acute hepatitis or 
hypersensitivity such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, or eosinophilia;

ALT ≥5xULN and <8xULN that persists ≥2 weeks (with bilirubin <2 ULN & no 
signs or symptoms of acute hepatitis or hypersensitivity).

ALT ≥5xULN but <8xULN and cannot be monitored weekly for >2 weeks.
 
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5.5.1.1.
Liver Chemistry Stopping Criteria, Participant Management and Follow-
Up
Participants who develop ALT ≥5xULN must be followed weekly until resolution or 
stabilization (ALT <5xULN on 2 consecutive evaluations).
When any of the liver chemistry stopping criteria is met, do the following:

Immediately hold IP.  If on LA therapy, do not administer another injection until 
approval is received from the ViiV Safety and Labelling Committee.

Report the event to the Medical Monitor within 24 hours of learning its occurrence.

Complete the liver event eCRF and SAE eCRF, where applicable.

Complete the liver imaging and/or liver biopsy eCRFs if these tests are performed.

Perform liver event follow up assessments (described below), and monitor the
participant until liver chemistries resolve, stabilize, or return to Baseline values as 
described below.

Make every reasonable attempt to have participants return to clinic within 24 hours 
for repeat liver chemistries, liver event follow-up assessments (see below), and close 
monitoring.

A specialist or hepatology consultation is recommended.

Monitor participants twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within Baseline values.
Make every attempt to carry out the liver event follow-up assessments described below:

Viral hepatitis serology including:

Hepatitis A immunoglobulin M (IgM) antibody;

Hepatitis B surface antigen (HBsAg) and Hepatitis B Core Antibody (IgM);

Hepatitis C RNA;

Hepatitis E IgM antibody;

Cytomegalovirus IgM antibody;

Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);

Syphilis screening;

Drugs of abuse screen including alcohol;

Serum acetaminophen test (N-acetyl-para-aminophenol [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 during follow up 
assessments.  Record the date/time of the PK blood sample draw and the date/time of 
 
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the last dose of investigational product prior to blood sample draw on the eCRF.  If 
the date or time of the last dose is unclear, provide the participant’s best 
approximation.  If the date/time of the last dose cannot be approximated OR a PK 
sample cannot be collected in the time period indicated above, do not obtain a PK 
sample.  Instructions for sample handling and shipping are in the SPM.

Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH);

Fractionated bilirubin, if total bilirubin is greater than 1.5xULN;

Obtain complete blood count with differential to assess eosinophilia;

Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney 
microsomal antibodies, and quantitative total immunoglobulin G (IgG or gamma 
globulins);

Liver imaging (ultrasound, magnetic resonance, or computerized tomography) and/or 
liver biopsy to evaluate liver disease; complete Liver Imaging and/or Liver Biopsy 
CRF forms.

Record the appearance or worsening of clinical symptoms of hepatitis, or 
hypersensitivity, fatigue, decreased appetite, nausea, vomiting, abdominal pain, 
jaundice, fever, or rash as relevant on the AE report form;

Record use of concomitant medications, acetaminophen, herbal remedies, other over 
the counter medications, or putative hepatotoxins, on the concomitant medications 
report form.  Record alcohol use on the liver event alcohol intake case report form.
5.5.1.2.
Liver Event Adjudication Committee
A liver safety panel will be used to evaluate all participants who meet liver stopping 
criteria.  Uniform sets of data and standards for adjudication will be applied across cases 
to inform outcomes.  Full details of the analysis, timing, and the decision criteria will be 
pre-specified in an Adjudication Committee Charter. 
5.5.1.3.
Liver Chemistry Stopping Criteria – Restart / Rechallenge
Participants who meet liver toxicity stopping criteria should not be retreated with 
investigational product unless an exemption has been approved by the ViiV Safety and 
Labeling Committee (VSLC).  The guideline for Restart /Rechallenge approved by the 
VSLC, which is maintained as a separate document must be followed.
5.5.1.3.1.
Drug Restart / Rechallenge.  Following Liver Events that are Possibly 
Related to IP

Approval by the VSLC for drug restart or additional IM administration can be 
considered where:

The participant is receiving compelling benefit, benefit of drug restart exceeds risk, 
and no effective alternative therapy is available.  Ethics Committee or Institutional 
Review Board approval of drug restart / rechallenge must be obtained, as required.
 
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
If the restart / rechallenge is approved by the VSLC in writing, the participant must 
be provided with a clear description of the possible benefits and risks of drug 
administration, including the possibility of recurrent, more severe liver injury or 
death.

The participant must also provide signed informed consent specifically for the IP 
restart / rechallenge.  Documentation of informed consent must be recorded in the 
study chart.

Study drug must be administered at the dose specified by the VSLC.

Participants approved by the VSLC for rechallenge of IP must return to the clinic 
twice a week for liver chemistry tests for a minimum of one month and thereafter for 
as long as clinically indicated and then laboratory monitoring may resume as per 
protocol.  If protocol defined stopping criteria for liver chemistry elevations are met, 
study drug must be stopped.
5.5.1.3.2.
Drug Restart Following Transient Resolving Liver Events Not Related 
to IP
Approval by the VSLC for drug restart or additional IM administration can be considered 
where:

Liver chemistries have a clear underlying cause (e.g., biliary obstruction, 
hypotension and liver chemistries have improved to normal or are within 
1.5 x baseline and ALT <3xULN).  Ethics Committee or Institutional Review Board 
approval of drug restart/rechallenge must be obtained, as required.

If restart / redosing of drug is approved by the VSLC in writing, the participant must 
be provided with a clear description of the possible benefits and risks of drug 
administration, including the possibility of recurrent, more severe liver 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.
5.5.2.
QTc Stopping Criteria
A participant who has a QTc interval >550 msec considered causally related to IP will be 
withdrawn from the study. The QTc should be based on averaged QTc values of 
triplicate electrocardiograms obtained over a brief (e.g., 5 to 10 minute) recording 
period.
If an alternative cause of the QT prolongation is determined (e.g., participant receiving 
drug known to cause prolonged QT or TdP), the IP may be restarted (or continued) after 
 
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consultation and agreement with the Medical Monitor. RPV and RPV LA should not be 
administered to patients who are receiving a drug known to be associated with TdP.
When performing ECGs, the same QT correction formula must be used for each 
individual participant to determine eligibility for, and discontinuation from, the study.
This formula may not be changed or substituted once the participant has been enrolled.
For example, if a participant is eligible for the protocol based on QTcB, then QTcB must 
be used for discontinuation of this individual participant as well.
Once the QT correction formula has been chosen for a participant’s eligibility, the same 
formula must continue to be used for that participant for all QTc data being collected for 
data analysis. Safety ECGs and other non-protocol specified ECGs are an exception.
5.5.3.
Virologic Failure
Only plasma HIV-1 RNA values determined by the central laboratory will be used to 
assess virologic failure. 
5.5.4.
Definition of Protocol-Defined Confirmed Virologic Failure
For the purposes of clinical management in this study, CVF is defined as: 
Rebound as indicated by two consecutive plasma HIV-1 RNA levels 200 c/mL after 
prior suppression to <200 c/mL.
5.5.5.
Managing Virologic Failure
Following study entry, no changes, or intensification of ART will be permitted prior to 
protocol-defined virologic failure, outside of the planned protocol regimens.  Only 
plasma HIV-1 RNA values determined by the central laboratory will be used to assess 
virologic failure.  Baseline plasma HIV-1 RNA is the assessment completed on study 
Day 1.  The definition of confirmed virologic failure does not apply to participants in the 
LTFU Phase.  These participants will be followed for the emergence of viral resistance. 
Inadequate adherence is a common cause for virologic failure, and should be explored as 
a first step in the management of study participants (e.g., at the first indication of 
inadequate virologic response or rebound). Upon notification that a participant’s HIV-1 
RNA plasma level qualifies him/her as a suspected virologic failure, the Investigator 
should query the participant regarding intercurrent illness, recent immunization, or 
interruption of oral therapy.
5.5.5.1.
HIV-1 RNA Blips
HIV-1 RNA “blips” are not usually associated with subsequent virologic failure [DHHS, 
2016].  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.  
 
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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 the key analysis 
timepoints (Week 48 and Week 96) must return to the clinic as soon as possible (but no 
later than 4 weeks after the date of the Week 48 and 96 visit, respectively) for a repeat 
HIV-1 RNA test such that the result falls within the same analysis window.
In order to better characterize HIV-1 RNA ‘blips,’ if there is a known reason / 
explanation for the blip (e.g., immunization, allergies, etc.), the study team should be 
notified of the reason and case context.
If the Investigator has concerns regarding persistent low level viremia (HIV-1 RNA 
≥50 c/mL and <200 c/mL), the Medical Monitor should be contacted to discuss 
participant management.  Following discussion with the Medical Monitor, additional 
viral load testing may be performed between visits to determine the appropriate 
participant disposition for the next scheduled visit
5.5.5.2.
Suspected Virologic Failure
Upon notification that a participant’s HIV-1 RNA plasma level meets the definition of 
virologic failure, the Investigator should confirm the definition is met by initiating a 
repeat of the HIV-1 RNA assessment.
The following guidelines should be followed for scheduling confirmatory HIV-1 RNA 
testing in an effort to avoid false-positive results:

Confirmatory testing should be scheduled within 2 to 4 weeks following resolution 
of any intercurrent illness, during which time the participant should receive full dose 
of all IP.

Confirmatory testing should be scheduled at least 4 weeks following any 
immunization, during which time the participant should receive full dose of all IP.

If therapy is interrupted* due to toxicity management, non-compliance, or other 
reasons, confirmatory testing should be scheduled 2 to 4 weeks following resumption 
of full dose of all IP.

The participant should have received full dose of IP for at least 2 weeks at the time 
confirmatory plasma HIV-1 RNA testing is done.
*Note:  treatment interruption guidelines above may not apply for participants on CAB 
LA + RPV LA treatment.  The study team should be contacted to discuss any treatment 
interruptions for participants meeting the definition of virologic failure.
In addition, the Investigator should query the participant regarding intercurrent illness, 
recent immunization, or interruption of therapy.
Sites should contact the Medical Monitor to discuss individual participants, 
whenever necessary.
 
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5.5.5.3.
Confirmed Virologic Failure
Participants with confirmed virologic failure (CVF) must be discontinued from study 
treatment.  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 LTFU Phase.
A plasma sample from the suspected virologic failure visit as well as Day 1 (if baseline 
HIV-1 RNA level 200 c/mL) 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.
For all participants who meet CVF, baseline and suspected virologic failure plasma 
samples with HIV-1 RNA level 200 c/mL will be analyzed in an attempt to obtain 
genotype/phenotype data on as many samples as possible. Plasma samples for storage 
will also be obtained at unscheduled visits including confirmation of CVF. Participants 
may continue to receive study drug at the discretion of the investigator until results of 
resistance testing are available at which time the participant must be discontinued from 
the study. Even if genotype/phenotype data cannot be generated, participant must also be 
discontinued from the study treatment.
If a participant is prematurely discontinued from the study treatment, the investigator 
must make every effort to perform the Withdrawal Visit evaluations outlined in the Time 
and Events These data will be recorded as they comprise essential evaluations needed to 
be done before discharging any participant from the study.
5.6.
Participant and Study Completion
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the participant’s medical condition. 
Study Completion
Participants are considered to have completed the study if they remain on therapy (i.e., 
have not permanently discontinued IP) and satisfy one of the following:

Randomly assigned to either treatment group, completed the randomized 
Maintenance Phase including Week 100 (with or without Week 100 study treatment)
and did not enter the Extension Phase;

Randomly assigned to either treatment group, completed the randomized 
Maintenance Phase including Week 100, and entered and completed the Extension 
Phase (defined as remaining on study until commercial supplies of CAB LA + RPV 
LA Q4W or Q8W regimen become locally available or development of CAB LA + 
RPV LA is terminated).
 
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Participants who withdraw from CAB LA + RPV LA and go into the LTFU Phase will be 
considered to have prematurely withdrawn from the study treatment.
In addition to the 52-week Follow-Up phase required for participants who receive one or 
more injections with CAB LA or RPV LA, an in-clinic Follow-Up visit will be conducted 
approximately 4 weeks after the last dose of study medication for participants who 
withdraw during the oral lead-in phase with ongoing AEs, and serious adverse events 
(SAEs) and also any laboratory abnormalities that are considered to be AEs or potentially 
harmful to the participant, at the last on-study visit.  Assessments at the Follow-up visit 
should reflect any ongoing complaints (e.g., blood draws to follow a laboratory 
abnormality).  Follow-Up visits are not required for successful completion of the study.
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the participant as per the protocol design.  Study treatment is 
defined as any investigational treatment(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a study participant according to 
the study protocol. Study treatment may therefore refer to the individual study 
treatments or the combination of those study treatments.
Investigational product (IP) in this protocol refers to the investigational study drugs Oral 
Cabotegravir, Cabotegravir LA, Oral Rilpivirine and Rilpivirine LA.  These will be 
supplied by GlaxoSmithKline/ViiV Healthcare and Janssen Pharmaceuticals, 
respectively. 
Participants entering the Long-Term Follow-Up Phase will not have their selected 
HAART provided as clinical trial material.  The selected HAART will be recorded on the 
Concomitant Antiretroviral Therapy (ConART) eCRF page. 
6.1.1.
Formulations of CAB + RPV
6.1.1.1.
Cabotegravir Tablets (CAB)
CAB is manufactured by GlaxoSmithKline and is formulated as white to almost white 
oval shaped film coated 30 mg tablets for oral administration, packaged in high density 
polyethylene (HDPE) bottles with desiccant and child-resistant closure that include an 
induction seal. CAB tablets will be packaged in bottles of 30 tablets. Participants must 
keep all IP in its original pack container. GSK will notify sites if and when data are 
available to support the use of pill boxes.  CAB tablets are to be stored according to the 
product labeling.
CAB Tablet is composed of cabotegravir sodium, lactose monohydrate, microcrystalline 
cellulose, hypromellose, sodium starch glycolate, magnesium stearate, and white film-
coating.  The white film-coating contains hypromellose, titanium dioxide and
polyethylene glycol.
 
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6.1.1.2.
Rilpivirine Tablets (RPV)
RPV 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 a globally marketed product 
which includes approvals in the US and the European Union.  RPV will be overlabeled 
and packaged in bottles of 30 tablets.  RPV tablets should be stored according to the 
product labeling.
Each tablet contains 27.5 mg of rilpivirine hydrochloride, which is equivalent to 25 mg of 
RPV. Each tablet also contains the inactive ingredients croscarmellose sodium, lactose 
monohydrate, magnesium stearate, polysorbate 20, povidone K30 and silicified 
microcrystalline cellulose. The tablet coating contains hypromellose 2910 6 mPa.s, 
lactose monohydrate, PEG 3000, titanium dioxide and triacetin.
6.1.1.3.
Cabotegravir Injectable Suspension (CAB LA)
CAB LA (GSK1265744 LA) is manufactured by GlaxoSmithKline and is a sterile white 
to slightly pink suspension containing 200 mg/mL of GSK1265744 as free acid for 
administration by intramuscular (IM) injection.  The product is packaged in a glass vial 
with a 13 mm gray stopper and aluminum seal.  Each vial is for single-dose use 
containing a withdrawable volume of 2.0 mL (400 mg) or 3 mL (600 mg) and does not 
require dilution prior to administration.  CAB LA injectable suspension is to be stored 
according to the product labeling.
CAB LA is composed of cabotegravir free acid, polysorbate 20, polyethylene glycol 
3350, mannitol, and water for injection.
6.1.1.4.
Rilpivirine Injectable Suspension (RPV LA)
RPV LA (also named JNJ-16150108-AAA), 300 mg/mL Extended Release Suspension 
for Injection (G001), is provided by Janssen Research & Development, LLC, a division 
of Janssen Pharmaceuticals, as a sterile white suspension containing 300 mg/mL of RPV 
as the free base. The route of administration is by intramuscular (IM) injection. RPV LA 
is packaged in a single use 4 mL glass vial with a 13 mm grey stopper and aluminum 
seal. Each vial contains a nominal fill of 2.0 mL (600 mg) or 3.0 mL (900 mg), and does 
not require dilution prior to administration. RPV LA injectable suspension is to be stored 
according to product labeling. RPV LA should also be protected from light.
RPV LA is composed of RPV free base, poloxamer 338, sodium dihydrogen phosphate 
monohydrate, citric acid monohydrate, glucose monohydrate, sodium hydroxide, water 
for injection.
6.2.
Treatment Assignment
Informed consent must be obtained prior to any study procedures, including Screening 
visit activities. Participants will be assigned to study treatment in accordance with the 
randomization schedule. The randomization schedule, including stratification, will be 
generated using the GSK validated randomization software RANDALL NG. The 
 
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randomization schedule is comprised of a series of blocks, with equal treatment 
allocation within each block, which are shared across centers 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. 
Randomization and study treatment assignment will be facilitated by the interactive 
response technology (IRT) through the central Randomization and Medication Ordering 
System Next Generation (RAMOS NG). 
Following confirmation of fulfillment of study entry criteria, study site personnel will be 
required to register participants using RAMOS NG for assignment of a unique identifier 
(designating the participant’s randomization code and treatment sequence assignment) for 
each participant participating in the study.  A unique treatment number will be assigned 
for each participant participating in the study. Participants will be randomized in a 1:1 
ratio to CAB LA + RPV LA Q4W or to CAB LA + RPV LA Q8W in accordance with 
the computer generated randomization schedule. 
Participants who successfully complete 100 weeks of treatment and have a viral load 
<50 c/ml at Week 96 (or upon retest by Week 100) will be given the opportunity to enter 
the Extension Phase in which they will continue to receive their CAB LA + RPV LA 
regimen.  In addition, RAMOS NG will facilitate the initial supply and subsequent 
resupply of IP to study sites.
6.3.
Dosage and Administration
Participants will be randomly assigned to receive treatment with CAB LA + RPV LA 
either Q4W or Q8W.  Patients transitioning from oral standard of care therapy will 
initiate their randomized treatment regimen with Oral CAB 30 mg + RPV 25 mg once 
daily for 4 to 5 weeks during the Oral Phase, followed by CAB LA + RPV LA IM 
injections initiating at Week 4b. Patients transitioning from the ATLAS study and on 
CAB LA + RPV LA Q4W treatment will be randomized at Day 1 to either continue Q4W 
administration or transition to Q8W administration of CAB LA + RPV LA. Regardless 
of treatment arm assignment, the investigator should instruct all participants on the 
importance of treatment adherence.  This study has an open-label design.  Dosing is 
outlined in Table 7 Figure 8 below.
 
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Table 7
Dosage and Administration
Maintenance Phase and Extension Phase (Day 1 to End of Study+)
Q4W  Arm - Transitioning from SOC
Oral Lead-In
Day 1 to Week 4b
(2 tablets once daily)

Take 1 tablet CAB 30 mg once daily.

Take 1 tablet RPV 25 mg once daily.
Should be taken together once daily at approximately the same 
time each day, with a meal.
First Injections (Loading Dose) – Week 4b
Week 4b
(two 3mL injections once)

Receive last dose of oral CAB + RPV regimen

Receive CAB LA 600 mg given as 1 X 3 mL IM injection

Receive RPV LA 900 mg given as 1 X 3 mL IM injection 
Maintenance Injections – every 4 Weeks (Q4W) following Week 4b
Week 8 to End of Study+
(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
Q8W Arm-Transitioning from SOC
Oral Lead-In
Day 1 to Week 4b
(2 tablets once daily)

Take 1 tablet CAB 30 mg once daily.

Take 1 tablet RPV 25 mg once daily.
Should be taken together once daily at approximately the same 
time each day, with a meal.
First Injections (Loading Doses) – Week 4b
Week 4b
(two 3 mL injections once)

Receive last dose of oral CAB + RPV regimen

Receive CAB LA 600 mg given as 1 X 3 mL IM injection

Receive RPV LA 900 mg given as 1 X 3 mL IM injection 
 
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Maintenance Injections – every 8 Weeks (Q8W) following Week 8
Week 8 to End of Study+
(two 3mL injections every 8 
weeks)

Receive CAB LA 600 mg given as 1 X 3 mL IM injection

Receive RPV LA 900 mg given as 1 X 3 mL IM injection
Q4W Arm – Continuing Q4W injections from ATLAS 
Day 1 to End of Study+
(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
Q8W Arm- Transitioning from ATLAS Q4W
Day 1 to End of Study+
(two 3 mL injections every 8 
weeks)

Receive CAB LA 600 mg given as 1 X 3 mL IM injection

Receive RPV LA 900 mg given as 1 X 3 mL IM injection
+Until locally approved and commercially available, the participant no longer derives clinical benefit, the participant 
meets a protocol-defined reason for discontinuation or until development of CAB LA or RPV LA is terminated
Participants will be given an option to continue their randomized Q4W or Q8W CAB LA + RPV LA regimen (or 
complete trial participation) at Week 100.  If the participant decides not to continue participation in the study, any 
arrangements for off-study ART should be made in advance of the Week 100 visit.
^See Section 6.6.1 for Dosing Considerations for CAB LA + RPV LA
6.4.
Blinding
This will be an open-label study and therefore no blinding is required. No summaries of 
the study data according to actual randomized treatment groups will be available to 
sponsor staff prior to the planned Week 24 preliminary analysis. The Week 24 results 
will be restricted to only those study team members and GSK/ViiV Healthcare senior 
management who need to be involved in the analysis and interpretation of the results for 
reporting to regulatory authorities. Public presentation of the Week 24 analysis will not 
be done prior to Week 48 analysis complete.
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

The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.

Only participants enrolled in the study may receive study treatment and only
authorized site staff may supply or administer study treatment. All study treatments 
 
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must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access limited 
to the investigator and authorized site staff.

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.

Further guidance and information for the final disposition of unused study treatment 
are provided in the Study Reference Manual. 

Under normal conditions of handling and administration, study treatment 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.

Product accountability records must be maintained throughout the course of the 
study.
IP accountability will be evaluated using pill counts of unused IP for patients receiving 
oral treatment (oral CAB, oral RPV).  This assessment will be conducted, when the 
participant completes oral CAB and RPV lead-in treatment in the Maintenance or 
Extension Phase, or any withdrawal that occurs during an oral treatment phase.
IP accountability for participants receiving CAB LA + RPV LA will be performed at the 
‘vial’ level (e.g., correct number of vials were used for each injection).  There may be a 
small amount of solution remaining in the vial which does not require quantification.  
Used vials may be discarded at the site once accountability is complete.
6.6.1.
Dosing Considerations for CAB LA + RPV LA
Vials of CAB LA and RPV LA are each supplied as a suspension and need no further 
dilution or reconstitution.  Since RPV LA requires refrigeration, sites should allow the 
vial to come to approximately room temperature prior to injecting. The vials should be 
gently inverted a few times to re-suspend sediments and allow bubbles to subside, and 
then use a syringe to withdraw the required volume of suspension for IM injection.  
 
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All injections must be given intramuscularly in the gluteus medius.  Sites may use their 
discretion as to where in the gluteus muscle each injection is given according to 
individual participant circumstance.  If possible, injections should be spaced 
approximately 2 cm from one another, from the site of any previous injection or any 
injection site reaction.  The time and location of injection will be captured in the eCRF.  
IM injections should be administered at a 90 degree angle into the gluteus medius muscle 
using a needle of appropriate gauge and length (In most participants, a 1.5” 23 gauge 
needle for CAB LA and a 1.5” 23 gauge needle for RPV LA is recommended).  The 
needle should be long enough to reach the muscle mass and prevent study drug from 
seeping into subcutaneous tissue, but not so long as to involve underlying nerves, blood 
vessels, or bone.  Variable needle lengths and/or needles with different gauge (CAB LA: 
21 to 25 gauge; RPV LA: 21 to 23 gauge) are permitted if needed to accommodate 
individual body types.  Longer needle lengths may be required for participants with 
higher body mass indexes (BMIs, example > 30), to ensure that injections are 
administered intramuscularly as opposed to subcutaneously.  BMI, needle gauge and 
length used will 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 transitioning from oral SOC should be dosed with the 
IM regimen within 2 hours of taking the last oral regimen dose where possible. 
Should IM maladministration be suspected at any time (e.g., suspected under or overdose 
or inadvertent IV dosing), the investigator may consider requesting the participant stay 
onsite for approximately 2-3 hours post dose for safety monitoring and notifying the 
Medical Monitor.  An ECG or any other supportive testing may be obtained at the 
discretion of the investigator. Additionally, a PK sample may be drawn approximately 
2 hours post dosing for future evaluation of CAB and RPV plasma concentrations.
Additional dosing instructions and considerations can be found in the SPM.
6.7.
Compliance with Study Treatment Administration
When participants are dosed at the site, they will receive study treatment directly from 
the investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the participant’s eCRF.  The dose of study 
treatment and study participant identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study treatment. 
When participants self-administer oral study treatments at home, compliance with CAB + 
RPV dosing will be assessed through querying the participant during the site visits and 
documented in the source documents and CRF.  IP accountability will be evaluated using 
pill counts of unused IP (CAB and RPV tablets).  This assessment will be conducted each 
time the participant receives a new (refill) supply of oral study medication, completes the 
oral lead-in or any oral bridging phase.  A record of the number of CAB and RPV tablets 
dispensed to and taken by each participant must be maintained and reconciled with study 
treatment and compliance records.  Treatment start and stop dates will also be recorded in 
the eCRF. 
 
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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 instructions.  As part of the screening and participant 
selection process, it is imperative that Investigators discuss with potential participants the 
long-term commitments for the trial, and the importance of adhering to treatment 
regimens.  Sites are to have plans in place for adherence counselling for both treatment 
arms of the study for the duration of the study including the LTFU Phase.  In addition, 
Investigators must have plans in place to perform visit reminders, utilizing patient 
trackers provided by the study team as needed, and to verify the participant’s contact 
information at each visit.  Investigators should contact patients directly in the event that a 
participant misses any scheduled visit. 
6.8.
Protocol Permitted Substitutions
6.8.1.
Oral Bridging
In exceptional circumstances, to address pre-planned missed CAB LA + RPV LA dosing 
visits, in consultation with the medical monitor, Investigators may provide daily oral 
CAB 30 mg and RPV 25 mg as a short-term “bridging” strategy for participants who 
have begun CAB LA + RPV LA.  In certain circumstances (e.g., prior to steady state 
dosing and following a >4 week oral bridge) repeating the loading doses of CAB IM and 
RPV IM may be required.  Should a participant require “oral bridging”, sites must contact 
the study Medical Monitor for guidance with treatment and dosing strategies prior to a 
missed CAB LA + RPV LA dose.
6.9.
Interruption of Study Treatment and Visit/Dosing Windows
IP may be interrupted at the discretion of the Investigator in the event of an AE, 
according to the severity of the AE.
If one or more antiretroviral medications is held due to toxicity or adverse events, all 
antiretroviral medications must be held to reduce the risk of development of resistance 
taking into account both the length of the planned interruption and the pharmacokinetic 
half-life of each antiretroviral of the regimen, in a way to minimize the risk of 
development of resistance.
It is important to note that keeping to the participant’s visit schedule is a very 
important component to the study.  
Note: All decisions regarding dose interruption / resumption must be discussed with 
the medical monitor in advance.
6.9.1.
IM Dosing
Participants receiving CAB LA and/or RPV LA are anticipated to be at risk for 
development of virologic resistance if ART is interrupted.  The time period during which 
participants are at risk for development of virologic resistance may be determined by the 
period between when drug levels fall below therapeutic values and when they fall below 
levels which exert selective pressure on HIV.  This time period will vary by ART agent 
and is dependent upon effective concentration, inhibitory concentration, and half-life.  
 
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Plasma concentrations of both LA drugs may be measurable for more than one year 
following IM injections. Any interruption in IM dosing should be discussed with the 
Medical Monitor.  Investigators should ensure that the participant initiates alternative 
highly active ART to minimize the risk of developing resistance as concentrations of 
CAB and RPV decline over time.
IM dosing is expected to occur during the week in which the participant’s projected visit 
falls (as according to the date of the first injection).  The first injections for participants 
from ATLAS on CAB LA + RPV LA Q4W will occur at Day 1.  The first injections for 
participants transitioning from oral SOC are administered at Week 4b (can be performed 
as soon as lab results from Week 4a become available and should be performed where 
possible within 2 weeks of visit 4a), and the second injections are given at Week 8. 
Between the Week 4a and 4b visits, participants must continue daily treatment with oral 
CAB and RPV tablets.  
Since the first injection visit (Day 1 or 4b) will determine the future injection visit 
schedule for participants, planning for the first injection visit date (within allowed visit 
windows) should take into consideration the availability of the participants to adhere to 
future visit windows (planned vacations, business trips, etc.).
CAB LA + RPV LA dosing for participants transitioning from SOC treatment is as 
follows:
All injections should be planned as single injections per drug.
6.9.1.1.
IM injections every 4 weeks (Q4W):
Week 4b only - CAB LA 600 mg + RPV LA 900 mg, each given as 1 X 3 mL IM 
injection
Week 8 and Q4W thereafter - CAB LA 400 mg IM + RPV LA 600 mg IM every 4 weeks 
for 100 weeks, each given as 1 X 2 mL IM injection
At Week 4b, participants transitioning from SOC will return to the clinic, take the last 
dose of oral CAB 30 mg + RPV 25 mg, and receive the first CAB LA 600 mg + RPV LA 
900 mg injections (within 2 hours of the final oral dose of CAB + RPV).  The first 
injection visit with IM CAB LA + RPV LA at Week 4b can be performed once central 
lab results are available and safety parameters are reviewed from the Week 4a visit.  
The second and third IM injections with CAB LA 400 mg and RPV LA 600 mg will be 
performed at Week 8 and Week 12.  There will be a -7 day dosing window for the second 
and third IM injections such that the second injection occurs within the window of Week 
7 and Week 8 but no later than Week 8 and the third injection occurs within the window 
of Week 11 and Week 12 but no later than Week 12.  Subsequent injections with CAB 
LA 400 mg and RPV LA 600 mg will occur every 4 weeks (7 days) thereafter.  In 
addition, starting after the Week 16 injection, efforts should be made to limit time 
between injection visits to a maximum of 5 weeks.  The Medical Monitor must be 
contacted if the length of time between injections exceeds or is projected to exceed 5 
weeks.
 
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6.9.1.2.
IM injections every 8 weeks (Q8W):
Week 4b – CAB LA 600 mg + RPV LA 900 mg IM, each given as 1 X 3 mL IM 
injection
Week 8 - CAB LA 600 mg + RPV LA 900 mg IM, each given as 1 X 3 mL IM injection
Week 16 and Q8W thereafter - CAB LA 600 mg + RPV LA 900 mg IM, every 8 weeks 
for 100 weeks, each given as 1 X 3 mL IM injection
At Week 4b, subjects will return to the clinic, take the last dose of their oral (CAB 30 mg 
+ RPV 25 mg), and receive the first CAB LA (600 mg) + RPV LA (900 mg) injections 
(within 2 hours of the final oral dose of CAB + RPV).  The first injection visit with IM 
CAB LA + RPV LA at Week 4b can be performed once central lab results are available 
and safety parameters are reviewed from the Week 4a visit.  
The second loading injection will be administered at Week 8 (CAB LA 600 mg + RPV 
LA 900 mg, with subsequent injections (CAB LA 600 mg + RPV LA 900 mg) occurring 
every 8 weeks thereafter.  The dosing window for the second injection allows 
administration between Week 7 and Week 8, but preferably not later than Week 8.  After 
Week 16, a dosing window (7 days) for injections is allowed, but not preferred. Starting 
at the Week 16 injection, the interval between injection visits should be limited to a 
maximum of 9 weeks.  If the length of time between injections exceeds, or is projected to 
exceed 9 weeks, the Medical Monitor must be contacted to discuss individual subject 
case management
Participants transitioning from ATLAS and currently receiving CAB LA + RPV LA 
Q4W
Patient transitioning from the ATLAS study and on CAB LA + RPV LA Q4W treatment 
will be randomized at Day 1 to either continue Q4W administration or transition to Q8W 
administration of CAB LA + RPV LA.  The first injection visit for the ATLAS-2M study 
can be performed once the final central lab results from the ATLAS study are available 
and safety parameters have been reviewed. For participants who received three or more 
Q4W CAB LA + RPV LA injections within ATLAS, the transition from ATLAS to 
ATLAS-2M Day 1 dosing must occur 4 weeks (7 days) from the final injections 
received in ATLAS.  For those who received less than three Q4W injections within 
ATLAS, this transition to ATLAS-2M Day 1 injections must occur within 4 weeks (-7 
days) from the final ATLAS injections
Dosing for participants transitioning from CAB LA + RPV LA Q4W in ATLAS is as 
follows:
6.9.1.3.
IM injections every 4 weeks (Q4W) (Q4W from ATLAS Q4W):
Starting at Day 1, all injections will continue with the maintenance dose of CAB LA 
400 mg and RPV LA 600 mg administered every 4 weeks (7 days).  In addition, efforts 
should be made to limit time between injection visits 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.
6.9.1.4.
IM injections every 8 weeks (Q8W) (Q8W from ATLAS Q4W):
Participants transitioning from ATLAS and receiving CAB LA + RPV LA Q8W will 
initiate dosing at the Day 1 visit:
Day 1- CAB LA 600 mg + RPV LA 900 mg IM, each given as 1 X 3 mL IM injection
Week 8 and Q8W thereafter- CAB LA 600 mg + RPV LA 900 mg IM, each given as 1 X 
3 mL IM injection
The second injection will be administered at Week 8 (CAB LA 600 mg + RPV LA 
900 mg, with subsequent injections (CAB LA 600 mg + RPV LA 900 mg) every 8 weeks 
thereafter.  The dosing window for the second injection allows administration between 
Week 7 and Week 8, but preferably not later than Week 8.  After Week 16, a dosing 
window (7 days) for injections is allowed, but not preferred. Starting at the Week 16 
injection, the interval between injection visits should be limited to a maximum of 
9 weeks.  If the length of time between injections exceeds, or is projected to exceed 
9 weeks, the Medical Monitor must be contacted to discuss individual subject case 
management.
Any request for the visit/dosing to occur outside of the allowed window must be 
discussed and agreed with the Medical Monitor prior to dosing.  In the event of a late 
dose, a revised dosing schedule for subsequent dosing may be required and will be 
communicated to the site staff at the time of approval for continued dosing.  Temporary 
switch to oral dosing of CAB and/or RPV may be an option based on individual 
participant circumstance as described in Section 6.8.
See the SPM for scheduling guidance and further information and examples.
Note: All decisions regarding dose interruption/ resumption must be discussed with 
the Medical Monitor in advance.
6.9.2.
Oral Dosing
The Week 4a Visit during the Oral Lead-in Phase for participants transitioning from SOC 
is expected to occur 4 weeks (3 days) after to the Day 1 Baseline visit.  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 LTFU are expected to occur as projected according to the last 
injection.  
 
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6.10.
Discontinuation of Study Treatment
Participants unable to manage drug toxicity or tolerate investigational product (IP, either 
formulations of CAB or RPV) must have IP discontinued.  Any participant receiving at 
least one dose of CAB LA and /or RPV LA who discontinue IP / Withdraw will initiate 
treatment with HAART enter the LTFU Phase for 52 weeks of follow up (see Section
4.2.4).
6.11.
Treatment of Study Treatment Overdose
For participants receiving Oral CAB, any tablet intake exceeding a total daily dose of    
30 mg will be considered an overdose.  For participants receiving oral RPV, any dose 
exceeding a total daily dose of 25 mg will be considered an overdose. 
For CAB LA and RPV LA, any single dose in excess of the studied doses will be 
considered an overdose.
Should IM maladministration, specifically overdose or inadvertent IV dosing, be 
suspected at any time, the participant will stay onsite for approximately 2-3 hours post 
dose for safety monitoring and an ECG will be performed at 2 hours post dose.  The 
Medical Monitor will be notified in the event of a suspected maladministration. 
In the event of suspected maladministration, additional PK samples will be drawn at 
2 hours post dosing for evaluation of CAB and RPV concentrations.
For the purposes of this study, an overdose is not an AE (refer to Section 11.6.1 ) 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 11.6.2).
If an overdose occurs and is associated with an adverse event requiring action, all study 
medications must be temporarily discontinued until the adverse event resolves. 
The Investigator should use clinical judgement in treating overdose, as ViiV Healthcare 
is unable to recommend specific treatment.
In the event of an overdose the investigator or treating physician should:
1. Contact the Medical Monitor immediately
2. Closely monitor the participant for adverse events (AEs)/serious adverse events 
(SAEs) and laboratory abnormalities until the IP can no longer be detected 
systemically (at least 5 days for oral CAB and oral RPV, and 52 weeks for CAB LA 
and RPV LA
3. Obtain a plasma sample for pharmacokinetic (PK) analysis if possible within 2 days 
from the date of the last dose of study treatment if requested by the Medical Monitor 
(determined on a case-by-case basis).
4. Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
 
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Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.
6.12.
Treatment after the End of the Study
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the participant’s medical condition, whether or not GSK is providing 
specific post-study treatment.  Participants who have successfully completed 100 weeks 
of treatment will continue to have access to both CAB LA and RPV LA in the Extension 
Phase until study treatment is either locally approved and commercially available, the 
participant no longer derives clinical benefit, the participant meets a protocol-defined 
reason for discontinuation or until development of either CAB LA or RPV LA is 
terminated.
6.13.
Concomitant Medications and Non-Drug Therapies
Participants must be advised to notify their Investigator of any current or proposed 
concomitant medication, whether prescribed or over-the-counter, because of the potential 
for interactions between such treatments and the study medications.  Concomitant 
medications (prescription and non-prescription) will be permitted during the course of the 
study at the investigator’s discretion (except for prohibited medications described in 
Section 6.13.2) and should be administered only as medically necessary during the study.  
All concomitant medication, blood products, and vaccines taken during the study will be 
recorded in the eCRF.  The minimum requirement is that the drug name, route, and the 
dates of administration are to be recorded.
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrollment or receives during the study must be recorded along with:

reason for use

dates of administration including start and end dates

dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
6.13.1.
Permitted Medications and Non-Drug Therapies
Chemoprophylaxis for HIV-associated conditions is encouraged, if appropriate, at the 
discretion of the participant and their physician.  All concomitant medications, blood 
products, and vaccines taken during the study will be recorded in the eCRF with dates of 
administration.
Because non-HIV vaccines may cause a temporary increase in the level of plasma HIV-1 
RNA, it is recommended that a vaccine, if necessary, be given during or immediately 
after a scheduled visit after all laboratory tests have been drawn.  This approach will 
 
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minimize the risk of non-specific increases in the level of plasma HIV-1 RNA at the next 
scheduled assessment.
Other IM injectables (with exceptions below) are permitted but must be administered 
away from the site of IP administration (should be spaced 2 cm or more away from site of 
IP injection).
Antacid and H2 Antagonist Use:
Since co-administration of oral CAB and RPV is required in this study, the most 
restrictive dosing requirements must be taken into consideration.
CAB oral administration only: Antacid products containing divalent cations (e.g., 
aluminium, calcium and magnesium) must be taken at least 2 hours before or at least 4 
hours after CAB.
Concurrent administration of multivitamins is acceptable.
RPV oral administration only: Antacid products must be taken at least 2 hours before 
or at least 4 hours after RPV. H2-Receptor antagonists (e.g. cimetidine, famotidine, 
nizatidine, ranitidine) may cause significant decreases in RPV plasma concentrations.  
H2-receptor antagonists should only be administered at least 12 hours before or at least 4 
hours after RPV.  RPV should not be co-administered with proton pump inhibitors, such 
as esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole.
RPV:  Administration of clarithromycin, erythromycin and telithromycin is not 
recommended with RPV due to possible increase in plasma concentration of RPV due to 
CYP3A enzyme inhibition.  Where possible, alternatives such as azithromycin should be 
considered.  Please refer to the local rilpivirine prescribing information for guidance 
regarding other drugs that are prohibited, should be used with caution, require dose 
adjustment, or increased clinical monitoring if taken with rilpivirine.
Drugs with a known risk of Torsade des Pointes (TdP) should be used with caution when 
on rilpivirine (see SPM for list of drugs associated with TdP).
6.13.2.
Prohibited Medications and Non-Drug Therapies
The following concomitant medications or therapies are not permitted at any time during 
the study:

HIV immunotherapeutic vaccines are not permitted at any time during the 
study. 

Other experimental agents, antiretroviral drugs not otherwise specified in the 
protocol, cytotoxic chemotherapy, or radiation therapy may not be 
administered (see Exclusion Criteria #35-36, 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.  
 
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
Acetaminophen (paracetamol) cannot be used in patients with acute viral 
hepatitis (James, 2009).

Chronic use of systemic (oral or parenteral) glucocorticoids must be avoided 
due to their immunosuppressive effect; however, short treatment courses with 
oral prednisone/ prednisolone/methylprednisolone (e.g. adjunctive treatment 
of Pneumocystis pneumonia with ≤ 21 days of tapering prednisone) are 
allowed. A single dose of systemic dexamethasone is permitted (more than a 
single dose in a treatment course may cause significant decrease in RPV 
plasma concentration and is prohibited). Topical, inhaled or intranasal use of 
glucocorticoids will be allowed.  

Hepatitis C infection therapy is prohibited during the Maintenance Phase 
before the Week 48 primary endpoint, and interferon-based HCV therapy or 
use of any drugs that have a potential for adverse drug:drug interactions with 
study treatment is prohibited throughout the entire study. 
For information on concurrent therapies and interactions suspected to be relevant to other 
antiretroviral therapy in the regimen, please consult the local prescribing information.
6.13.2.1.
Concurrent with CAB and/or RPV
For participants receiving either formulation of CAB and/or RPV, the following 
medications could significantly decrease the levels of CAB and/or RPV due to enzyme 
induction and therefore must not be administered concurrently: 

Carbamazepine

Oxcarbazepine

Phenobarbital 

Phenytoin

Rifabutin

Rifampicin / Rifampin

Rifapentine

St. John’s wort (Hypericum perforatum)
Concurrent with CAB
CAB is a potent inhibitor of OAT1 and OAT3 transport in vitro, however, no clinically 
significant interaction risk is expected for most drugs that are substrates of these 
transporters.  Monitoring may be required for drugs with a narrow therapeutic index and 
dependent on OAT1 and OAT3 transport (e.g. methotrexate) with concomitant CAB 
administration.  Refer to the current Investigator’s Brochure (Section 4.3.6.1 and Section 
6.4) for additional information. 
Concurrent with RPV
In addition, participants must discontinue the following (or change to an allowable 
alternative) while receiving treatment with oral RPV:

proton pump inhibitors, such as esomeprazole, lansoprazole, omeprazole, 
pantoprazole, rabeprazole;
 
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
systemic dexamethasone (more than a single dose)
If the participant cannot discontinue use or change to an allowable alternative while 
receiving treatment with RPV, the participant should not be randomized into the study.
6.13.2.2.
Concurrent with either CAB LA or RPV LA
In addition, for participants receiving CAB LA and RPV LA, use of anticoagulation 
agents for greater than 14 days is prohibited, with the exception of the use of 
anticoagulation for deep vein thrombosis (DVT) prophylaxis (e.g., postoperative DVT 
prophylaxis) or the use of low dose acetylsalicylic acid (≤325 mg). Systemic 
anticoagulation (including prophylaxis doses) on the day of an IM injection should be 
avoided.
Note: Any prohibited medications that decrease cabotegravir or rilpivirine concentrations 
should be discontinued for a minimum of four weeks or a minimum of three half-lives 
(whichever is longer) prior to the first dose and any other prohibited medications should 
be discontinued for a minimum of two weeks or a minimum of three half-lives 
(whichever is longer) prior to the first dose.
6.13.2.3.
Prohibited Medications for Participants Receiving HAART during the 
Long-Term Follow-Up Phase
For participants taking HAART during the Long-Term Follow-Up Phase, refer to local 
prescribing information for details regarding concurrent therapies.
7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table (Section 7.1).
The following points must be noted: 

If assessments are scheduled for the same nominal time, THEN the assessments 
should occur in the following order:
1. 12-lead ECG
2. vital signs
3. blood draws  
Note: The timing of the assessments should allow the blood draw to occur at the 
exact nominal time.

The timing and number of planned study assessments, including safety, 
pharmacokinetic, pharmacodynamic/biomarker assessments may be altered 
during the course of the study based on newly available data (e.g., to obtain data 
 
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closer to the time of peak plasma concentrations) to ensure appropriate 
monitoring. 

The IRB/IEC will be informed of any safety issues that require alteration of the 
safety monitoring scheme or amendment of the Informed Consent Form. 
7.1.
Time and Events Table
Note:  While some assessments included in the Time and Events Table are conducted less 
frequently following the primary endpoint (Week 48), IM injections for participants 
during the Extension Phase will continue to be administered Q4W or Q8W based on 
original study randomization assignment.
All patients will be randomized at Day 1 to initiate either Q4 weekly or Q8 weekly 
administration of IM CAB LA + RPV LA. Only participants randomized from oral SOC 
treatment will participate in the Day 1 to Week 4 Oral CAB + Oral RPV lead-in 
treatment.
 
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7.1.1.
Time and Events Table for CAB LA + RPV LA Q4 Weekly Administration
Procedure
Screening Visit a
Maintenance Phase
Extension 
Phase
Withdrawal
Assesssments y
Long-Term 
Follow-up z
Day 1
Week
Week 4A 
(Oral Lead-in 
ONLY)b
Week 4B
8
12
16
20
24
28
32
36
40
44
48
52
Q4W
56-92
Q8W
56-92
96
100
Q4W 
After 
Wee
k 100
Q8W 
After 
Week 
96
Written 
informed 
consent
X
Eligibility 
Verification 
(Inclusion/E
xclusion 
Criteria)
X
Xc
Xc
Randomization
X
Demography
X
Medical 
Historyd
X
Cardiovascular 
risk 
assessmentd
X
X
Medication 
History/ 
Prior ART 
history
X
Syphilis 
serology + 
Reflex Rapid 
Plasma 
Reagin 
(RPR)
X
X
 
 
 
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Procedure
Screening Visit a
Maintenance Phase
Extension 
Phase
Withdrawal
Assesssments y
Long-Term 
Follow-up z
Day 1
Week
Week 4A 
(Oral Lead-in 
ONLY)b
Week 4B
8
12
16
20
24
28
32
36
40
44
48
52
Q4W
56-92
Q8W
56-92
96
100
Q4W 
After 
Wee
k 100
Q8W 
After 
Week 
96
Symptom 
Directed 
Physical 
Exam and 
Medical 
Assessmente
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight, 
Height and 
BMIf
X
X
X
X
Vital Signs: 
BP, HR,
Temperature)g
X
X
X
X
X
12-lead ECG 
h
(triplicate at 
Day 1 pre-dose)
X
X
X
X
X
CDC HIV-1
stage
X
X
HIV 
Associated 
Conditions
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AEs, SAEs, 
Concomitant 
Medicationsi
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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Procedure
Screening Visit a
Maintenance Phase
Extension 
Phase
Withdrawal
Assesssments y
Long-Term 
Follow-up z
Day 1
Week
Week 4A 
(Oral Lead-in 
ONLY)b
Week 4B
8
12
16
20
24
28
32
36
40
44
48
52
Q4W
56-92
Q8W
56-92
96
100
Q4W 
After 
Wee
k 100
Q8W 
After 
Week 
96
ISR 
Assessment
for IM 
injections
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Columbia 
Suicide 
Severity 
Rating Scale 
(eC-SSRS) j
X
X
X
X
X
X
X
X
X
X
X
X
Clinical 
chemistry 
and 
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy 
Testingk
S
U
S
U
S
U
S
U
S
U
S
U
S
U
S
S
U
S
S
S
U
S
S
S
HIV-1 RNA
and sample 
for storage 
(S)l
X
X
X
X
X
X
X
X
X
X
S
X
X
S
X
X
X
CD4+ cell 
count
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CD8+ cell 
count
X
X
X
X
X
Urinalysism
X
X
X
X
X
X
 
 
 
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Procedure
Screening Visit a
Maintenance Phase
Extension 
Phase
Withdrawal
Assesssments y
Long-Term 
Follow-up z
Day 1
Week
Week 4A 
(Oral Lead-in 
ONLY)b
Week 4B
8
12
16
20
24
28
32
36
40
44
48
52
Q4W
56-92
Q8W
56-92
96
100
Q4W 
After 
Wee
k 100
Q8W 
After 
Week 
96
Fasting Lab 
Assessment:  
Glucose, 
Cholesterol 
(Total, HDL 
and LDL) 
and 
Triglyceridesn
X
X
X
Xo
Hepatitis B 
(HBsAg), 
Anti-HBc, 
and Anti-
HBsAG, 
Hepatitis C 
(anti-HCV 
Ab)
X
PT/PTT/INR 
X
X
PBMCsp
X
X
X
X
Genetics 
sampleq
X
PK 
samplingr
(S)=Storage 
only
X
X
S
X
S
X
S
X
S
X
S
X
S
S
S
X
S
X
S
 
 
 
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Procedure
Screening Visit a
Maintenance Phase
Extension 
Phase
Withdrawal
Assesssments y
Long-Term 
Follow-up z
Day 1
Week
Week 4A 
(Oral Lead-in 
ONLY)b
Week 4B
8
12
16
20
24
28
32
36
40
44
48
52
Q4W
56-92
Q8W
56-92
96
100
Q4W 
After 
Wee
k 100
Q8W 
After 
Week 
96
Oral CAB 
and Oral 
RPV 
Dispensations
X
X
IP 
accountability 
(Pill Counts)s
X
X
IM treatment 
administratio
n when 
transitioning 
from SOCt
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
IM treatment 
administration 
when 
transitioning 
from CAB + 
RPV LA 
Q4W
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient Reported Outcomesu
HAT-QoL 
(short-form)
X
X
X
X
HIV TSQs
X
X
X
X
HIV TSQc v
X
X
ACCEPT
X
X
X
X
 
 
 
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Procedure
Screening Visit a
Maintenance Phase
Extension 
Phase
Withdrawal
Assesssments y
Long-Term 
Follow-up z
Day 1
Week
Week 4A 
(Oral Lead-in 
ONLY)b
Week 4B
8
12
16
20
24
28
32
36
40
44
48
52
Q4W
56-92
Q8W
56-92
96
100
Q4W 
After 
Wee
k 100
Q8W 
After 
Week 
96
Reason for 
Switch or 
Reason for 
continuation w
X
Preference x
X
X
PIN
X
X
X
X
Safety Follow Up Visit:  Conduct approximately 4 weeks after the last dose of IP.  Required only if the participant has ongoing AEs or lab 
abnormalities at the last on-study visit.  This visit may be conducted by telephone.
a.
Complete all Screening assessments within 35 days.  Participants may begin the Maintenance Phase as soon as all Screening assessments are complete.  
Participants may be rescreened once and will be assigned a new participant number.   Participants transitioning from the 201585 (ATLAS) study must reach 
ATLAS Week 48 (at minimum) prior to initiating Screening procedures for ATLAS-2M and must reach ATLAS Week 52 (at minimum) prior to 
randomization in ATLAS-2M. 
b.
Visits Week 4a is part of the CAB + RPV Oral Lead-in period and is required only for participants transitioning from current SOC to CAB LA + RPV LA.
c.
Confirmation of eligibility to continue the Maintenance Phase and eligibility to enter the Extension Phase. 
d.
Collect full routine medical history plus (report at Baseline visit): HIV risk factors (may be collected at a later study visit), cardiovascular risk factors 
(assessments include smoking status and history, family history of cardiac events), recent [6 months] illicit drug use, intravenous drug use, gastrointestinal 
disease, metabolic, psychiatric, renal, bone, and neurologic disorders.
e.
Physical exams should be conducted as part of normal routine clinical care.  Medical assessments include any decisions the study staff must make for 
participants management and/or care of participant.  
f.
Height collected at Baseline Day 1 only.
g.
Measure vital signs after about 5 minutes of rest in a semi-supine position.
 
 
 
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h.
A 12-lead ECG will be performed after resting in a semi-supine position for at least 5 minutes.  ECGs will be performed pre-dose. For participants 
transitioning from ATLAS, the pre-dose Week 48 ECG can also serve as the ATLAS-2M Screening ECG. ECG pre-dose will be performed in triplicate at 
Day 1.  A 2-hour post-dose ECG will also be performed at Days 1 and Week 48 for participants receiving CAB LA + RPV LA with an allowable window of 
30 minutes.
i.
Only SAEs related to study participation or to a concomitantly administered ViiV/GSK product will be collected between obtaining informed consent and 
administration of study drug at Day 1.
j.
On Day 1, the eC-SSRS is to be administered prior to randomization.  The eC-SSRS will preferably be completed at the beginning of the visit following 
administration of other PROs required prior to injections.  The eC-SSRS is not required during the Withdrawal visit if withdrawal occurs during the Extension 
Phase.
k.
Women of childbearing potential only.  SR=serum, UR=urine.  Pregnancy events will be captured starting at Day 1 following initial exposure to study drug.  
Urine pregnancy test performed at Day 1 prior to administration of study drug, at Week 4b, and at study visits when other blood draws are not required in 
order to limit needle sticks.  Serum pregnancy test can substitute for urine pregnancy test if locally required but must be appropriately timed to confirm 
pregnancy status prior to randomization and first IM administration.
l.
Week 48 and Week 96 HIV-1 RNA retest (within 4 weeks) for results > 50 c/mL will be captured as unscheduled visit. Plasma for storage samples will be 
used for possible future analyses.
m.
A morning specimen is preferred.  To assess biomarkers: urine albumin/creatinine ratio; urine protein/creatinine ratio; and urine phosphate. Urine phosphate 
results from visit 4a are not required by protocol to inform the safety review at visit 4b prior to receipt of initial CAB LA + RPV LA injections.
n.
An overnight fast is preferred; however, a minimum of a 6-hour fast is acceptable.
o.
Only collect if the Withdrawal visit occurs at Week 48 or Week 96.
p.
Whole blood/PBMC collection samples may be used for virologic analyses.  PBMCs will be collected at baseline Day 1, Week 48, Week 96, or Withdrawal if 
prior to Week 96.
q.
Genetics sample should be collected only for patients who did not participate in the 201585(ATLAS) study (sample was previously collected and stored). 
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 Day 1 visit .
r.
One blood sample for CAB and RPV each to be collected at each PK timepoint.  At Day 1, for participants from the ATLAS Q4W arm, PK samples are to be 
collected pre-dose relative to IM administration.  At Week 4b, for participants randomized from SOC, Pre dose PK samples are to be collected: AFTER review 
of the PK diary to ensure that the samples are taken 20/28 hours after previous oral dose (diaries to be given at Day 1 or W4a); PRIOR to the final oral dose of 
CAB + RPV; PRIOR to the first IM injection.
s.
Only for Participants entering CAB + RPV Oral Treatment
 
 
 
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t.
Participants switching to CAB LA + RPV LA will take final dose of oral lead-in regimen in the clinic at the Week 4b visit and begin injections.  If possible, 
injections should be spaced approximately 2 cm from one another and from the site of any previous injection and or any injection site reaction.  Bring RPV LA 
to approximately room temperature prior to injecting.  Time and location of injection (right or left) as well as needle length used will be collected in the eCRF.
The first injection can be performed as soon as central lab results become available and safety parameters are reviewed.  
u.
All Patient Report Questionnaires/Surveys will be administered via paper instrument at the beginning of the visit before any other assessments are conducted 
and prior to administration of the eC-CSSRS.  Conduct questionnaires/surveys at Withdrawal only if occurring at or prior to Week 48.
v.
The HIV-TSQc is to be administered to all participants transitioning from ATLAS and new participants transitioning from oral SOC.  For participants 
transitioning from ATLAS, the version of the HIV-TSQc instrument to be administered will be based on the initial randomization arm at ATLAS Day 1. 
w.
For patients randomized to oral SOC at Day 1 in ATLAS or new patients on SOC, the reasons for willingness to switch ART will be assessed at Day 1.  For 
patients randomized to CAB LA + RPV LA Q4W in ATLAS, the reasons for willingness to continue long-acting ART in ATLAS-2M will be assessed at Day 
1.
x.
Preference Questionnaire will be administered to all participants.
y.
Refer to Section 5.5 of the protocol for additional information on performing withdrawal assessments.  HIV-1 RNA will be collected as Storage sample only if 
withdrawal assessments coincide with Week 52 or Week 100 (as per Section 5.5) 
z.
Participants receiving one or more injections with CAB LA and/or RPV LA will be assessed with clinic visits at months 3, 6, 9 and 12 during the Long-Term 
Follow-Up Phase
Note: BP – Blood pressure, HR – Heart Rate, HDL – High Density Lipoprotein, LDL – Low Density Lipoprotein, PT Prothrombin Time, 
PTT Partial Thromboplastin Time, INR International normalized ratio
 
 
 
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7.1.2.
Time and Events Table for CAB LA + RPV LA Q8 Weekly Administration
Procedure
Screening Visit a
Maintenance Phase
Extension 
Phase
Withdrawal
Assessmentsy
Long-Term 
Follow-up z
Day 1
Week
Week 4A 
(Oral lead-in 
ONLY) b
Week 4B
(Oral lead-in 
ONLY) b
8
9
16
24
32
40
41
48
56
64
72
80
88
96
100
Q8W After 
Week 96
Written 
informed 
consent
X
Eligibility 
Verification 
(Inclusion/
Exclusion 
Criteria)
X
Xc
Xc
Randomization
X
Demography
X
Medical
Historyd 
X
Cardiovascular 
risk 
assessmentd
X
X
Medication 
History/ Prior 
ART history
X
Syphilis 
serology + 
reflex Rapid 
Plasma 
Reagin (RPR)
X
X
 
 
 
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Procedure
Screening Visit a
Maintenance Phase
Extension 
Phase
Withdrawal
Assessmentsy
Long-Term 
Follow-up z
Day 1
Week
Week 4A 
(Oral lead-in 
ONLY) b
Week 4B
(Oral lead-in 
ONLY) b
8
9
16
24
32
40
41
48
56
64
72
80
88
96
100
Q8W After 
Week 96
Symptom 
Directed
Physical 
Exam and 
Medical 
Assessmente
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight, 
Height and 
BMIf
X
X
X
X
Vital Signs
(BP, HR,
Temperature)g
X
X
X
X
X
12-lead ECG h
(triplicate at 
Day 1 pre-dose)
X
X
X
X
X
CDC HIV-1 
stage
X
X
HIV 
Associated 
Conditions
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AEs, SAEs, 
Concomitant 
Medications
X
i
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ISR 
Assessment
for IM 
injection
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
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Procedure
Screening Visit a
Maintenance Phase
Extension 
Phase
Withdrawal
Assessmentsy
Long-Term 
Follow-up z
Day 1
Week
Week 4A 
(Oral lead-in 
ONLY) b
Week 4B
(Oral lead-in 
ONLY) b
8
9
16
24
32
40
41
48
56
64
72
80
88
96
100
Q8W After 
Week 96
Columbia 
Suicide 
Severity 
Rating Scale 
(eC-SSRS) j
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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
Pregnancy 
Testingk
S
U
S
U
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
HIV-1 RNA
and sample 
for storage 
(S)l
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
S
X
X
X
CD4+ cell 
count
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CD8+ cell 
count
X
X
X
X
X
Urinalysism
X
X
X
X
X
X
Fasting Labs
Glucose, 
Cholesterol 
(Total, HDL 
and LDL) and 
Triglyceridesn
X
X
X
Xo
 
 
 
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Procedure
Screening Visit a
Maintenance Phase
Extension 
Phase
Withdrawal
Assessmentsy
Long-Term 
Follow-up z
Day 1
Week
Week 4A 
(Oral lead-in 
ONLY) b
Week 4B
(Oral lead-in 
ONLY) b
8
9
16
24
32
40
41
48
56
64
72
80
88
96
100
Q8W After 
Week 96
Hepatitis B 
(HBsAg), 
Anti-HBc, and 
Anti-HBsAG, 
Hepatitis C 
(anti-HCV 
Ab)
X
PT/PTT/INR 
X
X
PBMCs p
X
X
X
X
Genetics 
sample q
X
PK sampling 
when 
transitioning 
from SOC r
(S)=Storage 
only
X
X
X
X
X
X
X
X
X
S
S
S
S
S
X
S
X
S
PK sampling 
when 
transitioning 
from CAB + 
RPV Q4W r
(S)=Storage 
only
X
X
X
X
X
X
X
X
X
S
S
S
S
S
X
S
X
S
Oral CAB and 
Oral RPV 
Dispensation s
X
X
 
 
 
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Procedure
Screening Visit a
Maintenance Phase
Extension 
Phase
Withdrawal
Assessmentsy
Long-Term 
Follow-up z
Day 1
Week
Week 4A 
(Oral lead-in 
ONLY) b
Week 4B
(Oral lead-in 
ONLY) b
8
9
16
24
32
40
41
48
56
64
72
80
88
96
100
Q8W After 
Week 96
IP 
accountability 
(Pill Counts)
X
X
IM treatment 
administration 
when 
transitioning 
from SOC t
X
X
X
X
X
X
X
X
X
X
X
X
X
X
IM treatment 
administration 
when 
transitioning 
from CAB + 
RPV Q4W
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient Reported Outcomes u
HAT-QoL 
(short-form)
X
X
X
X
HIV TSQs
X
X
X
X
HIV TSQc v
X
X
ACCEPT
X
X
X
X
 
 
 
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Procedure
Screening Visit a
Maintenance Phase
Extension 
Phase
Withdrawal
Assessmentsy
Long-Term 
Follow-up z
Day 1
Week
Week 4A 
(Oral lead-in 
ONLY) b
Week 4B
(Oral lead-in 
ONLY) b
8
9
16
24
32
40
41
48
56
64
72
80
88
96
100
Q8W After 
Week 96
Reason for 
Switch or 
Reason for 
continuation
w
X
Preference x
X
X
PIN 
X
X
X
X
Safety Follow Up Visit:  Conduct approximately 4 weeks after the last dose of IP.  Required only if the participant has ongoing AEs or lab 
abnormalities at the last on-study visit.  This visit may be conducted by telephone.
a.
Complete all Screening assessments within 35 days.  Participants may begin the Maintenance Phase as soon as all Screening assessments are complete.  
Participants may be rescreened once and will be assigned a new participant number.  Participants transitioning from the 201585 (ATLAS) study must reach 
ATLAS Week 48 (at minimum) prior to initiating Screening procedures for ATLAS-2M and must reach ATLAS Week 52 (at minimum) prior to
randomization in ATLAS-2M. 
b.
Visits Weeks 4A and 4B are part of the CAB + RPV Oral Lead-in period and are required only for participants transitioning from current SOC to CAB LA + 
RPV LA.
c.
Confirmation of eligibility to continue the Maintenance Phase, and eligibility to enter the Extension Phase. 
d.
Collect full routine medical history plus (report at Baseline visit): HIV risk factors (may be collected at a later study visit), cardiovascular risk factors 
(assessments include smoking status and history, family history of cardiac events), recent [6 months] illicit drug use, intravenous drug use, gastrointestinal 
disease, metabolic, psychiatric, renal, bone, and neurologic disorders.
e.
Physical exams should be conducted as part of normal routine clinical care.  Medical assessments include any decisions the study staff must make for 
participants management and/or care of participant.  
f.
Height collected at Baseline Day 1 only.
g.
Measure vital signs after about 5 minutes of rest in a semi-supine position.
 
 
 
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h.
A 12-lead ECG will be performed after resting in a semi-supine position for at least 5 minutes.  ECGs will be performed pre-dose. For participants 
transitioning from ATLAS, the pre-dose Week 48 ECG can also serve as the ATLAS-2M Screening ECG. ECG pre-dose will be performed in triplicate at 
Day 1.  A 2-hour post-dose ECG will also be performed at Days 1 and Week 48 for participants receiving CAB LA + RPV LA with an allowable window of 
30 minutes.
i.
Only SAEs related to study participation or to a concomitantly administered ViiV/GSK product will be collected between obtaining informed consent and 
administration of study drug at Day 1.
j.
On Day 1, the eC-SSRS is to be administered prior to randomization.  The eC-SSRS will preferably be completed at the beginning of the visit following 
administration of other PROs required prior to injections.  The eC-SSRS is not required during the Withdrawal visit if withdrawal occurs during the 
Extension Phase.
k.
Women of childbearing potential only.  SR=serum, UR=urine.  Pregnancy events will be captured starting at Day 1 following initial exposure to study drug.  
Serum pregnancy test can substitute for urine pregnancy test if locally required but must be appropriately timed to confirm pregnancy status prior to 
randomization and first IM administration.
l.
Week 48 and Week 96 HIV-1 RNA retest (within 4 weeks) for results > 50 c/mL will be captured as unscheduled visit. Plasma for storage samples will be 
used for possible future analyses.
m.
A morning specimen is preferred.  To assess biomarkers: urine albumin/creatinine ratio; urine protein/creatinine ratio; and urine phosphate.  Urine phosphate 
results from visit 4a are not required by protocol to inform the safety review at visit 4b prior to receipt of initial CAB LA + RPV LA injections.
n.
An overnight fast is preferred; however, a minimum of a 6-hour fast is acceptable.
o.
Only collect if the Withdrawal visit occurs at Week 48 or Week 96.
p.
Whole blood/PBMC collection samples may be used for virologic analyses.  PBMCs will be collected at baseline Day 1, Week 48, Week 96, or Withdrawal 
if prior to Week 96.
q.
Genetics sample should be collected only for patients who did not participate in the 201585(ATLAS) study (sample was previously collected and stored). 
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 Day 1 visit.
r.
One blood sample for CAB and RPV each to be collected at each PK timepoint.  At Day 1, for participant from the ATLAS Q4W arm, PK samples are to be 
collected pre-dose relative to IM administration. injection. At Week 4b, for participants randomized from SOC, Pre dose PK samples are to be collected: 
AFTER review of the PK diary to ensure that the samples are taken 20/28 hours after previous oral dose (diaries to be given at Day 1 or W4a); PRIOR to the 
final oral dose of CAB + RPV; and PRIOR to the first IM injection.  At Week 9 and 41, the PK samples should be collected 3 to 10 days after the Week 8 
and Week 40 visits, respectively.
s.
Only for Participants entering CAB + RPV Oral Treatment 
t.
Participants switching to CAB LA + RPV LA will take final dose of oral lead-in regimen in the clinic at the Week 4b visit and begin injections.  If possible, 
injections should be spaced approximately 2 cm from one another and from the site of any previous injection and or any injection site reaction.  Bring RPV 
LA to approximately room temperature prior to injecting.  Time and location of injection (right or left) as well as needle length used will be collected in the 
eCRF.  The first injection can be performed as soon as central lab results become available and safety parameters are reviewed.  
u.
All Patient Report Questionnaires/Surveys will be administered via paper instrument at the beginning of the visit before any other assessments are conducted 
and prior to administration of the eC-CSSRS. Conduct questionnaires/surveys upon Withdrawal only if occurring at or prior to Week 48
v.
The HIVTSQc is to be administered to all participants transitioning from ATLAS and new participants transitioning from oral SOC. For participants 
transitioning from ATLAS, the version of the HIV-TSQc instrument to be administered will be based on the initial randomization arm at ATLAS Day 1
 
 
 
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w.
For patients randomized to oral SOC at Day 1 in ATLAS or new patients on SOC, the reasons for willingness to switch ART will be assessed at Day 1.  For 
patients randomized to CAB LA + RPV LA Q4W in ATLAS, the reasons for willingness to continue long-acting ART in ATLAS-2M will be assessed at 
Day 1.
x.
Preference Questionnaire will be administered to all participants
y.
Refer to Section 5.5 of the protocol for additional information on performing withdrawal assessments.  HIV-1 RNA will be collected as Storage sample only 
if withdrawal assessments coincide with Week 52 or Week 100 (as per Section 5.5)
z.
Participants receiving one or more injections with CAB LA and/or RPV LA will be assessed with clinic visits at months 3, 6, 9 and 12 during the Long-Term 
Follow-Up Phase
Note: BP – Blood pressure, HR – Heart Rate, HDL – High Density Lipoprotein, LDL – Low Density Lipoprotein, PT Prothrombin Time, 
PTT Partial Thromboplastin Time, INR International normalized ratio
 
 
 
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7.2.
Screening and Critical Baseline Assessments
Written informed consent must be obtained from each potentially eligible participant by 
study site personnel prior to the initiation of any Screening procedures as outlined in this 
protocol. The consent form must have been approved by the Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC). After signing an informed consent, 
participants will complete Screening assessments to determine participant eligibility. 
Each participant being screened for study enrollment evaluation will be assigned a 
participant number at the Screening visit. This number will be given sequentially in 
chronological order of participant presentation according to a numeric roster provided by 
GSK.
7.2.1.
Screening Assessments
Eligibility criteria must be carefully assessed at the Screening visit. Physical 
examinations should be conducted as part of normal routine clinical care. Background 
information to be collected at Screening includes demography and prior ART history.
Eligible participants may be randomly assigned immediately as soon as all Screening 
assessments are complete and the results are available and documented. All participants 
will complete the screening period of approximately 14 days prior to Baseline (Day 1) 
during which all clinical and laboratory assessments of eligibility must be performed and 
reviewed. The Screening period may be extended to 35 days to accommodate availability 
of all Screening assessment results, completion of source document verification to satisfy 
the Inclusion and Exclusion Criteria, and scheduling. All Screening results must be 
available prior to randomization. 
All information about the participant’s current regimen must be available for 
review by the Principal Investigator or designee prior to randomization.  Source 
documents from other medical facilities must be located/received during the 14 day 
(up to 35 days) screening period and under no circumstances may the participant be 
randomized in the absence of source documentation even if there are delays in 
receipt of this information.
Any available prior genotypic resistance testing must be provided to GSK, after screening 
and before randomization according to guidance in the SPM, to provide direct evidence 
of no pre-existing exclusionary resistance mutations. The lack of exclusionary resistance 
mutations must be confirmed by the study virologist, which will be provided before the 
screening window closes. Details on use of RAMOS for tracking historic resistance 
report availability and submission to ViiV Healthcare Virology for evaluation are 
described in the SPM. Details regarding baseline or prior resistance data must be noted in 
the source documentation.
Participants infected with HBV will not be enrolled in the study.  Evidence of HBV 
infection is based on the results of testing at Screening for hepatitis B surface antigen 
(HBsAg), hepatitis B core antibody (anti-HBc), hepatitis B surface antibody (anti-HBs), 
and HBV DNA.  HBV DNA will only be performed for participants with positive anti-
HBc and negative HBsAg and negative anti-HBs (past and/or current evidence). 
 
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Participants with an anticipated need for HCV therapy during the study must not be 
enrolled into this study, as HCV therapy currently includes the prohibited medication 
interferon.  The length of this study should be considered when assessing the potential 
need for therapy.
All participants will be screened for syphilis. Participants with untreated syphilis 
infection, defined as a positive RPR without clear documentation of treatment, are 
excluded.  Participants with a serofast RPR result despite history of adequate therapy and 
no evidence of re-exposure may enrol after consultation with the Medical Monitor. 
Participants with a positive RPR test who have not been treated may be rescreened at 
least 30 days after completion of antibiotic treatment for syphilis.
The eCSSRS (see Section 7.4.6) assessed at the Screening visit will assess the 
participant’s lifetime risk (any suicidal ideation, behavior, etc. occurring over the 
participant’s lifetime).  A positive alert (indicating some risk) is not necessarily 
exclusionary, rather a means to assess overall risk.
Participants who meet all entry criteria are randomized and assigned a randomization 
number. A single repeat of a procedure/lab parameter is allowed to determine eligibility 
(unless otherwise specified).  Participants not meeting all inclusion and exclusion criteria 
at initial screen may be rescreened and receive a new participant number one time unless 
they were excluded for reason of having exclusionary historic genotypic resistance.  
Participants who are randomized into the trial and subsequently withdrawn from the 
study for any reason may not be rescreened.
7.2.2.
Baseline Assessments
At Day 1 and prior to randomization, any changes to the eligibility parameters must be 
assessed and any results required prior to randomization (e.g., Day 1 urine pregnancy test 
for women of childbearing potential) must be available and reviewed. The following 
demographic parameters will be captured: year of birth, sex, race and ethnicity. 
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5. 
HIV-1 genotypic resistance testing and plasma HIV-1 RNA measurement results from 
Screening must be available prior to the Baseline visit.
Baseline information to be collected at Day 1 includes general medical history and 
current medical conditions. Laboratory and health outcomes assessments will also be 
assessed.  Questionnaire/surveys are recommended to be administered at the beginning of 
the visit before any other assessments are conducted, in the order specified.  For 
participants who agree to the optional assessment, a whole blood sample for genetic 
research should be collected at Day 1 (if not already collected during participation in the 
ATLAS study).
In addition to a full routine medical history at Baseline, more detailed information will be 
collected for some disease processes such as:
 
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
Cardiovascular medical history/risk factors (as detailed in the eCRF) will be 
assessed at Baseline and assessments will include height, weight, blood pressure, 
smoking status and history, pertinent medical conditions (e.g., hypertension, 
diabetes mellitus), and family history of premature cardiovascular disease.  In 
addition, medical history/risk factors for renal disease such as nephropathy, renal 
failure, and nephrolithiasis will be assessed.

history of illicit drug use [e.g., cocaine, heroin, and methamphetamine use]);

intravenous drug use history;

gastrointestinal disease (e.g., GI bleeding, PUD, etc.);

metabolic (e.g., Type I or II diabetes mellitus);

psychiatric (e.g., depression);

renal (e.g., nephrolithiasis, nephropathy, renal failure); and,

neurologic disorders
Procedures conducted as part of the participant’s routine clinical management [e.g., 
laboratory assessments] and obtained prior to signing of informed consent may be 
utilized for Screening or baseline purposes provided the procedure meets the protocol-
defined criteria and has been performed in the timeframe of the study.  Where possible 
local lab results should be confirmed by submission of samples to the central lab. 
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 (see Section 11.4).  
 
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7.4.
Safety
7.4.1.
Clinical Evaluations
The following clinical evaluations will be performed according to the Time and Events 
schedule:

Monitoring and recording of all AEs and SAEs.  Additional information on the 
Time Period and Frequency of Detecting AEs and SAEs is provided in Section 
7.4.3.1.

Physical exams should be conducted as part of normal routine clinical care.  
Abnormalities noted during any exam must be recorded in the eCRF (e.g., in the 
current medical conditions or AE logs).

Height and weight will be measured and recorded.  Height collected on the Day 1 
(Baseline) only.

Vital signs will include systolic and diastolic blood pressure and heart rate 
collected after resting for about 5 minutes.  Temperature will also be collected.

Past medical history, family history, social history, medication history.  Targeted 
history on cardiovascular risk (smoking history, family and personal history).

HIV-associated conditions will be recorded.

Electrocardiogram:  A 12-lead ECG will be performed in a semi-supine position 
after 5 minutes of rest.  On Day 1 (Baseline) of the Maintenance Phase, ECGs 
should be performed in triplicate prior to first dose.  An ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals is preferred, and these calculated numbers can be used for reporting 
purposes.  Otherwise, an appropriately qualified ECG reader must interpret the 
results.  The same interpreter should assess all ECGs for each participant for the 
site.  Regardless, each ECG should be reviewed by a qualified ECG reader.  The 
qualified ECG reader will make the non-calculated ECG interpretations.  The 
same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study. This formula may 
not be changed or substituted once the participant has been enrolled.

Regular monitoring of hematology, blood chemistry, urinalysis and fasting 
glucose and lipids (parameters to be tested listed below).  

Periodic assessment of glucose, insulin, and bone, cardiovascular, and renal 
markers;

Pregnancy testing.  A negative urine pregnancy test is required prior to initiation 
of IP, any dose of CAB LA or RPV LA or as required by the Medical Monitor 
following a treatment interruption(s).  If serum testing is required locally, the 
results should be available prior to the visit where urine testing is indicated per the 
Time and Events Schedule (Section 7.1).

Evaluation and documentation of all concomitant medications and blood products. 
 
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
Injection Site Reactions (ISRs) will be assessed clinically during the Maintenance 
and Extension Phases for the following:
Pain, tenderness, pruritis, warmth, bruising, discoloration, infections, rash, 
erythema, swelling, induration, and nodules (granulomas or cysts).  

A clinical assessment (using Division of Acquired Immunodeficiency Syndrome 
[DAIDS] grading scale) should be performed both before and after an injection to 
identify resolving and new ISRs.  All injection site reactions are considered 
adverse events.  The clinical assessment and interpretation of any ISR, will be 
documented in the ISR AE eCRF.  

Columbia Suicide Severity Rating Scale (eC-SSRS) will be assessed as per the 
Time and Events Schedule (see Section 7.1 and Suicidal Risk Monitoring Section 
7.4.6).
Any appropriately qualified site personnel (e.g., Investigator, sub-Investigator, or study 
coordinator/nurse) can perform assessments.
7.4.2.
Laboratory Assessments
All protocol required laboratory assessments, as defined in the Time and Events Schedule 
(see Section 7.1), must be performed by the central laboratory.  Laboratory assessments 
must be conducted in accordance with the Central Laboratory Manual and Protocol Time 
and Events Schedule.  Laboratory requisition forms must be completed and samples must 
be clearly labeled with the participant number, protocol number, site/centre number, and 
visit date.  Details for the preparation and shipment of samples will be provided by the 
central laboratory.  Reference ranges for all safety parameters will be provided to the site 
by the central laboratory.

The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study should be repeated until the values return to 
normal or baseline or are no longer considered significantly abnormal by the 
investigator or medical monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, must be conducted in accordance 
with the laboratory manual and the protocol Time and Events table.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
 
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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 11.2 “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.
Table 8 includes lab parameters to be assessed as per the Time and Events Schedule (see 
Section 7.1).  In addition to the protocol-specified laboratory assessments the study 
Medical Monitor, in collaboration with the site investigator, may request additional 
central laboratory assessments be performed to support safety profiling and case 
management of individual study participants.
Table 8
Safety Laboratory Assessments
Hematology
Platelet count 
Automated WBC differential:
RBC count
Neutrophils
WBC count (absolute) 
Lymphocytes
Hemoglobin
Monocytes
Hematocrit
Eosinophils
MCV
Basophils
Clinical Chemistry
BUN
Potassium
AST 
Total bilirubina
Creatinine
Chloride
ALT 
Albumin 
Glucosec
Total CO2
Alkaline phosphatase
Creatine phosphokinase
Sodium
Lipase
Phosphate
Creatinine clearanceb
Fasting Lipid Paneld
Total cholesterol
HDL cholesterol
LDL cholesterol
Triglycerides
Other Tests
Plasma HIV-1 RNAe
CD4+ and CD8+ cell counts [CD4/CD8 ratio]f
Peripheral Blood Mononuclear Cells (PBMCs):  Day 1, Week 48, Week 96, Withdrawal only
Hepatitis B (HBsAg), anti-HBc, anti-HBsAg, and hepatitis C antibody (Screening)g
Syphilis serology + Reflex Rapid Plasma Reagin (RPR) (Screening and Baseline)
Prothrombin Time (PT)/International Normalized Ratio (INR)/ Partial Thromboplastin Time (PTT)
Pregnancy test for women of childbearing potentialh
Urinalysis, urine albumin/creatinine ratio, and urine protein/creatinine ratio, urine phosphate
Genetics Sample 
Follicle stimulating hormone (FSH) and estradiol (only for instances when postmenopausal status is questionable)
MCV = mean corpuscular volume, RBC = red blood cells, WBC = white blood cells, BUN = Blood urea nitrogen, 
AST=aspartate aminotransferase, ALT = alanine aminotransferase, CO2 = carbon dioxide, HDL = high density 
 
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lipoprotein, LDL = low density lipoprotein, HBsAg= hepatitis B virus surface antigen, PT/INR = prothrombin
time/international normalized ratio.
a)
Direct bilirubin will be reflexively performed for all total bilirubin values >1.5 × ULN.
b)
Glomerular filtration rate (GFR) will be estimated by the central laboratory using the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) [Levey, 2009].
c)
For fasting glucose assessments, an overnight fast is preferred; however, a minimum of a 6-hour fast is 
acceptable for participants with afternoon appointments.
d)
For fasting lipids assessments, an overnight fast is preferred; however, a minimum of a 6-hour fast is acceptable 
for participants with afternoon appointments.
e)
For participants meeting virologic withdrawal criteria, plasma samples will be analyzed in attempt to obtain 
genotype/phenotype data.
f)
CD8+ cells will only be reported at Baseline, Day 1, Weeks 4b, 24, 48, and 96.
g)
HBV DNA will only be performed for participants with a positive anti-HBc and negative HBsAg and negative anti-
HBs (past and/or current evidence).
h)
Urine pregnancy test/ serum pregnancy test will be performed according to the Time and Events Table (Section 
7.1).  
7.4.3.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
7.4.3.1.
Time period and Frequency for collecting AE and SAE information

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded from the time a participant consents to participate in 
the study up to and including any follow-up contact. 

All SAEs will be recorded and reported to the sponsor or designee immediately 
and under no circumstance should this exceed 24 hours. The investigator will 
submit any updated SAE data to the sponsor within 24 hours of it being 
available.

AEs will be collected from the start of Study Treatment until the final follow-
up contact, at the timepoints specified in the Time and Events Table (Section 
7.1).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the eCRF.

The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are 
provided in Section 11.6, Appendix 6

Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she 
considers the event reasonably related to the study treatment or study 
participation, the investigator must promptly notify GSK.
 
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7.4.3.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the participant is the preferred method to inquire 
about AE occurrence.  Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, 
since your last visit/contact?”
7.4.3.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts.  All SAEs, and non-serious AEs of special 
interest (as defined in Section 7.4.5) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the participant is lost to follow-
up (as defined in Section 5.5). Further information on follow-up procedures is given in 
Section 11.6, Appendix 6).
7.4.3.4.
Prompt Reporting of Serious Adverse Events and Other Events
SAEs, pregnancies, and liver function abnormalities meeting pre-defined criteria will be 
reported promptly by the investigator to the medical monitor as described in Table 9 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 9.
Criteria for liver chemistry stopping and follow-up criteria are in Section 5.5.1.
 
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Table 9
Reporting of Serious Adverse Events and Other Events
Initial Reports
Follow-up Information on a Previous 
Report
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
“SAE” data 
collection tool
24 hours
Updated “SAE” data 
collection tool
Cardiovascular or 
death event
Initial and 
follow-up 
reports to be 
completed when 
the 
cardiovascular 
event or death 
is reporteda
“CV events” and/or 
“death” data 
collection tool(s) if 
applicable
Initial and follow-up 
reports to be 
completed when 
the cardiovascular 
event or death is 
reporteda
Updated “CV events” 
and/or “death” data 
collection tool(s) if 
applicable
Pregnancy
24 hours
“Pregnancy 
Notification Form”
Within 24 hours of 
investigator 
awareness of 
pregnancy outcome
“Pregnancy Follow-
up Form” and SAE if 
required
Seizure or suspected 
seizure
24 hours
eCRF
24 hours
eCRF
Suspected ABC HSR in 
participants receiving 
Oral SOC during the 
Long-Term Follow-Up 
Phaseb
1 week
ABC HSR eCRF
1 week
Updated ABC HSR 
eCRF
ALT3×ULN and
bilirubin2×ULN (>35% 
direct) (or ALT3×ULN)
24 hoursc
“SAE” data 
collection tool. 
“Liver Event eCRF” 
and “Liver Imaging” 
and/or “Liver 
Biopsy” eCRFs, if 
applicabled
24 hours
Updated “SAE” data 
collection tool/“Liver 
Event” documentsd
ALT≥5×ULN that 
persists ≥2 weeks 
24 hoursc
Liver Event eCRFd
24 hours 
Updated Liver Event 
eCRFd
ALT ≥8×ULN 
24 hoursc
Liver Event eCRFd
24 hours 
Updated Liver Event 
eCRFd
ALT ≥3×ULN (if 
baseline ALT is <ULN) 
or ALT ≥3 fold increase 
from baseline value
with appearance or 
worsening of symptoms 
of hepatitis or 
hypersensitivity
24 hoursc
Liver Event eCRFd
24 hours 
Updated Liver Event 
eCRFd
a.
Additional details and time frames for reporting supplementary information for cardiovascular and death events 
are provided in Section 7.4.3.7 and Section 7.4.3.8, respectively.
b.
ABC HSR eCRF only required if event meets one of the ICH E2A definitions of seriousness.
c.
GSK must be contacted at onset of liver chemistry elevations to discuss participant safety.
d.
Liver event documents (i.e., “Liver Event eCRF” and updates, “Liver Imaging eCRF” and/or “Liver Biopsy eCRF”, 
as applicable) should be completed as soon as possible.
 
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SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool.

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the Medical Monitor.

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, the site can report this information on a paper SAE form or to the 
Medical Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.
The method of recording, evaluating, and follow-up of AEs and SAEs plus procedures 
for completing and transmitting SAE reports to the medical monitor are provided in the 
SPM.  Procedures for post study AEs/SAEs are provided in the SPM.  Primary and 
secondary Medical Monitor/SAE contact information is provided on the Medical 
Monitor/Sponsor Information Page of the current protocol.
7.4.3.5.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
Disease related events (DREs) or outcomes listed in the CDC Classification System for 
HIV-1 Infections (Appendix 4) can be serious/life threatening and will be recorded on the 
HIV-Associated Conditions eCRF page if they occur. However, these individual events 
or outcomes, as well as any sign, symptom, diagnosis, illness, and/or clinical laboratory 
abnormality that can be linked to any of these events or outcomes are not reported to 
GSK as AEs and SAEs even though such event or outcome may meet the definition of an 
AE or SAE. However, if either of the following conditions applies, then the event must 
be recorded and reported as an SAE (instead of a DRE):

The investigator determines that the event or outcome qualifies as an SAE 
under part ‘other situations’ of the SAE definition (see Section 11.6.2), or

The event is, in the investigator’s opinion, of greater intensity, frequency, 
or duration than expected for the individual participant, or
 
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
The investigator considers that there is a reasonable possibility that the 
event was related to treatment with the investigational product, or

Death occurring for any reason during a study, including death due to a 
disease-related event, will always be reported promptly.

Lymphomas and invasive cervical carcinomas are excluded from this 
exemption; they must be reported as SAEs even if they are considered to 
be HIV-related.
If any of the above conditions is met then record the DRE on the SAE page rather 
than the HIV Associated Conditions eCRF page and report promptly (i.e., expedited 
reporting, see Section 7.4.3.4) to GSK.
7.4.3.6.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs related to study treatment (even 
for non- interventional post-marketing studies) is essential so that legal obligations and 
ethical responsibilities towards the safety of participants and the safety of a product under 
clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a product under clinical investigation.  GSK 
will comply with country specific regulatory requirements relating to safety reporting to 
the regulatory authority, Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.4.3.7.
Cardiovascular and Death Events
Investigators will be required to fill out the specific CV event page of the eCRF for the 
following AEs and SAEs:  

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularisation
 
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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.
For any cardiovascular events detailed above, whether or not they are considered SAEs, 
and all deaths, specific Cardiovascular (CV) and Death sections of the eCRF will be 
required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the eCRF within one week of receipt of a CV Event data query prompting its completion. 
7.4.3.8.
Death Events
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
In addition, all deaths will require a specific death data collection tool to be completed.  
The death data collection tool includes questions regarding cardiovascular (including 
sudden cardiac death) and noncardiovascular death.
7.4.4.
Toxicity Management
Adverse events that occur during the trial should be evaluated by the Investigator and 
graded according to the Division of AIDS (DAIDS) toxicity scales (See Section 11.2.
“Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events”).  Additional information regarding detecting, documenting and reporting AEs 
and SAEs are available in Section 7.4.3 and Section 11.6.
7.4.4.1.
Treatment Interruption Due to an Adverse Event
IP may be interrupted at the discretion of the investigator and according to the severity of 
the AE. If one or more ART medication is held due to toxicity or AEs, all ART 
medications should be held to reduce the risk of development of resistance taking into 
account the length of the planned interruptions and the PK half-life of each ART of the 
regimen, in order to minimize the risk of development of resistance.
No toxicity-related dose reductions of IP will be allowed.  IP should be restarted as soon 
as medically appropriate; in general, for oral dosing, this should be no longer than 14 
days after discontinuation (unless Grade 3 or 4 toxicities persist).  Any interruption in 
therapy during the Maintenance Phase, oral dosing, of greater than 7 consecutive days 
must be discussed with and agreed by the Medical Monitor prior to resumption of 
therapy.  The Medical Monitor must be contacted upon becoming aware of resumption in 
therapy, if therapy was resumed without prior approval (Section 6.9).  IM dosing is 
expected to occur during the week in which the participant’s projected visit falls (as 
according to the first injection visit).  An additional (+ or -) 7 day window, from the 
 
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projected visit date, is allowable for IM dosing but not preferred.  Any interruption 
outside of this guidance MUST be discussed with the Medical Monitor prior to 
reinitiating IM IP (see Section 6.9.1).
Guidance is provided below on general participant management and IP interruptions 
based on the severity of the AE.  Information regarding permitted substitutions \ is 
provided in Section 6.8.  All changes in the IP regimen must be accurately recorded in the 
participant’s eCRF.
Note: For participants receiving an ABC-containing product as part of the background 
regimen during the Long-Term Follow-Up (LTFU) Phase, in the event of a 
discontinuation of ABC for any reason, re-initiation of this drug should be undertaken 
with caution. The investigator should obtain a complete history of the events surrounding 
the discontinuation of the ABC-containing product, evaluate for the possibility of a 
clinically suspected HSR, and initiate participant management as outlined in the Local 
Country Prescribing Information, regardless of a participant’s HLA-B*5701 status. 
Screening for the presence of HLA-B*5701 is recommended prior to reinitiating 
treatment with ABC-containing products in participants of unknown HLA-B*5701 status 
who have previously tolerated ABC but is not required to confirm study eligibility.
7.4.4.2.
Grade 1 or Grade 2 Toxicity/Adverse Event
Participants who develop a Grade 1 or Grade 2 AE or toxicity may continue study drug at 
the discretion of the investigator.  Participants who choose to withdraw from the study 
due to a Grade 1 or 2 AE should have study withdrawal and follow-up evaluations 
completed.
Participants who develop ALT ≥3 times ULN while on study must consult with 
Medical Monitor prior to initiation or continuation of CAB LA + RPV LA
7.4.4.3.
Grade 3 Toxicity/Adverse Event
Participants who develop a Grade 3 AE or toxicity should be managed as follows:

If the Investigator has compelling evidence that the Grade 3 AE or toxicity has 
not been caused by IP, dosing may continue after discussion with the Medical 
Monitor.

Participants who develop a Grade 3 AE or toxicity, which the Investigator 
considers related or possibly related to the IP, should have the IP withheld and be 
rechecked each week until the AE returns to Grade 2.  Once the AE is Grade 2, 
IP may be re-started. 

Should the same Grade 3 AE recur within 28 days in the same participant, the IP 
should be permanently discontinued and the participant withdrawn from study. 

Participants experiencing Grade 3 AEs requiring permanent discontinuation of 
IP should be followed weekly until resolution of the AE and to have withdrawal 
study evaluations completed.  A follow-up visit should be performed 4 weeks 
after the last dose of IP.  Any participant receiving at least one dose of CAB LA 
and /or RPV LA who discontinue IP / Withdraw will initiate treatment with 
HAART and enter the LTFU Phase for 52 weeks of follow up. 
 
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
Participants with Grade 3 asymptomatic laboratory abnormalities should be 
investigated for all potential non-drug related causes, and, following discussion 
with the Medical Monitor, may continue IP if the Investigator has compelling 
evidence that the toxicity is not related to IP, with the exception of liver chemistry 
stopping criteria (See Section 7.4.5.1).  Isolated Grade 3 lipid abnormalities do 
not require withdrawal of IP.
7.4.4.4.
Grade 4 Toxicity/Adverse Event

Participants who develop a Grade 4 AE or toxicity must have IP permanently 
discontinued.  However, if the Investigator has compelling evidence that the AE is 
not causally related to the IP, dosing may continue after discussion with, and 
assent from, the Medical Monitor.  Participants should be rechecked each week 
until the AE returns to Grade 2.

Participants experiencing Grade 4 AEs requiring permanent discontinuation of 
IP should be followed weekly until resolution of the AE and encouraged to 
complete the withdrawal and follow-up study evaluations as noted above.  Any 
participant receiving at least one dose of CAB LA and /or RPV LA who 
discontinue IP / Withdraw will initiate treatment with HAART and enter the 
LTFU Phase for 52 weeks of follow up. 

Participants with Grade 4 asymptomatic laboratory abnormalities should be 
investigated for all potential non-drug related causes, and, following discussion 
with the Medical Monitor, may continue therapy if the Investigator has 
compelling evidence that the toxicity is not related to IP, with the exception of 
liver chemistry stopping criteria (See Section 7.4.5.1).  An in-clinic follow-up 
visit will be performed approximately 4 weeks after the last dose of study 
medication if AEs, SAEs, or laboratory abnormalities considered potentially 
harmful to the participant are ongoing at the last on-study visit.  Isolated Grade 4 
lipid abnormalities do not require withdrawal of IP.
7.4.5.
Specific Toxicities/Adverse Event Management
General guidelines for the management of specific toxicities that are considered to be 
associated with treatment of HIV patients. 
Participants who permanently discontinue study drug for reasons of toxicity should be 
followed weekly until resolution of the AE and encouraged to complete the withdrawal 
and Follow-up study evaluations as noted in Section 7.4.3.3.
7.4.5.1.
Liver Chemistry Stopping and Follow-up Criteria
Liver chemistry threshold stopping criteria have been designed to assure participant 
safety and to evaluate liver event etiology during administration of study drug and the 
follow-up phase. All Phase 3 participants who meet liver stopping criteria will be 
adjudicated by the ViiV Safety and Labelling Committee (VSLC) – resulting in a case 
summary, adjudication, and management plan. The VSLC contains an external expert 
hepatologist, familiar with both DILI and cabotegravir, who will participate in this 
review. This committee meets on a 3-weekly basis, and can be convened on an ad hoc 
basis as needed.
 
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7.4.5.2.
Diarrhea
Participants with Grade 1 or 2 diarrhea may continue study treatment without 
interruption.  Participants with diarrhea of any toxicity grade may be treated 
symptomatically with anti-motility agents; however, the recommended daily dose of the 
chosen anti-motility agent must not be exceeded.  If symptoms persist or get worse on the 
recommended daily dose of the chosen anti-motility agent then the anti-motility agent 
must be discontinued and consultation made with the Medical Monitor.
For participants with Grade 3 diarrhea that is unresponsive to the recommended dose of 
the anti-motility agents and for which an alternative etiology (e.g., infectious diarrhea) is 
not established, the treatment with the anti-motility agent and IP must be interrupted until 
resolution of diarrhea to Grade 2 or Baseline, after which IP and background ART may 
be resumed after discussion and agreement with the Medical Monitor.  If Grade 3 
diarrhea recurs within 28 days upon the resumption of IP, the IP should be permanently 
discontinued and the participant withdrawn from the study.  Any participant receiving at 
least one dose of CAB LA and /or RPV LA who discontinue IP / Withdraw will initiate 
treatment with HAART and enter the LTFU 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.
7.4.5.3.
Hypertriglyceridemia/ Hypercholesterolemia
Samples for lipid measurements must be obtained in a fasted state according to the Time 
and Events table (Section 7.1).  Participants who experience asymptomatic triglyceride or 
cholesterol elevations may continue to receive IP.  Clinical management of participants 
with hypertriglyceridemia/hypercholesterolemia should not be based upon non-fasting 
samples (obtained in the fed state).  A confirmatory fasting triglyceride and/or cholesterol 
level should be obtained prior to the institution of medical therapy for hyperlipidemia.  
Isolated Grade 3 and Grade 4 lipid abnormalities do not require withdrawal of IP.
Please see the Recommendations of the Adult AIDS Clinical Trial Group Cardiovascular 
Disease Focus Group [Dube, 2003] for full discussion of management of hyperlipidemia 
in the context of HIV therapy.
7.4.5.4.
Seizures
Three cases of seizures have occurred in the CAB program cumulatively through 01 
October 2015.  
ViiV Healthcare has reviewed these cases in detail and does not believe they constitute a 
reasonable likelihood of causation associated with CAB.  This assessment is supported by 
the lack of preclinical signal, class effect or known CNS mechanism, the relatively low 
frequency of seizures relative to expected rates in both healthy and HIV positive 
participants and clinical confounders in each case.  The Sponsor considers the risk of 
developing seizures on the study as being no higher than that of the rest of the HIV-1 
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Seizures that occur on study should be managed according to the local guidelines on 
emergency seizure management which may include treatment with benzodiazepines, 
general supportive treatment, exclusion of metabolic and toxicological abnormalities 
using laboratory tests, septic workup and excluding underlying structural abnormalities 
with neuroimaging.
Where seizures occur, the Sponsor would like to better characterize these occurrences to 
enable systematic analyses.
Investigators are requested to document and report seizure or possible seizure events 
promptly (within 24 hours of learning of the event) to the Sponsor for evaluation and 
onward reporting.  Data should be documented on the appropriate eCRF seizure page.
7.4.5.5.
Creatine Phosphokinase (CPK) Elevation
A Grade 3 or higher elevation in CPK should result in a repeat assessment within 2-4 
weeks to ensure the result is transient or due to exercise and will not require a change in 
study treatment.  A history regarding use of drugs known to cause increase of CPK (such 
as statins) physical activity or exercise preceding the CPK evaluation should be obtained. 
Grade 4 elevations in CPK should have a repeat assessment after the participant has 
abstained from exercise for >24 hours.  For persistent Grade 4 CPK elevations that are 
considered possibly or probably related to the IP, IP should be discontinued and the 
participant withdrawn from the study.  Any participant receiving at least one dose of 
CAB LA and /or RPV LA who discontinue IP / Withdraw will initiate treatment with 
HAART enter the LTFU Phase for 52 weeks of follow-up.
7.4.5.6.
Lipase Elevations and Pancreatitis
Participants with asymptomatic Grade 1 or 2 elevations in lipase may be followed closely 
for the development of symptoms.
Participants with asymptomatic Grade ≥3 elevations in lipase that are considered possibly 
or probably related to IP should have IP interrupted until serum lipase returns to 
Grade 2.  The lipase assay should be repeated within 2 weeks of any Grade ≥3 result.  
Participants with persistence of Grade ≥3 lipase in the absence of other diagnoses or 
reoccurrence of lipase elevation (at Grade ≥2) following reintroduction of IP should 
permanently discontinue IP.
Participants with a confirmed diagnosis of clinical pancreatitis that is considered possibly 
or probably related to IP should have IP held.  After complete resolution of the episode, 
participants may be re-challenged with IP after discussion with the Medical Monitor, 
only if the Investigator has compelling evidence that the event was not caused by IP.  
Upon re-challenge, lipase determinations should be performed every 2 weeks for at least 
6 weeks after re-initiation of treatment.  With any elevation of lipase of Grade ≥2 or any 
recurrence of symptoms, the participant should discontinue IP and be withdrawn from 
study.
 
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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 LTFU Phase for 52 
weeks of follow up.
Drug Restart Following Transient Resolving Liver Events Not Related to Study Drug
Approval by VSLC for drug restart can be considered where:
Liver chemistries have a clear underlying cause (e.g., biliary obstruction, hypotension, 
and liver chemistries have improved to normal or are within 1.5 × baseline and 
ALT <3 × ULN). Ethics Committee or IRB approval of drug restart must be obtained, as 
required.
If restart of drug is approved by VSLC in writing, the participant must be provided with a 
clear description of the possible benefits and risks of drug administration, including the 
possibility of recurrent, more severe liver injury or death.
The participant must also provide signed informed consent specifically for the restart. 
Documentation of informed consent must be recorded in the study chart.
Study drug must be administered at the dose specified by VSLC. 
Participants approved by VSLC for restarting study drug must return to the clinic once a 
week for liver chemistry tests for a minimum of one month and thereafter for as long as 
clinically indicated and then laboratory monitoring may resume as per protocol. If 
protocol defined stopping criteria for liver chemistry elevations are met, study drug must 
be stopped.
Refer to Section 11.2, 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 2.1. [March 2017]. Available from:
https://rsc.tech-res.com/docs/default-source/safety/daids-ae-grading-table-mar2017.pdf
Refer to Section 11.3, Appendix 3: Liver Safety – Study Treatment Restart Guidelines for 
further details.
7.4.5.7.
Decline in Renal Function
Participants who experience an increase in serum creatinine from Baseline of 
45 micromoles/liter (Mol/L) (or 0.5 milligrams/deciliter [mg/dL]) should return for a 
confirmatory assessment within 2 to 4 weeks.  A urinalysis and urine albumin/creatinine 
and urine total protein/albumin ratios should also be done at this confirmatory visit.  If 
the creatinine increase is confirmed, the investigator should contact the study medical 
monitor to discuss additional follow-up and medical management.
Participants who have a decline in the estimated GFR (using the CKD-EPI method) of 
>50% from Baseline must return for a confirmatory assessment as soon as possible 
[Levey, 2009]. A urinalysis and urine albumin/creatinine and urine protein/creatinine 
 
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ratios should also be done at this confirmatory visit. If the estimated GFR has declined by 
>50% (confirmed), then study drug should be withheld and the investigator should 
contact the study medical monitor to discuss the rationale for restarting study drugs (if 
appropriate).  Consideration for confounding factors (e.g., background therapy, other 
medications, dehydration, concurrent conditions) should be taken into account, and a 
nephrology consult may be obtained.  
7.4.5.7.1.
Proximal Renal Tubule Dysfunctions (PRTD)
PRTD is defined as:
Confirmed rise in serum creatinine of ≥0.5 mg/dL from Baseline AND serum phosphate 
<2.0 mg/dL;
Either of the above accompanied by any two of the following:
Glycosuria (≥250 mg/dL) in a non-diabetic;
Low serum potassium (<3 mEq/L);
Low serum bicarbonate (<19 mEq/L).
Participants meeting criteria for PRTD must return for a confirmatory assessment within 
2 weeks of diagnosis. A urinalysis should also be performed at the time of the 
confirmatory assessment.  If PRTD is confirmed participants should have study drug 
withheld and the investigator should contact the Study medical monitor to discuss the 
rationale for restarting study drugs (if appropriate). Consideration for confounding factors 
(e.g., NRTI backbone, other medications, dehydration, concurrent conditions) should be 
taken into account, and a nephrology consult may be obtained.  If study drug is 
reinitiated, it should have been withheld for no more than 4 weeks.
7.4.5.8.
Proteinuria
Participants with an abnormal urine microalbumin/creatinine ratio (>0.3 mg/mg, 
>300 mg/g, or >34 mg/mmol) that represents a change from Baseline and no associated 
increase in creatinine, should have a repeat spot urine microalbumin/creatinine ratio 
performed within 2-4 weeks. If confirmed, then consideration should be given to 
additional evaluation after consultation with the study medical monitor. Additional 
evaluation may include a 24-hour urine protein and creatinine measurement and 
nephrology referral.
Participants with an abnormal urine albumin/creatinine ratio (>0.3 mg/mg, 300 mg/g, or 
>34 mg/mmol and representing a change from Baseline) and a serum creatinine increase 
>45 μmol/L (or 0.5 mg/dL) should have confirmation of both results within 2 weeks. If 
confirmed, the study medical monitor should be contacted immediately. Agreement on 
further management should be agreed between the investigator and medical monitor. 
 
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7.4.5.9.
QTc Prolongation
Participants with an average QTc interval >550 msec from three or more tracings 
separated by at least 5 minutes should have IP discontinued.  These criteria are based on 
an average QTc value of triplicate ECGs.  If an ECG demonstrates a prolonged QT 
interval, obtain 2 more ECGs over a brief period (~5-10 minutes) and use the averaged 
QTc values of the 3 ECGs to determine whether the participant should be discontinued 
from the study.  If an alternative cause of the QT prolongation is determined (e.g., 
participant receiving drug known to cause prolonged QT or TdP), then IP may be 
restarted after consultation with, and agreement by, the Medical Monitor. 
7.4.5.10.
Injection Site Reactions (ISRs)
Injection site reactions will be managed through investigator assessment throughout the 
study.  All ISRs that are either serious, Grade 3 or higher, or persisting beyond 2 weeks 
must be discussed with the Medical Monitor to determine etiology and assess appropriate 
continued study participation.  
Digital photographs may be documented where possible on all participants who have an 
injection site reaction, with observable findings, that is either serious or Grade 3 or 
higher, or that persists beyond 2 weeks.  Dermatology will be consulted on all 
participants who have an injection site reaction considered serious, Grade 3 or above, or 
if clinically significant and persistent beyond 30 days and others if the Investigator or 
Medical Monitor feels it is medically necessary.
Details regarding photo collection and any other follow up will be given by the Medical 
Monitor at the time of assessment.
ISR discomfort can be managed symptomatically (e.g., cold/warm compress, 
acetaminophen, ibuprofen) if the reaction is interfering with the participant’s ability to 
perform activities of daily living.  The required intervention should be documented on the 
appropriate eCRF page.
7.4.5.11.
Allergic reaction
Participants may continue study drug for Grade 1 or 2 allergic reactions at the discretion 
of the Investigator.  The participant should be advised to contact the Investigator 
immediately if there is any worsening of symptoms or if further systemic signs or 
symptoms develop. Antihistamines, topical corticosteroids, or antipruritic agents may be 
prescribed. 
Participants with Grade ≥3 allergic reactions that are considered to be possibly or 
probably related to the study drug should permanently discontinue the CAB LA + RPV 
LA regimen and the participant should be withdrawn from the study.  Participants should 
be treated as clinically appropriate and followed until resolution of the AE.
7.4.5.12.
Abacavir Hypersensitivity Reaction (ABC HSR)
The most significant toxicity associated with ABC is the well-characterized drug-related 
hypersensitivity reaction (HSR).  A detailed clinical description of this reaction 
 
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(including the type and severity of events that can occur on re-challenge or reintroduction 
following ABC interruption for non-HSR reasons) and guidance regarding its 
management are included in the Local Country Prescribing Information for EPZICOM.  
Investigators must familiarize themselves with this information on ABC HSR in the 
Local Country Prescribing Information for each of these products prior to initiating 
participants on ABC therapy.
Studies have shown that carriage of the HLA-B*5701 allele is associated with a 
significantly increased risk of a HSR to ABC.  In the prospective study CNA106030 
(PREDICT-1), the use of pre-therapy screening for the presence of HLA-B*5701 and 
subsequently avoiding ABC in HLA-B*5701 positive patients, significantly reduced the 
incidence of clinically suspected ABC HSR from 7.8% (66 of 847) to 3.4% (27 of 803) 
(p<0.0001).  In clinical studies EPZ108859 (ARIES) and CNA109586 (ASSERT), 0.8% 
(4/515) and 3.1% (6/192) of participants who were HLA-B*5701 negative and who 
received ABC developed a clinically suspected ABC HSR, respectively.
In any participant treated with ABC, the clinical diagnosis of suspected HSR (as 
detailed in the Local Country Prescribing Information) must remain the basis of 
clinical decision making.  Regardless of HLA-B*5701 status, it is important to 
permanently discontinue ABC and not re-challenge with ABC (i.e., ZIAGEN, 
EPZICOM/KIVEXA, TRIZIVIR, or TRIUMEQ) if a HSR cannot be ruled out on 
clinical grounds, due to the potential for a severe or even fatal reaction.
7.4.5.12.1. Essential Patient Information
With reference to Local Country Prescribing Information and the ‘Participant Information 
and Consent Form’, Investigators must ensure that participants are fully informed 
regarding the following information on the hypersensitivity reaction prior to commencing 
ABC therapy:

Participants must be made aware of the possibility of a hypersensitivity reaction 
to abacavir that may result in a life-threatening reaction or death and that the risk 
of a hypersensitivity reaction is increased in individuals who are HLA-B*5701
positive.

Participants must also be informed that HLA-B*5701 negative individuals can 
also experience abacavir hypersensitivity reaction.  Therefore, ANY participant 
who develops signs or symptoms consistent with a possible hypersensitivity 
reaction to abacavir MUST CONTACT their doctor IMMEDIATELY.

Participants who are hypersensitive to abacavir should be reminded that they must 
never take any abacavir containing medicinal products (e.g., ZIAGEN, 
EPZICOM, KIVEXA, TRIZIVIR, or TRIUMEQ) again, regardless of their HLA-
B*5701 status.

In order to avoid restarting abacavir, participants who have experienced a 
hypersensitivity reaction should be asked to return any remaining EPZICOM / 
KIVEXA tablets to the Investigator or site staff.
 
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
Participants, who have stopped abacavir for any reason, and particularly due to 
possible adverse reactions or illness, must be advised to contact their doctor 
before restarting EPZICOM / KIVEXA as more severe symptoms may recur 
within hours and may include life-threatening hypotension and death.

Each participant should be reminded to read the Package Leaflet included in the 
EPZICOM / KIVEXA pack.  They should be reminded of the importance of 
removing the Alert Card included in the pack, and keeping it with them at all 
times. 
7.4.5.12.2. Reporting of Hypersensitivity Reactions
If a clinically suspected case of HSR to ABC meets one of the International Conference 
on Harmonization (ICH E2A, 1994 definitions of seriousness listed in Section 11.6.2
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.
7.4.5.13.
Rash Without ABC HSR Symptoms
Including serious skin reactions such as Stevens-Johnson Syndrome, Toxic 
Epidermal Necrolysis, Erythema Multiforme or rash with significant liver 
dysfunction. 
Participants should be instructed to contact the Investigator as soon as possible if they 
develop a rash on study.
Participants who develop rash of any grade should be evaluated for the possibility of an 
ABC HSR or a serious skin reaction such as Stevens - Johnson syndrome (SJS), Toxic 
Epidermal Necrolysis (TEN) or Erythema Multiforme.  SJS, TEN, and Erythema 
Multiforme have been reported very rarely in patients taking ABC-containing products.  
These patients generally do not have the cluster of additional symptoms (e.g., 
gastrointestinal and respiratory) that characterize the ABC HSR, but they do have 
features typical of these serious skin reactions.
If a serious skin reaction develops, ABC (and / or all other concurrent medication(s) 
suspected in the Investigators causality assessment) should be discontinued, and the 
participant should not be re-challenged with any ABC-containing medicinal product (i.e., 
ZIAGEN, TRIZIVIR, EPZICOM, or KIVEXA).
As many products other than abacavir also cause rash and/or serious skin reactions, all 
other medicinal products that the participant is receiving should also be reviewed and 
discontinued as appropriate.
The following guidance is provided for clinical management of participants who 
experience rash alone in the absence of accompanying diagnosis of ABC HSR, systemic 
or allergic symptoms or signs of mucosal or target lesions.
CAB is an analogue of DTG and mild to moderate rash is an expected adverse reaction 
for DTG-containing ART.  Episodes generally occur within the first ten weeks of 
 
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treatment, rarely require interruptions or discontinuations of therapy and tend to resolve 
within two to three weeks.  No instances of serious skin reaction, including 
Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and erythema 
multiforme, have been reported for DTG in clinical trials.  For further characterization of 
HSR and rash observed with DTG-containing ART, please see the current version of the 
IB [GlaxoSmithKline Document Number RH2009/00003/06].
Rash is an adverse drug reaction (ADR) for RPV.  In clinical trials, most rashes emerged 
during the first 4 weeks of treatment, were transient, and usually mild (Grade 1) to 
moderate (Grade 2).  There were no Grade 4 rashes and none were serious.  Treatment-
related Grade 3 rash was reported in 0.1% of participants in the RPV group.  Treatment-
related rash led to permanent discontinuation in 0.1% of participants in the RPV group.  
No cases of erythema multiforme, SJS or TEN have been reported during clinical 
development of RPV.
Participants with an isolated Grade 1 rash may continue study drug at the Investigator’s 
discretion.  The participant should be advised to contact the Investigator immediately if 
there is any worsening of the rash, if any systemic signs or symptoms appear, or if 
mucosal involvement develops.
Participants may continue study drug for an isolated Grade 2 rash.  However, study drug 
(and all other concurrent medication(s) suspected in the Investigators causality 
assessment) should be permanently discontinued for any Grade ≥2 rash that is associated 
with an increase in ALT.  The participant should be advised to contact the physician 
immediately if rash fails to resolve (after more than two weeks), if there is any worsening 
of the rash, if any systemic signs or allergic symptoms develop, or if mucosal 
involvement develops.
Participants should permanently discontinue study drug [and all other concurrent 
medication(s) suspected in the Investigators causality assessment] for an isolated Grade 3 
or 4 rash, except where the etiology of the rash has been definitively diagnosed as NOT 
attributable to study drug (see below), and the participant should be withdrawn from the 
study.  Participants should be treated as clinically appropriate and followed until 
resolution of the AE.  Every effort should be made to collect as much information as 
possible about the evolution of the event and any relationship with potentially related 
medical events (e.g., viral infection) or start of concomitant medication.
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 11.2, 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. 
 
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Participants in the Follow-Up Phase who are receiving ABC as part of their regimen 
should be evaluated for the possibility of a clinically suspected ABC HSR and managed 
appropriately as outlined in the local prescribing information for ABC.
Any rash that is possibly related to study drug, and is present between Day 1 and 
The Week 4b visit for participants in the Oral Lead-in Phase, 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 LTFU Phase for 52 
weeks of follow-up.
7.4.6.
Suicidal Risk Monitoring
Participants with HIV infection may occasionally present with symptoms of depression 
and/or suicidal ideation or behavior.  In addition, there have been some reports of 
depression, suicidal ideation and behavior (particularly in participants with a pre-existing 
history of depression or psychiatric illness) in some patients being treated with INIs.  
Additionally, depression and anxiety has been reported in some participants being treated 
with RPV.  Therefore, it is appropriate to monitor and closely observe participants 
prospectively before and during treatment for suicidal ideation and/or behavior, or any 
other unusual changes in behavior.  It is recommended that the Investigator consider 
mental health consultation or referral for participants who experience signs of suicidal 
ideation or behavior.
Participants presenting with new onset/treatment emergent depression should be advised 
to contact the investigator immediately if symptoms of severe acute depression (including 
suicidal ideation/attempts) develop, because medical intervention and discontinuation of 
the study medication may be required.
Assessment of treatment-emergent suicidality will be monitored during this study using 
the electronic version of the Columbia Suicide-Severity Rating Scale (eC-SSRS).  The 
definitions of behavioural suicidal events used in this scale are based on those used in the 
Columbia Suicide History Form [Posner, 2007]. Questions are asked on suicidal 
behavior, suicidal ideation, and intensity of ideation.  Screening visit questions will be in 
relation to lifetime experiences and current experiences (within the past 2 months) and all 
subsequent questioning in relation to the last assessment.  The eC-SSRS is to be 
administered as a patient completed questionnaire specified in the Time and Events Table 
(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 
 
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within one week of the investigator diagnosing a possible suicidality-related adverse 
event.  All sites should have a plan in place for managing possible risks for suicide 
related events.  
7.4.7.
Pregnancy
7.4.7.1.
Pregnancy testing
Women of childbearing potential must have a negative pregnancy test at Screening, and 
at Baseline (Day 1). Pregnancy testing will also be conducted as per the Time and Events 
Table (Section 7.1) and at anytime during the trial when pregnancy is suspected.
Additionally, the Medical Monitor may request that a urine pregnancy test be performed 
in the event of a treatment interruption greater than 7 days.
7.4.7.2.
Time Period for Collecting Pregnancy Information
Pregnancy information will be collected from Day 1 until the last follow-up assessment.  
This includes the entirety of the LTFU Phase.
Female participants that have received at least one dose of CAB LA or RPV LA and do 
not enter the LTFU Phase should use an acceptable method of contraception (see the 
SPM for a listing of examples of acceptable hormonal contraception) until at least 52 
weeks after the last dose of study drug.  If a participant becomes pregnant within 52 
weeks of the last dose of study drug the participant should notify the study site.
7.4.7.3.
Action to be Taken if Pregnancy Occurs
Any individual who becomes pregnant (intrauterine) while participating in this study 
must be withdrawn from the study and must immediately discontinue study drug.  
Participants who have received at least one dose of CAB LA and/or RPV LA should 
discontinue further dosing and continue oral HAART in the LTFU Phase (see Section
4.2.4 above), after discussion with the Medical Monitor.  
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form.  To ensure participant safety, if a pregnancy is reported then the 
investigator should inform GSK within 24 hours of learning of the pregnancy and should 
follow the procedures outlined in Appendix 7.
Participants who have received at least one IM injection of CAB LA and RPV LA and 
become pregnant during the study will have additional PK samples collections to monitor 
CAB LA and RPV LA exposure throughout the pregnancy and at the time of delivery.  
Additionally, there will be an optional umbilical cord blood collection at time of delivery 
and/or breast milk after delivery, requiring additional parental informed consent.  Cord 
blood and breast milk samples would be used to better understand the level of PK 
exposure to the neonate, if any.
The pregnancy must be followed up to determine outcome (including premature 
termination) and status of mother and child(ren).  Pregnancy complications and elective 
 
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terminations for medical reasons must be reported as an AE or SAE.  Spontaneous 
abortions must be reported as SAEs.
Any SAE occurring in association with a pregnancy brought to the investigator’s 
attention after the participant has completed the study and considered by the investigator 
as possibly related to the study treatment, must be promptly reported to ViiV/GSK.
GSK’s central safety department will also forward this information to the Antiretroviral 
Pregnancy Registry.  The international registry is jointly sponsored by manufacturers or 
licensees of ARV products.  Additional information and a list of participating 
manufacturers/licensees are available from http://apregistry.com/index.htm.
7.4.8.
Physical Exams
Physical exams should be conducted as part of normal routine clinical care.  
Abnormalities noted during any exam must be recorded in the eCRF (e.g., in the current 
medical conditions or AE logs).

A complete physical examination will include, at a minimum, assessment of 
the Cardiovascular, Respiratory, Gastrointestinal, and Neurological systems.  
Height and weight will also be measured and recorded as per the Time and 
Events Table in Section 7.1 above. 

A brief physical examination will include, at a minimum assessments of the 
skin, lungs, cardiovascular system, and abdomen (liver and spleen).

The site of IM injection administration should be assessed at every visit for 
signs of any possible reaction.  See Section 7.4.5.10 for additional information.

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
7.4.9.
Vital Signs
Vital signs will be measured in semi-supine position after 5 minutes rest and will include 
temperature, systolic and diastolic blood pressure and pulse rate. These will be recorded 
as per the Time and Events Table in Section 7.1.
7.4.10.
Electrocardiogram (ECG)
A 12-lead ECG will be performed in a semi-supine position.  On Day 1, (Baseline), 
ECGs should be performed in triplicate prior to first dose.  At Day 1 and Week 48 of the 
Maintenance Phase, a 2 hour post dose ECG will be performed for participants receiving 
CAB LA + RPV LA with an allowable window of 30 minutes. An ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals is 
preferred, and these calculated numbers can be used for reporting purposes.  Otherwise, 
an appropriately qualified ECG reader must interpret the results.  The same interpreter 
should assess all ECGs for each participant.  Regardless, each ECG should be reviewed 
by a qualified ECG reader.  The qualified ECG reader will make the non-calculated ECG 
interpretations.  Refer to the Time and Events Table for collection timepoints (Section 
 
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7.1).  Refer to Section 5.5.2 for [QTc] withdrawal criteria and additional [QTc] readings 
that may be necessary
7.5.
Pharmacokinetics
Plasma samples for determination of CAB and RPV concentrations will be collected 
throughout the Maintenance and Extension Phases of the study. Additional samples will 
be collected for storage during the LTFU Phase (blood and plasma). Samples (blood and 
plasma) for determination of RPV concentrations will be protected from light at all times, 
from sampling collection through analysis.
7.5.1.
PK Sample Collection
Blood samples for evaluation of CAB (2mL each) and RPV (2 mL each) plasma PK 
concentrations will be collected from all participants as described in Table 10. 
For participants transitioning from oral SOC, at Week 4b PK samples should be collected 
within the window of 20-28 hours after the last oral dose of CAB + RPV was taken the 
day prior to the clinic visit. Participants will take their final dose of oral CAB + RPV in 
the clinic at Week 4b after the pre-dose PK sample. 
These 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.  
The information from the diary card and the actual date and time of the PK samples will 
be recorded in the eCRF.  Additionally, dosing information on the clinic day, including 
dosing and the actual date and time of the PK samples, must be recorded on the eCRF.  
Plasma concentrations will be summarized and used to evaluate potential exposure-
response relationships.
The timing of PK samples may be altered and/or PK samples may be obtained at 
additional time points to ensure thorough PK monitoring.  
 
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Table 10
CAB and RPV Plasma Pharmacokinetic Sample Schedule
Group
Analytes
Sample Times Relative to Dose
Participants receiving 
CAB LA + RPV LA 
Q4W injections
CAB and RPV
Pre-Dose: Weeks 4b, 8, 16, 24, 32, 40, 48, and 96 
A PK sample will be taken at Withdrawal.
PK samples for storage only:
Pre-dose: Week 12, 20, 28, 36, 44, 52, 56, 60, 64, 
68, 72, 76, 80, 84, 88, 92, 100
Long-term follow-up Period (off-drug; storage 
sample)
Months 3, 6, 9, and 12
Participants receiving 
CAB LA + RPV LA 
Q8W injections
CAB and RPV
Pre-Dose: Day 1*, Weeks 4b**, 8, 16, 24, 32, 40, 
48, and 96
1 Week Post Dose:  Week 9 and Week 41
A PK sample will be taken at Withdrawal
PK samples for storage only:
Pre-dose: Weeks 56, 64, 72, 80, 88, 100
LTFU Period (off-drug; storage sample)
Months 3, 6, 9, and 12
* Day 1 sample required only for those transitioning 
from ATLAS on Q4W injections.
**Week 4b sample required only for participants 
transitioning from oral SOC and requiring oral CAB 
+ RPV Lead-in
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. Pre-dose sample collection at Week 4b (for participants transitioning from the 
current ART arm) should be collected 20 to 28 hours after the last oral dose of CAB and 
RPV was taken.
If a participant withdraws from the study a PK sample should be collected as early as 
practically possible (i.e., at withdrawal visit or on the day the withdrawal decision was 
made). 
Additional details concerning handling of PK samples, labeling and shipping directions 
will be supplied in the central laboratory manual.
Samples for determination of RPV will be protected from light until analysed. 
 
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7.5.2.
Rationale of PK Sampling Strategy
Blood sampling for CAB and RPV concentrations will be performed during the 
Maintenance Phase of the study to evaluate PK in HIV infected participants.  The 
proposed PK visits and sampling scheme at each visit presented in Section 7.1 is based on 
consideration of available PK data to support interim and final PK and 
PK/Pharmacodynamic (PD) analysis planned in this study.
7.5.3.
Sample Analysis
7.5.3.1.
CAB Sample Analysis
Plasma CAB analysis will be performed under the control of PTS-DMPK, 
GlaxoSmithKline, the details of which will be included in the Study Reference Manual 
(SRM). Concentrations of CAB will be determined in plasma samples using the 
currently approved bioanalytical methodology. Raw data will be archived at the 
bioanalytical site (detailed in the SRM).
Once the plasma has been analyzed for CAB any remaining plasma may be analyzed for 
other compound-related metabolites and the results reported under a separate GSK PTS-
DMPK, GSK protocol.  No human DNA analysis will be performed on these samples.
7.5.3.2.
RPV Sample Analysis
Plasma RPV analysis will be performed under the control of Janssen R&D. 
Concentrations of RPV will be determined in plasma samples using the currently 
approved bioanalytical methodology.  Raw data will be archived at the bioanalytical site.
Once the plasma has been analyzed for RPV any remaining plasma may be used by the 
sponsor for further exploratory work on pharmacokinetics, metabolites, plasma protein 
binding, protein analysis, and biochemistry.  No human DNA analysis will be performed 
on these samples.
7.6.
Genetics
Information regarding genetic research is included in Appendix 5:  Genetic Research. 
7.7.
Viral Genotyping and Phenotyping
Whole venous blood samples will be obtained from each participant to provide PBMCs 
and plasma for storage samples according to the Time and Events Table (see Section 7.1) 
for potential viral genotypic and phenotypic analyses.
Details concerning the handling, labeling and shipping of these samples will be supplied 
separately. Genotypic and phenotypic analyses may be carried out by Monogram 
Biosciences using, but not limited to, their Standard PhenoSense and GenoSure testing 
methods for protease (PRO), reverse transcriptase (RT), and integrase assays.
 
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7.7.1.
HIV-1 Polymerase Viral Genotyping and Phenotyping
Participants meeting confirmed virologic failure will have plasma samples tested for 
HIV-1 PRO and RT genotype and phenotype and HIV-1 integrase genotype and 
phenotype from samples collected at the time of meeting suspected virologic failure; 
these results will be reported to the investigator as soon as available to provide guidance 
for election of an alternative regimen.
7.7.2.
HIV-1 Exploratory Analysis
Additional analyses for HIV-1 resistance may, for example, be carried out on peripheral 
blood mononuclear cell (PBMC) samples collected at Baseline and/or on stored blood 
samples from other relevant time points.  These analyses may include but are not limited 
to additional viral genotyping and/or phenotyping, as well as other virologic evaluations 
such as linkage and minority species analyses, low level HIV-1 RNA quantitation and 
measurement of viral replicative capacity. HIV-1 PRO and RT genotype and phenotype 
and HIV-1 integrase genotype and phenotype will also be determined on the last on-
treatment isolates from participants who have HIV-1 RNA 200 c/mL regardless of 
confirmatory HIV-1 RNA.
7.8.
Value Evidence and Outcomes
Health outcomes assessments will be conducted according to the Time and Events Table 
(Section 7.1).  Assessments are recommended to be administered with a paper instrument 
at the beginning of the visit prior to collection of blood for analysis and other scheduled 
assessments.
The “Preference” questionnaire will assess whether patients prefer the CAB LA + RPV 
LA injectable treatment or the daily oral ARV regimen, and assess preference for the 
CAB LA + RPV LA Q8W regimen or CAB LA + RPV LA Q4W regimen. The 
“Preference” questionnaire will include 3 questions evaluating preference of HIV 
treatment and the attributes supporting this preference. 
The HIV Treatment Satisfaction Questionnaire (HIVTSQ) [Woodcock, 2001 and 
Woodcock, 2006] was developed to evaluate treatments for HIV and patient satisfaction.
The original HIVTSQ included 10 items and underwent two stages of psychometric 
validation (Woodcock, 2001, Woodcock, 2006). Recently, the HIVTSQ was adapted to 
include injectable treatment for HIV following a qualitative study with HIV patients in 
five European countries.  The adaptation of the HIVTSQ included two additional items 
related to the mode of administration (i.e., long acting intramuscular injection).  These 
are:
 
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Psychometric analyses from three datasets (one from the UK, one from the USA and one 
from the LATTE-2 trial) reveal that the addition of two items in the original version of 
the HIVTSQ is suitable and does not reduce the overall validity of the questionnaire.  The 
current study will be using the HIVTSQs (status version) and the revised HIVTSQc 
(change version) of this recently developed HIVTSQ 12-item questionnaire. The 
HIVTSQ 12-item questionnaire retains the option of calculating the total score as if it 
only had the original 10 items (as the original 10 items are included in the HIV-TSQ12). 
In addition, it allows for calculation of an 11-item scale score including the 
“
” item (item-11). The “
” item (item-12) will be included in 
the questionnaire as a stand-alone item to evaluate potentially painful injectables. These 
measures will assess change in treatment satisfaction over time (in the same participants) 
and compare current satisfaction with previous treatment satisfaction, from an earlier 
time point.
The Perception of Injection (PIN) questionnaire explores the bother of pain at the 
injection site and ISR, anxiety before and after injection, willingness to receive an HIV 
injectable treatment the following visit and satisfaction with the mode of treatment 
administration of individuals receiving injection and perceptions of individuals associated 
with receiving injections. The PIN questionnaire was derived from the Vaccines' 
Perception of Injection (VAPI) questionnaire (Chevat, 2009), and adapted for HIV-
infected patients who will receive the CAB LA and RPV LA regimen. This measure 
contains 21 items that measure pain at injection site, local site reactions, impact on 
functioning and willingness to pursue injectable treatment outside of a clinical trial.  
Scores range from 1 to 5, and questions are phrased in such a way as to ensure that 1 
always equated with the most favourable perception of vaccination, and 5 the most 
unfavourable.
The ACCEPT questionnaire is a generic medication acceptance measure assessing how 
patients weigh advantages and disadvantages of long-term medications (Marant, 2012). 
ACCEPT may be a predictor of patients' future adherence to and/or persistence with their 
treatment. While the ACCEPT questionnaire consists of 25 items that capture six 
dimensions, we will use three questions that focus on general acceptance of study 
medication.
The HIV/AIDS Targeted Quality of Life (HAT-QoL) instrument [Holmes, 1998] 
originally contained 42 items, grouped into nine dimensions, assessing overall function 
and well-being. For the purposes of this study, ViiV Healthcare is using a shorter version 
adapted from the original version. This shorter version contains 14 items grouped into the 
three following dimensions: “life satisfaction”, “disclosure worries” and “HIV 
medication”. All items use a ‘‘past 4 weeks’’ timeframe and a Likert response scale from 
1=‘‘all of the time’’ to 5=‘‘none of the time’’
The “Reason for Switch” question will contain a single item exploring the reasons why 
patients choose to switch study medication. The single item will include six possible 
response options.
 
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Qualitative interviews may be conducted regarding their experience with study treatment. 
These would be conducted under a separate IRB approved consent. Participation in the 
interviews would be voluntary.
7.8.1.
Value Evidence and Outcomes Endpoints (Secondary)

The “Preference” questionnaire will assess preference for CAB LA + RPV LA 
every 8 weeks or CAB LA + RPV LA every 4 weeks compared to oral ARV 
regimen, and preference for CAB LA + RPV LA every 4 weeks compared to 
CAB LA + RPV LA every 8 weeks at Week 48 (or Withdrawal).

Change from Week 8 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) at Weeks 24, and 48 
(or Withdrawal). 

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 (Day 1) in total “treatment satisfaction” score, and 
individual item scores of the HIVTSQs at Weeks 24, 48 (or Withdrawal).

Change in treatment satisfaction over time (using the HIVTSQc) at Week 48 (or 
Withdrawal).

Change from Baseline (Day1) in treatment acceptance (at Weeks 24 and 48 (or 
Withdrawal from the study) using the “General acceptance” dimension of the 
Chronic Treatment Acceptance (ACCEPT) questionnaire.

Change from Baseline (Day1) in HR QoL (using the HAT-QoL short form) at 
Weeks 24, and 48, (or Withdrawal).
7.8.2.
Value Evidence and Outcomes Endpoints (Exploratory)

The “Reason for Switch” question will be administered at Day 1 (Baseline) for 
patients randomized from oral SOC, to assess the reasons for willingness to 
switch ART.

The “Reason for Switch” question will be administered at Day 1(Baseline) for 
patients randomized from CAB LA + RPV LA every 4 weeks in ATLAS, to 
assess the reasons for willingness to continue long-acting ART.
 
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7.8.3.
Guidance for administering the different versions of HIVTSQc, 
Preference and Reason for Switch Questionnaires in ATLAS-2M
For the questionnaires not included below, HIVTSQs, HAT-QoL, ACCEPT and PIN, 
there only exists one version of each PRO that will be administered to all patients.
Questionnaire
Version
Week visit 
in ATLAS-
2M
Treatment 
Arm in 
ATLAS-2M
Treatment 
before entering 
ATLAS-2M
Patients in 
Extension 
phase in 
ATLAS
HIVTSQc
Q4W 
ATLAS to 
Q4W 
ATLAS-
2M
Week 48 / 
Withdrawal
Currently on 
Q4W
Randomized at 
Day 1 in Q4W 
arm in ATLAS
Even if patients 
remained in 
extension phase 
in ATLAS 
consider only 
the initial arm 
they were 
randomized in 
Day 1 in 
ATLAS 
Q4W 
ATLAS to 
Q8W 
ATLAS-
2M
Week 48 / 
Withdrawal
Currently on 
Q8W
Randomized at 
Day 1 in Q4W 
arm in ATLAS
SOC to 
Q4W or 
Q8W 
ATLAS-
2M
Week 48 / 
Withdrawal
Currently on 
Q4W or 
Q8W
Any SOC 
treatment: 
Randomized at 
Day 1 in SOC 
in ATLAS or 
coming outside 
of ATLAS
Preference
Injection to 
Injection 
treatment
Week 48 / 
Withdrawal
Currently on 
Q8W 
Randomized at 
Day1 in Q4W 
arm in ATLAS
Even if patients 
remained in 
extension phase 
in ATLAS 
consider only 
the initial arm 
they were 
randomized in 
Day 1 in 
ATLAS 
Oral to 
Injection 
treatment
Week 48 / 
Withdrawal
Currently on 
Q4W or
Q8W
Any SOC 
treatment: 
Randomized at 
Day 1 in SOC 
in ATLAS or 
coming outside 
of ATLAS
Continuing 
Q4W from 
ATLAS
 
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Questionnaire
Version
Week visit 
in ATLAS-
2M
Treatment 
Arm in 
ATLAS-2M
Treatment 
before entering 
ATLAS-2M
Patients in 
Extension 
phase in 
ATLAS
Reason for 
Switch
Day 1
Currently on 
Q4W or 
Q8W
Any SOC 
treatment: 
Randomized at 
Day 1 in SOC 
in ATLAS or 
coming outside 
of ATLAS
Administer 
again even if 
patients were 
administered 
the “reason for 
switch” at week 
52 in ATLAS.
Reason for 
Continuation 
Day 1
Currently on 
Q4W or 
Q8W
Randomized at 
Day 1 in Q4W 
arm in ATLAS
8.
DATA MANAGEMENT

For this study participant data will be entered into GSK defined eCRFs, 
transmitted electronically to GSK or designee and combined with data provided 
from other sources in a validated data system.  

Management of clinical data will be performed in accordance with applicable 
GSK standards and data cleaning procedures to ensure the integrity of the data, 
e.g., removing errors and inconsistencies in the data.

Adverse events and concomitant medications terms will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA) and an internal validated 
medication dictionary, GSKDrug.  

eCRFs (including queries and audit trails) will be retained by GSK, and copies 
will be sent to the investigator to maintain as the investigator copy.  Participant 
initials will not be collected or transmitted to GSK according to GSK policy.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
The study is designed to demonstrate that the antiviral effect of Q8W dosing with CAB 
LA + RPV LA is non-inferior to Q4W dosing CAB LA + RPV LA in subjects stably 
suppressed on an oral SOC regimen or Q4W CAB LA + RPV LA regimen prior to 
randomization.  Non-inferiority in the proportion of participants with HIV-RNA 50 
c/mL at Week 48 (defined by the US FDA snapshot algorithm) can be concluded if the 
upper bound of a two-sided 95% confidence interval for the difference between the two 
treatment arms (Q8W – Q4W) is less than 4%.
 
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If fQ8W is the snapshot failure rate for Q8W CAB LA + RPV LA, and fQ4W is the snapshot 
failure rate for Q4W CAB LA + RPV LA then the hypotheses can be written as follows:
H0: fQ8W – fQ4W 4%  vsH1: fQ8W – fQ4W < 4%
9.1.
Sample Size Considerations
.  This study will randomize approximately 510 participants per arm. Assuming the true 
proportion with HIV-1 RNA 50 c/mL is 3% for the Q8W arm and 2% for the Q4W arm, 
a non-inferiority margin of 4%, and a 2.5% one-sided significance level, this sample size 
would provide at least 85% power to show non-inferiority at Week 48 (using unpooled Z 
test statistic).  With this sample size, 90% power would be achieved assuming a 1% 
treatment difference and true proportions with HIV-1 RNA 50 c/mL of 2.63% for the 
Q8W arm and 1.63% for the Q4W arm.
With 510 subjects per arm and assuming an observed proportion HIV-RNA 50 c/mL is 
2% for Q4W, the largest observed treatment difference to achieve non-inferiority with 
respect to a 4% margin is 1.92 percentage points.  This equates approximately to 
observing an excess of 10 subjects on the Q8W arm (10 subjects on Q4W vs. 20 subjects 
on Q8W).
This sample size of 510 participants per arm will also provide at least 90% power (using 
unpooled Z test statistic) 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 Figure 15).  For example, assuming true response rate for the Q8W 
arm and Q4W arm are both 92%, the power is 99% to show non-inferiority for this key 
secondary endpoint.
9.1.1.
Rationale for non-inferiority margin
A non-inferiority margin of 4% has been chosen for this study because a snapshot 
proportion with HIV-1 RNA 50 c/mL at Week 48 in this range is considered clinically 
tolerable given the Q8W regimen will offer important advantages over the Q4W regimen 
such as reduced injection frequency, and may offer better adherence and treatment 
satisfaction.  This margin is also in concordance with the current FDA Guidance for 
Industry (FDA, 2015), which is the most current regulatory guidance from either the 
European Medicines Agency (EMA) or FDA and includes specific recommendations 
regarding switch studies.
9.1.2.
Assumption for Snapshot Proportion with HIV-RNA 50 c/mL at 
Week 48 (Primary Endpoint)
For the sample size calculation, assumptions regarding the true proportion with HIV 
RNA 50 c/mL for each arm were informed by data from the LATTE-2 Phase 2b study 
(Table 11).  These data suggest a rate of 2% for Q4W and a possibly higher rate in the 
neighbourhood of 3% for Q8W.
 
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Two important changes to the current study in relation to the LATTE-2 study were also 
considered in setting the sample size. Firstly, the loading dose schedule for Q8W has 
been modified in an attempt to optimize the pharmacokinetics of CAB LA + RPV LA. 
Secondly, a re-testing strategy (see Section 5.5.5.1) has been added to reduce the number 
of subjects counted as having HIV RNA 50 c/mL in the primary analysis at key 
timepoints because of transient blips (consistent with the FDA’s guidance for the 
Snapshot endpoint).  Through these changes, it is possible that the proportions with HIV 
RNA 50 copies/mL will be lower than that observed in the LATTE-2 study.
Table 11
Snapshot Analysis Outcomes for LATTE-2 Phase IIb Study of CAB 
LA + RPV LA (Intent-to-Treat Maintenance Exposed Population)
Week 48
Study
Maintenance Treatment Arm
HIV-RNA <50
HIV-RNA 50
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%)
Pooled LA (N=230)
92%
6/230 (4%)
Oral CAB + 2NRTIs (N=56)
89% 
1/56 (2%)
Week 96
LATTE-2 (ITT-ME) b
CAB LA + RPV LA Q8W (N=115)
94%
5/115 (4%)
CAB LA + RPV LA Q4W (N=115)
87%
0/115 (0%)
Pooled LA (N=230)
90%
5/230 (2%)
Oral CAB + 2NRTIs (N=56)
84% 
5/56 (2%)
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.
9.1.3.
Assumption for Response Rate at Week 48 (Secondary Endpoint)
Given the response rates shown in Table 11, a reasonable assumption for the true 
response rate (HIV-1 RNA <50 c/mL) for both arms is 92%.
9.1.4.
Sample Size Sensitivity
Figure 15a (left panel) shows the sensitivity of the power curve for the primary 
comparison to different assumed ‘true’ proportions with HIV-RNA 50c/mLwith 510 
randomized participants per arm based on calculations using an unpooled Z test statistic 
and asymptotic approximation.  For example, if the true rate for Q8W is 1.5 percentage 
points higher than Q4W (green line), then the study would still have over 80% power to 
meet its primary objective if the Q4W rate is less than 1.3%.  
Figure 15b (right panel) shows the impact on power to changes in the sample size 
assuming a 2% true-rate for Q4W.  Power remains at least 80% for sample sizes as low as 
425 per arm if the true Q8W rate is at most 1-percentage point inferior to Q4W.  
 
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Figure 15
Sensitivity of Estimated Power for Snapshot Proportion with HIV-
RNA 50 c/mL
Figure 16a (left panel) shows the sensitivity of the estimated power for the secondary 
endpoint comparison of response rates (HIV-1 RNA <50 c/mL at Week 48) to different 
assumed ‘true’ response rates based on calculations using an unpooled Z test statistic and 
asymptotic approximation.  For example, if the true Q8W rate is two percentage points 
inferior to Q4W (blue line), then power is at least 90% for Q4W rates greater than 82%.  
Figure 16b (right panel) shows the impact on power to changes in the sample size 
assuming an 92% response rate for Q4W.  For example, if the true Q8W rate is 3-
percentage points inferior to Q4W (green line), then power remains at least 90% for 
sample sizes as low as 368 per arm.
 
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Figure 16
Sensitivity of Estimated Power for Snapshot Proportion with HIV-
RNA <50 c/mL
9.1.5.
Sample Size Re-estimation or Adjustment
No sample-size re-estimation based on response data is planned for this study.
9.2.
Data Analysis Considerations
9.2.1.
Analysis Populations
9.2.1.1.
Intent-to-Treat Exposed (ITT-E)
The ITT-E population will consist of all randomly assigned participants who receive at 
least one dose of study drug. Participants will be assessed according to their randomized 
treatment, regardless of the treatment they received.  The population used in the primary 
efficacy analysis will be the ITT-E population.
9.2.1.2.
Per-Protocol Population (PP)
The Per-Protocol (PP) Population will consist of all participants in the ITT-E Population 
with the exception of major protocol violators. The PP will be used for sensitivity 
analysis of the primary endpoint.
 
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9.2.1.3.
PK Population
The PK Population will include all participants who receive CAB and / or RPVand 
undergo PK sampling during the study, and provide evaluable CAB and /or
RPV plasma concentration data.  Participants in this population will be included in the 
PK analysis.
9.2.1.4.
Safety Population
The Safety Population will consist of all randomly assigned participants who receive at 
least one dose of study drug. Participants will be assessed according to actual treatment 
received.  Unless otherwise stated, the Safety Population will be used for safety analyses.
9.2.2.
Treatment Comparisons
9.2.2.1.
Primary Comparison of Interest
The primary analysis will be based on the ITT-E population.  The primary comparison 
will be made at a one-sided 2.5% level of significance.  Treatment with Q8W will be 
declared non-inferior to Q4W if the upper end of a two-sided 95% confidence interval for 
the difference between the two groups (Q8W – Q4W) in the proportion of participants 
with HIV-RNA 50 c/mL at Week 48 (defined by the US FDA snapshot algorithm) lies 
below 4%.
9.2.2.2.
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.  
If the primary comparison on interest using the ITT-E population demonstrates non-
inferiority of Q8W compared to Q4W then the following key secondary comparisons 
will be tested: Treatment with Q8W will be declared non-inferior to Q4W with 
respect to the proportion of participants with HIV-1 RNA < 50 copies/mL at Week 48 
(defined by the US FDA snapshot algorithm) if the lower end of a two-sided 95% 
confidence interval for the difference between in rates (Q8W – Q4W) lies above
-10% using the ITT-E population

Superiority of Q8W compared to Q4Wwith respect to change from baseline 
HIVTSQs total score at Week 48 using the ITT-E population and a two-sided 5% 
level of significance
9.2.3.
Planned Analyses
At least three analyses will be conducted to evaluate the objectives of the protocol after 
all subjects have completed their visits at Week 24, Week 48 and Week 96, respectively. 
Further data cuts and analyses may be conducted as necessary in order to support 
regulatory submissions and publications (first publication at Week 48).  The Week 48 
analysis will be primary and no results will be shared publicly until Week 48 analysis is 
complete. Full details for the primary Week 48 analysis (and preliminary Week 24 
 
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analysis) will be prespecified in the RAP prior to the database freeze for the Week 24 
analysis and sponsor review of any summary of data grouped by actual treatment arm.
9.2.3.1.
Week 24 data analyses
An analysis of data through Week 24 will be conducted when all subjects have completed 
their Week 24 visit, with the intent of expediting submission of results to health 
authorities.
The analyses described in Section 9.3.2.2, Section 9.3.3 and Section 9.3.6  will be 
performed. Health outcomes analyses will not be performed.
There is no intention to stop the study early if positive efficacy findings are seen at Week 
24 and a formal hypothesis test of non-inferiority at Week 24 will not be evaluated. The 
analysis at Week 48 is primary and will overrule the findings based on the Week 24 data.  
Therefore, no multiplicity adjustment to the primary Week 48 treatment comparisons is
needed because of the analysis of Week 24 data.
Neither investigators nor subjects will be informed of the results of the Week 24 data 
analysis.  Sponsor staff will only review aggregate data by actual treatment arm after the 
Week 24 IDMC evaluation is complete as required in the preparation of submission 
documents.
9.2.3.2.
IDMC analyses
Independent review will be provided by an IDMC 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.  An ad-hoc 
review of data by the IDMC will be triggered whenever the number of confirmed 
virologic failures in the CAB LA + RPV LA Q8W 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 Q8W arm when 
approximately 50% of subjects have completed their visit at Week 24; the sponsor will 
remain blinded to this analysis.  Any additional Week 24 analyses will also be shared 
with the IDMC. 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 due to positive 
efficacy findings for the Q8W regimen, these planned analyses will not inflate the type I 
error rate for the primary treatment comparison at Week 48.
9.3.
Key Elements of Analysis Plan
9.3.1.
Primary Analyses
For the primary efficacy analysis, virologic outcome for each participant in the Intent-to-
Treat Exposed population 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. 
 
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As defined by the Snapshot algorithm, HIV-RNA 50 copies/mL is determined by the 
last available HIV-1 RNA measurement while the participant is on treatment within the 
analysis visit window of interest.  In addition, participants without evaluable HIV-RNA 
data for the visit of interest and who discontinue from the maintenance phase for reasons 
not related to adverse event with HIV-1 RNA result at the time of discontinuation 
50 copies/mL or who change study treatment not permitted per protocol before the 
analysis window are classified as having HIV-RNA 50 copies/mL.
For the primary efficacy analysis, the adjusted difference between the randomized arms 
for the proportion of participants with HIV-1 RNA 50 c/mL at Week 48 (according to 
the FDA snapshot algorithm) and its confidence interval will be calculated according to a 
stratified analysis with Cochran-Mantel Haenszel (CMH) weights.  This analysis will 
adjust for the randomization strata (rederived for analysis to correct for stratification 
errors) according to prior exposure to CAB + RPV (0 weeks, 1-24 weeks, >24 weeks).  
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 proportion 
between the two arms as follows:
•
If nk is the number of Q8W treated participants, mk is the number of Q4W arm 
treated participants, and Nk = nk + mk is the total number of participants in the 
kth stratum, then the CMH estimate is given by



k
k
k
cmh
W
d
W
d
ˆ
ˆ
where
k
k
k
k
N
m
n
W 
are CMH weights and 
k
dˆ
are estimates of the differences in proportions between 
the two treatment arms, fQ8W-fQ4W, for the kth stratum.
The corresponding two-sided 95% CI will be calculated as:
using the variance estimator given by [Sato, 1989], which is consistent in both sparse data 
and large strata.  The formula for computing the Sato variance estimate will be provided 
in the RAP.  Non-inferiority will be declared if the upper bound of the two-sided 95% 
confidence interval for the difference (Q8W – Q4W) is less than 4%.
The weighted least squares chi-squared statistic [Fleiss, 1981] will be used to assess 
evidence of treatment difference heterogeneity across strata.  strata, Following Lui and 
 
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Kelly [Lui, 2000], 0.50 will be added to each cell in any strata for which the stratum-
specific rate estimates of either fQ8W or fQ4W are zero or one.  Any heterogeneity found to 
be statistically significant will be explored.  Stratum-specific analyses will also be 
provided.  Investigation of heterogeneity will be confined to the primary endpoint.  Tests 
of homogeneity will be assessed at the one-sided 10% level of significance.  Full details 
will be contained in the RAP.
On-treatment data collected from extra visits within a window will be included in the 
derivation of the Snapshot response/failure but summary tables using observed case (OC) 
datasets will only use the data captured closest to the target visit date.  Detailed 
explanations of the derivation of visit windows will be included in the RAP.  Any 
changes to the original analysis plan in the protocol will be described in the RAP and/or 
clinical study report (CSR).
9.3.2.
Secondary Analyses
9.3.2.1.
Key Secondary Efficacy Analysis
A key secondary analysis will evaluate the proportion of participants with HIV-1 RNA 
<50 c/mL (according to the FDA’s Snapshot algorithm) at Week 48 for the ITT-E 
population.  Participants with last available HIV-1 RNA measurement less than 
50 copies/mL while the participant is on treatment within the analysis visit window of 
interest are classified as responders; participants without evaluable HIV-RNA data for the 
visit of interest or who change treatment not permitted per protocol before the analysis 
window are considered non-responders. Full details on the Snapshot algorithm for 
computation of the proportion with HIV-1 RNA < 50 copies/mL will be contained in the 
RAP.  The adjusted difference between the randomized arms for the proportions (Q8W –
Q4W) and its confidence interval will be calculated according to a stratified analysis with 
Cochran-Mantel Haenszel (CMH) weights, as described for primary endpoint (Section 
9.3.1).
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 between the rates 
(Q8W – Q4W) is greater than -10%, non-inferiority will be demonstrated.
9.3.2.2.
Other Secondary Endpoint Analyses
The primary analysis (Section 9.3.1) and key secondary efficacy analysis (Section
9.3.2.1) will be repeated at Week 96, with the only difference being a change in time 
point from Week 48 to Week 96 for determining the snapshot outcomes.
For the Week 24 planned analyses, the adjusted treatment difference in proportion of 
participants with plasma HIV-1 RNA 50 c/mL (FDA Snapshot algorithm, with 95% 
confidence interval) at Week 24 will be calculated using the methodology described in 
Section 9.3.1, but no formal test of non-inferiority will be performed at this early 
timepoint.
 
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Proportion of participants with plasma HIV-1 RNA 50 c/mL and HIV-1 RNA <50 c/mL
(FDA Snapshot algorithm) at Week 24, Week 48 and Week 96 respectively, will be 
summarized using the Snapshot algorithm for the ITT-E population.  Proportion of 
participants with confirmed virologic failures will also be summarized over time. 
Absolute values and change from Baseline in CD4+ lymphocyte count will be 
summarized over time including Week 48 and Week 96.
The proportion of participants with HIV-1 RNA 50 c/mL  based on the snapshot 
algorithm, will be summarized at Week 24, Week 48 and Week 96 by duration of prior 
CAB + RPV exposure (0 weeks, 1-24 weeks, >24 weeks). 
The proportion of participants with HIV-1 RNA < 50 c/mL based on snapshot algorithm, 
will be summarized at Week 48 and Week 96 by duration of prior CAB + RPV exposure 
(0 weeks, 1-24 weeks, >24 weeks).
An observed case dataset, with no imputation for missing data, 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 will be summarized by visit and treatment group 
including Week 48 and Week 96.  In addition, the number and percentage of participants 
with graded laboratory toxicities (based on DAIDS categories) will be summarized by 
treatment group.
Further details for secondary efficacy, safety, and exploratory endpoint analyses will be 
included in the RAP.
9.3.3.
Pharmacokinetic Analyses
The GSK Division of Clinical Pharmacology Modeling and Simulation (CPMS) will be 
responsible for the PK analysis of CAB.  The Division of Clinical Pharmacology 
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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9.3.4.
Population PK Analysis:
CAB LA and RPV LA 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.
9.3.5.
Pharmacokinetic/Pharmacodynamic Analyses
Relationships between various plasma CAB LA and/or RPV LA 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 HIV-1 stage, 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.
9.3.6.
Viral Genotyping/Phenotyping Analyses
The incidence of treatment emergent genotypic and phenotypic resistance to NRTIs and 
INIs, PIs, and NNRTIs and in particular to current antiretroviral regimen and to CAB or 
RPV will be summarized by treatment arm for subjects meeting confirmed virologic 
failure criteria.  Limited analyses will be conducted for Week 24 planned analyses. 
Details of the analyses to be performed will be specified in the reporting and analysis 
plan (RAP).
9.3.7.
Health Outcomes Analyses
Details of the analyses to be performed for the endpoints described in Section 7.8 will be 
specified in the reporting and analysis plan.  Participant preference for CAB LA + RPV 
LA every 8 weeks or CAB LA + RPV LA every 4 weeks compared to oral ARV regimen, 
and preference for CAB LA + RPV LA every 4 weeks compared to CAB LA + RPV LA 
every 8 weeks will be a key secondary treatment analysis based on the ITT-E population.
As another key secondary treatment comparison, superiority of Q8W compared to Q4W 
 
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with respect to change from baseline in HIVTSQs total score at Week 48 will be tested at 
a two-sided 5% significance level using a linear model based on the ITT-E population.
9.3.8.
Genetic Analyses
See the full protocol for details about the Genetics Analysis Plan.
9.3.9.
Other Analyses
Planned subgroup analyses include: proportion of participants by patient subgroup(s) 
(e.g., by age, gender, BMI, race, HIV-1 subtype, Baseline CD4+, type of oral treatment 
[NNRTI, PI, or INSTI], duration prior CAB LA and RPV LA exposure [0 weeks, 1-24 
weeks, >24 weeks]) with HIV-1 RNA 50 c/mL, and with protocol defined confirmed 
virologic failure, respectively, over time including Week 48 and Week 96. 
In addition, stratum-specific analyses (unadjusted treatment difference and corresponding 
95% confidence interval) of the primary endpoint (proportion of participants with HIV-1 
RNA 50 c/mL) and key secondary endpoint (proportion of participants with HIV-1 
RNA <50 c/mL) at Week 48 (and Week 96) will be performed within each of the 
following patient populations: (Group 1) those currently receiving Standard of Care 
antiretroviral therapy [no prior CAB + RPV exposure] and (Group 2) those receiving 
Q4W CAB LA + RPV LA therapy in the ongoing ATLAS study).  For Group 2, a stratum-
adjusted analysis will also be provided, with adjustment for prior CAB + RPV exposure 
(1 to 24 weeks vs. >24 weeks) using Cochran-Mantel Haenszel (CMH) weights, as 
described in Section 9.3.1.
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 provide in 
the RAP.  
Further details of exploratory analyses will be presented in the RAP.
 
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10.
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Margolis D, Brinson C, Smith G, de Vente J, Hagins D, Eron J,, et. al.  Cabotegravir plus 
rilpivirine, once a day, after induction with cabotegravir plus nucleoside reverse 
transcriptase inhibitors in antiretroviral-naive adults with HIV-1 infection (LATTE): a 
randomised, phase 2b, dose-ranging trial. Lancet Infect Dis. 2015; 15: 1145-55. 
McGowan I, Siegel A, Engstrom J, et al. Persistence of rilpivirine following single dose 
of long-acting injection. 21st International AIDS Conference (AIDS 2016). July 18-22, 
2016. Durban, South Africa. Abstract TUAC0103.
Papay JI, Clines D, Rafi R, et al. Drug-induced liver injury following positive 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.
Rilpivirine Clinical Investigator Brochure [RPV IB], Edition 10, April 2017.
Sato T, Greenland S, Robins JM. On the variance estimator for the Mantel-Haenszel risk 
difference. Biometrics.1989;45:1323-1324.
UNAIDS, 2016, Geneva Switzerland,  AIDS Data
 
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Woodcock A, Bradley C. Validation of the HIV Treatment Satisfaction QUestionnaire 
(HIVTSQ). Quality of Life Research. 2001: 10, 517-531.
Woodcock, A,  Bradley C . Validation of the revised 10-item HIV Treatment Satisfaction 
Questionnaire status version (HIVTSQs) and the new change version (HIVTSQc). Value 
in Health,2006: 9(5) 320-333.
 
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11.
APPENDICES
11.1.
Appendix 1:  Abbreviations and Trademarks
Abbreviations
3TC
Lamivudine, EPIVIR
ABC
Abacavir, ZIAGEN
ABC/3TC
Abacavir/lamivudine, EPZICOM, KIVEXA
ABC/DTG/3TC
Abacavir/dolutegravir/lamivudine, TRIUMEQ
ACCEPT
General acceptance” dimension of the Chronic Treatment 
Acceptance
ADR
Adverse drug reaction
AE
Adverse event
AIDS
Acquired immunodeficiency syndrome
ALT
Alanine aminotransferase
Anti-HBc
Hepatitis B core Antibody
Anti-HbsAg
Antibodies against Hepatitis B surface Antigen
APAP
N-acetyl-para-aminophenol
ARV
Antiretroviral
ART
Antiretroviral therapy
ATV
Atazanavir
ATLAS
Antiretroviral Therapy as Long Acting Suppression every 2
Months
AST
Aspartate aminotransferase
AUC
Area under the curve
AUC(0-)
Area under the concentration curve from 0 hours to the time 
of next dosing
BP
Blood Pressure
BUN
Blood Urea Nitrogen
CAB
Cabotegravir
CAB LA
Cabotegravir long-acting
c/mL
Copies/milliliter
cART
Combination antiretroviral therapy
CD4
Cluster of Differentiation 4
CD8
Cluster of Differentiation 8
CDC
Centers for Disease Control and Prevention
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
Cmax
Maximum concentration
CMH
Cochran-Mantel Haenszel
ConART
Concomitant Antiretroviral Therapy
CSR
Clinical Study Report
C-SSRS
Columbia Suicidality Severity Rating Scale
CI
Confidence interval
CONSORT
Consolidated Standards of Reporting Trials
CPK
Creatine phosphokinase
 
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CPMS
Clinical Pharmacology Modelling and Simulation
CSR
Clinical Study Report
CV
Cardiovascular
CVF
Confirmed Virologic Failure
DAIDS
DILI
Division of Acquired Immunodeficiency Syndrome
Drug induced liver injury
DNA
Deoxyribonucleic acid
DRE
Disease-Related Events
DRV
Darunavir
DTG
Dolutegravir, TIVICAY
DVT
Deep vein thrombosis
ECG
Electrocardiogram
eC-SSRS
Columbia Suicide Severity Rating Scale
eCRF
Electronic case report form
EFV
eGFR
EMA
EQ-5D-5L
ETR
EU
Efavirenz
Estimated glomerular filtration rate
European Medicines Agency
European Quality of Life-5 Dimensions-5 Levels
Etravirine
European Union
EVG
Elvitegravir
FDA
Food and Drug Administration
FDC
Fixed-dose combination
FTC
Emtricitabine
GCP
Good Clinical Practice
GSK
HAART
GlaxoSmithKline
Highly active antiretroviral therapy
HbsAg
Hepatitis B surface Antigen
HAT-QoL
HIV/AIDS-targeted quality of life
HBV
Hepatitis B virus
HCG
human chorionic gonadotrophin
HCV
HDL
HDPE
Hepatitis C virus
High density lipoprotein
High density polyethylene
HIV
HIV TSQ
Human immunodeficiency virus 
HIV treatment satisfaction questionnaire
HLA
Human leukocyte antigen
HSR
Hypersensitivity reaction
IB
ICH
IDMC
Investigator’s Brochure
International Conference on Harmonisation
Independent data monitoring committee
IEC
IgM
Independent Ethics Committee
Immunoglobulin M
IM
Intramuscular
INI
Integrase inhibitor
INR
International normalized ratio
 
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INSTI
Integrase strand transfer inhibitor
IP
Investigational Product
IRB
Institutional Review Board
ITT-E
Intent-to-treat exposed
IUD
Intrauterine device
IRT
Interactive response technology
ISR
Injection Site Reaction
LA
Long Acting
LDL 
Low density lipoprotein
LPV
Lopinavir
LPV/r
Lopinavir-ritonavir
LTFU
Long-Term Follow-UP
MCV
Mean corpuscular volume
MedDRA
Medical dictionary for regulatory activities
Mg
Milligram
Mg/dL
Milligram
MSD=F
Missing, switch, or discontinuation equals failure
NNRTI
Non-nucleoside reverse transcriptase inhibitor
NRS
Numeric Rating Scale
NRTI
Nucleoside reverse transcriptase inhibitor
PI
Protease inhibitor
PIN
Perception of Injection
PK
Pharmacokinetic
PP
Per-protocol
PRO
Protease
PRTD
Proximal Renal Tubule Dysfunction
PSRAE
Possible suicidality-related adverse event
QTc
Corrected QT interval 
Q8W
Every 8 weeks
Q4W
Every 4 weeks
RAL
Raltegravir
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
Ritonavir
SAE
Serious adverse event
SJS
Stevens-Johnson syndrome
SOC
Standard of Care
SPM
Study Procedures Manual
STR
Single tablet regimen
 
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SVW
Suspected Virologic Withdrawal
TDF
Tenofovir disoproxil fumarate
TEN
Toxic epidermal necrolysis
TMC278
Tibotec Medicinal Compound 278
TSQ
Treatment Satisfaction Questionnaire
ULN
Upper limit of normal
US
United States
VAPI
Vaccines’ Perception of Injection
VAS
Visual Analog Scale
VSLC
WBC
ViiV Safety and Labeling Committee
White blood cell
Trademark Information
Trademarks of ViiV Healthcare
Trademarks not owned by ViiV 
Healthcare
EPIVIR
Edurant
EPZICOM/KIVEXA
Genosure
TIVICAY
InForm
TRIUMEQ
MedDRA
ZIAGEN
Monogram Biosciences
NONMEM
PhenoSense
RAMOS NG
RANDALL NG
TRIZIVIR
 
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11.2.
Appendix 2:  Division of AIDS Table for Grading the Severity 
of Adult and Pediatric Adverse Events Version 2.1, March
2017
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.
 
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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 
2.1. [March 2017]. Available from:
https://rsc.tech-res.com/docs/default-source/safety/daids-ae-grading-table-mar2017.pdf
 
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11.3.
Appendix 3:  Liver Safety – Study Treatment Restart or 
Rechallenge Guidelines
11.3.1.
VSLC Guidelines for Drug Restart or Rechallenge after stop for 
Liver criteria
Drug Rechallenge refers to resuming study treatment following drug induced liver injury 
(DILI). Because of the risks associated with rechallenge after DILI (see Drug 
Rechallenge Background below) this should only be considered for a participant for 
whom there is compelling evidence of benefit from a critical or life-saving medicine, 
there is no alternative approved medicine available, and a benefit:risk assessment of 
rechallenge is considered to be favorable (Table 12, Figure 17).
Drug Restart refers to resuming study treatment following liver events meeting stopping 
criteria in which there is a clear underlying cause (other than DILI) of the liver event 
(e.g., biliary obstruction, pancreatic events, hypotension, acute viral hepatitis). 
Furthermore, there should be no evidence of alcoholic hepatitis or hypersensitivity, and 
the drug should not be associated with HLA markers of liver injury. (Table 13; Figure 
18).
As this determination can be difficult, for the purpose of these guidelines, cases 
should be treated as rechallenges if there is any reasonable likelihood that the liver 
event is related to study drug. Restarts should be limited to cases in which there is 
clear evidence that the underlying cause of the liver event is not related to study 
drug.
DRUG RECHALLENGE
Background: Following drug-induced liver injury, drug rechallenge is associated with a 
13% mortality across all drugs in prospective studies [Andrade, 2009].  Clinical outcomes 
vary by drug, with nearly 50% fatality with halothane re-administered within one month 
of initial injury.  However, some drugs seldom result in recurrent liver injury or fatality.
Risk factors for a fatal drug rechallenge outcome include:

hypersensitivity [Andrade, 2009] with initial liver injury (e.g. fever, rash, 
eosinophilia)

jaundice or bilirubin >2xULN with initial liver injury (direct bilirubin >35% of 
total)

participant currently exhibits severe liver injury defined by: ALT3xULN, 
bilirubin 2xULN (direct bilirubin >35% of total), or INR1.5

prior serious adverse event or fatality has earlier been observed with drug 
rechallenge [Papay, 2009; Hunt, 2010]

evidence of drug-related nonclinical liability (e.g. reactive metabolites; 
mitochondrial impairment [Hunt, 2010])
 
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11.3.2.
VSLC Decision Process for Drug Rechallenge Approval or 
Disapproval

Principal Investigator (PI) requests consideration of drug rechallenge for a 
participant receiving compelling benefit from a critical or life-saving drug, who 
exhibits liver chemistry elevation meeting participant stopping criteria in relation 
to DILI, with no alternative treatment

By definition treatment naïve participants will only be considered for rechallenge 
if they were infected with a multi-resistant virus.

Medical Monitor and Global Clinical Safety and Pharmacovigilance (GCSP) 
Physician review the participant’s rechallenge risk factors (consultation with the 
Hepatotoxicity Panel is available) and complete checklist (Table 12).

The local operating company (LOC) medical directors (ViiV and/or GSK where 
applicable) should be informed that study drug rechallenge is under consideration 
and of the final decision, whether or not to proceed.

The Medical Monitor and GCSP Physician are accountable to review and agree 
on the following prior to preparing request for rechallenge documentation for 
presentation to VSLC:
–
Compelling benefit of the investigational product (IP) for this participant and 
no alternative therapy 
o
must present source data defining the patient’s current resistance 
profile with documented evidence of extensive drug resistance and 
previous drug history 

Relative benefit-risk of drug rechallenge, with consideration of the following high 
risk factors:

Initial liver injury event included: fever, rash, eosinophilia, or bilirubin
2xULN (or direct bilirubin >35% of total, if available)

Participant currently exhibits severe liver injury defined by: ALT 
>3xULN, bilirubin >2xULN (direct bilirubin >35% of total, if available), 
or INR>1.5

SAE or fatality has earlier been observed with IP rechallenge

IP is associated with known nonclinical hepatic liability/ injury

Relevant physicians (listed below) must review and agree on action to be taken 
regarding request for drug rechallenge:  

Safety Review Team Leader, Safety Development Leader, or Senior 
Safety Physician

Medicines Development Leader (MDL) and Project Physician Leader 
(PPL) 

Request is taken to full VSLC for final decision
 
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Table 12
Checklist for drug rechallenge for critical medicine (Following drug-
induced liver injury, drug rechallenge is associated with 13% 
mortality across all drugs in prospective studies)
Yes
No
Compelling benefit of IP for this participant and no alternative therapy.  
Provide brief explanation:
Relative benefit-risk favorable for drug rechallenge, after considering the 
following high risk factors:
Initial liver injury event included:
fever, rash, eosinophilia, or hypersensitivity
bilirubin2xULN (direct bilirubin >35% of total)
Participant currently exhibits ALT >3xULN, bilirubin >2xULN (direct 
bilirubin >35% of total, if available), or INR>1.5
SAE or fatality has earlier been observed with IP rechallenge
If yes, please provide brief explanation:
IP associated with known nonclinical hepatic liability/ injury
Source data defining the patient’s current resistance profile
Previous drug history
 
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Figure 17
VSLC process for drug rechallenge approval or disapproval
Participant exhibits liver injury on drug while disease condition 
stable or improving
Medical Monitor and Safety Physician(s) to discuss benefit:risk 
and
Any fever, rash, eosinophilia, hypersensitivity with initial liver injury 
[Andrade, 2009] in this patient?
Currently ALT>3xULN and Bilirubin >2xULN or INR >1.5x in this 
patient suggesting failing liver
Any prior severe/fatal outcomes reported on drug rechallenge [Papay, 
2009; Hunt, 2010] with this drug?
Any Evidence of nonclinical hepatic liability/injury with this drug?
LOC Medical Director to be informed of rechallenge consideration and 
final decision
Relevant physicians (from Safety and Clinical functions) review and 
agree on rechallenge request
Request is 
submitted to 
VSLC
VSLC Approves Re-initiation of IP
VSLC Does NOT Approve Re-
initiation of IP
PI promptly informed of decision and 
dosing regimen
Ethics Committee or IRB review, if needed
Benefits/Risks discussed with participant 
and consent recorded in chart 
Liver chemistries obtained twice weekly for 
a minimum of one month and thereafter for 
as long as clinically indicated
Safety Review Teams record rechallenge 
outcome
VSLC notified of rechallenge outcome
PI promptly informed of decision
DRUG RESTART
“Drug restart” can be approved by the VSLC for transient, defined non-drug-induced 
liver injury if no evidence of:
•
immunoallergic injury /HLA association with injury
•
alcoholic hepatitis
Study drug must be held while labs and evaluation are completed to assess diagnosis.
 
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11.3.3.
VSLC Decision Process for Drug Restart Approval or Disapproval

Principal Investigator (PI) requests consideration of drug re-initiation for a 
participant stable or improving on IP, who exhibits liver chemistry elevation 
meeting participant stopping criteria, which is transient, non-drug-related, and 
liver chemistries have improved to normal or are within 1.5x baseline and 
ALT< 5xULN. 

GSK Medical Monitor and GCSP Physician to review the participant’s diagnosis 
restart risk factors (Hepatotoxicity Panel consultation is available) and complete 
checklist (Table 13).
–
must present source data defining the patient’s current resistance profile 
with documented evidence of extensive drug resistance and previous drug 
history.

The local operating company (LOC) medical director should be informed that 
study drug restart is under consideration and of the final decision, whether or not 
to proceed.

Relevant physicians (listed below) must review and agree on action to be taken  
regarding request for drug restart:  

Safety ReviewTeam Leader, Safety Development Leader, or Senior Safety 
Physician

MDL and PPL

Request is taken to VSLC for final decision
Table 13
Checklist for Phase III drug restart after well-explained liver injury 
(e.g. biliary, pancreatic, hypotensive events, congestive heart failure 
(CHF), acute viral hepatitis), and improvement of liver chemistry to 
normal or 1.5x baseline & ALT<5xULN
Yes
No
Is participant stable or improving on IP?
Do not restart if the following risk factors at initial liver injury:
fever, rash, eosinophilia, or hypersensitivity 
drug-induced liver injury 
alcoholic hepatitis (AST>ALT, typically <10xULN)
IP has an HLA genetic marker associated with liver injury (e.g. lapatinib, 
abacavir, amoxicillin/clavulanate)
Source data defining the patients current resistance profile
Previous drug history
 
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Figure 18
VSLC process for drug restart approval or disapproval
Participant exhibits transient, non-drug related liver injury while 
disease condition stable or improving
Medical Monitor and Safety Physician(s) to discuss etiology of 
liver injury and
Have liver injuries decreased to normal or to <1.5x Baseline and ALT 
<5xULN
Any fever, rash, eosinophilia in this patient or HLA genetic marker 
associated with liver injury [Andrade, 2009]?
Any evidence of alcoholic hepatitis or DILI in this patient?
Any prior sever/fatal outcomes reported on drug restart [Papay, 2009; 
Hunt, 2010] with this drug?
Any Evidence of nonclinical hepatic liability/injury with this drug?
LOC Medical Director to be informed of restart consideration and final 
decision
Relevant physicians (from Safety and Clinical functions) review and 
agree on restart request
Request is 
submitted to VSLC
VSLC Approves Re-initiation of IP
VSLC Does NOT Approve Re-
initiation of IP
PI promptly informed of decision and 
dosing regimen
Ethics Committee or IRB review, if needed
Benefits/Risks discussed with participant 
and consent recorded in chart 
Liver chemistries obtained once weekly for 
a minimum of one month and thereafter for 
as long as clinically indicated
Safety Review Teams record rechallenge 
outcome
VSLC notified of rechallenge outcome
PI promptly informed of decision
11.3.4.
Medical monitor, GCSP Physician and PI actions for Restart or 
Rechallenge following VSLC decision
11.3.4.1.
Medical Monitor and GCSP Physician Actions

Medical Monitor must notify PI of VSLC’s rechallenge (or restart) decision and 
recommended dosing regimen in writing and Medical Monitor must record note 
in study files.

The Safety Review Team must record rechallenge (or restart) outcomes and the 
GCSP Physician must send these to the VSLC (see template below).

All severe reactions (rechallenge associated with bilirubin>2xULN or jaundice, 
or INR1.5), SAEs or fatalities which occur following a drug rechallenge (or 
restart) must be immediately reported to Line Management including, VSLC 
 
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Chair, VP Global Medical Strategy and EU Qualified Person for 
Pharmacovigilance. 
11.3.4.2.
PI Actions:

The PI must obtain Ethics Committee or Institutional Review Board approval of
drug rechallenge or restart, as required. 

If VSLC approves drug rechallenge or restart, the patient must sign a new 
informed consent containing a clear description of possible benefits and risks of 
drug administration including recurrent, more severe liver injury or possible 
death.

Targeted drug rechallenge or drug restart consent form must be used.

The patient’s informed consent must be recorded in the study chart, and the drug 
administered at agreed dose, as communicated by Medical Monitor.

Liver chemistries must be followed twice weekly for ‘rechallenge’ cases and 
once weekly for ‘restart’ cases for a minimum of one month and thereafter for as 
long as clinically indicated following drug re-initiation.  If participant exhibits 
protocol-defined liver chemistry elevations, IP should be discontinued as protocol 
specified.

Medical Monitor and the Ethics Committee or Institutional Review Board must 
be informed of the patient’s outcome following drug rechallenge or restart.
Drug Rechallenge or Drug Restart Outcomes Table Template
To be completed/updated and provided to VSLC with each event recorded across 
studies and indications
Drug Rechallenge/Restart Outcomes Table – Update with each event
Protocol#
Participant#
Rechallenge or 
Restart?
Safety 
outcome*
Drug 
benefit
Rechallenge/restart safety outcomes:
0 = no liver chemistry elevation
1 = recurrent liver chemistry elevation not meeting participant stopping criteria
2 = recurrent liver chemistry elevation meeting participant stopping criteria
3 = serious adverse event
4 = fatality
 
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11.4.
Appendix 4:  CDC Classification for HIV-1 Infection (2014)
Note that the CD4+ T-lymphocyte count takes precedence over the CD4+ T-lymphocyte 
percentage in HIV infection stages 1, 2, and 3.  The CD4+ T-lymphocyte should only be 
considered if the count is missing.
HIV infection, stage 0
Indicates early HIV infection, inferred from a negative or indeterminate HIV test result 
within 180 days of a positive result.  The criteria for stage 0 supersede and are 
independent of criteria used for other stages.
HIV infection, stage 1

Laboratory confirmation of HIV infection with no AIDS-defining condition, and
o
CD4+ T-lymphocyte count of ≥500 cells/L, or
o
CD4+ T-lymphocyte percentage of total lymphocytes of ≥26%.
HIV infection, stage 2

Laboratory confirmation of HIV infection with no AIDS-defining condition, and
o
CD4+ T-lymphocyte count of 200 to 499 cells/L, or
o
CD4+ T-lymphocyte percentage of total lymphocytes of 14% to 25%.
HIV infection, stage 3 (AIDS)

Laboratory confirmation of HIV infection, and
o
CD4+ T-lymphocyte count of <200 cells/L, or
o
CD4+ T-lymphocyte percentage of total lymphocytes of <14%, or
o
Documentation of an AIDS-defining condition (see below).
Documentation of an AIDS-defining condition supersedes a CD4+ T-lymphocyte count 
of >200 cells/L and a CD4+ T-lymphocyte percentage of total lymphocytes of >14%. 
HIV infection, stage unknown

Laboratory confirmation of HIV infection, and
o
No information on CD4+ T-lymphocyte count or percentage, and
o
No information on presence of AIDS-defining conditions.
Stage-3-defining opportunistic illnesses in HIV infection

Candidiasis of bronchi, trachea, or lungs 

Candidiasis of oesophagus 

Cervical cancer, invasive
 
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
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.
Reference
CDC. Revised Surveillance Case Definition for HIV Infection – United States, 2014. 
MMWR 2014; 63 (RR-03);1-10.
 
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11.5.
Appendix 5:  Genetic Research
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate a relationship between genetic 
variants and: 

Response to medicine, including CAB + RPV or any concomitant medicines; 

HIV-1 susceptibility, severity and progression and related conditions. 
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a RAP prior to initiation of the 
analysis. Planned analyses and results of genetic investigations will be reported either as 
part of the clinical RAP and study report, or in a separate genetics RAP and report, as 
appropriate.
Study Population
Any participant who is enrolled in the clinical study can participate in genetic research. 
Any participant who has received an allogeneic bone marrow transplant must be excluded 
from genetic research.
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.  

A 6 mL blood sample will be taken for deoxyribonucleic acid (DNA) extraction.  
A blood sample is collected at the baseline visit, after the participant has been 
randomized and provided informed consent for genetic research. Instructions for 
collection and shipping of the genetic sample are described in the laboratory 
manual. The DNA from the blood sample may undergo quality control analyses to 
confirm the integrity of the sample.  If there are concerns regarding the quality of 
the sample, then the sample may be destroyed.  The blood sample is taken on a 
single occasion unless a duplicate sample is required due to an inability to utilize 
the original sample.
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study.   This number can be traced or linked back to 
 
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the participant by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number).
Samples will be stored securely and may be kept for up to 15 years after the last 
participant completes the study, or GSK may destroy the samples sooner.  GSK or those 
working with GSK (for example, other researchers) will only use samples collected from 
the study for the purpose stated in this protocol and in the informed consent 
form.  Samples may be used as part of the development of a companion diagnostic to 
support the GSK medicinal product.
Participants can request their sample to be destroyed at any time.
Informed Consent
Participants who do not wish to participate in the genetic research may still participate in 
the study.  Genetic informed consent must be obtained prior to any blood being taken.
Participant Withdrawal from Study
If a participant who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the participant will be 
given a choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA 
sample is retained 

Discontinue participation in the genetic research and destroy the genetic DNA 
sample. 
If a participant withdraws consent for genetic research or requests sample destruction for 
any reason, the investigator must complete the appropriate documentation to request 
sample destruction within the timeframe specified by ViiV/GSK and maintain the 
documentation in the site study records. 
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis.

If a participant withdraws consent for genetic research and genotype data has not 
been analyzed, it will not be analyzed or used for future research.

Genetic data that has been analyzed at the time of withdrawn consent will 
continue to be stored and used, as appropriate.
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the 
participant does not meet the entry criteria for participation in the study, then the 
investigator should instruct the participant that their genetic sample will be destroyed. No 
forms are required to complete this process as it will be completed as part of the consent 
 
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and sample reconciliation process.  In this instance a sample destruction form will not be 
available to include in the site files.
Provision of Study Results and Confidentiality of Participant’s Genetic Data
ViiV/GSK may summarize the genetic research results in the CSR, or separately, and 
may publish the results in scientific journals. 
ViiV/GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the 
participant, family members, insurers, or employers of individual genotyping results that 
are not known to be relevant to the participant’s medical care at the time of the 
study, unless required by law. This is due to the fact that the information generated from 
genetic studies is generally preliminary in nature, and therefore the significance and 
scientific validity of the results are undetermined.  Further, data generated in a research 
laboratory may not meet regulatory requirements for inclusion in clinical care.
 
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11.6.
Appendix 6:  Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
11.6.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
participant, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE.  However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition 
of an AE or SAE.
 
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Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
11.6.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc.).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
Results in death
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event.  It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
 
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from baseline is not considered an AE.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption
Is a congenital anomaly/birth defect
Other situations:

Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the participant or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.

Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
participants receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
 
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11.6.3.
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
11.6.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the eCRF

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all participant identifiers, with the exception of 
the participant number, will be blinded on the copies of the medical records prior to 
submission 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.
 
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11.6.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important 
that the investigator always make an assessment of causality for every event 
prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
 
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Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings, including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
11.6.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the Medical Monitor.

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, the site can report this information on a paper SAE form or to the 
Medical Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
 
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SAE reporting to GSK via paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the Medical Monitor or the SAE coordinator

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable, with a copy of the SAE data collection tool sent by 
overnight mail

Initial notification via the telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE receipt can be found at this beginning of the protocol on the 
Sponsor/Medical Monitor Contact Information page.
 
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11.7.
Appendix 7:  Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)
Women in the following categories are not considered WOCBP
a. Premenarchal
b. Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
c. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment.
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 14. 
 
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Table 14
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with 
inhibition of ovulation

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulationb

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.) 
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the participant.)
NOTES: 
a.
Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for participants in clinical 
studies. 
b.
Two highly effective methods of contraception should be utilized from 30 days prior to the first dose of study 
medication, throughout the study,  and for at least 52 weeks after discontinuation of CAB LA and RPV LA .
Pregnancy Testing
o
WOCBP should only be included after a confirmed menstrual period and a 
negative highly sensitive serum pregnancy test 
o
Additional pregnancy testing should be performed as per the study Time and 
Events Table.
 
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o
Pregnancy testing will be performed whenever a menstrual cycle is missed or 
when pregnancy is otherwise suspected 
o
Pregnancy testing will be performed and assayed in the central laboratory OR 
using the test kit provided by the central laboratory / provided by the sponsor 
/approved by the sponsor and in accordance with instructions provided in its 
package insert]  
11.7.1.
Collection of Pregnancy Information

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK 
within 24 hours of learning of a participant's pregnancy.

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on mother and infant, which will 
be forwarded to GSK.  Generally, follow-up will not be required for longer than 6 
to 8 weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence 
or absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy 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 this section.  While the investigator is not obligated to 
actively seek this information in former study participants, he or she may learn of 
an SAE through spontaneous reporting.
Any individual participant who becomes pregnant while participating will 
discontinue study medication and be withdrawn from the study.  If the female 
participant is receiving CAB LA + RPV LA, they will be followed for 52 weeks in 
the LTFU Phase.
 
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11.8.
Appendix 8: Study governance Considerations
11.8.1.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process
Prior to initiation of a site, ViiV/GSK will obtain favorable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with International 
Conference on Harmonisation (ICH) Good Clinical Practice (GCP) and applicable 
country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (e.g., advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
11.8.2.
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
 
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Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
11.8.3.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all
questions regarding the study.

Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center.

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative.

Participants who are rescreened are required to sign a new ICF.
The ICF may contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research in accordance with SOP-GSKF-410. The 
investigator or authorized designee will explain to each participant the objectives of the 
exploratory research. Participants will be told that they are free to refuse to participate 
and may withdraw their consent at any time and for any reason during the storage period. 
A separate signature will be required to document a participant's agreement to allow any 
remaining specimens to be used for exploratory research. Participants who decline to 
participate will not provide this separate signature.
11.8.4.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred.

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant.

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
 
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11.8.5.
Independent Data Monitoring Committee
An IDMC will be utilized in this study to ensure external objective medical and/or 
statistical review of safety and/or efficacy issues in order to protect the ethical and safety 
interests of participants and to protect the scientific validity of the study.  The schedule of 
any planned interim analysis and the analysis plan for IDMC review is described in 
Section 9.2.3 and the IDMC the charter, which is available upon request..
11.8.6.
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
11.8.7.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., 
laboratory data). The investigator is responsible for verifying that data entries 
are accurate and correct by physically or electronically signing the CRF.

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
 
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currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 
Records and documents, including signed ICF, pertaining to the conduct of this study 
must be retained by the investigator for 25 years from the issue of the final Clinical Study 
Report (CSR)/ equivalent summary unless local regulations or institutional policies 
require a longer retention period. No records may be destroyed during the retention 
period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor
11.8.8.
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous
medical records or transfer records, depending on the study. Also, current 
medical records must be available.
11.8.9.
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP 
guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study treatment development

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.

Upon completion or premature discontinuation of the study, the GSK monitor 
will conduct site closure activities with the investigator or site staff, as 
 
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appropriate, in accordance with applicable regulations including GCP, and 
GSK Standard Operating Procedures.

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.
11.8.10.
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 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.
11.8.11.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers and 
Publication

Study information from this protocol will be posted on publicly available clinical 
trial registers before enrolment of participants begins.
 
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
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.

A manuscript will be progressed for publication in the scientific literature if the 
results provide important scientific or medical knowledge.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
 
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11.9.
Appendix 9: Country-Specific Requirements
11.9.1.
Study Duration
In this study, the Extension Phase is intended to provide access to CAB LA + RPV LA 
Q4W or Q8W based on original randomization assignment until the regimen receives 
local (by country) Regulatory approval, and becomes commercially available. Therefore, 
the duration of the Extension Phase will vary from country to country and is dependent 
on the recruitment time for the study and the time taken to achieve local approval for 
marketing. During this time, participants will be monitored at minimum every 8 weeks to 
ensure they continue to derive clinical benefit from CAB LA + RPV LA.
 
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11.10.
Appendix 10: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).
Amendment 01 14-Sep-2017
Overall Rationale for Amendment #1: The primary purpose of protocol amendment #1 
is to revise the study sample size to randomize approximately 1020 participants including 
510 participants per arm based on a non-inferiority margin of 4% between the CAB LA + 
RPV LA Q8W and Q4W arms. Assuming the true proportion with HIV-RNA >=50 
c/mL is 3% for the Q8W arm and 2% for the Q4W arm, the revised sample size will 
provide at least 85% power to show non-inferiority at Week 48.  Additional minor 
clarifications and corrections have been added to the protocol text.
Section # and 
Name
Description of Change
Brief Rationale
Synopsis Short Title
Protocol short title updated to be 
consistent with short title of title 
page.
Short title consistency
General Updates 
throughout protocol
Update of noninferiority margin 
and corresponding study 
participant size and statistical 
powering.
Increase of sample size to 1020 
participants to support 4% non-
inferiority margin and 85% power 
assuming a true 3% failure rate for 
Q8W arm and 2% failure rate for the 
Q4W arm.
Section 4.2.6 
Independent Data 
Monitoring 
Committee
Clarification of IDMC analysis
Clarification added that IDMC will focus 
evaluation of efficacy, tolerability, 
safety, and PK on accumulating CAB 
LA + RPV LA Q8W data
Section 5.5 
Withdrawal/Stopping 
Criteria.
Bullet # 4 under reasons 
participants must be 
discontinued from study 
treatment updated to: “
“Participant requires substitution 
of ART”.
Dose modification of CAB or RPV is not 
an available option to participants. 
 
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Section # and 
Name
Description of Change
Brief Rationale
Section 5.6 
Participant and 
Study Completion
Text updated to: In addition to 
the 52-week Follow-Up phase 
required for participants who 
receive one or more injections 
with CAB LA or RPV LA, an in-
clinic Follow-Up visit will be 
conducted approximately 4 
weeks after the last dose of 
study medication for participants 
who withdraw during the oral 
lead-in phase with ongoing AEs, 
and serious adverse events 
(SAEs) and also any laboratory 
abnormalities that are 
considered to be AEs or 
potentially harmful to the 
participant, at the last on-study 
visit.
Clarification of required procedures for 
Long-term Follow-up Phase and follow-
up visit for participants with ongoing 
AEs, SAEs, or laboratory abnormalities.
Section 6.1 
Investigational 
Product and other 
Study Treatment
Text updated to: Participants 
entering the Long-Term Follow-
Up Phase will not have their 
selected HAART provided as
clinical trial material. The 
selected HAART will be recorded 
on the Concomitant Antiretroviral 
Therapy (ConART) eCRF page. 
Clarification that HAART selected 
during Long-Term Follow-Up Phase will 
not be provided as clinical trial material 
and removal of reference to current 
ART.
Section 6.9 
Interruption of Study 
Treatment and 
Visit/Dosing 
Windows
Text updated to:
IP may be interrupted at the 
discretion of the Investigator in 
the event of an AE, according to 
the severity of the AE.
Removal of reference to current ART
Section 6.9.1.1: IM
injections every 4 
weeks (Q4W)
Text updated to: The first 
injection visit with IM CAB LA + 
RPV LA at Week 4b can be 
performed once central lab 
results are available and safety 
parameters are reviewed from 
the Week 4a visit.  
Text updated to indicate first injections 
received at Week 4b rather than Day 1 
for consistency with Time and Events 
Table. 
 
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Section # and 
Name
Description of Change
Brief Rationale
Section 6.13.2.3:  
Prohibited 
Medications for 
Participants
Receiving HAART 
during the Long-
Term Follow-Up 
Phase
Text updated to: For participants 
taking HAART during the Long-
Term Follow-Up Phase, refer to 
local prescribing information for 
details regarding concurrent 
therapies.
Clarification that local prescribing 
information should be referenced for 
HAART taken during Long-Term 
Follow-Up Phase regarding prohibited 
concurrent therapies.
Section 7.1, Time 
and Events Table 
for Q4W and Q8W 
arms.
Text added to footnote q, for 
genetics sample. Sample may be 
collected at any visit after signing 
informed consent, but preferably 
at the Day 1 visit.
Footnotes added to Preference 
and HIVTSQc questionnaires.
eCSSRS questionnaire removed 
from study Extension Phase.
Removal of reference to 
collection of Health Outcomes 
data via electronic site pads for 
footnote “u”
Adds flexibility to when genetic sample 
for genetic research can be obtained.
Added clarification for intended 
administration of questionnaires to 
participant groups. 
Suicidality assessment tool 
administered through study Week 96 or 
withdrawal.
Collection of Health Outcomes data will 
be performed via paper instruments.
Section 7.4.3.4: 
Prompt Reporting of 
Serious Adverse 
Events and Other 
Events
Table 9: Reporting 
of Serious Adverse 
Events and Other 
Events
Text updated to: Suspected ABC 
HSR in participants receiving Oral 
SOC during the Long-Term Follow-
Up Phaseb
Initial report of pregnancy and 
completion of Pregnancy 
Notification Form has been updated 
to within 24 hours of identification of 
a Pregnancy event.  Follow-up 
Pregnancy form (and SAE if 
required) has been updated to 
within 24 hours of investigator 
awareness of pregnancy outcome.
Clarification for reporting suspected 
ABC HSR adverse event is relevant 
only during the Long-Term Follow-Up 
Phase for participants returning to Oral 
Standard of Care
Reporting timelines and documentation 
requirements have been updated to 
reflect current Sponsor requirements.
 
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Section # and 
Name
Description of Change
Brief Rationale
Section 7.4.5.7.1 
Proximal Renal 
Tubule Dysfunctions 
(PRTD)
Text removal: ). If a participant in 
the current ART arm is also 
receiving TDF, then a dose 
adjustment may be considered if 
restarting study drug unless 
participants met renal toxicity 
stopping criteria (see Section 
7.4.5.7)
Removal of reference to current ART 
therapy dose adjustments.
Section 7.8 Value 
Evidence and 
Outcomes
Removal of reference to 
collection of Health Outcomes 
data via electronic site pads.
Collection of Health Outcomes data will 
be performed via paper instruments.
Section 9 Statistical
Considerations and 
Data Analyses
Updates to sample size, analysis 
considerations, and planned 
analysis within Section 9.1-
Section 9.3. have been added
Updates to statistical section required 
based on change of noninferiority 
margin from 5% to 4%, corresponding 
increase in study participant size, 
impact on sample size sensitivity 
analysis.
Additional details for subgroup and 
stratum-specific analysis plan are 
included. 
General Updates
Additional minor clarifications 
and corrections to typographical 
errors/formatting to protocol text 
have been added.
Text clarifications and formatting
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 2
03-Jul-2018
Amendment 1
14-Sep-2017
Original Protocol
17-Jul-2017
 
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