Clinical trial NCT04001803
Conditions: HIV Infections
Keywords: Antiretroviral therapy, HIV infections, cabotegravir, rilpivirine, long-acting intramuscular injection,
Sponsor: ViiV Healthcare
Start date: 2019-07-08; Completion date: 2022-03-18
Enrollment: 115 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Chronic human immunodeficiency virus (HIV) infection in adults continues to be characterized by increased development of resistant virus, increased transmission of resistant virus and issues associated with the long-term toxicity of anti-retroviral therapy (ART), despite advances in development of new ART, which provides extensive insight in management of HIV-infected individuals. Cabotegravir (CAB) is a potent integrase inhibitor (INI) and rilpivirine (RPV) is a potent non-nucleoside reverse transcriptase inhibitor (NNRTI). A two-drug regimen (DR)with CAB plus RPV long acting (LA) product offers many potential advantages over daily oral regimens including better tolerability, improved compliance, adherence, less likely to develop resistance, and overall treatment satisfaction in virologically suppressed subjects. This is a single-arm, open-label, multicenter, short term facilitation study to evaluate the effect of an implementation strategy on the degree of acceptability, appropriateness, feasibility, fidelity and sustainability of clinical practices to deliver the CAB+RPV LA regimen to HIV infected subjects and to also measure subject satisfaction by recording timeliness of visits, length of visit and their education. Approximately 135 subjects will be enrolled in the study and the total duration of the study will be approximately 52-weeks.

Detailed description:

Arms: arm 1: HIV-infected subjects receiving CAB LA+RPV LA will be included in this arm.
Interventions: intervention 1: CAB LA+RPV LA
Intervention descriptions: intervention 1: Subjects will receive one tablet of CAB 30 milligram(mg) + RPV 25 mg once daily from Day 1 for 1 month. During month 1, subjects will receive 600 mg of CAB LA injection+ 900 mg of RPV LA injection. Following Month 1, subjects will receive 400mg of CAB LA + 600mg of RPV LA at each subsequent injection.

Protocol documents:
SAP_002.pdf: 
Reporting and Analysis Plan (RAP)
Study ID:  209493
Official Title of Study: Reporting and Analysis Plan for A qualitative hybrid III 
implementation study to identify and evaluate strategies for successful implementation of 
the cabotegravir + rilpivirine long-acting injectable regimen in the US 
Date of Document: 11 Mar 2022 


TMF-14552026 
CONFIDENTIAL 
209493
The GlaxoSmithKline group of companies 
1 
Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
Title 
: Reporting and Analysis Plan for A qualitative hybrid III 
implementation study to identify and evaluate strategies for 
successful implementation of the cabotegravir + rilpivirine 
long-acting injectable regimen in the US 
Compound Number  : GSK1265744 
Clinical Study 
Identifier 
: 209493 
Effective Date 
: Refer to Document Date 
Description: 
•
The purpose of this RAP is to describe the planned analyses and output to be
included in the Clinical Study Report for Protocol 209493, specifically for clinical
data. Any implementation science/health outcome analyses will be detailed in a
separate Evidera SAP.
•
This RAP will be provided to the study team members to convey the content
pertaining to clinical data for the End of Study (EOS) analyses.
RAP Author(s): 
Author 
Date 
Lead 
08-MAR-2022
Principal Statistician (Dev Biostats Stats Dev) 
Copyright 2022 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD


TMF-14552026 
CONFIDENTIAL 
209493 
2 
RAP Team Reviews: 
RAP Team Review Confirmations 
(Method: E-mail) 
Reviewer 
Date 
10-MAR-2022
(Clinical Scientists, Early 
Development, ViiV Healthcare) 
(CMO GCSP SERM) 
10-MAR-2022
11-MAR-2022
, Innovation and & Implementation Science (US Health 
Outcomes, ViiV Healthcare) 
09-MAR-2022
Principal Programmer/Analyst (Dev Biostats Prog Dev) 
Clinical Statistics & Clinical Programming Line Approvals 
(Method: Veeva Vault TMF Approval) 
Approver 
(Dev Biostats Stats Dev) 
(Dev Biostats Prog Dev) 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


TMF-14552026 
CONFIDENTIAL 
209493 
3 
TABLE OF CONTENTS 
PAGE 
1.
INTRODUCTION ...................................................................................................... 6 
1.1. 
RAP Amendments ........................................................................................ 7 
2.
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 8 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 8 
2.2. 
Study Objective(s) and Estimand(s) / Endpoint(s) ......................................... 8 
2.3. 
Study Design .............................................................................................. 10 
2.4. 
Statistical Hypotheses / Statistical Analyses ............................................... 10 
3.
PLANNED ANALYSES .......................................................................................... 11 
3.1. 
Interim Analyses ......................................................................................... 11 
3.2. 
Final Analyses ............................................................................................ 11 
4.
ANALYSIS POPULATIONS ................................................................................... 12 
4.1. 
Protocol Deviations ..................................................................................... 12 
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING
CONVENTIONS ..................................................................................................... 13 
5.1. 
Study Treatment & Sub-group Display Descriptors ..................................... 13 
5.2. 
Baseline Definitions .................................................................................... 13 
5.3. 
Multicentre Studies ..................................................................................... 13 
5.4. 
Examination of Covariates, Other Strata and Subgroups ............................ 13 
5.4.1. 
Covariates and Other Strata ........................................................ 13 
5.4.2. 
Examination of Subgroups ........................................................... 13 
5.5. 
Other Considerations for Data Analyses and Data Handling 
Conventions ................................................................................................ 14 
6.
STUDY POPULATION ANALYSES ....................................................................... 15 
6.1. 
Overview of Planned Study Population Analyses ........................................ 15 
7.
EFFICACY ANALYSES .......................................................................................... 15 
7.1. 
Secondary Efficacy Analyses ...................................................................... 15 
7.1.1. 
Endpoint / Variables ..................................................................... 15 
7.1.2. 
Population of Interest ................................................................... 15 
7.1.3. 
Strategy for Intercurrent (Post-Randomization) Events ................ 15 
7.1.4. 
Statistical Analyses / Methods ..................................................... 16 
7.1.4.1. 
Statistical Methodology Specification .......................... 16 
8.
SAFETY ANALYSES ............................................................................................. 17 
8.1. 
Adverse Events Analyses ........................................................................... 17 
8.1.1. 
Injection Site Reaction Adverse Events ....................................... 17 
8.2. 
Adverse Events of Special Interest Analyses .............................................. 17 
8.3. 
Clinical Laboratory Analyses ....................................................................... 18 
8.4. 
Other Safety Analyses ................................................................................ 18 
9.
PHARMACOKINETIC ANALYSES ......................................................................... 19 
9.1. 
Drug Concentration Measures .................................................................... 19 


TMF-14552026 
CONFIDENTIAL 
209493 
 
4 
10. VIROLOGY ............................................................................................................ 19 
10.1. 
Genotypic and Phenotypic Data .................................................................. 19 
11. OTHER ANALYSES ............................................................................................... 19 
11.1. 
Study Visit Length ....................................................................................... 19 
12. REFERENCES ....................................................................................................... 20 
13. APPENDICES ........................................................................................................ 21 
13.1. 
Appendix 1: Exclusions from Per Protocol Population ................................. 21 
13.2. 
Appendix 2: Schedule of Activities .............................................................. 22 
13.2.1. 
Protocol Defined Schedule of Events ........................................... 22 
13.2.1.1. Schedule of Activities for Patient Study 
Participants (CAB LA + RPV LA Monthly 
Administration) ........................................................... 22 
13.2.1.2. Schedule of Assessments Table for Staff Study 
Participants ................................................................ 27 
13.2.1.3. Schedule of Activities Table for Patient Study 
Participants (Long Term Follow Up) a ......................... 28 
13.3. 
Appendix 3: Assessment Windows ............................................................. 29 
13.3.1. 
Definitions of Assessment Windows for Analyses ........................ 29 
13.3.2. 
Assessment Windows for PK Concentration Data ........................ 34 
13.4. 
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................ 35 
13.4.1. 
Study Phases .............................................................................. 35 
13.4.2. 
Treatment State ........................................................................... 37 
13.4.3. 
Oral Lead-in Period ...................................................................... 38 
13.5. 
Appendix 5: Data Display Standards & Handling Conventions .................... 40 
13.5.1. 
Reporting Process ....................................................................... 40 
13.5.2. 
Reporting Standards .................................................................... 40 
13.5.3. 
Reporting Standards for Pharmacokinetic .................................... 41 
13.6. 
Appendix 6: Derived and Transformed Data ............................................... 42 
13.6.1. 
General ........................................................................................ 42 
13.6.2. 
Study Population .......................................................................... 43 
13.6.3. 
Efficacy ........................................................................................ 44 
13.6.4. 
Safety .......................................................................................... 45 
13.6.5. 
Virology ....................................................................................... 48 
13.6.6. 
Other Assessments ..................................................................... 49 
13.7. 
Appendix 7: Reporting Standards for Missing Data ..................................... 50 
13.7.1. 
Premature Withdrawals ................................................................ 50 
13.7.2. 
Handling of Missing Data ............................................................. 50 
13.7.2.1. Handling of Missing and Partial Dates ........................ 50 
13.7.2.2. Handling of Missing Data for Statistical 
Analysis ...................................................................... 53 
13.8. 
Appendix 8: Values of Potential Clinical Importance ................................... 54 
13.9. 
Appendix 9: Snapshot Algorithm Details ..................................................... 55 
13.10. Appendix 10: AESI identification ................................................................. 60 
13.10.1. Hepatic Safety Profile .................................................................. 60 
13.10.2. Hyperglycaemia ........................................................................... 65 
13.10.3. Hypersensitivity Reactions ........................................................... 67 
13.10.4. Rash including severe cutaneous adverse reactions ................... 68 


TMF-14552026 
CONFIDENTIAL 
209493 
 
5 
13.10.5. Prolongation of the Corrected QT Interval of the ECG in 
Supra Therapeutic Doses ............................................................ 71 
13.10.6. Suicidal Ideation/Behaviour ......................................................... 72 
13.10.7. Depression .................................................................................. 73 
13.10.8. Bipolar Disorder ........................................................................... 74 
13.10.9. Psychosis .................................................................................... 74 
13.10.10. Mood Disorders ........................................................................... 78 
13.10.11. Anxiety ......................................................................................... 79 
13.10.12. Sleep Disorders ........................................................................... 83 
13.10.13. Injection site Reactions ................................................................ 87 
13.10.14. Seizures ...................................................................................... 87 
13.10.15. Weight Gain ................................................................................. 92 
13.10.16. Rhabdomyolysis .......................................................................... 93 
13.10.17. Pancreatitis .................................................................................. 94 
13.10.18. Impact on Creatinine .................................................................... 95 
13.10.19. Safety During Pregnancy ............................................................. 97 
13.11. Appendix 11: Identification of COVID-19 Adverse Events ........................... 98 
13.12. Appendix 12: Abbreviations & Trade Marks .............................................. 100 
13.12.1. Abbreviations ............................................................................. 100 
13.12.2. Trademarks ............................................................................... 101 
13.13. Appendix 13: List of Data Displays............................................................ 102 
13.13.1. Data Display Numbering ............................................................ 102 
13.13.2. Mock Example Shell Referencing .............................................. 102 
13.13.3. Deliverables ............................................................................... 103 
13.13.4. Study Population Tables ............................................................ 104 
13.13.5. Efficacy Tables .......................................................................... 109 
13.13.6. Efficacy Figures ......................................................................... 112 
13.13.7. Safety Tables ............................................................................. 115 
13.13.8. Safety Figures ........................................................................... 125 
13.13.9. Virology Tables .......................................................................... 126 
13.13.10. Other Tables .............................................................................. 127 
13.13.11. ICH Listings ............................................................................... 128 
13.13.12. Non-ICH Listings ........................................................................ 132 
13.14. Appendix 14: Example Mock Shells for Data Displays .............................. 136 
 


TMF-14552026 
CONFIDENTIAL 
209493 
 
6 
1. 
INTRODUCTION 
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol: 
Revision Chronology: 
2018N382441_00 
02-JAN-2019 
Original 
2018N382441_01 
02-APR-2019 
Amendment No. 1 
The reasons for this amendment include: addition of exclusion criterion regarding known major 
resistance mutations at Screening, clarification of timing for collection of visit length, removal of 
consent requirement for study staff, correction to allowable window around the Month 3 dosing 
visit, clarification of pregnancy testing requirements at Screening, clarification of wording to allow 
a single re-screen per subject, removal of color of vial stopper in product description to allow 
flexibility of packaging for cabotegravir and rilpivirine suspension, clarification of ECG collection 
during the study, clarification of wording to allow qualitative analyses to be performed by a CRO 
under GSK oversight. 
2018N382441_02 
15-MAY-2020 
Amendment No.2 
The purpose of this amendment is to include an Appendix related to COVID-19 Pandemic and 
Clinical Trial Continuity. This appendix will replace the previous Appendix 11, and “Protocol 
Amendment History,” will be included as Appendix 12. 
2018N382441_03 
16-NOV-2020 
Amendment No. 3 
The primary purpose of this amendment is to allow participants who become pregnant while in 
the study to remain in the study and not be withdrawn as a result of the pregnancy. Allowing 
pregnant participants to continue in the study will negate any subsequent fetal exposures to new 
antiretrovirals agents that would occur if the pregnant participant was withdrawn from study and 
placed on an oral SOC regimen. An Appendix, “Information and Guidance for Managing 
Pregnant Participants” was inserted as Appendix 8 and all subsequent appendices were 
renumbered accordingly. 
Minor additional edits were made which were previously addressed with a note to file 
(NTF), for clarity and/or correction. 


TMF-14552026 
CONFIDENTIAL 
209493 
 
7 
1.1. 
RAP Amendments 
Revision Chronology: 
RAP Section 
Amendment Details 
Reporting and Analysis Plan_Study209493_Final_V1 [29-OCT-2020] 
Reporting and Analysis Plan_Study209493_Amendment_1_Final_V1 
Data Displays for End of 
Study Analysis 
• Added the displays for summarizing and listing the data collected 
from the newly added eCRF form, Transition to CAB + RPV LA 
Marketed Product Status. 
• Updated the standard shells for COVID-19 assessment and 
symptom displays per changes of the data collection. 
• Updated the standard shell for the country level listing of COVID-
19 pandemic measures to include the start and end dates of 
each wave of the pandemic. 
• Added age group (18-24, 25-40, >40) and BMI group (<30, >=30) 
to the summary table of demographic characteristics. 
• Added an efficacy table for summarizing the proportion of plasma 
HIV-1 RNA < 50 c/mL over time from the observed case 
analysis. 
• Added a listing of COVID-19 vaccine. 
• Updated the Extension phase visit slotting algorithm for HIV-1 
RNA data . 
General Updates 
• Updated Schedule of Activities and other relevant sections per 
protocol amendment 03. 
• Added additional minor clarifications and corrections to 
typographical errors/formatting to RAP text. 


TMF-14552026 
CONFIDENTIAL 
209493 
 
8 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
There were no changes or deviations to the originally planned statistical analysis 
specified in protocol amendment 03 [(Dated: 16/November/2020)]. 
2.2. 
Study Objective(s) and Estimand(s) / Endpoint(s) 
Objectives 
Estimands / Endpoints 
Primary 
Primary  
• To evaluate acceptability, 
appropriateness, and feasibility of 
delivering CAB+RPV LA 
• Acceptability of Intervention Measure (AIM), 
Intervention Appropriateness Measure (IAM), and 
Feasibility of Intervention Measure (FIM). Assessed 
quantitatively by staff study participants at baseline- 
prior to any Month 1 visits, after at least 4 monthly 
facilitation calls and upon completion of all Month 
12 visits at that site. 
• Acceptability of Intervention Measure (AIM) and 
Intervention Appropriateness Measure (IAM). 
Assessed quantitatively by patient study 
participants at Month 1 prior to first injection, Month 
4 and Month 12 
Secondary 
Secondary  
• To evaluate organizational 
facilitators and barriers 
• Facilitators/Barriers: Semi-Structured Interview 
(SSI) conducted with staff study participants at 
baseline- prior to any Month 1 visits, after at least 4 
monthly facilitation calls and upon completion of at 
least 50% of Month 12 visits at that site.  
• Barriers, facilitators and best practice sharing 
amongst clinics assessed by short-term facilitation 
(coaching calls) for at least 6 months. These will be 
a combination of structured questions and open-
ended questions. 
• Use of support materials/toolkit assessed via 
Survey responses of staff study participants prior to 
any Month 1 visits, after at least 4 monthly 
facilitation calls and upon completion of all Month 
12 visits at a site.  
• Use of support materials/toolkit assessed via 
Survey responses of patient study participants via 
Survey responses at Month 1 and Month 4 and 
Month 12, as well as SSI responses prior to Month 
1 and at Month 12. 
• Patient Facilitators and Barriers 
• Facilitators/Barriers: Semi-Structured Interviews 
(SSI) conducted with patient study participants prior 
to Month 1 and at Month 12. 


TMF-14552026 
CONFIDENTIAL 
209493 
 
9 
Objectives 
Estimands / Endpoints 
• Implementation Fidelity 
• Injections occurring within target window from the 
expected injection date 
• Use of support materials/toolkit assessed through 
SSI of staff study participants at Day 1, after at 
least 4 monthly facilitation calls and upon 
completion of at least 50% of Month 12 visits at that 
site 
• Implementation Sustainability 
• Program Sustainability Assessment Tool (PSAT) 
assessed by staff study participants at Month 12 
• To measure patient satisfaction 
with process (timeliness of visits, 
length of visit, patient education) 
• Patient Survey responses at Month 1, Month 4 and 
Month 12. 
• Patient SSI responses prior to Month 1 and at 
Month 12 
• Length of patient visit from arrival until departure 
from clinic at Month 1, Month 5 and Month 11 
• To evaluate the safety and 
efficacy measures of CAB LA + 
RPV LA 
• Proportion of participants with plasma HIV-1 RNA 
<50 c/mL over time 
• Proportion of participants with confirmed virologic 
failure (CVF) over time 
• Incidence of treatment emergent genotypic and 
phenotypic resistance to CAB and RPV in patients 
with CVF 
• Incidence and severity of AEs and laboratory 
abnormalities over time 
• Proportion of participants who discontinue 
treatment due to AEs over time 
• Reported injection site reactions over time 
• Absolute values and changes in laboratory 
parameters over time 


TMF-14552026 
CONFIDENTIAL 
209493 
 
10 
2.3. 
Study Design 
Overview of Study Design and Key Features 
N=115 patients; Open label with respect to treatment; patients randomized to CAB LA+RPV LA Interview: 
CAB LA + RPV LA Non-Interview 
Design 
Features 
• 
A qualitative hybrid III implementation study to identify and evaluate strategies for 
successful implementation of the cabotegravir + rilpivirine long-acting injectable 
regimen in the US 
• 
The CUSTOMIZE study comprises of screening phase (up to 21 days), Intervention 
Phase from Day 1 to Month 12, including Oral Lead-in, long term follow-up (LTFU) 
phase, and extension phase. During screening phase all clinical and laboratory 
assessments of eligibility must be performed and reviewed. Participants may be re-
screened once 
Dosing 
• 
Intervention Phase is Open label with respect to treatment;  
• 
Intervention Phase: randomized 1:3 to CAB LA+RPV LA Interview:CAB LA + RPV 
LA Non-Interview 
• 
Randomized at Day 1 (1:3) to receive CAB LA + RPV LA Interview or CAB LA + 
RPV LA Non-interview respectively 
• 
GSK Randall NG used to generate randomization schedule for interview group 
assignments 
Time & 
Events 
• 
Refer to Appendix 2: Schedule of Activities 
Treatment 
Assignment 
• 
CAB LA+RPV LA (N=115) 
Interim 
Analysis 
• 
Analysis at Month 4 to provide preliminary data to inform planning for the initial 
commercial availability of the CAB LA + RPV LA regimen 
• 
Primary analysis will be conducted at Month 12 
2.4. 
Statistical Hypotheses / Statistical Analyses 
No formal hypothesis testing is planned. 


TMF-14552026 
CONFIDENTIAL 
209493 
 
11 
3. 
PLANNED ANALYSES 
This RAP describes standard analyses that will be applied to descriptively summarize 
clinical adverse events, laboratory evaluations, virologic parameters and other clinical 
safety and efficacy outcomes.  
Details pertaining to reporting of survey/interview data and health 
outcomes/effectiveness analyses will be described in a separate analysis plan provided by 
Evidera or other CRO partner under GSK’s oversight. 
At least two analyses will be conducted to evaluate primary and secondary objectives of 
the protocol: an interim analysis at Month 4 and a primary analysis at Month 12.  
A final end-of-study (EOS) analysis will be conducted when all subjects have completed 
the study. 
3.1. 
Interim Analyses 
One interim analysis at Month 4 was performed to provide preliminary data to inform 
planning for the initial commercial availability of the CAB + RPV LA regimen. No 
formal criteria for stopping or amending the study based on the interim analysis are 
envisioned.  Analysis and reporting details can be found in the standalone Month 4 
interim analysis RAP. 
3.2. 
Final Analyses 
The planned Month 12 primary analysis will be performed after the completion of the 
following sequential steps: 
1. All participants have completed Month 12 of the study as defined in the protocol.  
2. All required database cleaning activities have been completed and final database 
release (DBR), source data lock (SDL) and database freeze (DBF) have been 
declared by Data Management. 
The planned EOS analysis will be conducted after the completion of the following 
sequential steps: 
1. All participants have completed the study as defined in the protocol.  
2. All required database cleaning activities have been completed and final database 
release (DBR), source data lock (SDL) and database freeze (DBF) have been 
declared by Data Management. 


TMF-14552026 
CONFIDENTIAL 
209493 
 
12 
4. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses Evaluated 
Screened  
• All participants who were screened for eligibility 
• Study Population 
Enrolled 
• All participants who passed screening and 
entered the study (i.e. were administered study 
treatment). 
• Study Population 
Safety 
• All participants who received at least one dose of 
study treatment. 
• Study Population, 
Safety, Efficacy, 
Virology, PK, Other 
Assessments 
Refer to Appendix 13: List of Data Displays which details the population used for each display. 
4.1. 
Protocol Deviations 
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed. 
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan [Version 4,12-May-2021]. 
o Data will be reviewed prior to freezing the database to ensure all important 
deviations are captured and categorised on the protocol deviations dataset.  
o This dataset will be the basis for the summaries and listings of protocol 
deviations. 
A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion 
page of the eCRF. 
Protocol deviations related to the implementation process, and not the clinical conduct of 
the study will be reported separately. The identification and categorization of PDs as 
important may be different for implementation PDs vs those associated with the clinical 
conduct of the study. 


TMF-14552026 
CONFIDENTIAL 
209493 
 
13 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
5.1. 
Study Treatment & Sub-group Display Descriptors 
Treatment Group Descriptions 
Data Displays for Reporting  
Description 
Order in TLF  
CAB LA +RPV LA 
1 
5.2. 
Baseline Definitions 
For all endpoints the baseline value will be the latest pre-treatment (See Table 10)  
assessment with a non-missing value, including those from unscheduled visits. If time is 
not collected, assessments taken on the same date as treatment start date are assumed to 
be taken prior to first dose and used as baseline. 
Electrocardiograms (ECGs) are to be performed in triplicate on Screening visit. The 
baseline value for an ECG parameter will be the mean of the last pre-treatment set of 
assessments from the same date so long as at least one of the triplicate assessments is 
available. 
5.3. 
Multicentre Studies 
In this multicentre global study, enrolment will be presented by investigator and Site 
type. 
5.4. 
Examination of Covariates, Other Strata and Subgroups 
5.4.1. 
Covariates and Other Strata 
The list of covariates and other strata may be used in descriptive summaries and 
statistical analyses, some of which may also be used for subgroup analyses. Additional 
covariates and other strata of clinical interest may also be considered. 
Category 
Details 
Covariates 
Site Type 
5.4.2. 
Examination of Subgroups 
The list of subgroups may be used in descriptive summaries and statistical analyses. 
Additional subgroups of clinical interest may also be considered. 
• 
If the percentage of participants is small within a subgroup category, then the 
subgroup categories may be combined. 
Subgroup 
Categories  
Site Type 
AIDS Healthcare Foundation, Federally Qualified Health 
Center, Health Maintenance Organization, Private Practice, 
University 


TMF-14552026 
CONFIDENTIAL 
209493 
 
14 
5.5. 
Other Considerations for Data Analyses and Data Handling 
Conventions 
Other considerations for data analyses and data handling conventions are outlined in the 
appendices: 
Section Component 
13.3 
Appendix 3: Assessment Windows 
13.4 
Appendix 4: Study Phases and Treatment Emergent Adverse Events 
13.5 
Appendix 5: Data Display Standards & Handling Conventions 
13.6 
Appendix 6: Derived and Transformed Data 
13.7 
Appendix 7: Reporting Standards for Missing Data 
13.8 
Appendix 8: Values of Potential Clinical Importance 
 


TMF-14552026 
CONFIDENTIAL 
209493 
 
15 
6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Study Population Analyses 
The study population analyses will be based on the Safety population, unless otherwise 
specified. 
Study population analyses including analyses of participant’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure and treatment compliance will be based on GSK Core Data Standards.  
Details of the planned displays are presented in Appendix 13: List of Data Displays. 
7. 
EFFICACY ANALYSES 
Implementation Science/Health Outcomes endpoints will form the basis for the overall 
primary analysis of the study, and details of implementation science/health outcomes 
analyses are documented in a separate Evidera SAP.  Clinical efficacy endpoints are 
evaluated as secondary objectives for this study. 
7.1. 
Secondary Efficacy Analyses 
7.1.1. 
Endpoint / Variables 
• Proportion of participants with Plasma HIV-RNA < 50 copies/mL and plasma HIV-1 
RNA ≥ 50 c/mL, respectively, over time using the FDA Snapshot Algorithm. See 
Section 13.9 for Snapshot Algorithm details. 
Other secondary efficacy endpoints: 
• Proportion of participants with confirmed virologic failure (CVF) over time 
• Absolute values and changes from Baseline CD4+ cell count over time 
7.1.2. 
Population of Interest  
Secondary efficacy analyses will be based on the Safety population, unless otherwise 
specified. 
7.1.3. 
Strategy for Intercurrent (Post-Randomization) Events 
• 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 HIV-1 RNA < 50 c/mL.  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.  
• Participants with last available HIV-1 RNA measurement greater or equal to 50 
copies/mL while the participant is on treatment within the analysis visit window of 
interest are classified as HIV-1 RNA ≥ 50 c/mL. Participants without evaluable HIV-
RNA data for the visit of interest and who discontinue treatment for reasons not 
related to adverse event while having HIV-1 RNA ≥50 copies/mL at time of 


TMF-14552026 
CONFIDENTIAL 
209493 
 
16 
discontinuation or who change study treatment not permitted per protocol before the 
analysis window are also classified as having HIV-RNA ≥50 copies/mL.  
Missing viral load values for reasons related to COVID-19 issues (e.g. participant is 
unable to have viral load assessed due to barriers in attending the clinic during the 
pandemic or COVID-19 related adverse events leading to treatment discontinuation) will 
be imputed using an LOCF approach in which the last on-treatment viral load value will 
be carried forward and used in place of missing values. 
7.1.4. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 13: List of Data Displays and 
will be based on GSK data standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 7.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. 
7.1.4.1. 
Statistical Methodology Specification 
Endpoint / Variables 
• Proportion of participants with plasma HIV-1 RNA < 50 c/mL over time using the FDA 
Snapshot algorithm (Safety population) 
• Proportion of participants with plasma HIV-1 RNA ≥ 50 c/mL over time using the FDA 
Snapshot algorithm (Safety population) 
Results Presentation 
• The proportion of participants with HIV-1 RNA < 50 c/mL and HIV-1 RNA ≥ 50 c/mL, 
respectively, at each planned visit with corresponding 95% confidence intervals calculated 
using the Clopper-Pearson exact method. 
• The proportion of participants in each Snapshot study outcome category and sub-category 
will be summarized at Month 12, in which default sub-categories have been expanded to 
present COVID-19 vs. non COVID-19 related impact (as described in Section 13.9). 


TMF-14552026 
CONFIDENTIAL 
209493 
 
17 
8. 
SAFETY ANALYSES 
The safety analyses will be based on the Safety population, unless otherwise specified. 
For the Month 12 and EOS analyses, safety displays will summarize data across the 
combined   Intervention + Extension Phases, unless otherwise specified in the display 
title presented in Appendix 13: List of Data Displays. 
8.1. 
Adverse Events Analyses 
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs), 
COVID-19 AEs, and other significant AEs will be based on GSK Core Data Standards. 
The details of the planned displays are provided in Appendix 13: List of Data Displays. 
8.1.1. 
Injection Site Reaction Adverse Events 
Injection Site Reaction (ISR) adverse events of interest are those from study drug 
injections.  
For the summary of Injection Site Reaction Adverse Events by Visit and Maximum 
Severity (Overall and by Common ISRs), ISRs will be assigned based on onset date to 
the most recent planned IM injection visit prior or equal to the AE onset date.   
Maximum grade at each visit will be derived as the maximum grade among ISRs 
assigned to the particular visit, with consideration for whether the summary applies to a 
particular preferred term (vs. across preferred terms), or drug-related associated to CAB 
and/or RPV. 
Drug-related ISRs (based on investigator discretion) will be attributed to the causal agent 
(CAB vs. RPV) when this can be determined specifically based on the side of injection 
administration and the side of the reported ISR (as collected in the eCRF). If we are 
unable to determine the causal agent in those cases where both drugs are given on one 
side and the ISR is reported non-specifically, then the attribution to a specific causal 
agent will remain unknown. 
Common study drug ISR adverse events are defined by MedDRA preferred terms 
including injection site pain, injection site induration, injection site nodules and preferred 
terms of any other ISR reported by ≥5% of participants overall.   
8.2. 
Adverse Events of Special Interest Analyses 
A comprehensive list of MedDRA terms based on clinical review will be used to identify 
Adverse Events of Special Interest (AESI). Changes to the MedDRA dictionary may 
occur between the start of the study and the time of reporting and/or emerging data from 
on-going studies may highlight additional adverse events of special interest, therefore the 
list of terms to be used for each event of interest and the specific events of interest will be 
based on the safety review team (SRT) agreements in place at the time of reporting. The 
details of the current planned grouping, including Standardized MedDRA Query (SMQ) 


TMF-14552026 
CONFIDENTIAL 
209493 
 
18 
values (as applicable), and planned displays are provided in Appendix 10: AESI 
identification and Appendix 13: List of Data Displays. 
8.3. 
Clinical Laboratory Analyses 
Laboratory evaluations will be based on GSK Core Data Standards. The details of the 
planned displays are in Appendix 13: List of Data Displays. 
8.4. 
Other Safety Analyses 
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. The details of the 
planned displays are presented in Appendix 13: List of Data Displays. 


TMF-14552026 
CONFIDENTIAL 
209493 
 
19 
9. 
PHARMACOKINETIC ANALYSES 
9.1. 
Drug Concentration Measures  
Available concentration-time data for CAB and RPV will be presented in listings as 
specified in Appendix 13: List of Data Displays and will be based on GSK Data 
Standards and statistical principles. 
Refer Appendix 5: Data Display Standards & Handling Conventions (Section 13.5.3 
Reporting Standards for Pharmacokinetic). 
10. 
VIROLOGY 
 
10.1. 
Genotypic and Phenotypic Data 
Available genotypic and phenotypic data at all collection timepoints will be presented by 
subject (separately for CVF and Non-CVF subjects), as specified in Appendix 13: List of 
Data Displays. 
11. 
OTHER ANALYSES 
11.1. 
Study Visit Length 
The details of the planned displays for study visit length data are in Appendix 13: List of 
Data Displays and will be based on GSK Data Standards and statistical principles. 


TMF-14552026 
CONFIDENTIAL 
209493 
 
20 
12. 
REFERENCES 
Wensing AM, et al. 2019 update of the drug resistance mutations in HIV-1. Topics in 
antiviral medicine. 2019;27:111-121.  


TMF-14552026 
CONFIDENTIAL 
209493 
 
21 
13. 
APPENDICES 
13.1. 
Appendix 1: Exclusions from Per Protocol Population 
Instream and final analysis population reviews as per SOP 130050 are not planned for 
this study because it does not include a Per-Protocol population. 
 
 


TMF-14552026 
CONFIDENTIAL 
209493 
 
22 
13.2. 
Appendix 2: Schedule of Activities 
13.2.1. 
Protocol Defined Schedule of Events 
13.2.1.1. Schedule of Activities for Patient Study Participants (CAB LA + RPV LA Monthly Administration) 
 


TMF-14552026 
CONFIDENTIAL 
209493 
 
23 
 
 


TMF-14552026 
CONFIDENTIAL 
209493 
 
24 
 
 


TMF-14552026 
CONFIDENTIAL 
209493 
 
25 
 


TMF-14552026 
CONFIDENTIAL 
209493 
 
26 
 


TMF-14552026 
CONFIDENTIAL 
209493 
 
27 
13.2.1.2. Schedule of Assessments Table for Staff Study Participants 
 


TMF-14552026 
CONFIDENTIAL 
209493 
 
28 
13.2.1.3. Schedule of Activities Table for Patient Study Participants (Long Term Follow Up) a 
 
 


TMF-14552026 
CONFIDENTIAL 
209493 
 
29 
13.3. 
Appendix 3: Assessment Windows 
13.3.1. 
Definitions of Assessment Windows for Analyses 
Laboratory data, vital signs, ECGs, and genotypic/phenotypic data will be assigned to 
assessment windows according to actual dates rather than the nominal visit labels as 
recorded on the eCRF or in the laboratory database. 
Prior to visit slotting, assessments are first assigned to a study phase (Screening, 
Intervention Phase, Extension, or Long Term Follow Up) as defined in Section 13.4.1. 
According to the protocol, the nominal target study visit date will be based on the first 
injection, the Month 1 date. For instance, if Month 1 occurred on July 7th, all subsequent 
visits are expected to occur on the 7th of each month such that subsequent visits will be 
August 7th, September 7th, October 7th, etc. Since there are not >28 days in each month 
of the year, if the Month 1 injection occurred on the 29th, 30th, or 31st of the month, then 
the target study visit date for the remainder of the visits will be the 28th of the month.   
The nominal target study visit day is derived as 
• M1 Target Day = Date of Actual M1 Injection Visit Date – Date of First Oral lead-in 
Dose + 1, if subject receives M1 injection; else M1 Target Day = 30. 
• Mx Target Day = Mx Nominal Target Study Visit Date – Date of First Oral lead-in 
Dose + 1, for x=2,3, … 
Assessment windows will be derived based on the midpoint between two consecutive 
planned target study visit dates. For the Snapshot efficacy data, the same approach will be 
used, except for Month 12, which will use a ± 6-week window around the projected 
target study visit date at Month 12. 
For parameters which are not scheduled to be assessed at visits, the all-inclusive 
assessment windows will still be used; however, data summaries will only report 
scheduled visits. Assessments at unscheduled visits will be included in summaries of 
worst-case values across visit (e.g. during the intervention phase) and in data listings, as 
well any algorithms that make use of additional data (e.g., Snapshot). 


TMF-14552026 
CONFIDENTIAL 
209493 
 
30 
Table 1 
Assessment Windows for Screening, Intervention and 
Extension Phase Data (Excluding HIV-1 RNA and PK data) 
Target 
(Study 
Day)  
Analysis Window 
Analysis 
Timepoint 
Beginning Timepoint 
Ending Timepoint 
Day of 
earliest 
record 
Assessment Study Day ≤1 
Screening 
For subjects discontinuing prior to receiving first injection: 
30 
Assessment Study Day = 2 
Study Day of Last CAB/RPV 
Oral Dose+1 
Month 1 
 
Assessment Study Day >  
(Study Day of Last CAB/RPV Oral Lead-in Dose +1) 
Follow-up 
For subjects receiving first injection: 
Day of First 
Injection 
Study Day = 2 
M1 target day + floor [(M2 
target day – M1 target day)/2] 
Month 1 
M2  
Target Day 
M1 target day + floor [(M2 target day 
– M1 target day)/2] + 1 
M2 target day + floor [(M4 
target day – M2 target day)/2] 
Month 2 
M4  
Target Day 
M2 target day + floor [(M4 target day 
– M2 target day)/2] + 1 
M4 target day + floor [(M6 
target day – M4 target day)/2]  
Month 4 
M6  
Target Day 
M4 target day + floor [(M6 target day 
– M4 target day)/2] + 1 
M6 target day + floor [(M9 
target day – M6 target day)/2]  
Month 6 
M9  
Target Day 
M6 target day + floor [(M9 target day 
– M6 target day)/2] + 1 
M9 target day + floor [(M12 
target day – M9 target day)/2]  
Month 9 
M12  
Target Day 
M9 target day + floor [(M12 target 
day – M9 target day)/2] + 1 
M12 target day + floor [(M15 
target day – M12 target 
day)/2]  
Month 12 
M15  
Target Day 
M12 target day + floor [(M15 target 
day – M12 target day)/2] + 1 
M15 target day + floor [(M18 
target day – M15 target 
day)/2]  
Month 15 
M18  
Target Day 
M15 target day + floor [(M18 target 
day – M15 target day)/2] + 1 
M18 target day + floor [(M21 
target day – M18 target 
day)/2] 
Month 18 
Mx  
Target Day 
M(x-3) target day - floor [(Mx target 
day – M(x-3) target day)/2] + 1 
Mx target day + floor 
[(M(x+3) target day – Mx 
target day)/2] 
Month x 
For x = 
21, 24, 
etc. 


TMF-14552026 
CONFIDENTIAL 
209493 
 
31 
Target 
(Study 
Day)  
Analysis Window 
Analysis 
Timepoint 
Beginning Timepoint 
Ending Timepoint 
For subjects who permanently discontinue study treatment: 
 
Assessment Study Day > 
 Max (Study Day of Last Dose of Oral Study Treatment (CAB+RPV 
or SOC Bridging) + 1, Study Day of Last CAB + RPV Injection + 35) 
Follow-up 
Table 2 
Assessment Windows for Screening and Intervention Phase 
HIV-1 RNA Data 
Target 
(Study Day)  
Analysis Window 
Analysis 
Timepoint 
Beginning Timepoint 
Ending Timepoint 
Day of earliest 
record 
Assessment Study Day ≤1 
Screening 
 
For subjects discontinuing prior to receiving first injection: 
28 
Assessment Study Day = 2 
Study Day of Last Oral Lead-
in Dose +1 
Month 1 
 
Assessment Study Day > 
 (Study Day of Last CAB/RPV Oral Lead-in Dose +1) 
Follow-up 
 
For subjects receiving first injection: 
Date of First 
Injection 
Study Day = 2 
M1 target day + floor [(M2 
target day – M1 target day)/2] 
Month 1 
M2 Target Day 
M1 target day + floor [(M2 
target day – M1 target day)/2] 
+1 
M2 target day + floor [(M4 
target day – M2 target day)/2] 
Month 2 
M4 Target Day 
M2 target day + floor [(M4 
target day – M2 target day)/2] + 
1 
M4 target day + floor [(M6 
target day – M4 target day)/2] 
Month 4 
M6 Target Day 
M4 target day + floor [(M6 
target day – M4 target day + 1 
M6 target day + floor [(M8 
target day – M6 target day)/2] 
Month 6 
M8 Target Day 
M6 target day + floor [(M8 
target day – M6 target day)/2] + 
1 
M8 target day + floor [(M10 
target day – M8 target day)/2] 
Month 8 
M10 Target 
Day 
M8 target day + floor [(M10 
target day – M8 target day)/2] + 
1 
M12 target day – 43 
Month 10 
M12 Target 
Day 
M12 target day - 42 
M12 target day + 42 
Month 12 
M13 Target 
Day 
Assessment Study Day > M12 target day + 42 
Month 13 


TMF-14552026 
CONFIDENTIAL 
209493 
 
32 
Target 
(Study Day)  
Analysis Window 
Analysis 
Timepoint 
Beginning Timepoint 
Ending Timepoint 
For subjects who permanently discontinue study treatment during the Intervention Phase: 
 
Assessment Study Day > 
Max (Study Day of Last Dose of Oral Study Treatment 
(CAB+RPV or SOC Bridging) +1, Study Day of Last CAB + RPV 
Injection + 35) 
Follow-up 
 


TMF-14552026 
CONFIDENTIAL 
209493 
 
33 
Table 3 
Assessment Windows for Extension Phase HIV-1 RNA Data 
Target 
(Study Day)  
Analysis Window 
Analysis 
Timepoint 
Beginning Timepoint 
Ending Timepoint 
M13 Target 
Day 
Study Day of Nominal Month 
13 Visit 
M13 target day + floor [(M15 
target day – M13 target day)/2]  
Month 13 
M15 Target 
Day 
M13 target day + floor [(M15 
target day – M13 target day)/2] 
+ 1 
M15 target day + floor [(M16 
target day – M15 target day)/2] 
Month 15 
M16 Target 
Day 
M15 target day + floor [(M16 
target day – M15 target day)/2] 
+ 1 
M16 target day + floor [(M18 
target day – M16 target day)/2] 
Month 16  
. 
 
M18 Target 
Day 
M16 target day + floor [(M18 
target day – M16 target day)/2] 
+ 1 
M18 target day + floor [(M19 
target day – M18 target day)/2] 
Month 18  
Mx Target Day 
M(x-1) target day + floor [(Mx 
target day – M(x-1) target 
day)/2] + 1 
Mx target day + floor [(M(x+2) 
target day – Mx target day)/2] 
Month x 
For x =19, 
22, 25, 28 
etc. 
 
Mx Target Day 
M(x-2) target day + floor [(Mx 
target day – M(x-2) target 
day)/2] + 1 
Mx target day + floor [(M(x+1) 
target day – Mx target day)/2] 
Month x 
For x =21, 
24, 27, 30 
etc. 
 
For subjects who permanently discontinue study treatment during the Extension Phase: 
 
Assessment Study Day > 
Max (Study Day of Last Dose of Oral Study Treatment 
(CAB+RPV or SOC Bridging) +1, Study Day of Last CAB + RPV 
Injection + 35) 
Follow-up 


TMF-14552026 
CONFIDENTIAL 
209493 
 
34 
Table 4 
Assessment Windows for Study Visit Length Data 
(Intervention and Extension Phase) 
Target 
(Study Day)  
Analysis Window 
Analysis 
Timepoint 
Beginning 
Timepoint 
Ending Timepoint 
Study Day of Actual M1 
Injection 
Study Day of Actual M1 Injection 
Month 1 
Study Day of Actual M5 
Injection 
Study Day of Actual M5 Injection 
Month 5 
Study Day of Actual M11 
Injection 
Study Day of Actual M11 Injection 
Month 11 
Study Day of Actual M14 
Injection 
Study Day of Actual M14 Injection 
Month 14 
Study Day of Actual Mx 
Injection 
Study Day of Actual Mx Injection 
Month x 
For x=17, 20, 
etc. 
 
If none of the above, then 
 Analysis Timepoint = Other 
 
Table 5 
Assessment Windows for Summaries of Long-Term Follow-up 
Phase Data from Subjects who Received at Least One Injection 
of CAB+RPV and Permanently Discontinued from the Study 
Day of Assessment 
Assessment Window 
Target LTFU Study Day of 
Window 
1 ≤ LTFU Study Day ≤ 135 
LTFU Month 3 
90 
136≤ LTFU Study Day ≤ 225 
LTFU Month 6 
180 
226 ≤ LTFU Study Day ≤ 315 
LTFU Month 9 
270 
316 ≤ LTFU Study Day ≤ 405 
LTFU Month 12 
360 
(30*m-44) ≤ LTFU Study Day ≤ 
(30*m+45) 
LTFU Month m  
M = 15, 18, 21 
30*m 
• LTFU Study Day is defined in 13.6.1 
13.3.2. 
Assessment Windows for PK Concentration Data 
PK data will be presented in data listings according to planned nominal visits (i.e. as 
collected in the eCRF), without additional assignment to assessment windows. 


TMF-14552026 
CONFIDENTIAL 
209493 
 
35 
13.4. 
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events 
13.4.1. 
Study Phases 
AEs will be assigned to study phases as defined in Table 6. Laboratory data (efficacy, 
safety, and virology), HIV associated Conditions, health outcomes assessments, vital 
signs, and ECGs will be assigned to study phases as defined in Table 7. 
Assessments/events are assigned to study phases sequentially, starting from the top of 
each table. 
Table 6 
Study Phases for AEs 
Study Phase 
Definition 
Screen  
Date < Intervention Phase Treatment Start Date 
 
Intervention 
For subjects continuing into the Extension Phase: 
Intervention Phase Treatment Start Date ≤ Date < Date of Nominal Month 
13 Visit 
 
For subjects not continuing into the Extension Phase: 
Intervention Phase Treatment Start Date ≤ Date < LTFU ART Start Date [a] 
 
For AEs leading to treatment withdrawal with start date equal to the LTFU 
ART Start Date, Intervention Phase instead of Long-term Follow-up Phase 
will be assigned. 
Extension Phase 
Date of Nominal Month 13 Visit ≤ Date < LTFU ART Start Date [a] 
 
For AEs leading to treatment withdrawal with start date equal to the LTFU 
ART Start Date, Extension Phase instead of Long-Term Follow-up Phase 
will be assigned. 
Long Term 
Follow-Up 
For subjects who receive at least one CAB/RPV injection and 
permanently discontinue study treatment: 
AE Start Date ≥ LTFU ART Start Date 
AEs with completely missing start date: 
• If AE end date is ≤ Intervention Phase Treatment Start Date, then assign to Screening 
Phase; 
• Else if AE end date is completely missing or Intervention Phase Treatment Start Date < 
AE end date ≤ Date of Nominal Month 13 Visit, then assign to Intervention Phase; 
• Else if AE end date > Date of Nominal Month 13 Visit, then assign to Extension Phase. 
Date=AE Start Date  
• [a] If participants have missing LFTU ART start date, only the lower bound will be considered in 
the derivation. 


TMF-14552026 
CONFIDENTIAL 
209493 
 
36 
Table 7 
Study Phases for Laboratory, PK, ECG, Vital Signs, HIV-1 
Associated Conditions, and Protocol Deviation Data 
Study Phase 
Definition 
Screen 
Date ≤ Study Treatment Start Date 
Intervention 
For subjects continuing into the Extension Phase: 
Intervention Phase Treatment Start Date < Date < Date of Nominal Month 
13 Visit 
 
For subjects not continuing into the Extension Phase: 
Intervention Phase Treatment Start Date < Date ≤ LTFU ART Start Date [a]   
Extension Phase 
For subjects continuing into Extension Phase: 
Date of Nominal Month 13 Visit ≤ Date ≤ LTFU ART Start Date [a] 
Long Term 
Follow-Up 
For subjects who receive at least one CAB/RPV injection and 
permanently discontinue study treatment: 
Assessment Date > LTFU ART Start Date  
• Date = start or assessment date 
• [a] If participants have missing LFTU ART start date, only the lower bound will be considered 
in the derivation. 
Study phase of discontinuation will be determined according to Table 8. 
Table 8 
Study Phases for Study Conclusion/IP Discontinuation 
Study Phase 
Definition 
Intervention 
Phase 
For IP Discontinuation: Discontinuation Date is not missing, and no 
assessments collected at any extension phase nominal visits (e.g. Month 
13, Month 15, Month 17 etc.). 
For Study Conclusion: Discontinuation or Completion Date is not missing, 
and no assessments collected at any extension phase nominal visits (e.g. 
Month 13, Month 15, Month 17 etc.) and at any LTFU phase nominal visits 
(e.g. LTFU Month 3, LTFU Month 6, etc.) 
Extension Phase 
For IP Discontinuation: Discontinuation Date is not missing, and 
assessments collected at any extension phase nominal visits (e.g. Month 
13, Month 15, Month 17 etc.). 
For Study Conclusion: Discontinuation or Completion Date is not missing, 
and assessments collected at any extension phase nominal visits (e.g. 
Month 13, Month 15, Month 17 etc.) but no assessments collected at any 
LTFU phase nominal visits (e.g. LTFU Month 3, LTFU Month 6, etc.) 
LTFU Phase 
Not applicable for IP Discontinuation. 
For Study Conclusion: Discontinuation or Completion Date is not missing, 
and assessments collected at any LTFU phase nominal visits or has taken 
any LTFU ART medications (e.g. LTFU Month 3, LTFU Month 6, etc.) 
• Discontinuation or Completion Date = date of failure to complete study/date of completing 
study/date of IP discontinuation 


TMF-14552026 
CONFIDENTIAL 
209493 
 
37 
Medication use will be classified as prior and concomitant with study treatment according 
to Table 9, noting that a medication can be assigned as “taken” during more than one 
study phase. 
Table 9 
Study Phases for Non-ART Medications/ART Medications 
 
Definition 
Prior  
Medication Taken < Intervention Treatment Start Date 
Concomitant during 
Intervention Phase 
For subjects continuing into Extension Phase: 
Intervention Treatment Start Date[a] ≤ Medication Taken < Date of 
Nominal Month 13 Visit  
 
For subjects not continuing into Extension Phase[b]: 
Intervention Treatment Start Date[a] ≤ Medication Taken < LTFU ART 
Start Date 
Concomitant during 
Extension Phase 
For subjects continuing into Extension Phase[b]: 
Date of Nominal Month 13 Visit ≤ Medication Taken < LTFU ART Start 
Date 
 
Received during 
Long-term Follow-
up 
For subjects who received at least one CAB and/or RPV injection 
and have started LTFU ART: 
Medication Taken ≥ LTFU ART Start Date 
NOTES:  
• Please refer to Appendix 7: Reporting Standards for Missing Data for handling of 
missing and partial dates for medications. Use the rules in this table if medication date is 
completely missing. 
a. The ART medication stopped on start date of Intervention treatment will be considered a 
prior medication and will not be considered concomitant during the Intervention phase. If 
the stop date of ART medication is completely missing and this medication is recorded 
in eCRF as prior, it will be considered a prior medication and will not be considered 
concomitant during the intervention phase. 
b. If subjects have missing LFTU ART start date, only the lower bound will be considered 
in the derivation. 
13.4.2. 
Treatment State 
Within each study phase (based on assignment of study phase described in Section  
13.4.1), only those events/assessments which occur within the ranges shown in Table 10 
will be considered ‘on-treatment’ for the given phase.  No treatment states will be 
assigned to medications. 
For adverse events, partial AE start date will use imputation as described in 13.7.2.1. 


TMF-14552026 
CONFIDENTIAL 
209493 
 
38 
Table 10 
Treatment State within Study Phases 
Study Phase 
State 
Definition 
Screen 
Pre-Treatment 
All assessments/events within phase 
Intervention/Extensio
n 
On-treatment 
Date ≤ max (Date of Last CAB LA +RPV LA IM 
Dose + 35, Date of Last Dose of Oral Study 
Treatment (CAB+RPV or SOC Bridging) +1) 
Post-Treatment 
Date > max (Date of Last CAB LA +RPV LA IM 
Dose + 35, Date of Last Dose of Oral Study 
Treatment (CAB+RPV or SOC Bridging) +1) 
Long Term Follow-Up 
Post-Treatment 
All assessments/events within phase 
NOTES:  
• Date = Assessment/Start Date 
a. Treatment State is determined after data has been assigned to the study phases as defined in 
Section 13.4.1. 
b. Last injection and/or last dose of oral study treatment (CAB+RPV or SOC bridging) are only 
applied to participants who permanently discontinued the study treatment. The assessments 
for participants who did not permanently discontinue the study treatment will be considered 
‘On-treatment’. For participants continuing into extension phase, all data assigned to 
intervention phase per Section 13.4.1 will be considered ‘On-treatment’ 
13.4.3. 
Oral Lead-in Period 
Certain displays will be produced for data collected or events occurring during the oral-
lead-in period as defined in Table 11 and Table 12. 


TMF-14552026 
CONFIDENTIAL 
209493 
 
39 
Table 11 
Oral Lead-in Period for AEs 
Study Period 
Date Range 
Oral Lead-in 
For participants receiving at least one Injection: 
Intervention Treatment Start Date ≤ Date [a] < Date of First IM Injection  
 
For participants withdrawing prior to first Injection: 
Date ≥ Intervention Treatment Start Date 
Note that the oral lead-in period is only applicable to the participants who 
received at least one dose of study treatment during the oral lead-in period in 
the study. Oral lead-in period is within the intervention phase. 
[a] AEs with completely missing start date which have been assigned to the Intervention Phase 
based on Table 6 will not be assigned to the Oral Lead-in Period. 
NOTES: 
• Date = AE Start date 
Table 12 
Oral Lead-in Period for Laboratory Data 
Period 
Date Range 
Oral Lead-in 
For participants receiving at least one Injection: 
Intervention Treatment Start Date < Date ≤ Date of First IM 
Injection  
 
For participants withdrawing prior to first Injection: 
Date > Intervention Treatment Start Date 
 
Note that the oral lead-in period is only applicable to the 
participants who received at least one dose of study treatment 
during the oral lead-in period in the study. Oral lead-in period is 
within the intervention phase. 
NOTES: 
• Date = Date of assessment 


TMF-14552026 
CONFIDENTIAL 
209493 
 
40 
13.5. 
Appendix 5: Data Display Standards & Handling Conventions 
13.5.1. 
Reporting Process 
Software 
• The currently supported versions of SAS software will be used. 
Reporting Area 
HARP Server 
us1salx00259 
HARP Compound 
  \ARPROD\GSK1265744\mid209493\primary_01 
Analysis Datasets  
• Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2 & 
ADaM IG Version 1.1).  
Generation of RTF Files 
• RTF files will be generated for all reporting efforts described in the RAP. 
13.5.2. 
Reporting Standards 
General 
• The current GSK Statistical Display Standards in the GSK Standards Library (IDSL) will be 
applied for reporting, unless otherwise stated (Library Location: 
https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx): 
• 4.03 to 4.23: General Principles 
• 5.01 to 5.08: Principles Related to Data Listings 
• 6.01 to 6.11: Principles Related to Summary Tables 
• 7.01 to 7.13: Principles Related to Graphics  
Formats 
• GSK Statistical Display Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted 
for reporting of data based on the raw data collected, unless otherwise stated. 
• Numeric data will be reported at the precision collected on the eCRF. 
• The reported precision from non eCRF sources will follow the GSK Standard Statistical 
Display Principles but may be adjusted to a clinically interpretable number of DP’s.  
Planned and Actual Time 
• Reporting for tables, figures and formal statistical analyses: 
• Planned time relative to dosing will be used in figures, summaries, statistical analyses 
and calculation of any derived parameters, unless otherwise stated. 
• The impact of any major deviation from the planned assessment times and/or scheduled 
visit days on the analyses and interpretation of the results will be assessed as 
appropriate. 
• Reporting for Data Listings:  
• Planned and actual time relative to study drug dosing will be shown in listings (Refer to 
GSK Standard Statistical Display Principle 5.05.1). 
• Unscheduled or unplanned readings will be presented within the participant’s listings. 
  


TMF-14552026 
CONFIDENTIAL 
209493 
 
41 
Unscheduled Visits 
• Unscheduled visits will be assigned to an analysis visit using the all-inclusive windows 
defined in Section 13.3. 
• However, data summaries will only report visits that are planned assessment time points for 
each parameter (according to the Schedule of Activities in Section 13.2.1). 
• Evaluable assessments at unscheduled visits will be used when categorizing values across 
visits, such as ‘maximum grade during the intervention phase’ or ‘at any time post-baseline’, 
and for any algorithm that has specific rules for which observation to use (e.g. snapshot 
algorithm, LOCF or CVF identification). 
Descriptive Summary Statistics 
Continuous Data 
Refer to GSK Standard Statistical Display Principle 6.06.1 
Categorical Data 
N, n, frequency, % 
Graphical Displays 
• Refer to GSK Standard Statistical Display Principals 7.01 to 7.13. 
13.5.3. 
Reporting Standards for Pharmacokinetic 
Pharmacokinetic Concentration Data 
Descriptive 
Summary 
Statistics, 
Graphical Displays 
and Listings 
Refer to the GSK Standard PK Display Standard. 
Refer to the GSK Standard Statistical Display Principle 6.06.1. 
Note: Concentration values will be imputed as per GUI_51487 for 
descriptive summary statistics/analysis and summarized graphical 
displays only.  


TMF-14552026 
CONFIDENTIAL 
209493 
 
42 
13.6. 
Appendix 6: Derived and Transformed Data 
13.6.1. 
General 
Multiple Measurements at One Analysis Time Point 
• 
If there are two values within a time window (as per Section 13.3.1) the value closest to the target 
day for that window will be used. If values are the same distance from the target, then the mean 
(geometric mean for HIV-1 RNA, arithmetic mean for all other measurement) will be taken. 
• 
Assessments not chosen for use in summary statistics by this algorithm will still appear in the 
associated listings.  
• 
All applicable valid assessments, irrespective of proximity to the target study day, will be used when 
categorizing values across visits, such as ‘maximum grade during the intervention phase’ or ‘at any 
time post-baseline’, and for any algorithm that has specific rules for which observation to use (e.g. 
snapshot algorithm, LOCF or CVF identification). 
• 
Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance 
summary tables. 
Treatment Start Date 
• 
Intervention Phase Treatment Start Date = Earliest date of CAB + RPV oral lead-in entered in the IP 
exposure eCRF form 
Nominal Month 13 Visit Date 
• 
For participants who received Month 13 injection, the nominal Month 13 visit date is defined by the 
Month 13 injection date. 
• 
Otherwise, nominal Month 13 visit date is defined by the date of latest Month 13 assessment. 
• 
For participants who continued into Extension Phase but missed the Month 13 visit, the nominal 
Month 13 visit date is defined by the last contact date prior to the date of the first nominal extension 
phase visit (e.g. Month 15, Month 17, etc.). 
Study Day 
• 
The Study Day of an event (e.g., lab assessment, vital sign, ECG, start date of AE or HIV associated 
condition) will be derived as the number of days between the date of the event and the Intervention 
Phase treatment start date as follows:  
o If date of event ≥ start date of study treatment, then 
 
Study Day = Date of Event - Intervention Phase Treatment Start Date +1 
o If date of event < start date of study treatment, then 
 
Study Day = Date of Event - Intervention Phase Treatment Start Date 
• 
Note that the start date of intervention phase study treatment is on Study Day 1 and the day before 
this is Study Day -1; i.e., there is no Study Day 0. 
Long Term Follow-up Study Day 
• 
The Long-Term Follow Up (LTFU) Study Day of an event (e.g., lab assessment, start date of AE or 
HIV associated condition) will be derived as the number of days between the date of the event and 
the end of IP treatment [i.e. max(Last IM Injection Date, Last Oral Bridging End Date)] as follows: 
o If the date of event falls in Long-term Follow up phase, then 
 
LTFU Study Day = Date of event - End date of IP + 1 
Study Treatment 
• 
Refers to CAB+RPV oral lead-in, CAB + RPV oral bridging, SOC oral bridging, CAB LA + RPV LA 
 


TMF-14552026 
CONFIDENTIAL 
209493 
 
43 
13.6.2. 
Study Population 
Demographics 
Age 
• Age, in whole years, will be calculated with respect to the subject’s Screening visit. 
• GSK standard IDSL algorithms will be used for calculating age where birth date will be 
imputed as follows: 
• Any subject with a missing date and month will have this imputed as ‘30th June’. 
• Birth date will be presented in listings as ‘YYYY’. 
• Completely missing dates of birth will remain as missing, with no imputation applied. 
Consequently, the age of the subject will not be calculated and will remain missing. 
Body Mass Index 
• Calculated as Weight (kg)/Height (m)² 
Hepatitis Status 
• Hepatitis C status will be determined using antibody and/or hepatitis C virus (HCV) RNA 
assessments performed during screening or during the conduct of the study.  
• If both antibody and virus RNA assessments are available, then the latter will take 
precedence and positive/negative status will be based on whether HCV RNA is detectable 
(i.e., ≥ limit of quantification) or not. 
• A participant will be considered positive for hepatitis B virus (HBV) if they have a positive 
surface antigen or detectable HBV DNA result. “HBV DNA DETECTED” in the lab comment 
takes precedence over HBV DNA test result for positive hepatitis B status; for example, if a 
participant has HBV DNA test result below level of detection and the lab comment shows 
that HBV DNA detected, this participant will be considered positive for hepatitis B. If HBV 
DNA result is available, it will be used to qualify hepatitis B status as positive or negative 
(positive if ≥ limit of quantification); otherwise Hepatitis B status will be determined using the 
surface antigen result. 
• Hepatitis status at entry will be based on the assessments prior to/on the start of the study 
treatment. 
Adherence to CAB/RPV Injection Schedule 
• Timeliness of Injections relative to Date of Projected Dosing Visits are assessed by using 
"actual injection visit date - projected visit date from first injection". The injections of interest 
in adherence analysis are those after first injection at Month 1. (. Each injection visit is 
counted only once. Individual CAB and RPV injections administered at the same visit are not 
counted twice. "Extra" unscheduled injections are excluded from all derivations. For 
example, if during a scheduled visit a participant receives 1 ml of injection instead of 2 ml 
due to a dosing error, but this participant returns one week later for the remaining 1 ml 
injection, then the additional visit is excluded. If a participant receives an extra injection at an 
unscheduled visit by mistake, this visit will also be excluded. 
• The categories of Timeliness of Injections relative to Date of Projected Dosing Visits are 
listed below: 
• < -14 days 
• -14 to   - 8 days 
• -7   to   1 


TMF-14552026 
CONFIDENTIAL 
209493 
 
44 
Demographics 
• 0 
• 1 to 7 days  
• 8 to 14 days 
• >14 days 
• Missed Injection without Oral Bridging (COVID-19 related) 
• Missed Injection without Oral Bridging (Non COVID-19 related) 
• Missed Injection with Oral Bridging (COVID-19 related) 
• Missed Injection with Oral Bridging (non COVID-19 related) 
• Injection visits are expected monthly from Month 2 until the nominal month of a participant’s 
last injection visit during the phase(s) of interest.  For example: 
• If a participant discontinues study treatment with last injection visit occurring at nominal 
visit Month 6 (without oral bridging), then injection visits are expected at Month 2, Month 
3, Month 4, Month 5 and Month 6. 
• Missed injections occurring during periods of on-going oral bridging (e.g. oral bridging is 
ongoing at the time of the data analysis cutoff or participant discontinues study treatment 
where last study treatment received is oral bridging) are not considered to be expected 
visits. 
Site Type 
• AIDS Healthcare Foundation (Site Id.= 
) 
• Federally Qualified Health Center (Site Id.= 
) 
• Health Maintenance Organization (Site Id.= 
) 
• Private Practice (Site Id.= 
)  
• University (Site Id.=
) 
13.6.3. 
Efficacy 
Efficacy 
Snapshot 
• The Snapshot algorithm is intended to be primarily a virologic assessment of the endpoint, 
and as such follows a “virology first” hierarchy. 
• ‘HIV-1 RNA < 50 c/mL’ or ‘HIV-1 RNA ≥ 50 c/mL’ within an analysis window (see Table 2 
and Table 3) is typically determined by the last available HIV-1 RNA measurement in that 
window while the participant is On-treatment in the Intervention Phase (as assigned based 
on Section 13.3). 
• When no HIV-1 RNA data is available within a window, a participant cannot be assigned to 
the category of ‘HIV-1 RNA < 50 c/mL’.  Depending on the reason for lack of data, the 
participant will be classified as ‘HIV-1 RNA ≥ 50 c/mL’ or reported as ‘No Virologic Data at 
Week X’; in the latter case, the algorithm further classifies the nature of the missing data. 
Typically, a participant withdrawn (i) due to AE or, (ii) for another reason yet was suppressed 
at the time, will be counted as ‘No Virologic Data at Week X’.  Should a participant withdraw 
for reasons other than AE and was not suppressed at the time, they will be categorized as 
‘HIV-1 RNA ≥ 50 c/mL’. 
PPD
PPD
PPD
PPD
PPD


TMF-14552026 
CONFIDENTIAL 
209493 
 
45 
Efficacy 
• Full details of the algorithm, including the handling of special cases, are included in 
Appendix 9: Snapshot Algorithm Details. 
Plasma HIV-1 RNA 
• For summaries and analyses which use HIV-1 RNA level as a continuous measure, the 
logarithm to base 10 of the value will be used. 
•  HIV-1 RNA results may be provided as censored values, such as <40 or >9,999,999 c/mL. 
For the purposes of summary statistics, such values will be replaced by the next value 
beyond the limit of detection, e.g., 39 or 10,000,000 c/mL, respectively, for the given 
examples. Data listings will show the censored values as provided. 
Confirmed Virologic Failure (CVF) 
• For the purposes of clinical management in this study, CVF is defined as:  
o Rebound as indicated by two consecutive plasma HIV-1 RNA levels ≥ 
200 c/mL. 
• The CVF definition is provided in the protocol Section 7.1.3 
• Only plasma HIV-1 RNA values determined by the central laboratory will be used to assess 
virologic failure.  
CDC Classification for HIV-1 Infection (2014) 
• CDC HIV-1 Classification at Baseline is collected in eCRF and no derivation with be 
performed programmatically for analysis purposes. Please refer to study protocol for detail 
description of CDC HIV-1 Classification. 
13.6.4. 
Safety 
Adverse Events 
DAIDS Grading 
• Clinical adverse events will be graded based on the Division of AIDS Table for Grading the 
Severity of Adult and Pediatric Adverse Events Version 2.1, March 2017, as specified in the 
protocol Appendix 10.2. 
• If a grade value is expected per DAIDS but is missing in the eCRF, then the missing grade 
will be given an ordinal grade value of -1 for determining the maximum grade within and 
across preferred terms.  For example: 
• if a participant has two separate instances of the same preferred term, one with grade 2 
and one with missing grade, then the maximum grade for the preferred term will be set 
to grade 2. 
• if a participant reports two different AE preferred terms overall, one with grade 1 and 
one with missing grade (where a DAIDS grade is expected), then the maximum grade 
across preferred terms (i.e. in the ANY EVENT row) will be set to grade 1. 
• If a participant reports only one AE overall and this has a missing grade (where a DAIDS 
grade is expected), then this will be presented under a grade = missing category  
Days since First Dose (Days) 
• AE Start Date – Intervention Phase Treatment Start Date + 1 


TMF-14552026 
CONFIDENTIAL 
209493 
 
46 
Adverse Events 
Days since Last Dose (Days) 
• AE Start Date – Date of Last Dose of Study Treatment (CAB+RPV, SOC bridging, CAB/RPV 
IM Injection) prior to/on the Start Date of AE + 1 
Days since Phase Start 
• For AEs in Intervention/Extension Phase: 
o AE Start Date - Intervention Treatment Start Date + 1 
• For AEs in Long-term Follow-up Phase: 
o AE Start Date – Date of Last Dose of Study Treatment  
o Date of Last Dose of Study Treatment = max (Last IM Injection Date, Last Oral 
Bridging End Date [CAB+RPV, SOC ART]), only applicable to participants who 
permanently discontinued study treatment. 
Duration (Days) 
• AE Resolution Date – AE Start Date + 1 
Drug-related 
• If relationship is marked ‘YES’ on Inform/eCRF 
• Injection site reactions will be considered as drug-related if the relationship to study drug 
value is missing in the eCRF. 
 
Laboratory Parameters 
• If a laboratory value which is expected to have a numeric value for summary purposes, has 
a non-detectable level reported in the database, where the numeric value is missing, but 
typically a character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than 
x in the comment field) is present, the number of significant digits in the observed values will 
be used to determine how much to add or subtract in order to impute the corresponding 
numeric value. If a character value starting with “<=x”, then the numeric value will be x. 
o Example 1: 2 Significant Digits = ‘< x ‘becomes x – 0.01 
o Example 2: 1 Significant Digit = ‘> x’ or ‘>=x’ becomes x + 0.1 
o Example 3: 0 Significant Digits = ‘< x’ becomes x – 1 
Lab Toxicities – DAIDS Grading  
• Toxicities will be based on the Division of AIDS (DAIDS) grading system, Version 2.1, March 
2.17, as specified in the protocol of Appendix 10.2  
• Toxicity grades provided by the central laboratory do not distinguish between abnormally 
high or low criteria, when both are relevant for a particular parameter. 
• When summarizing toxicity grades for such parameters, they will be categorized as to 
whether they are above or below the midpoint of normal range. 
Parameter 
Below Midpoint for 
those ≥Grade 1 
Above Midpoint for those 
≥Grade 1 
Glucose 
Hypoglycaemia 
Hypoglycaemia 
Sodium 
Hyponatremia 
Hyponatremia 
Potassium 
Hypokalaemia 
Hypokalaemia 
 


TMF-14552026 
CONFIDENTIAL 
209493 
 
47 
Other Safety Endpoints 
Corrected QT (QTc) 
• When not entered directly in the eCRF, corrected QT intervals by Bazett’s (QTcB) and 
Fridericia’s (QTcF) formulas will be calculated, in msec, depending on the availability of 
other measurements. 
• If RR interval (in msec) is provided, then missing QTcB and/or QTcF will be derived as 
1000
RR
QT
QTcB =
  
3
1000
RR
QT
QTcF =
 
• where uncorrected QT interval is also measured in msec. 
• If RR interval is not provided directly and one of QTcB or QTcF has been entered, then RR 
interval can be obtained from the above formulas and used to calculate the other correction 
method value; i.e., 
QT
QTcF
QTcB
3
=
 
 
3
2
QTcB
QT
QTcF
⋅
=
 
Extent of Exposure 
• Exposure to CAB+RPV (oral lead-in or oral bridging) and CAB LA+RPV LA will be calculated 
from the IP eCRF pages. 
For Intervention Phase: 
• Exposure to CAB+RPV Oral Lead-in = IP (oral lead-in) stop date - IP (oral lead-in) start 
date +1 
• Exposure to CAB LA + RPV LA = Number of IP injection visits received during the 
Intervention Phase (up to but not including injections administered at Month 13) 
• Exposure to SOC oral bridging: Duration of the SOC ART medication taken as oral 
bridging during the Intervention Phase. If the SOC oral bridging is taken in different periods 
during the Intervention Phase, the duration will be calculated by the sum of non-overlapped 
periods.  
• Exposure to CAB+RPV Oral Bridging (COVID-19 Related): Duration of the CAB+RPV 
taken as oral bridging for reasons related to COVID-19 during the Intervention Phase. If 
COVID-19 related CAB+RPV oral bridging is taken in different periods during the 
Intervention Phase, the duration will be calculated by the sum of the non-overlapped 
periods.  
• Exposure to CAB+RPV Oral Bridging (Non COVID-19 Related): Duration of the 
CAB+RPV taken as oral bridging for reasons not related to COVID-19 during the 
Intervention Phase. If non COVID-19 related CAB+RPV oral bridging is taken in different 
periods during the Intervention Phase, the duration will be calculated by the sum of the non-
overlapped periods.  
• Overall Exposure to Study Treatment: min [Date of Latest Intervention Phase Visit up to 
and including Month 13, max (Date of Last Injection + 35, Date of Last Dose of Oral 
CAB+RPV, Date of Last Dose of SOC Oral Bridging)] – min (Start Date for Oral lead-in 
CAB+RPV, Date of First CAB/RPV Injection) + 1 
o Note: Conditions in the above formula pertaining to Last Injection/Last Dose of 
Oral CAB+RPV/Last Dose of SOC Oral Bridging are only applicable to those 
who permanently discontinued study treatment. 


TMF-14552026 
CONFIDENTIAL 
209493 
 
48 
Other Safety Endpoints 
• Overall Exposure to CAB + RPV = Overall Exposure to Study Treatment – Exposure to 
SOC Oral Bridging 
For Intervention + Extension Phase: 
• Exposure to CAB LA + RPV LA = Number of IP injection visits received during Intervention 
Phase and Extension Phase 
• Exposure to SOC or CAB+RPV Oral Bridging during the Intervention and Extension Phase 
will be calculated similarly to that during the Intervention Phase except that the exposure 
includes both Intervention and Extension Phase.  
• Overall Exposure to Study Treatment: min [Date of Latest Intervention/Extension Phase 
Visit, max (Date of Last Injection + 35, Date of Last Dose of Oral CAB+RPV, Date of Last 
Dose of SOC Oral Bridging)] – min (Start Date for Oral lead-in CAB+RPV, Date of First 
Study Injection) + 1 
o Note: Conditions in the above formula pertaining to Last Injection/Last Dose of 
Oral CAB+RPV/Last Dose of SOC Oral Bridging are only applicable to those 
who permanently discontinued study treatment. 
• Overall Exposure to IP = Overall Exposure to Study Treatment – Exposure to SOC Oral 
Bridging 
• Duration of dosing in participant years will be calculated as the sum of participant duration of 
dosing in days (across all participants)/365.25 
13.6.5. 
Virology 
Genotype  
Amino Acid Changes 
• A mutation is considered present whenever the encoded amino acid residue differs from the 
amino acid that would have been encoded by the wild-type (e.g., HXB2, NL43) comparator 
gene; e.g., Q148K.  
• If the encoded amino acid is seen as a mixture of wild-type and mutant amino acid, e.g., 
Q148Q/K, the mutated amino acid is considered present at the codon of interest.  
• If the encoded amino acid is seen as a mixture of two or more amino acids, which may or 
may not include wild type, e.g., Q184K/H or Q184K/H/Q, etc., for the purposes of calculating 
the number of mutated amino acids, only one mutation is considered to be present at the 
codon of interest. 
 
Representation of Amino Acid Changes  
Mutations 
Amino Acid Change 
T69S 
Single mutation from amino acid 'T' (vendor reference) to 'S' (sample) at 
codon '69 
Q148H/K/R Mixture of amino acid mutations ‘H’, ‘K’ and ‘R’ (sample) from amino acid ‘Q 
(vendor reference) at codon ‘148’ 
_69_1T 
First insertion of amino acid 'T' (sample) at codon '69' 
_69_2S 
Second insertion of amino acid 'S' (sample) at codon '69' 
_69_3S/A 
Third insertion of a mixture of amino acids 'S' and 'A' (sample) at codon '69' 


TMF-14552026 
CONFIDENTIAL 
209493 
 
49 
Genotype  
L74L/- 
Mixture of amino acid 'L' (sample) and a deletion at codon '74' 
V75- 
Single deletion of amino acid (sample) at codon '75' 
Resistance Associated mutations 
Known INI mutations associated with the development of resistance to Integrase Strand Transfer 
Inhibitors: 
Amino Acids in 
HIV Integrase 
for Analysis 
H51Y, T66A/I/K, L68V/I, L74I/M, E92Q/V/G, Q95K, T97A, G118R, F121Y, 
E138A/D/K/T, G140A/C/R/S, Y143C/H/R/K/S/G/A, P145S, Q146P, 
S147G, Q148H/K/R/N, V151/IL/A, S153F/Y, N155H/S/T, E157Q, 
G163R/K, G193E, S230R, R263K 
• Draft listing; may be modified in case of additional substantive data availability. 
• Based on the IAS-USA list of mutations associated with resistance to Bictegravir, 
Cabotegravir, Dolutegravir, Elvitegravir, or Raltegravir (IAS-USA 2019 resistance 
mutations update volume 27 issue 3, 2019): T66A/I/K, L74M, E92Q/G, T97A, G118R, 
F121Y, E138A/K/T, G140A/C/R/S, Y143C/H/R, S147G, Q148H/K/R, S153F/Y, N155H, 
R263K) and observed mutations during in vitro passage of DTG or seen in a previous 
DTG study in INI-experienced subjects (study ING112574): H51Y, L74I, L68V/I, E92V, 
Q95K, E138D, Y143K/S/G/A, P145S, Q146P, V151I/L/A, N155S/T, E157Q, G163R/K, 
G193E, S230R.  
• Major USA-IAS mutations associated with resistance to INSTI are bolded. 
 
• Major resistance mutations to other classes (i.e., NRTI, NNRTI, PI) as defined by the 
International Antiviral Society-USA (IAS-USA). The most up to date IAS-USA guidelines 
available at the time of DBF will be used in the analysis [Wensing, 2019]. 
Class 
Mutations 
NRTIs 
M41L, A62V, K65R/E/N, D67N, 69 insert, K70E/R, L74V, V75I, F77L, Y115F, 
F116Y, 
Q151M, M184V/I, L210W, T215Y/F, K219Q/E 
NNRTIs 
L100I, K101E/P, K103N/S, V106A/M, V108I, E138/A/G/K/Q/R, V179L, 
Y181C/I/V, Y188C/L/H, G190S/A, H221Y, P225H, F227C, M230I/L 
PIs 
D30N, V32I, M46I/L, I47A/V, G48V, I50V/L, I54V/M/L, Q58E, T74P, L76V, 
V82A/T/F/L/S, N83D, I84V, N88S, L90M 
• Draft listing; may be modified in case of additional substantive data availability. 
 
13.6.6. 
Other Assessments 
Study Visit Length 
• Lead Time = Actual Start Time of Appointment – Arrival Time 
• Process Time = Actual End Time of Appointment – Actual Start Time of Appointment 
• Total Time = Actual End Time of Appointment – Arrival Time 
 


TMF-14552026 
CONFIDENTIAL 
209493 
 
50 
13.7. 
Appendix 7: Reporting Standards for Missing Data 
13.7.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
• Withdrawn participants were not replaced in the study. 
• All available data from participants who were withdrawn from the study will be 
listed and all available planned data will be included in summary tables and 
figures, unless otherwise specified.  
• Withdrawal visits will be slotted according to Appendix 3: Assessment 
Windows (excluding PK data) 
13.7.2. 
Handling of Missing Data 
Element 
Reporting Detail 
General 
• Missing data occurs when any requested data is not provided, leading to blank 
fields on the collection instrument: 
o These data will be indicated by the use of a “blank” in participant listing 
displays. Unless all data for a specific visit are missing in which case the 
data is excluded from the table.  
o Answers such as “Not applicable” and “Not evaluable” are not considered 
to be missing data and should be displayed as such. 
Outliers 
• Any participants excluded from the summaries and/or statistical analyses will 
be documented along with the reason for exclusion in the clinical study report. 
13.7.2.1. Handling of Missing and Partial Dates 
Element 
Reporting Detail 
General 
• Partial dates will be displayed as captured in participant listing displays.  
• Where necessary, display macros may impute dates as temporary variables 
for sorting data in listings only. In addition, partial dates may be imputed for 
‘slotting’ data to study phases or for specific analysis purposes as outlined 
below. 
Adverse 
Events 
• Imputations in the adverse events dataset are used for slotting events to the 
appropriate study time periods and for sorting in data listings. 
• Partial dates for AEs recorded in the CRF will be imputed using the following 
conventions: 
 
Missing start day 
• 
If study treatment start date is missing (i.e. 
participant did not start study treatment), then set 
start date = 1st of month. 
• 
Else if study treatment start date is not missing: 
o If month and year of start date = month and 
year of study treatment start date, then 


TMF-14552026 
CONFIDENTIAL 
209493 
 
51 
Element 
Reporting Detail 
 
If stop date contains a full date and stop date 
is earlier than study treatment start date, 
then set start date= 1st of month. 
 
Else set start date = study treatment start 
date. 
o Else  
 
For Non-ISR AEs: set start date = 1st of 
month 
 
For ISR AEs: if oral bridging taken during the 
month and year, set start date = min(last day 
of the month, day of AE stop date if 
available, day of study treatment 
discontinuation if occurring during the month 
and year); else set start date = 1st of month. 
Missing start day 
and month 
• 
If study treatment start date is missing (i.e. 
participant did not start study treatment), then set 
start date = January 1. 
• 
Else if study treatment start date is not missing: 
o If year of start date = year of study treatment 
start date, then 
 
If stop date contains a full date and stop date 
is earlier than study treatment start date, 
then set start date = January 1. 
 
Else set start date = study treatment start 
date. 
o Else set start date = January 1. 
Missing stop day  Last day of the month will be used. 
Missing stop day 
and month 
No Imputation 
Completely 
missing start/end 
date 
No imputation 
 
• Completely missing start or end dates will remain missing, with no imputation 
applied.  
Non-ART 
Medications 
• Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention: 
 
Missing start day 
• 
If study treatment start date is missing (i.e. 
participant did not start study treatment), then set 
start date = 1st of month. 
• 
Else if study treatment start date is not missing: 
o If month and year of start date = month and 
year of study treatment start date, then 


TMF-14552026 
CONFIDENTIAL 
209493 
 
52 
Element 
Reporting Detail 
 
If stop date contains a full date and stop date 
is earlier than study treatment start date, then 
set start date= 1st of month. 
 
Else set start date = study treatment start 
date. 
o Else set start date = 1st of month. 
Missing start day 
and month 
• 
If study treatment start date is missing (i.e. 
participant did not start study treatment), then set 
start date = January 1. 
• 
Else if study treatment start date is not missing: 
o If year of start date = year of study treatment 
start date, then 
 
If stop date contains a full date and stop date 
is earlier than study treatment start date, then 
set start date = January 1. 
 
Else set start date = study treatment start 
date.       
• 
Else set start date = January 1. 
Missing end day 
A '28/29/30/31' will be used for the day (dependent on 
the month and year)  
Missing end day 
and month 
A '31' will be used for the day and 'Dec' will be used for 
the month. 
Completely 
missing start/end 
date 
No imputation 
• The recorded partial date will be displayed in listings. 
ART 
Medications 
• Partial dates recorded in the eCRF will be imputed using the following 
convention: 
o If the partial date is a start date, a '01' will be used for the day and 'Jan' 
will be used for the month. 
o If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month. 
If medications recorded in the PRIOR ART form of the eCRF, then the 
earlier date of the imputed and the day prior to the Intervention phase 
treatment start date will be used, i.e. min (imputed stop date, Intervention 
phase treatment start date - 1). 
• For medications with completely missing start date, they will be considered 
started prior to the Intervention phase treatment start date. 
• For medications with completely missing stop date, they will be considered 
ongoing unless recorded in the PRIOR ART form of the eCRF. 
• For ART booster medications, the start and stop dates are not recorded in the 
database (i.e. missing), the dates will be imputed to be the same as the dates 
of their parent medications.  
• The recorded partial or missing date will be displayed in listings. 
 


TMF-14552026 
CONFIDENTIAL 
209493 
 
53 
13.7.2.2. Handling of Missing Data for Statistical Analysis 
Element 
Reporting Detail 
Snapshot 
•  In the Snapshot dataset, subjects without HIV – 1 RNA data in the 
assessment window for the visit of interest (due to missing data or 
discontinuation of IP prior to the visit window) do not belong to 
‘HIV-1< 50 c/mL (or 200 c/mL) The nature of this missing data will 
be further classified in Snapshot summaries as either ‘HIV-1 
RNA≥50’ or ‘No Virologic Data at Week X’; 
• See Appendix 9: Snapshot Algorithm Details  
LOCF (COVID-19 
Related) 
• Missing HIV-1 RNA values within an analysis visit for reasons 
related to COVID-19 will be imputed using the last on-treatment 
value from earlier analysis timepoints. 
• This approach will be used in the primary snapshot analysis to 
address missing data due to COVID-19. 
 


TMF-14552026 
CONFIDENTIAL 
209493 
 
54 
13.8. 
Appendix 8: Values of Potential Clinical Importance 
ECG values of potential clinical importance are defined as QTc > 500 msec or increase 
from baseline in QTc ≥ 60 msec. 
 


TMF-14552026 
CONFIDENTIAL 
209493 
 
55 
13.9. 
Appendix 9: Snapshot Algorithm Details 
Detailed Algorithm Steps 
 
• 
Consider an analysis visit window for Month X as defined in Table 2.  
• 
The HIV-1 RNA threshold of 50 will be analysed,  in this study  
• 
The COVID-19 pandemic presents significant logistical challenges for many clinical sites 
around the world, with variable restrictions being placed on site resources and operations, 
and on an individual participants ability to attend clinic visits. The snapshot algorithm is 
modified to allow for the presentation of full scope of COVID-19 relatedness. The analysis 
window for ‘Month 12’ and HIV-1 RNA threshold of ’50 c/mL’ are used for the purpose of 
illustration. A participant’s Snapshot response and reason at Month 12 are categorized as 
below. 
 
o HIV-1 RNA < 50 c/mL 
o HIV-1 RNA ≥ 50 c/mL 
   Data in window not below 50 
  Non-COVID-19 related  
Discontinued for lack of efficacy 
Discontinued for other reason while not 
below 50 
  COVID-19 related 
Discontinued for lack of efficacy 
Discontinued for other reason while not 
below 50 
 
o No Virologic Data at Month 12 Window 
  Non-COVID-19 related 
Discontinued study due to AE or death 
Discontinued study for other reasons 
On study but missing data in window 
              COVID-19 related 
Discontinued study due to AE or death  
Discontinued study for other reasons 
On study but missing data in window 
            Change in background therapy* 
 
* Note: Use of CAB + RPV oral bridging and SOC oral bridging medication, where the latter is 
due to unavailability of CAB/RPV IM injections or oral CAB+RPV during the pandemic, will not 
be considered a “Change in background therapy” in the Snapshot algorithm.  All other 
permanent changes in ART are not permitted in this protocol. 


TMF-14552026 
CONFIDENTIAL 
209493 
 
56 
• 
The steps in determining response and reasons are indicated in the table below, in the order 
stated. 
 
• 
Background therapy is not given to participants while on study. The “change in background 
therapy” in detailed steps below refers to the “change in ART” in this study. 
 
Detailed steps 
• Please note that the following scenarios will NOT be penalized in the Snapshot 
algorithm Oral bridging (CAB+RPV or SOC, where SOC oral bridging medication is 
permitted during COVID-19 pandemic due to the unavailability of the CAB/RPV IM 
injections and oral CAB+RPV)  
Condition (‘Month 12’ indicates Month 12 window) 
Response  
Reasons 
1. If non-permitted change in background therapy 
prior to Month 12   
HIV-1 RNA ≥ 
50 
Change in 
background 
therapy 
2. If non-permitted change in background therapy 
during Month 12 
 
 
• Last on-treatment VL during Month 12 prior 
to/on the date of change ≥ 50 c/mL 
HIV-1 RNA ≥ 
50 
Data in window not 
below 50 
• Last on-treatment VL during Month 12 prior 
to/on the date of change < 50 c/mL 
HIV-1 RNA < 
50 
 
• No VL during Month 12 prior to/on the date of 
change  
HIV-1 RNA ≥ 
50 
Change in 
background 
therapy  
3. If none of the above conditions met 
 
 
3.1. On-treatment VL available during Month 12 
 
 
• Last on-treatment VL during Month 12 ≥ 
50 c/mL 
HIV-1 RNA ≥ 
50 
Data in window not 
below 50 
• Last on-treatment VL during Month 12 < 
50 c/mL 
HIV-1 RNA < 
50 
 
3.2. No on-treatment VL during Month 12 
 
 
3.2.1. If participants are still on study, i.e. a 
participant has not permanently 
discontinued the study treatment yet, or 
if a participant permanently 
discontinued the study treatment and 
the upper bound of analysis snapshot 
window is prior to the following date:  
• Min[max(Date of last injection + 35, 
Date of Last  Dose of Oral Study 
Treatment (CAB+RPV, SOC 
Bridging) + 1), LTFU ART Start Date] 
 
 


TMF-14552026 
CONFIDENTIAL 
209493 
 
57 
3.2.1.1. 
If no on-treatment VL during 
Month 12 is not due to COVID-19 
No virologic 
data at Month 
12 Window 
On study but 
missing data in 
window (Non-
COVID-19 related) 
3.2.1.2. 
If no on-treatment VL during 
Month 12 is due to COVID-19 
No virologic 
data at Month 
12 Window 
On study but 
missing data in 
window (COVID-19 
related) 
3.2.2. If participants withdraw before/during 
Month 12 due to 
 
 
3.2.2.1. 
Non-COVID-19 related 
safety reasons (e.g. AE/death, 
liver chemistry stopping criteria, 
renal toxicity withdrawal criteria, 
QTc withdrawal criteria etc., as 
recorded in eCRF Conclusion 
form) 
No virologic 
data at Month 
12 Window 
Disc due to 
AE/death (Non-
COVID-19 related) 
3.2.2.2. 
COVID-19 related safety 
reasons (e.g. AE/death, liver 
chemistry stopping criteria, renal 
toxicity withdrawal criteria, QTc 
withdrawal criteria etc., as 
recorded in eCRF Conclusion 
form) 
No virologic 
data at Month 
12 Window 
Disc due to 
AE/death (COVID-
19 related) 
3.2.2.3. 
 Non-safety and Non-
COVID-19 related reasons (e.g. 
Lack of efficacy, protocol 
deviation, withdrew consent, loss 
to follow-up, study 
closed/terminated, investigator 
discretion etc., as recorded in 
eCRF Treatment Discontinuation 
Form) 
 
 
o Last on-treatment VL <50 
c/mL OR no on-treatment VL 
available during study   
No virologic 
Data at Month 
12 Window 
Disc for other 
reasons (Non-
COVID-19 related) 
o Last on-treatment VL ≥ 50 
c/mL AND withdrawal due to 
Lack of efficacy 
HIV-1 RNA ≥ 
50 
Disc. for lack of 
efficacy (Non-
COVID-19 related) 
o Last on-treatment VL ≥ 50 
c/mL AND withdrawal due to 
all other non-safety related 
reasons 
HIV-1 RNA ≥ 
50 
Disc. for other 
reason while not 
below 50 (Non-
COVID-19 related) 
3.2.2.4. 
Non-safety and COVID-19 
related reasons (e.g. protocol 
deviation, withdrew consent, loss 
to follow-up, study 
 
 


TMF-14552026 
CONFIDENTIAL 
209493 
 
58 
closed/terminated, investigator 
discretion etc., as recorded in 
eCRF Conclusion Form) 
o Last on-treatment VL <50 
c/mL OR no on-treatment VL 
available during study   
No virologic 
Data at Month 
12 Window 
Disc for other 
reasons (COVID-
19 related) 
o Last on-treatment VL ≥ 50 
c/mL AND withdrawal due to 
Lack of efficacy 
HIV-1 RNA ≥ 
50 
Disc. for lack of 
efficacy (COVID-19 
related) 
o Last on-treatment VL ≥ 50 
c/mL AND withdrawal due to 
all other non-safety related 
reasons 
HIV-1 RNA ≥ 
50 
Disc. for other 
reason while not 
below 50 (COVID-
19 related) 
a. Excluding permitted change in background therapy where change or decision to change is 
made prior to/on the first on-treatment viral result  
Examples from FDA guidance 
Data in Window 
Virologic outcome should be determined by the last available measurement while the patient is on 
treatment and continued on trial within the time window: 
• HIV-1 RNA = 580 c/mL at Day 336, HIV-1 RNA below 50 c/mL on Day 350. This should be 
categorized as HIV-1 RNA below 50 c/mL. 
No Data in Window 
Discontinued study due to Adverse Event or Death: 
• Any patient who discontinues because of an AE or death before the window should be 
classified as Discontinued due to AE or Death (as appropriate), regardless of the HIV-1 
RNA result, even if the HIV-1 RNA is below 50 c/mL at the time of discontinuation.  
• However, if a patient has an HIV-1 RNA value in the time window and also discontinues in 
the time window, the viral load data should be used to classify the patient’s response. This 
is the Virology First hierarchy: 
a. HIV-1 RNA below 50 c/mL at Day 336 and discontinues because of AE or even 
dies on Day 360 — this person is categorized as having HIV-1 RNA below 50 
c/mL.  
b. HIV-1 RNA is 552 c/mL on Day 336 and the patient discontinues on Day 360, the 
patient is categorized as having HIV-1 RNA ≥ 50 c/mL. 
Discontinued for Other Reasons: 
• Only patients who have achieved virologic suppression can be counted as Discontinued 
for Other Reasons. 
• If a patient discontinues the study before the time window because of lack of efficacy, then 
the patient should be included in the HIV-1 RNA ≥ 50 row and not in the Discontinued for 
Other Reasons row. 


TMF-14552026 
CONFIDENTIAL 
209493 
 
59 
Detailed Algorithm Steps 
 
• If a patient discontinues because participant withdrew consent and his or her HIV-1 RNA 
result at the time of discontinuation was equal to or above 50 c/mL, then he or she should 
be categorized as HIV-1 RNA ≥ 50 and NOT as Discontinued for Other Reasons.  
• If a patient discontinued because of Lost to Follow-Up and the last HIV-1 RNA result was 
49 c/mL, then the patient can be categorized as Discontinued for Other Reasons. 
• If patients changed background treatment — not permitted by protocol— they should be 
considered an efficacy failure and captured in the HIV-1 RNA ≥ 50 c/mL row. 
On study but missing data in window: 
• If there are no data during Days 294 to 377, but there is an HIV-1 RNA below 50 c/mL on 
Day 380, this patient should be considered On Study but Missing Data in Window. 
• If there are no data during Days 294 to 377, but there is an HIV-1 RNA equal to or above 
50 c/mL on Day 280, this patient also should be classified as On Study but Missing Data in 
Window. 
 


TMF-14552026 
CONFIDENTIAL 
209493 
 
60 
13.10. 
Appendix 10: AESI identification 
SMQ and PT codes based on MedDRA dictionary version 23.0 for the Month 12 
analysis. 
13.10.1. 
Hepatic Safety Profile  
Medical concept of hepatic failure and hepatitis. Sub- SMQs (1) 'Hepatic failure, fibrosis 
and cirrhosis and other liver damage-related conditions' and (2) 'Hepatitis, non-
infectious', both of parent SMQ 'Hepatic Disorders (SMQ code 20000005)'; only narrow 
terms selected from sub-SMQs. Some preferred terms, e.g. PT 'hepatitis fulminant' are 
duplicated. 
SMQ: 'Hepatic Disorders'; SMQ Code: 20000005 
Sub-SMQ: 'Hepatic failure, fibrosis and cirrhosis and other liver damage-related 
conditions' 
Category: A 
Scope: Narrow 
Preferred Term 
PT Code 
Acquired hepatocerebral degeneration 
10080860 
Acute hepatic failure 
10000804 
Acute on chronic liver failure 
10077305 
Acute yellow liver atrophy 
10070815 
Ascites 
10003445 
Asterixis 
10003547 
Bacterascites 
10068547 
Biliary cirrhosis 
10004659 
Biliary fibrosis 
10004664 
Cardiohepatic syndrome 
10082480 
Cholestatic liver injury 
10067969 
Chronic hepatic failure 
10057573 
Coma hepatic 
10010075 
Cryptogenic cirrhosis 
10063075 
Diabetic hepatopathy 
10071265 
Drug-induced liver injury 
10072268 
Duodenal varices 
10051010 


TMF-14552026 
CONFIDENTIAL 
209493 
 
61 
SMQ: 'Hepatic Disorders'; SMQ Code: 20000005 
Sub-SMQ: 'Hepatic failure, fibrosis and cirrhosis and other liver damage-related 
conditions' 
Category: A 
Scope: Narrow 
Preferred Term 
PT Code 
Gallbladder varices 
10072319 
Gastric variceal injection 
10076237 
Gastric variceal ligation 
10076238 
Gastric varices 
10051012 
Gastric varices haemorrhage 
10057572 
Gastrooesophageal variceal haemorrhage prophylaxis 
10066597 
Hepatectomy 
10061997 
Hepatic atrophy 
10019637 
Hepatic calcification 
10065274 
Hepatic cirrhosis 
10019641 
Hepatic encephalopathy 
10019660 
Hepatic encephalopathy prophylaxis 
10066599 
Hepatic failure 
10019663 
Hepatic fibrosis 
10019668 
Hepatic hydrothorax 
10067365 
Hepatic infiltration eosinophilic 
10064668 
Hepatic lesion 
10061998 
Hepatic necrosis 
10019692 
Hepatic steato-fibrosis 
10077215 
Hepatic steatosis 
10019708 
Hepatitis fulminant 
10019772 
Hepatobiliary disease 
10062000 
Hepatocellular foamy cell syndrome 
10053244 
Hepatocellular injury 
10019837 
Hepatopulmonary syndrome 
10052274 


TMF-14552026 
CONFIDENTIAL 
209493 
 
62 
SMQ: 'Hepatic Disorders'; SMQ Code: 20000005 
Sub-SMQ: 'Hepatic failure, fibrosis and cirrhosis and other liver damage-related 
conditions' 
Category: A 
Scope: Narrow 
Preferred Term 
PT Code 
Hepatorenal failure 
10019845 
Hepatorenal syndrome 
10019846 
Hepatotoxicity 
10019851 
Immune-mediated cholangitis 
10083406 
Immune-mediated hepatic disorder 
10083521 
Intestinal varices 
10071502 
Intestinal varices haemorrhage 
10078058 
Liver dialysis 
10076640 
Liver disorder 
10024670 
Liver injury 
10067125 
Liver operation 
10062040 
Liver transplant 
10024714 
Lupoid hepatic cirrhosis 
10025129 
Minimal hepatic encephalopathy 
10076204 
Mixed liver injury 
10066758 
Nodular regenerative hyperplasia 
10051081 
Nonalcoholic fatty liver disease 
10082249 
Non-alcoholic steatohepatitis 
10053219 
Non-cirrhotic portal hypertension 
10077259 
Oedema due to hepatic disease 
10049631 
Oesophageal varices haemorrhage 
10030210 
Peripancreatic varices 
10073215 
Portal fibrosis 
10074726 
Portal hypertension 
10036200 
Portal hypertensive colopathy 
10079446 


TMF-14552026 
CONFIDENTIAL 
209493 
 
63 
SMQ: 'Hepatic Disorders'; SMQ Code: 20000005 
Sub-SMQ: 'Hepatic failure, fibrosis and cirrhosis and other liver damage-related 
conditions' 
Category: A 
Scope: Narrow 
Preferred Term 
PT Code 
Portal hypertensive enteropathy 
10068923 
Portal hypertensive gastropathy 
10050897 
Portal vein cavernous transformation 
10073979 
Portal vein dilatation 
10073209 
Portopulmonary hypertension 
10067281 
Primary biliary cholangitis 
10080429 
Regenerative siderotic hepatic nodule 
10080679 
Renal and liver transplant 
10052279 
Retrograde portal vein flow 
10067338 
Reye's syndrome 
10039012 
Reynold's syndrome 
10070953 
Splenic varices 
10067823 
Splenic varices haemorrhage 
10068662 
Steatohepatitis 
10076331 
Subacute hepatic failure 
10056956 
Sugiura procedure 
10083010 
Varices oesophageal 
10056091 
Varicose veins of abdominal wall 
10072284 
White nipple sign 
10078438 
SMQ: 'Hepatic Disorders'; SMQ Code: 20000005 
Sub-SMQ: 'Hepatitis, non-infectious’ 
Category: A 
Scope: Narrow 
Preferred Term 
PT Code 
Acute graft versus host disease in liver 
10066263 
Allergic hepatitis 
10071198 


TMF-14552026 
CONFIDENTIAL 
209493 
 
64 
SMQ: 'Hepatic Disorders'; SMQ Code: 20000005 
Sub-SMQ: 'Hepatic failure, fibrosis and cirrhosis and other liver damage-related 
conditions' 
Category: A 
Scope: Narrow 
Preferred Term 
PT Code 
Alloimmune hepatitis 
10080576 
Autoimmune hepatitis 
10003827 
Chronic graft versus host disease in liver 
10072160 
Chronic hepatitis 
10008909 
Graft versus host disease in liver 
10064676 
Hepatitis 
10019717 
Hepatitis acute 
10019727 
Hepatitis cholestatic 
10019754 
Hepatitis chronic active 
10019755 
Hepatitis chronic persistent 
10019759 
Hepatitis fulminant 
10019772 
Hepatitis toxic 
10019795 
Immune-mediated hepatitis 
10078962 
Ischaemic hepatitis 
10023025 
Lupus hepatitis 
10067737 
Non-alcoholic steatohepatitis 
10053219 
Radiation hepatitis 
10051015 
Steatohepatitis 
10076331 


TMF-14552026 
CONFIDENTIAL 
209493 
 
65 
13.10.2. 
Hyperglycaemia 
Medical concept of Hyperglycaemia/new onset diabetes mellitus - SMQs (1) 
'Hyperglycaemia/new onset diabetes mellitus (SMQ) Narrow SMQ code 20000041. 
SMQ: 'Hyperglycaemia/new onset diabetes mellitus '; SMQ Code: 20000041 
Sub-SMQ: 'Hepatic failure, fibrosis and cirrhosis and other liver damage-related  
Category: A 
Scope: Narrow 
Preferred Term 
PT Code 
Acquired lipoatrophic diabetes 
10073667 
Blood 1,5-anhydroglucitol decreased 
10065367 
Blood glucose increased 
10005557 
Diabetes complicating pregnancy 
10012596 
Diabetes mellitus 
10012601 
Diabetes mellitus inadequate control 
10012607 
Diabetes with hyperosmolarity 
10012631 
Diabetic arteritis 
10077357 
Diabetic coma 
10012650 
Diabetic coronary microangiopathy 
10080788 
Diabetic hepatopathy 
10071265 
Diabetic hyperglycaemic coma 
10012668 
Diabetic hyperosmolar coma 
10012669 
Diabetic ketoacidosis 
10012671 
Diabetic ketoacidotic hyperglycaemic coma 
10012672 
Diabetic ketosis 
10012673 
Diabetic metabolic decompensation 
10074309 
Diabetic wound 
10081558 
Euglycaemic diabetic ketoacidosis 
10080061 
Fructosamine increased 
10017395 
Fulminant type 1 diabetes mellitus 
10072628 
Gestational diabetes 
10018209 


TMF-14552026 
CONFIDENTIAL 
209493 
 
66 
SMQ: 'Hyperglycaemia/new onset diabetes mellitus '; SMQ Code: 20000041 
Sub-SMQ: 'Hepatic failure, fibrosis and cirrhosis and other liver damage-related  
Category: A 
Scope: Narrow 
Preferred Term 
PT Code 
Glucose tolerance impaired 
10018429 
Glucose tolerance impaired in pregnancy 
10018430 
Glucose urine present 
10018478 
Glycated albumin increased 
10082836 
Glycosuria 
10018473 
Glycosuria during pregnancy 
10018475 
Glycosylated haemoglobin abnormal 
10018481 
Glycosylated haemoglobin increased 
10018484 
Hyperglycaemia 
10020635 
Hyperglycaemic hyperosmolar nonketotic syndrome 
10063554 
Hyperglycaemic seizure 
10071394 
Hyperglycaemic unconsciousness 
10071286 
Impaired fasting glucose 
10056997 
Insulin resistance 
10022489 
Insulin resistant diabetes 
10022491 
Insulin-requiring type 2 diabetes mellitus 
10053247 
Ketoacidosis 
10023379 
Ketonuria 
10023388 
Ketosis 
10023391 
Ketosis-prone diabetes mellitus 
10023392 
Latent autoimmune diabetes in adults 
10066389 
Monogenic diabetes 
10075980 
Neonatal diabetes mellitus 
10028933 
New onset diabetes after transplantation 
10082630 
Pancreatogenous diabetes 
10033660 


TMF-14552026 
CONFIDENTIAL 
209493 
 
67 
SMQ: 'Hyperglycaemia/new onset diabetes mellitus '; SMQ Code: 20000041 
Sub-SMQ: 'Hepatic failure, fibrosis and cirrhosis and other liver damage-related  
Category: A 
Scope: Narrow 
Preferred Term 
PT Code 
Steroid diabetes 
10081755 
Type 1 diabetes mellitus 
10067584 
Type 2 diabetes mellitus 
10067585 
Type 3 diabetes mellitus 
10072659 
Urine ketone body present 
10057597 
13.10.3. 
Hypersensitivity Reactions  
Notes: Medical concept of hypersensitivity reactions/DRESS. Only narrow terms selected 
from Category A of SMQ 'Drug reaction with eosinophilia and systemic symptoms 
syndrome'. Algorithmic approach for this SMQ not used due to complexity in applying 
and poor specificity of remaining categories. Category A selected as PTs because more 
specific for concept (only narrow terms) and a pre-requisite for any combination in 
algorithmic search. Overlap of some preferred terms with SMQ 'Severe Cutaneous 
Adverse Reactions'. Plus additional preferred terms selected from HGLT 'Allergic 
conditions' under SOC 'Immune system disorders'. 
SMQ: Drug reaction with eosinophilia and systemic symptoms syndrome 
SMQ Code: 20000225 
Category: A 
Scope: Narrow 
 
Preferred Term 
PT Code 
Drug reaction with eosinophilia and systemic symptoms 
10073508 
Pseudolymphoma 
10037127 
Additional preferred terms selected from HLGT 'Allergic conditions' 
under SOC 'Immune system disorders'; HLGT code 10001708 
Preferred Term 
PT Code 
Drug hypersensitivity 
10013700 
Hypersensitivity 
10020751 
Type IV Hypersensitivity reaction 
10053613 
Eosinophillia 
10014950 
Eye swelling 
10015967 


TMF-14552026 
CONFIDENTIAL 
209493 
 
68 
SMQ: Drug reaction with eosinophilia and systemic symptoms syndrome 
SMQ Code: 20000225 
Category: A 
Scope: Narrow 
 
Preferred Term 
PT Code 
Eyelid oedema 
10015993 
Lip swelling 
10024570 
Angioedema 
10002424 
Circumoral oedema 
10052250 
Face oedema 
10016029 
Idiopathic angioedema 
10073257 
Lip oedema 
10024558 
Mouth swelling 
10075203 
Oedema mouth 
10030110 
Periorbital oedema 
10034545 
Swelling face 
10042682 
Periorbital swelling 
10056647 
Swelling of eyelid 
10042690 
13.10.4. 
Rash including severe cutaneous adverse reactions 
Medical concept of rash including severe cutaneous adverse reactions. Only narrow terms 
from SMQ 'Severe cutaneous adverse reactions' selected. Plus several additional 
preferred terms selected from HLTs 'Rashes, eruptions and exanthems NEC', 'Pruritus 
NEC', 'Pustular conditions', 'Dermatitis ascribed to specific agent' all under SOC 'Skin 
and subcutaneous tissue disorders'. 
SMQ: Severe Cutaneous Adverse Reactions 
SMQ Code: 20000020 
Category: A 
Scope: Narrow 
 
SMQ 
PT Code 
Acute generalised exanthematous pustulosis 
10048799 
Bullous haemorrhagic dermatosis 
10083809 
Cutaneous vasculitis 
10011686 


TMF-14552026 
CONFIDENTIAL 
209493 
 
69 
SMQ: Severe Cutaneous Adverse Reactions 
SMQ Code: 20000020 
Category: A 
Scope: Narrow 
 
SMQ 
PT Code 
Dermatitis bullous 
10012441 
Dermatitis exfoliative 
10012455 
Dermatitis exfoliative generalised 
10012456 
Drug reaction with eosinophilia and systemic symptoms 
10073508 
Epidermal necrosis 
10059284 
Erythema multiforme 
10015218 
Erythrodermic atopic dermatitis 
10082985 
Exfoliative rash 
10064579 
Oculomucocutaneous syndrome 
10030081 
SJS-TEN overlap 
10083164 
Skin necrosis 
10040893 
Stevens-Johnson syndrome 
10042033 
Target skin lesion 
10081998 
Toxic epidermal necrolysis 
10044223 
Toxic skin eruption 
10057970 
Addition selected preferred terms from HLTs 'Rashes, eruptions and 
exanthems NEC', HLT Code 1005266; 'Pruritus NEC', HLT Code 
10049293, 'Pustular conditions', HLT Code 10037573; 'Dermatitis 
ascribed to specific agent', HLT Code 10012437. 
 
Preferred Term 
PT Code 
Eyelid rash 
10074620 
Genital rash 
10018175 
Mucocutaneous rash 
10056671 
Nodular rash 
10075807 
Perineal rash 
10075364 
Rash 
10037844 


TMF-14552026 
CONFIDENTIAL 
209493 
 
70 
SMQ: Severe Cutaneous Adverse Reactions 
SMQ Code: 20000020 
Category: A 
Scope: Narrow 
 
SMQ 
PT Code 
Rash erythematous 
10037855 
Rash generalised 
10037858 
Rash macular 
10037867 
Rash maculo-papular 
10037868 
Rash maculovesicular 
10050004 
Rash morbilliform 
10037870 
Rash papular 
10037876 
Rash rubelliform 
10057984 
Rash scarlatiniform 
10037890 
Rash vesicular 
10037898 
Rash pruritic 
10037884 
Rash follicular 
10037857 
Rash pustular 
10037888 
Drug eruption 
10013687 


TMF-14552026 
CONFIDENTIAL 
209493 
 
71 
13.10.5. 
Prolongation of the Corrected QT Interval of the ECG in Supra 
Therapeutic Doses 
Medical concept of QT prolongation and complications. Only narrow terms from SMQ 
'Torsade de pointes/QT prolongation' selected plus one additional PT under HLT 'ECG 
investigations'. 
SMQ: Torsade de pointes/QT prolongation 
SMQ Code: 20000001 
Category: A 
Scope: Narrow 
 
Preferred Term 
PT Code 
Electrocardiogram QT interval abnormal 
10063748 
Electrocardiogram QT prolonged 
10014387 
Long QT syndrome 
10024803 
Long QT syndrome congenital 
10057926 
Torsade de pointes 
10044066 
Ventricular tachycardia 
10047302 
Additional selected preferred terms from HLT 'ECG investigations', HLT 
Code 10053104. 
Preferred Term 
PT Code 
Electrocardiogram repolarisation abnormality 
10052464 


TMF-14552026 
CONFIDENTIAL 
209493 
 
72 
13.10.6. 
Suicidal Ideation/Behaviour  
Medical concept of suicidal ideation and behaviour. Sub-SMQ 'Suicide/self-injury' 
(SMQ) from parent SMQ of 'Depression and Suicide/Self Injury (SMQ Code 20000035)'. 
Only narrow terms from the sub-SMQ selected. 
SMQ: 'Depression and Suicide/Self Injury' 
SMQ Code: 20000035 
Sub-SMQ: 'Suicide/self-injury' 
Category: A 
Scope: Narrow 
 
Preferred Term 
PT Code 
Assisted suicide 
10079105 
Columbia suicide severity rating scale abnormal 
10075616 
Completed suicide 
10010144 
Depression suicidal 
10012397 
Intentional overdose 
10022523 
Intentional self-injury 
10022524 
Poisoning deliberate 
10036000 
Self-injurious ideation 
10051154 
Suicidal behaviour 
10065604 
Suicidal ideation 
10042458 
Suicide attempt 
10042464 
Suicide threat 
10077417 
Suspected suicide 
10082458 
Suspected suicide attempt 
10081704 


TMF-14552026 
CONFIDENTIAL 
209493 
 
73 
13.10.7. 
Depression  
Medical concept of Depression. Sub-SMQ 'Depression (excl suicide and self-injury)' 
(SMQ) from parent SMQ of 'Depression and Suicide/Self Injury'. Only narrow terms 
from the sub-SMQ selected. 
SMQ: ‘'Depression and Suicide/Self Injury' 
SMQ Code: 20000035 
Sub-SMQ: 'Depression (excl suicide and self-injury)'  
Category: A 
Scope: Narrow 
 
Preferred Term 
PT Code 
Activation syndrome 
10066817 
Adjustment disorder with depressed mood 
10001297 
Adjustment disorder with mixed anxiety and depressed mood 
10001299 
Agitated depression 
10001496 
Anhedonia 
10002511 
Antidepressant therapy 
10054976 
Childhood depression 
10068631 
Decreased interest 
10011971 
Depressed mood 
10012374 
Depression 
10012378 
Depression postoperative 
10012390 
Depressive symptom 
10054089 
Dysphoria 
10013954 
Electroconvulsive therapy 
10014404 
Feeling guilty 
10049708 
Feeling of despair 
10016344 
Feelings of worthlessness 
10016374 
Helplessness 
10077169 
Major depression 
10057840 
Menopausal depression 
10067371 
Mixed anxiety and depressive disorder 
10080836 


TMF-14552026 
CONFIDENTIAL 
209493 
 
74 
SMQ: ‘'Depression and Suicide/Self Injury' 
SMQ Code: 20000035 
Sub-SMQ: 'Depression (excl suicide and self-injury)'  
Category: A 
Scope: Narrow 
 
Preferred Term 
PT Code 
Perinatal depression 
10078366 
Persistent depressive disorder 
10077804 
Post stroke depression 
10070606 
Postictal depression 
10071324 
13.10.8. 
Bipolar Disorder 
Medical concept of bipolar disorder. All preferred terms from HLGT ‘Manic and Bipolar 
mood disorders and disturbances’ under SOC “Psychiatric disorders”; HLGT Code 
10026753. 
Preferred Term 
PT Code 
Bipolar I disorder 
10004939 
Bipolar II disorder 
10004940 
Bipolar disorder 
10057667 
Cyclothymic disorder 
10011724 
Hypomania 
10021030 
Mania 
10026749 
13.10.9. 
Psychosis 
Medical concept of psychosis. Only narrow terms from SMQ 'Psychosis and psychotic 
disorders' selected. 
SMQ: 'Psychosis and psychotic disorders' 
SMQ Code: 20000117 
Category: A 
Scope: Narrow 
 
Preferred Term 
PT Code 
Acute psychosis 
10001022 
Alcoholic psychosis 
10001632 


TMF-14552026 
CONFIDENTIAL 
209493 
 
75 
SMQ: 'Psychosis and psychotic disorders' 
SMQ Code: 20000117 
Category: A 
Scope: Narrow 
 
Alice in wonderland syndrome 
10001666 
Brief psychotic disorder with marked stressors 
10048549 
Brief psychotic disorder without marked stressors 
10056395 
Brief psychotic disorder, with postpartum onset 
10006362 
Charles Bonnet syndrome 
10063354 
Childhood psychosis 
10061040 
Clang associations 
10009232 
Cotard's syndrome 
10059591 
Delusion 
10012239 
Delusion of grandeur 
10012241 
Delusion of parasitosis 
10012242 
Delusion of reference 
10012244 
Delusion of replacement 
10012245 
Delusion of theft 
10084030 
Delusional disorder, erotomanic type 
10012249 
Delusional disorder, grandiose type 
10012250 
Delusional disorder, jealous type 
10012251 
Delusional disorder, mixed type 
10012252 
Delusional disorder, persecutory type 
10053195 
Delusional disorder, somatic type 
10012254 
Delusional disorder, unspecified type 
10012255 
Delusional perception 
10012258 
Dementia of the Alzheimer's type, with delusions 
10012295 
Depressive delusion 
10063033 
Derailment 
10012411 
Epileptic psychosis 
10059232 


TMF-14552026 
CONFIDENTIAL 
209493 
 
76 
SMQ: 'Psychosis and psychotic disorders' 
SMQ Code: 20000117 
Category: A 
Scope: Narrow 
 
Erotomanic delusion 
10015134 
Flight of ideas 
10016777 
Hallucination 
10019063 
Hallucination, auditory 
10019070 
Hallucination, gustatory 
10019071 
Hallucination, olfactory 
10019072 
Hallucination, synaesthetic 
10062824 
Hallucination, tactile 
10019074 
Hallucination, visual 
10019075 
Hallucinations, mixed 
10019079 
Hypnagogic hallucination 
10020927 
Hypnopompic hallucination 
10020928 
Hysterical psychosis 
10062645 
Ideas of reference 
10021212 
Illusion 
10021403 
Jealous delusion 
10023164 
Loose associations 
10024825 
Mixed delusion 
10076429 
Neologism 
10028916 
Neuroleptic-induced deficit syndrome 
10075295 
Paranoia 
10033864 
Paranoid personality disorder 
10033869 
Parkinson's disease psychosis 
10074835 
Paroxysmal perceptual alteration 
10063117 
Persecutory delusion 
10034702 
Postictal psychosis 
10070669 


TMF-14552026 
CONFIDENTIAL 
209493 
 
77 
SMQ: 'Psychosis and psychotic disorders' 
SMQ Code: 20000117 
Category: A 
Scope: Narrow 
 
Post-injection delirium sedation syndrome 
10072851 
Posturing 
10036437 
Psychosis postoperative 
10065617 
Psychotic behaviour 
10037249 
Psychotic disorder 
10061920 
Psychotic disorder due to a general medical condition 
10061921 
Reactive psychosis 
10053632 
Rebound psychosis 
10074833 
Schizoaffective disorder 
10039621 
Schizoaffective disorder bipolar type 
10068889 
Schizoaffective disorder depressive type 
10068890 
Schizophrenia 
10039626 
Schizophreniform disorder 
10039647 
Schizotypal personality disorder 
10039651 
Senile psychosis 
10039987 
Shared psychotic disorder 
10040535 
Somatic delusion 
10041317 
Somatic hallucination 
10062684 
Substance-induced psychotic disorder 
10072388 
Tangentiality 
10043114 
Thought blocking 
10043495 
Thought broadcasting 
10052214 
Thought insertion 
10043496 
Thought withdrawal 
10043497 
Transient psychosis 
10056326 
Waxy flexibility 
10047853 


TMF-14552026 
CONFIDENTIAL 
209493 
 
78 
13.10.10. Mood Disorders 
Medical concept of mood disorders. All preferred terms from HLGT 'Mood disorders and 
disturbances NEC', under SOC 'Psychiatric disorders'; HLGT Code 10027946. 
Preferred Term 
PT Code 
Affect lability 
10054196 
Affective ambivalence 
10077173 
Affective disorder 
10001443 
Alexithymia 
10077719 
Anger 
10002368 
Apathy 
10002942 
Blunted affect 
10005885 
Boredom 
10048909 
Constricted affect 
10010778 
Crying 
10011469 
Diencephalic syndrome of infancy 
10012774 
Dysphoria 
10013954 
Emotional disorder 
10014551 
Emotional distress 
10049119 
Emotional poverty 
10014557 
Euphoric mood 
10015535 
Flat affect 
10016759 
Frustration tolerance decreased 
10077753 
Inappropriate affect 
10021588 
Irritability 
10022998 
Laziness 
10051602 
Lethargy 
10024264 
Listless 
10024642 
Moaning 
10027783 
Mood altered 
10027940 


TMF-14552026 
CONFIDENTIAL 
209493 
 
79 
Preferred Term 
PT Code 
Mood disorder due to a general medical condition 
10027944 
Mood swings 
10027951 
Morose 
10027977 
Neuroleptic-induced deficit syndrome 
10075295 
Premenstrual dysphoric disorder 
10051537 
Premenstrual syndrome 
10036618 
Screaming 
10039740 
Seasonal affective disorder 
10039775 
Steroid withdrawal syndrome 
10042028 
Substance-induced mood disorder 
10072387 
13.10.11. Anxiety 
Notes: Medical concept of anxiety disorders. All preferred terms from HLGT “Anxiety 
disorders and symptoms”, under SOC “Psychiatric disorders”; HLGT Code 10002861. 
Preferred Terms 
PT Code 
Acrophobia 
10000605 
Activation syndrome 
10066817 
Acute stress disorder 
10001084 
Aerophobia 
10080300 
Agitation 
10001497 
Agitation postoperative 
10049989 
Agoraphobia 
10001502 
Akathisia 
10001540 
Algophobia 
10078056 
Animal phobia 
10002518 
Anniversary reaction 
10074066 
Anticipatory anxiety 
10002758 
Anxiety 
10002855 


TMF-14552026 
CONFIDENTIAL 
209493 
 
80 
Preferred Terms 
PT Code 
Anxiety disorder 
10057666 
Anxiety disorder due to a general medical condition 
10002859 
Arachnophobia 
10051408 
Astraphobia 
10078372 
Autophobia 
10071070 
Body dysmorphic disorder 
10052793 
Burnout syndrome 
10065369 
Catastrophic reaction 
10082329 
Cibophobia 
10082413 
Claustrophobia 
10009244 
Compulsions 
10010219 
Compulsive cheek biting 
10076510 
Compulsive handwashing 
10071263 
Compulsive hoarding 
10068007 
Compulsive lip biting 
10066241 
Compulsive shopping 
10067948 
Cryophobia 
10082662 
Dermatillomania 
10065701 
Dysmorphophobia 
10049096 
Emetophobia 
10070637 
Fear 
10016275 
Fear of animals 
10016276 
Fear of closed spaces 
10016277 
Fear of crowded places 
10050365 
Fear of death 
10066392 
Fear of disease 
10016278 
Fear of eating 
10050366 
Fear of falling 
10048744 


TMF-14552026 
CONFIDENTIAL 
209493 
 
81 
Preferred Terms 
PT Code 
Fear of injection 
10073753 
Fear of open spaces 
10016279 
Fear of pregnancy 
10067035 
Fear of weight gain 
10016280 
Fear-related avoidance of activities 
10080136 
Generalised anxiety disorder 
10018075 
Glossophobia 
10080077 
Haemophobia 
10073458 
Haphephobia 
10067580 
Herpetophobia 
10081809 
Hydrophobia 
10053317 
Hyperarousal 
10080831 
Immunisation anxiety related reaction 
10075205 
Kinesiophobia 
10078430 
Limited symptom panic attack 
10024511 
Mysophobia 
10078769 
Nail picking 
10066779 
Nervousness 
10029216 
Neurosis 
10029333 
Noctiphobia 
10057946 
Nocturnal fear 
10057948 
Nosocomephobia 
10083993 
Nosophobia 
10063546 
Obsessive need for symmetry 
10077179 
Obsessive rumination 
10056264 
Obsessive thoughts 
10029897 
Obsessive-compulsive disorder 
10029898 
Obsessive-compulsive symptom 
10077894 


TMF-14552026 
CONFIDENTIAL 
209493 
 
82 
Preferred Terms 
PT Code 
Ochlophobia 
10050095 
Osmophobia 
10060765 
Paediatric autoimmune neuropsychiatric disorders associated with 
streptococcal infection 
10072147 
Panic attack 
10033664 
Panic disorder 
10033666 
Panic reaction 
10033670 
Paruresis 
10069024 
Performance fear 
10034432 
Phagophobia 
10050096 
Pharmacophobia 
10069423 
Phobia 
10034912 
Phobia of driving 
10056676 
Phobia of exams 
10034913 
Phobic avoidance 
10034918 
Phonophobia 
10054956 
Photaugiaphobia 
10064420 
Postpartum anxiety 
10082233 
Postpartum neurosis 
10036419 
Postpartum stress disorder 
10056394 
Post-traumatic stress disorder 
10036316 
Procedural anxiety 
10075204 
Pseudoangina 
10056610 
Selective mutism 
10039917 
Separation anxiety disorder 
10040045 
Sitophobia 
10080170 
Social anxiety disorder 
10041242 
Social fear 
10041247 


TMF-14552026 
CONFIDENTIAL 
209493 
 
83 
Preferred Terms 
PT Code 
Stress 
10042209 
Tension 
10043268 
Terminal agitation 
10077416 
Thanatophobia 
10064723 
Thermophobia 
10075147 
Trichotemnomania 
10072752 
Trichotillomania 
10044629 
13.10.12. Sleep Disorders 
Medical concept of sleep disorders. All preferred terms from (1) HLGT 'Sleep Disorders 
and Disturbances', 'Psychiatric disorders' SOC plus (2) HLGT 'Sleep disturbances (incl 
subtypes)', 'Nervous system' SOC. Numerous duplicated preferred terms e.g. middle 
insomnia. 
HLGT Sleep Disorders and Disturbances, HLGT Code 10040991 
 
Preferred Term 
PT Code 
Abnormal dreams 
10000125 
Abnormal sleep-related event 
10061613 
Advanced sleep phase 
10001423 
Behavioural induced insufficient sleep syndrome 
10081938 
Behavioural insomnia of childhood 
10072072 
Breathing-related sleep disorder 
10006344 
Cataplexy 
10007737 
Circadian rhythm sleep disorder 
10009191 
Confusional arousal 
10067494 
Delayed sleep phase 
10012209 
Dyssomnia 
10061827 
Exploding head syndrome 
10080684 
Hypersomnia 
10020765 
Hypersomnia related to another mental condition 
10020767 


TMF-14552026 
CONFIDENTIAL 
209493 
 
84 
HLGT Sleep Disorders and Disturbances, HLGT Code 10040991 
 
Preferred Term 
PT Code 
Hypersomnia-bulimia syndrome 
10053712 
Hypnagogic hallucination 
10020927 
Hypnopompic hallucination 
10020928 
Hyposomnia 
10067530 
Initial insomnia 
10022035 
Insomnia 
10022437 
Insomnia related to another mental condition 
10022443 
Irregular sleep phase 
10022995 
Irregular sleep wake rhythm disorder 
10080301 
Loss of dreaming 
10065085 
Middle insomnia 
10027590 
Narcolepsy 
10028713 
Nightmare 
10029412 
Non-24-hour sleep-wake disorder 
10078086 
Parasomnia 
10061910 
Paradoxical insomnia 
10083337 
Periodic limb movement disorder 
10064600 
Pickwickian syndrome 
10035004 
Poor quality sleep 
10062519 
Rapid eye movement sleep behaviour disorder 
10077299 
Rapid eye movements sleep abnormal 
10037841 
Shift work disorder 
10078088 
Sleep apnoea syndrome 
10040979 
Sleep attacks 
10040981 
Sleep disorder 
10040984 
Sleep disorder due to a general medical condition 
10063910 
Sleep disorder due to general medical condition, hypersomnia type 
10040985 


TMF-14552026 
CONFIDENTIAL 
209493 
 
85 
HLGT Sleep Disorders and Disturbances, HLGT Code 10040991 
 
Preferred Term 
PT Code 
Sleep disorder due to general medical condition, insomnia type 
10040986 
Sleep disorder due to general medical condition, mixed type 
10040987 
Sleep disorder due to general medical condition, parasomnia type 
10040988 
Sleep inertia 
10067493 
Sleep paralysis 
10041002 
Sleep sex 
10067492 
Sleep talking 
10041009 
Sleep terror 
10041010 
Sleep-related eating disorder 
10067315 
Somnambulism 
10041347 
Somnolence 
10041349 
Somnolence neonatal 
10041350 
Sopor 
10058709 
Stupor 
10042264 
Terminal insomnia 
10068932 
Upper airway resistance syndrome 
10063968 
HLGT Sleep disturbances (incl subtypes), HLGT code 10040998 
 
Abnormal dreams 
10000125 
Abnormal sleep-related event 
10061613 
Advanced sleep phase 
10001423 
Behavioural induced insufficient sleep syndrome 
10081938 
Behavioural insomnia of childhood 
10072072 
Breathing-related sleep disorder 
10006344 
Cataplexy 
10007737 
Central-alveolar hypoventilation 
10007982 
Circadian rhythm sleep disorder 
10009191 
Confusional arousal 
10067494 


TMF-14552026 
CONFIDENTIAL 
209493 
 
86 
HLGT Sleep Disorders and Disturbances, HLGT Code 10040991 
 
Preferred Term 
PT Code 
Delayed sleep phase 
10012209 
Dyssomnia 
10061827 
Fatal familial insomnia 
10072077 
Hypersomnia 
10020765 
Hyposomnia 
10067530 
Initial insomnia 
10022035 
Insomnia 
10022437 
Irregular sleep phase 
10022995 
Irregular sleep wake rhythm disorder 
10080301 
Loss of dreaming 
10065085 
Microsleep 
10076954 
Middle insomnia 
10027590 
Narcolepsy 
10028713 
Non-24-hour sleep-wake disorder 
10078086 
Periodic limb movement disorder 
10064600 
Pickwickian syndrome 
10035004 
Poor quality sleep 
10062519 
Rapid eye movement sleep behaviour disorder 
10077299 
Rapid eye movements sleep abnormal 
10037841 
Shift work disorder 
10078088 
Sleep apnoea syndrome 
10040979 
Sleep deficit 
10080881 
Sleep inertia 
10067493 
Sleep paralysis 
10041002 
Sleep sex 
10067492 
Sleep talking 
10041009 
Sleep terror 
10041010 


TMF-14552026 
CONFIDENTIAL 
209493 
 
87 
HLGT Sleep Disorders and Disturbances, HLGT Code 10040991 
 
Preferred Term 
PT Code 
Sleep-related eating disorder 
10067315 
Somnambulism 
10041347 
Sudden onset of sleep 
10050014 
Terminal insomnia 
10068932 
Upper airway resistance syndrome 
10063968 
13.10.13. Injection site Reactions 
Use eCRF terms for ISR. 
13.10.14. Seizures  
Medical concept of seizures. Only narrow terms from SMQ 'Convulsions' selected plus 
selected PTs of possible seizure events from HLT 'Disturbances in consciousness NEC' 
under SOC 'Nervous systems disorders' and HLT 'Confusion and disorientation' under 
SOC 'Psychiatric disorders'. 
SMQ: ‘Convulsions’  
SMQ Code: 20000079 
Category: A 
Scope: Narrow 
 
Preferred Term 
PT Code 
1p36 deletion syndrome 
10082398 
2-Hydroxyglutaric aciduria 
10078971 
Acquired epileptic aphasia 
10052075 
Acute encephalitis with refractory, repetitive partial seizures 
10076948 
Alcoholic seizure 
10056347 
Alpers disease 
10083857 
Aspartate-glutamate-transporter deficiency 
10079140 
Atonic seizures 
10003628 
Atypical benign partial epilepsy 
10056699 
Automatism epileptic 
10003831 
Autonomic seizure 
10049612 


TMF-14552026 
CONFIDENTIAL 
209493 
 
88 
SMQ: ‘Convulsions’  
SMQ Code: 20000079 
Category: A 
Scope: Narrow 
 
Preferred Term 
PT Code 
Baltic myoclonic epilepsy 
10054895 
Benign familial neonatal convulsions 
10067866 
Benign rolandic epilepsy 
10070530 
Biotinidase deficiency 
10071434 
CEC syndrome 
10083749 
CDKL5 deficiency disorder 
10083005 
Change in seizure presentation 
10075606 
Clonic convulsion 
10053398 
Congenital bilateral perisylvian syndrome 
10082716 
Convulsion in childhood 
10052391 
Convulsions local 
10010920 
Convulsive threshold lowered 
10010927 
CSWS syndrome 
10078827 
Deja vu 
10012177 
Double cortex syndrome 
10073490 
Dreamy state 
10013634 
Drug withdrawal convulsions 
10013752 
Early infantile epileptic encephalopathy with burst-suppression 
10071545 
Eclampsia 
10014129 
Epilepsy 
10015037 
Epilepsy surgery 
10079824 
Epilepsy with myoclonic-atonic seizures 
10081179 
Epileptic aura 
10015049 
Epileptic psychosis 
10059232 
Febrile convulsion 
10016284 


TMF-14552026 
CONFIDENTIAL 
209493 
 
89 
SMQ: ‘Convulsions’  
SMQ Code: 20000079 
Category: A 
Scope: Narrow 
 
Preferred Term 
PT Code 
Febrile infection-related epilepsy syndrome 
10079438 
Focal dyscognitive seizures 
10079424 
Frontal lobe epilepsy 
10049424 
Gelastic seizure 
10082918 
Generalised onset non-motor seizure 
10083376 
Generalised tonic-clonic seizure 
10018100 
Glucose transporter type 1 deficiency syndrome 
10078727 
GM2 gangliosidosis 
10083933 
Grey matter heterotopia 
10082084 
Hemimegalencephaly 
10078100 
Hyperglycaemic seizure 
10071394 
Hypocalcaemic seizure 
10072456 
Hypoglycaemic seizure 
10048803 
Hyponatraemic seizure 
10073183 
Idiopathic generalised epilepsy 
10071081 
Infantile spasms 
10021750 
Juvenile myoclonic epilepsy 
10071082 
Lafora's myoclonic epilepsy 
10054030 
Lennox-Gastaut syndrome 
10048816 
Migraine-triggered seizure 
10076676 
Molybdenum cofactor deficiency 
10069687 
Multiple subpial transection 
10079825 
Myoclonic epilepsy 
10054859 
Myoclonic epilepsy and ragged-red fibres 
10069825 
Neonatal epileptic seizure 
10082068 


TMF-14552026 
CONFIDENTIAL 
209493 
 
90 
SMQ: ‘Convulsions’  
SMQ Code: 20000079 
Category: A 
Scope: Narrow 
 
Preferred Term 
PT Code 
Neonatal seizure 
10082067 
Partial seizures 
10061334 
Partial seizures with secondary generalisation 
10056209 
Petit mal epilepsy 
10034759 
Polymicrogyria 
10073489 
Post stroke epilepsy 
10076982 
Post stroke seizure 
10076981 
Postictal headache 
10052470 
Postictal paralysis 
10052469 
Postictal psychosis 
10070669 
Postictal state 
10048727 
Post-traumatic epilepsy 
10036312 
Schizencephaly 
10073487 
Seizure 
10039906 
Seizure anoxic 
10039907 
Seizure cluster 
10071350 
Seizure like phenomena 
10071048 
Severe myoclonic epilepsy of infancy 
10073677 
Simple partial seizures 
10040703 
Status epilepticus 
10041962 
Sudden unexplained death in epilepsy 
10063894 
Temporal lobe epilepsy 
10043209 
Tonic clonic movements 
10051171 
Tonic convulsion 
10043994 
Tonic posturing 
10075125 


TMF-14552026 
CONFIDENTIAL 
209493 
 
91 
SMQ: ‘Convulsions’  
SMQ Code: 20000079 
Category: A 
Scope: Narrow 
 
Preferred Term 
PT Code 
Topectomy 
10073488 
Transient epileptic amnesia 
10081728 
Tuberous sclerosis complex 
10080584 
Uncinate fits 
10045476 
Additional selected preferred terms from HLT Disturbances in 
consciousness NEC, HLT code 10013509 and HLT Confusion and 
disorientation, HLT code 10010301. 
Preferred Term 
PT Code 
Confusional state 
10010305 
Loss of consciousness 
10024855 
Syncope 
10042772 
Sopor 
10058709 
Stupor 
10042264 
Altered state of consciousness 
10050093 
Depressed level of consciousness 
10012373 
Consciousness fluctuating 
10050093 


TMF-14552026 
CONFIDENTIAL 
209493 
 
92 
13.10.15. Weight Gain 
Medical concept of weight gain. Selected PTs from HLT 'General nutritional disorders 
NEC', under SOC 'Metabolism and nutrition disorders', and HLT 'Physical examination 
procedures and organ system status', under SOC 'Investigations' and HLT 'General signs 
and symptoms NEC', under SOC 'General disorders and administration site conditions'. 
PTs (Select) from HLT General nutritional disorders NEC, HLT code 10018067 
Preferred Term 
PT Code 
Abdominal fat apron 
10077983 
Overweight 
10033307 
Abnormal weight gain 
10000188 
Central obesity 
10065941 
Obesity 
10029883 
Abdominal fat apron 
10077983 
Overweight 
10033307 
Abnormal weight gain 
10000188 
Central obesity 
10065941 
Obesity 
10029883 
PTs (Select) from HLT Physical examination procedures and organ system status, HLT 
Code 10071941 
Preferred Term 
PT Code 
Weight abnormal 
10056814 
Weight increased 
10047899 
Waist circumference increased 
10064863 
Body mass index abnormal 
10074506 
Body mass index increased 
10005897 
PTs (Select) from HLT General signs and symptoms NEC, HLT Code 10018072 
Preferred Term 
PT Code 
Fat tissue increased 
10016251 
Sarcopenic obesity 
10083992 


TMF-14552026 
CONFIDENTIAL 
209493 
 
93 
13.10.16. Rhabdomyolysis 
Medical concept of rhabdomyolysis. Only narrow terms only for SMQ 
'Rhabdomyolysis/myopathy' plus 2 additional preferred terms selected from HGLT 
'muscle disorders' under SOC 'Musculoskeletal and connective tissue disorders'. 
SMQ: 'Rhabdomyolysis/myopathy' 
SMQ Code: 20000002 
Category: A 
Scope: Narrow 
 
Preferred Term 
PT Code 
Muscle necrosis 
10028320 
Myoglobin blood increased 
10028625 
Myoglobin blood present 
10059888 
Myoglobin urine present 
10028631 
Myoglobinaemia 
10058735 
Myoglobinuria 
10028629 
Myopathy 
10028641 
Myopathy toxic 
10028648 
Necrotising myositis 
10074769 
Rhabdomyolysis 
10039020 
Thyrotoxic myopathy 
10081524 
PTs (Select) from HGLT muscle disorders, HLGT Code 10028302 
Preferred Term 
PT Code 
Myalgia 
10028411 
Myositis 
10028653 


TMF-14552026 
CONFIDENTIAL 
209493 
 
94 
13.10.17. Pancreatitis  
Medical concept of acute pancreatitis. Only narrow terms of SMQ 'Acute pancreatitis' 
selected. Algorithmic approach for this SMQ not used due to complexity in applying and 
poor specificity of remaining categories. Category A selected as PTs because more 
specific for concept (only narrow terms). 
SMQ: 'Acute pancreatitis'  
SMQ Code: 20000022  
Category: A 
Scope: Narrow 
 
Preferred Term 
PT Code 
Cullen's sign 
10059029 
Grey Turner's sign 
10075426 
Haemorrhagic necrotic pancreatitis 
10076058 
Hereditary pancreatitis 
10056976 
Immune-mediated pancreatitis 
10083072 
Ischaemic pancreatitis 
10066127 
Oedematous pancreatitis 
10052400 
Pancreatic abscess 
10048984 
Pancreatic cyst drainage 
10082531 
Pancreatic haemorrhage 
10033625 
Pancreatic necrosis 
10058096 
Pancreatic phlegmon 
10056975 
Pancreatic pseudoaneurysm 
10081762 
Pancreatic pseudocyst 
10033635 
Pancreatic pseudocyst drainage 
10033636 
Pancreatic pseudocyst haemorrhage 
10083813 
Pancreatic pseudocyst rupture 
10083811 
Pancreatitis 
10033645 
Pancreatitis acute 
10033647 
Pancreatitis haemorrhagic 
10033650 
Pancreatitis necrotising 
10033654 


TMF-14552026 
CONFIDENTIAL 
209493 
 
95 
SMQ: 'Acute pancreatitis'  
SMQ Code: 20000022  
Category: A 
Scope: Narrow 
 
Preferred Term 
PT Code 
Pancreatitis relapsing 
10033657 
Pancreatorenal syndrome 
10056277 
13.10.18. Impact on Creatinine 
Medical concept of worsening renal function/renal failure in the context of impact on 
creatinine. Only narrow terms from SMQ 'Acute renal failure' plus all PTs from HLT 
'Renal failure and impairment', under SOC 'Renal and urinary disorders'. Numerous 
duplicated preferred terms e.g. renal failure 
SMQ: ‘Acute renal failure’ 
SMQ Code: 20000003 
Category: A 
Scope: Narrow 
 
Preferred Term 
PT Code 
Acute kidney injury 
10069339 
Acute phosphate nephropathy 
10069688 
Anuria 
10002847 
Azotaemia 
10003885 
Continuous haemodiafiltration 
10066338 
Dialysis 
10061105 
Foetal renal impairment 
10078987 
Haemodialysis 
10018875 
Haemofiltration 
10053090 
Neonatal anuria 
10049778 
Nephropathy toxic 
10029155 
Oliguria 
10030302 
Peritoneal dialysis 
10034660 
Prerenal failure 
10072370 
Renal failure 
10038435 


TMF-14552026 
CONFIDENTIAL 
209493 
 
96 
SMQ: ‘Acute renal failure’ 
SMQ Code: 20000003 
Category: A 
Scope: Narrow 
 
Preferred Term 
PT Code 
Renal failure neonatal 
10038447 
Renal impairment 
10062237 
Renal impairment neonatal 
10049776 
Subacute kidney injury 
10081980 
Renal Failure and Impairment HLT, HLT Code 10038443 
Preferred Term 
PT Code 
Acute Kidney injury 
10069339 
Anuria 
10002847 
Atypical haemolytic uraemic syndrome 
10079840 
Cardiorenal syndrome 
10068230 
Chronic kidney disease 
10064848 
Crush syndrome 
10050702 
Diabetic end stage renal disease 
10012660 
End stage renal disease 
10077512 
Foetal renal impairment 
10078987 
Haemolytic uraemic syndrome 
10018932 
Hepatorenal failure 
10019845 
Hepatorenal syndrome 
10019846 
Nail-patella syndrome 
10063431 
Neonatal anuria 
10049778 
Oliguria 
10030302 
Pancreatorenal syndrome 
10056277 
Postoperative renal failure 
10056675 
Postrenal failure 
10059345 
Prerenal failure 
10072370 


TMF-14552026 
CONFIDENTIAL 
209493 
 
97 
SMQ: ‘Acute renal failure’ 
SMQ Code: 20000003 
Category: A 
Scope: Narrow 
 
Preferred Term 
PT Code 
Propofol infusion syndrome 
10063181 
Renal failure 
10038435 
Renal failure neonatal 
10038447 
Renal impairment 
10062237 
Renal impairment neonatal 
10049776 
Renal injury 
10061481 
Scleroderma renal crisis 
10062553 
Traumatic anuria 
10044501 
13.10.19. Safety During Pregnancy 
Use AE terms co-reported in pregnancy exposures to CAB. 


TMF-14552026 
CONFIDENTIAL 
209493 
 
98 
13.11. 
Appendix 11: Identification of COVID-19 Adverse Events 
COVID-19 adverse events are identified based on MedDRA coded values and/or AE 
referenced in the COVID-19 Coronavirus Infection assessment. The Lowest Level Terms 
(LLTs) and codes, Preferred Terms (PTs), High Level Terms (HLTs), High Level Group 
Terms (HLGTs), and System Organ Classes (SOCs), below are from MedDRA 23.0. In 
case there is a change to the version of MedDRA at time of reporting, the coded values 
based on the MedDRA version at the time of reporting will be used. The additional 
events may also be added based on the blinded review of AE data collected on study prior 
to the database freeze. 
SOC: Infections and infestations 
LLT code LLT 
PT 
HLT 
HLGT 
10084459 Asymptomatic COVID-19 
Asymptomatic 
COVID-19 
Coronavirus 
infections 
Viral 
infectious 
disorders 
10084467 Asymptomatic SARS-CoV-2 infection 
Asymptomatic 
COVID-19 
Coronavirus 
infections 
Viral 
infectious 
disorders 
10053983 Corona virus infection 
Coronavirus 
infection 
Coronavirus 
infections 
Viral 
infectious 
disorders 
10051905 Coronavirus infection 
Coronavirus 
infection 
Coronavirus 
infections 
Viral 
infectious 
disorders 
10084382 Coronavirus disease 2019 
COVID-19 
Coronavirus 
infections 
Viral 
infectious 
disorders 
10084268 COVID-19 
COVID-19 
Coronavirus 
infections 
Viral 
infectious 
disorders 
10084401 COVID-19 respiratory infection 
COVID-19 
Coronavirus 
infections 
Viral 
infectious 
disorders 
10084270 SARS-CoV-2 acute respiratory disease COVID-19 
Coronavirus 
infections 
Viral 
infectious 
disorders 
10084272 SARS-CoV-2 infection 
COVID-19 
Coronavirus 
infections 
Viral 
infectious 
disorders 
10084381 Coronavirus pneumonia 
COVID-19 
pneumonia 
Coronavirus 
infections 
Viral 
infectious 
disorders 
10084380 COVID-19 pneumonia 
COVID-19 
pneumonia 
Coronavirus 
infections 
Viral 
infectious 
disorders 


TMF-14552026 
CONFIDENTIAL 
209493 
 
99 
LLT code LLT 
PT 
HLT 
HLGT 
10084383 Novel COVID-19-infected pneumonia 
COVID-19 
pneumonia 
Coronavirus 
infections 
Viral 
infectious 
disorders 
10084451 Suspected COVID-19 
Suspected 
COVID-19 
Coronavirus 
infections 
Viral 
infectious 
disorders 
10084452 Suspected SARS-CoV-2 infection 
Suspected 
COVID-19 
Coronavirus 
infections 
Viral 
infectious 
disorders 
10084461 SARS-CoV-2 carrier 
SARS-CoV-2 
carrier 
Infectious 
disorders 
carrier 
Ancillary 
infectious 
topics 
 


TMF-14552026 
CONFIDENTIAL 
209493 
 
100 
13.12. 
Appendix 12: Abbreviations & Trade Marks 
13.12.1. 
Abbreviations 
Abbreviation 
Description 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
AIC 
Akaike's Information Criteria 
A&R 
Analysis and Reporting  
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
CPMS 
Clinical Pharmacology Modelling & Simulation 
CS 
Clinical Statistics 
CSR 
Clinical Study Report 
CTR 
Clinical Trial Register 
CVb / CVw 
Coefficient of Variation (Between) / Coefficient of Variation (Within) 
DBF 
Database Freeze 
DBR 
Database Release 
DOB 
Date of Birth 
DP 
Decimal Places 
eCRF 
Electronic Case Record Form 
EEP 
Efficacy Evaluable Population 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Clinical Results Disclosure Requirements 
GSK 
GlaxoSmithKline 
IA 
Interim Analysis 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee  
IDSL 
Integrated Data Standards Library 
IMMS 
International Modules Management System 
IP 
Investigational Product 
ITT 
Intent-To-Treat 
MMRM 
Mixed Model Repeated Measures 
PBMC 
Peripheral Blood Mononuclear Cells 
PCI 
Potential Clinical Importance  
PD 
Pharmacodynamic 
PDMP 
Protocol Deviation Management Plan 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PopPK 
Population PK 
QC 
Quality Control 
QTcF 
Frederica’s QT Interval Corrected for Heart Rate 
QTcB 
Bazett’s QT Interval Corrected for Heart Rate 
RAP 
Reporting & Analysis Plan 
RAMOS 
Randomization & Medication Ordering System  
SAC 
Statistical Analysis Complete 


TMF-14552026 
CONFIDENTIAL 
209493 
 
101 
Abbreviation 
Description 
SDSP 
Study Data Standardization Plan 
SDTM 
Study Data Tabulation Model 
SOP 
Standard Operation Procedure 
TA 
Therapeutic Area 
TFL 
Tables, Figures & Listings  
13.12.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
NONE 
 
SAS 
 
 
 
 
 
 
 
 


TMF-14552026 
CONFIDENTIAL 
209493 
 
102 
13.13. 
Appendix 13: List of Data Displays 
All data displays will use the term “subject” rather than “participant” in accordance with 
CDSIC and GSK Statistical Display Standards. 
Where applicable, all summary displays will present data across both the Intervention and 
Extension phases unless explicitly stated otherwise in the display title. 
13.13.1. 
Data Display Numbering 
The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Figures 
Study Population 
1.1 to 1.n 
1.1 to 1.n 
Efficacy 
2.1 to 2.n 
2.1 to 2.n 
Safety 
3.1 to 3.n 
3.1 to 3.n 
Pharmacokinetic 
4.1 to 4.n 
4.1 to 4.n 
Virology 
5.1 to 5.n 
5.1 to 4.n 
Other 
6.1 to 6.n 
6.1 to 6.n 
Section 
Listings 
ICH Listings 
1 to x 
Other Listings 
y to z 
 
13.13.2. 
Mock Example Shell Referencing 
Nonstandard specifications will be referenced as indicated below (where a study specific 
mock shell is available) or the location of a similar display produced for a different study 
in the HARP reporting environment will be provided as reference. The example mock-up 
displays from other reporting efforts will be named in the format: Study Number/HARP 
Reporting Effort/Output Type (T/ F/L)/Display Number, where T stands for Table, F 
stands for Figure and L stands for Listing. For example, the Table 1.1 from primary_02 
reporting effort for Study 201585 will be named by 201585/primary_02/T1.1. If required 
example mock-up displays provided in Appendix 14: Example Mock Shells for Data 
Displays.   
Section 
Figure 
Table 
Listing 
Study Population 
POP_Fn 
POP_Tn 
POP_Ln 
Efficacy 
EFF_Fn 
EFF_Tn 
EFF_Ln 
Safety 
SAF_Fn 
SAF_Tn 
SAF_Ln 
Pharmacokinetic 
PK_Fn 
PK_Tn 
PK_Ln 
Virology 
VIR_Fn 
VIR_Tn 
VIR_Ln 
Other 
OTR_Tn 
OTR_Fn 
OTR_Ln 
 


TMF-14552026 
CONFIDENTIAL 
209493 
 
103 
13.13.3. 
Deliverables 
Delivery 
Description 
HL 
Month 12 Headline 
M12 
Month 12 Analysis 
EOS 
End of Study Analysis 
Note that the TLFs with asterisk (i.e. EOS*) will only be produced 
when the underlying source data has been changed since Month 12 
analysis. 
 
 


TMF-14552026 
CONFIDENTIAL 
209493 
 
104 
13.13.4. 
Study Population Tables 
Study Population Tables 
No. 
Population 
GSK Standard 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
Subject Disposition 
1.1. 
Safety 
ES1 
Summary of Subject Disposition for the Subject 
Conclusion Record 
ICH E3, FDAAA, EudraCT 
HL, M12, EOS 
1.2. 
Safety 
SD1 
Summary of Treatment Status and Reasons for 
Discontinuation of Study Treatment 
ICH E3 
M12, EOS 
1.3. 
Safety 
ES4 
Summary of Subject Disposition at Each Study Phase 
ICH E3 
Intervention/Extension phase: 
status and reason for withdrawal 
based on date and reason 
collected in the study treatment 
discontinuation form. 
Long term Follow-up: 
completion/withdrawal based on 
data collected in the Study 
Conclusion form. 
M12, EOS 
1.4. 
Safety 
ES5 
Summary of Reason for Withdrawal at Each Study Phase 
FDAAA, EudraCT 
HL, M12, EOS 
1.5. 
Safety 
ES11 
Summary of Outcome of Adverse Events Which Led to 
Study Withdrawal/Treatment Discontinuation at Each 
Study Phase 
EudraCT 
M12, EOS 
1.6. 
Screened 
ES6 
Summary of Screening Status and Reasons for Screen 
Failure 
Journal Requirements 
M12, EOS 


TMF-14552026 
CONFIDENTIAL 
209493 
 
105 
Study Population Tables 
No. 
Population 
GSK Standard 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
1.7. 
Enrolled 
NS1 
Summary of Number of Subjects by Country and Site ID 
EudraCT/Clinical Operations 
M12, EOS 
1.8. 
Screened 
NS1 
Summary of Number of Subjects by Site Type and Site ID 
Replace Country with Site Type 
Add column for Investigator 
Name 
M12, EOS 
Protocol Deviation 
1.9. 
Enrolled 
DV1 
Summary of Important Protocol Deviations  
ICH E3 
M12, EOS 
1.10. 
Enrolled 
DV1 
Summary of Important COVID-19 Related Protocol 
Deviations  
Update the label for the first row 
to be “ANY IMPORTANT 
COVID-19 RELATED 
PROTOCOL DEVIATIONS” 
M12, EOS 
1.11. 
Enrolled 
DV1 
Summary of Important Non-COVID-19 Protocol 
Deviations  
Update the label for the first row 
to be “ANY IMPORTANT NON-
COVID-19 RELATED 
PROTOCOL DEVIATIONS” 
M12, EOS 
1.12. 
Enrolled 
DV1 
Summary of All COVID-19 Protocol Deviations by Site 
Update the label for the first row 
to be “ANY COVID-19 RELATED 
PROTOCOL DEVIATIONS”. 
Summary for each site and 
‘Total’ across sites. 
HL, M12, EOS 


TMF-14552026 
CONFIDENTIAL 
209493 
 
106 
Study Population Tables 
No. 
Population 
GSK Standard 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
1.13. 
Enrolled 
DV1 
Summary of All Implementation Protocol Deviations by 
Site 
Update the label for the first row 
to be “ANY IMPLEMENTATION 
RELATED PROTOCOL 
DEVIATIONS” 
Summary for each site and 
‘Total’ across sites. 
HL, M12, EOS 
Population Analysed 
1.14. 
Screened 
SP1 
Summary of Study Populations  
GSK Statistical Display Standard 
M12, EOS 
1.15. 
Enrolled 
SP2 
Summary of Exclusions from the Safety Population 
GSK Statistical Display Standard 
M12, EOS 
Demographic and Baseline Characteristics 
1.16. 
Safety 
DM1 
Summary of Demographic Characteristics 
ICH E3, FDAAA, EudraCT. For 
EOS: add age group (18 - 24, 25 
- 40, >40), BMI group (<30, 
>=30). 
HL, M12, EOS 
1.17. 
Enrolled 
DM11 
Summary of Age Ranges 
EudraCT 
M12, EOS 
1.18. 
Safety 
DM6 
Summary of Race and Racial Combinations 
ICH E3, FDA, FDAAA, EudraCT 
M12, EOS 
1.19. 
Safety 
BASELINE2 
Distribution of CD4+ Cell Count Results at Screening and 
Baseline 
 
M12, EOS* 
1.20. 
Safety 
BASELINE3 
Summary of Hepatitis Status at Entry 
 
M12, EOS* 
1.21. 
Safety 
CDC1 
Summary of CDC Classification of HIV-1 Infection at 
Baseline 
 
M12, EOS* 


TMF-14552026 
CONFIDENTIAL 
209493 
 
107 
Study Population Tables 
No. 
Population 
GSK Standard 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
Prior and Concomitant Medications 
1.22. 
Safety 
MH1 
Summary of Past Medical Conditions 
ICH E3 
M12, EOS* 
1.23. 
Safety 
MH4 
Summary of Past Cardiac, Gastrointestinal, Metabolism 
and Nutrition, Psychiatric, Renal and Urinary, Nervous 
System Conditions, and Hepatobiliary Disorders 
ICH E3 
M12, EOS* 
1.24. 
Safety 
MH1 
Summary of Current Medical Conditions 
ICH E3 
M12, EOS 
1.25. 
Safety 
MH4 
Summary of Current Cardiac, Gastrointestinal, 
Metabolism and Nutrition, Psychiatric, Renal and Urinary, 
Nervous System Conditions, and Hepatobiliary Disorders 
ICH E3 
M12, EOS 
1.26. 
Safety 
CM9 
Summary of Concomitant Medications by Ingredient 
Combinations 
ICH E3 
See GSK Statistical Display 
Standard 
Multi-ingredient medications will 
be labelled according to the sum 
of their ingredients, i.e., Generic 
Term. 
M12, EOS 
1.27. 
Safety 
207966/primary
_15/T1.30 
Summary of Prior Antiretroviral Therapy Medications 
Remove the footnote. Follow 
definitions in Section 13.4.1 to 
determine the prior ART 
medications. 
M12, EOS* 


TMF-14552026 
CONFIDENTIAL 
209493 
 
108 
Study Population Tables 
No. 
Population 
GSK Standard 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
1.28. 
Safety 
201585/primary
_02/T1.30 
Summary of Antiretroviral Therapy Taken During 
Screening by Baseline Third Agent Class 
Like Example shell but stratified 
by Baseline Third Agent Class 
(NNRTI, INI, PI); add ‘Any’ row 
under each class. 
M12, EOS* 
1.29. 
Safety 
RF1 
Summary of HIV Risk Factors 
 
M12, EOS* 
Other 
1.30. 
Safety 
POP_T1 
Summary of Transition to CAB + RPV LA Marketed 
Product Status by Site Type and Site ID 
 
EOS 


TMF-14552026 
CONFIDENTIAL 
209493 
 
109 
13.13.5. 
Efficacy Tables 
Efficacy: Tables 
No. 
Population 
GSK 
Standard/ 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
Snapshot 
2.1. 
Safety 
EFF_T1 
See Section 
13.14 
Summary of Study Outcomes (50 c/mL cutoff) at Month 12 
(Intervention Phase) – Modified Snapshot Analysis with 
COVID-19 related LOCF 
Missing HIV-1 RNA due to 
COVID-19 are imputing using 
last post baseline value carried 
forward. 
HL, M12 
2.2. 
Safety 
EFF_T2 
See Section 
13.14 
Summary of Study Outcomes (50 c/mL cutoff) at Month 12 
(Intervention Phase) –Snapshot Analysis 
With expanded COVID-19 
related/Non-related categories 
HL, M12 
2.3. 
Safety 
SNAPSHOT4 
Proportion of Subjects with Plasma HIV-1 RNA ≥ 50 c/mL 
Over Time (Intervention Phase) – Modified Snapshot 
Analysis with COVID-19 related LOCF 
Missing HIV-1 RNA due to 
COVID-19 are imputing using 
last post baseline value carried 
forward. 
Use Exact (Clopper-Pearson) 
method for 95% confidence 
Intervals. 
M12 


TMF-14552026 
CONFIDENTIAL 
209493 
 
110 
Efficacy: Tables 
No. 
Population 
GSK 
Standard/ 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
2.4. 
Safety 
SNAPSHOT4 
Proportion of Subjects with Plasma HIV-1 RNA < 50 c/mL 
Over Time (Intervention Phase) – Modified Snapshot 
Analysis with COVID-19 related LOCF 
Missing HIV-1 RNA due to 
COVID-19 are imputing using 
last post baseline value carried 
forward. 
Use Exact (Clopper-Pearson) 
method for 95% confidence 
Intervals. 
M12 
2.5. 
Safety 
SNAPSHOT7 
Summary of Study Outcomes (50 c/mL cutoff) at Month 12 
by Site Type (Intervention Phase) – Modified Snapshot 
Analysis with COVID-19 related LOCF 
Missing HIV-1 RNA due to 
COVID-19 are imputing using 
last post baseline value carried 
forward. 
M12 
CVF 
2.6. 
Safety 
VF1 
Cumulative Proportion of Subjects Meeting Confirmed 
Virologic Failure Criteria Over Time (Intervention Phase) 
 
HL, M12 
2.7. 
Safety 
207966/primar
y_15/T2.23 
Cumulative Proportion of Subjects Meeting Confirmed 
Virologic Failure Criteria Over Time 
 
M12, EOS 
CD4 
2.8. 
Safety 
LB1 
Summary of CD4+ Cell Count (cells/mm^3) by Visit 
 
M12, EOS 
2.9. 
Safety 
LB1 
Summary of Change from Baseline in CD4+ Cell Count 
(cells/mm^3) by Visit 
 
M12, EOS 


TMF-14552026 
CONFIDENTIAL 
209493 
 
111 
Efficacy: Tables 
No. 
Population 
GSK 
Standard/ 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
HIV Associated Conditions 
2.10. 
Safety 
CDC2 
Summary of Post-Baseline CDC Stage 3 HIV-1 Associated 
Conditions Including Recurrences 
 
M12, EOS 
2.11. 
Safety 
CDC2 
Summary of Post-Baseline CDC Stage 3 HIV-1 Associated 
Conditions Excluding Recurrences 
 
M12, EOS 
Plasma HIV-1 RNA 
2.12. 
Safety 
209493/primar
y_01/T2.4 
Proportion of Subjects with Plasma HIV-1 RNA < 50 c/mL 
Over Time – Observed Case 
 
EOS 
 


TMF-14552026 
CONFIDENTIAL 
209493 
 
112 
13.13.6. 
Efficacy Figures 
Efficacy: Figures 
No. 
Population 
GSK 
Standard 
 / Example 
Shell 
Title  
Programming Notes 
Deliverable  
2.1. 
Safety 
SNAPSHOT8 
Percent (95% CI) of Subjects with Plasma HIV-1 RNA ≥ 50 
copies/mL Over Time (Intervention Phase) – Modified 
Snapshot Analysis with COVID-19 related LOCF 
Missing HIV-1 RNA due to 
COVID-19 are imputing using 
last post baseline value carried 
forward. 
 
Use Exact (Clopper-Pearson) 
method for 95% confidence 
Intervals. 
M12 
2.2. 
Safety 
SNAPSHOT8 
Percent (95% CI) of Subjects with Plasma HIV-1 RNA < 50 
copies/mL Over Time (Intervention Phase) – Modified 
Snapshot Analysis with COVID-19 related LOCF 
Missing HIV-1 RNA due to 
COVID-19 are imputing using 
last post baseline value carried 
forward. 
 
Use Exact (Clopper-Pearson) 
method for 95% confidence 
Intervals. 
M12 


TMF-14552026 
CONFIDENTIAL 
209493 
 
113 
Efficacy: Figures 
No. 
Population 
GSK 
Standard 
 / Example 
Shell 
Title  
Programming Notes 
Deliverable  
2.3. 
Safety 
SNAPSHOT1
0 
Individual Plasma HIV-1 RNA for Subjects Snapshot 
Algorithm Plasma HIV-1 RNA >= 50 copies/mL at Month 
12 – Modified Snapshot Analysis with COVID-19 related 
LOCF 
The 1st vertical line indicates 
start of study treatment at 
Intervention Phase. The second 
vertical reference line indicates 
last IP on-treatment study day.  
i.e. min (last IP injection dose+35 
days, LTFU HAART start date, 
date of last oral CAB+RPV+1). 
This vertical line is only for 
subjects who withdraw from 
Intervention Phase/Extension 
phase. 
M12 


TMF-14552026 
CONFIDENTIAL 
209493 
 
114 
Efficacy: Figures 
No. 
Population 
GSK 
Standard 
 / Example 
Shell 
Title  
Programming Notes 
Deliverable  
2.4. 
Safety 
SNAPSHOT1
0 
Individual Plasma HIV-1 RNA for Subjects with Confirmed 
Virologic Failure 
The 1st vertical line indicates 
start of study treatment at 
Intervention Phase. The second 
vertical reference line indicates 
last IP on-treatment study day.  
i.e. min (last IP injection dose+35 
days, LTFU HAART start date, 
date of last oral CAB+RPV+1). 
This vertical line is only for 
subjects who withdraw from 
Intervention Phase/Extension 
phase. Include all plasma HIV-1 
RNA data for a subject. 
M12, EOS 
 


TMF-14552026 
CONFIDENTIAL 
209493 
 
115 
13.13.7. 
Safety Tables 
Note: The summary table for individual AESI may be added or removed per final AESI list for the analysis. 
Safety: Tables 
No. 
Population 
GSK 
Standard/ 
Example 
Shell 
Title  
Programming Notes 
Deliverable  
Exposure 
3.1. 
Safety 
207966/primar
y_15/T3.1 
Summary of Exposure to Study Treatment (Intervention 
Phase) 
 
M12 
3.2. 
Safety 
207966/primar
y_15/T3.1 
Summary of Exposure to Study Treatment 
 
M12, EOS 
3.3. 
Safety 
SAF_T1 
See Section 
13.14 
Summary of Adherence to CAB LA + RPV LA Dosing 
Schedule by Visit, Site Type and COVID-19 Impact /Non-
Impact (Intervention Phase) 
COVID Impact refers to missed 
or out of window injections for 
COVID-19 related reasons (as 
captured as COVID-19 related 
protocol deviations) 
HL, M12 
3.4. 
Safety 
SAF_T2 
See Section 
13.14 
Summary of Adherence to CAB LA + RPV LA Dosing 
Schedule by Visit, Site ID and COVID-19 Impact /Non-
Impact (Intervention Phase) 
COVID Impact refers to missed 
or out of window injections for 
COVID-19 related reasons (as 
captured as COVID-19 related 
protocol deviations) 
HL, M12 


TMF-14552026 
CONFIDENTIAL 
209493 
 
116 
Safety: Tables 
No. 
Population 
GSK 
Standard/ 
Example 
Shell 
Title  
Programming Notes 
Deliverable  
3.5. 
Safety 
SAF_T1 
See Section 
13.14 
Summary of Adherence to CAB LA + RPV LA Dosing 
Schedule by Visit, Site Type and COVID-19 Impact /Non-
Impact 
COVID Impact refers to missed 
or out of window injections for 
COVID-19 related reasons (as 
captured as COVID-19 related 
protocol deviations) 
EOS 
3.6. 
Safety 
SAF_T2 
See Section 
13.14 
Summary of Adherence to CAB LA + RPV LA Dosing 
Schedule by Visit, Site ID and COVID-19 Impact /Non-
Impact 
COVID Impact refers to missed 
or out of window injections for 
COVID-19 related reasons (as 
captured as COVID-19 related 
protocol deviations) 
EOS 
Adverse Events (AEs) 
3.7. 
Safety 
AE3 
Summary of Adverse Events by Overall Frequency 
ICH E3 
M12, EOS 
3.8. 
Safety 
AE5B 
Summary of Adverse Events by System Organ Class and 
Maximum Grade 
ICH E3 
HL, M12, EOS 
3.9. 
Safety 
AE5B 
Summary of Adverse Events by System Organ Class and 
Maximum Grade — Excluding Study Drug Injection Site 
Reactions  
 
M12, EOS 
3.10. 
Safety 
AE5B 
Summary of Adverse Events by System Organ Class and 
Maximum Grade (Oral Lead-in Period)  
 
M12 
3.11. 
Safety 
AE3 
Summary of Common (>=5%) Adverse Events by Overall 
Frequency 
ICH E3 
M12, EOS 


TMF-14552026 
CONFIDENTIAL 
209493 
 
117 
Safety: Tables 
No. 
Population 
GSK 
Standard/ 
Example 
Shell 
Title  
Programming Notes 
Deliverable  
3.12. 
Safety 
AE3 
Summary of Common (>=1%) Grade 2-5 Adverse Events 
by Overall Frequency 
ICH E3 
M12, EOS 
3.13. 
Safety 
AE3 
Summary Drug-Related Adverse Events by Overall 
Frequency 
ICH E3 
M12, EOS 
3.14. 
Safety 
AE5B 
Summary of Drug-Related Adverse Events by System 
Organ Class and Maximum Grade 
ICH E3 
 
HL, M12, EOS 
3.15. 
Safety 
AE5B 
Summary of Drug-Related Adverse Events by System 
Organ Class and Maximum Grade — Excluding Study 
Drug Injection Site Reactions 
 
M12, EOS 
3.16. 
Safety 
AE15 
Summary of Common (>=5%) Non-serious Adverse Events 
by System Organ Class and Preferred Term (Number of 
Subjects and Occurrences) 
FDAAA, EudraCT 
M12, EOS 
3.17. 
Safety 
AE3 
Summary of Common (>=1%) Drug-Related Grade 2-5 
Adverse Events by Overall Frequency 
ICH E3 
M12, EOS 
3.18. 
Safety 
AE3 
Summary of Non-Serious Drug-Related Adverse Events by 
Overall Frequency 
Plain Language Summary 
requirements. 
M12, EOS 


TMF-14552026 
CONFIDENTIAL 
209493 
 
118 
Safety: Tables 
No. 
Population 
GSK 
Standard/ 
Example 
Shell 
Title  
Programming Notes 
Deliverable  
Serious and Other Significant Adverse Events 
3.19. 
Safety 
AE5B 
Summary of Serious Adverse Events by System Organ 
Class and Maximum Grade 
ICH E3 
HL, M12, EOS 
3.20. 
Safety 
AE16 
Summary of Serious Adverse Events by System Organ 
Class and Preferred Term (Number of Subjects and 
Occurrences) 
FDAAA, EudraCT 
M12, EOS 
3.21. 
Safety 
AE1 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from 
Study by System Organ Class and Preferred Term 
GSK Statistical Display Standard 
HL, M12, EOS 
3.22. 
Safety 
AE20 
Summary of Serious Fatal and Non-Fatal Drug-Related 
Adverse Events by Overall Frequency 
Plain Language Summary 
requirements. 
M12, EOS 
Injection Site Reaction Adverse Events   
3.23. 
Safety 
201584/primar
y_7/T3.40 
Summary of Study Drug Injection Site Reaction Adverse 
Events (Event-level Summary) 
 
HL, M12, EOS 
3.24. 
Safety 
201584/primar
y_7/T3.43 
Summary of Subject-level Characteristics of Study Drug 
Injection Site Reaction Adverse Events – Overall and 
Common 
 
HL, M12, EOS 
3.25. 
Safety 
201584/primar
y_7/T3.46 
Summary of Study Drug Injection Site Reaction Adverse 
Events by Visit and Maximum Severity – Overall and 
Common 
 
HL, M12, EOS 


TMF-14552026 
CONFIDENTIAL 
209493 
 
119 
Safety: Tables 
No. 
Population 
GSK 
Standard/ 
Example 
Shell 
Title  
Programming Notes 
Deliverable  
Laboratory: Chemistry  
3.26. 
Safety 
LB1 
Summary of Chemistry Values  
Includes pre-specified 
parameters repeated in 
conventional units. 
Includes baseline values 
M12, EOS 
3.27. 
Safety 
LB1 
Summary of Chemistry Changes from Baseline  
ICH E3 
M12, EOS 
3.28. 
Safety 
LB16 
Summary of Chemistry Results by Maximum Grade 
Increase Post-Baseline Relative to Baseline 
ICH E3 
HL, M12, EOS 
3.29. 
Safety 
LB16 
Summary of Chemistry Results by Maximum Grade 
Increase Post-Baseline Relative to Baseline (Oral Lead-in 
Period) 
ICH E3 
M12 
Laboratory: Hematology 
3.30. 
Safety 
LB1 
Summary of Hematology Values  
Includes pre-specified 
parameters repeated in 
conventional units. 
M12, EOS 
3.31. 
 Safety 
LB1 
Summary of Hematology Changes from Baseline 
Includes pre-specified 
parameters repeated in 
conventional units. 
Includes baseline values 
M12, EOS 
3.32. 
Safety 
LB16 
Summary of Hematology Results by Maximum Grade 
Increase Post-Baseline Relative to Baseline 
ICH E3 
M12, EOS 


TMF-14552026 
CONFIDENTIAL 
209493 
 
120 
Safety: Tables 
No. 
Population 
GSK 
Standard/ 
Example 
Shell 
Title  
Programming Notes 
Deliverable  
3.33. 
Safety 
LB16 
Summary of Hematology Results by Maximum Grade 
Increase Post-Baseline Relative to Baseline (Oral Lead-in 
Period) 
ICH E3 
M12 
Laboratory: Hepatobiliary (Liver) 
3.34. 
 Safety 
LIVER1 
Summary of Liver Monitoring/Stopping Event Reporting 
GSK Statistical Display Standard 
M12, EOS 
3.35. 
 Safety 
LIVER10 
Summary of Hepatobiliary Laboratory Abnormalities 
GSK Statistical Display Standard  HL, M12, EOS 
3.36. 
 Safety 
LIVER11 
Summary of Liver Restart/Re-Challenges 
GSK Statistical Display Standard  
M12, EOS 
Vital Signs 
3.37. 
Safety 
VS1 
Summary of Change from Baseline in Vital Signs 
ICH E3 
Include Baseline values 
M12, EOS 
Cardiovascular Risk Factors 
3.38. 
Safety 
FH1 
Summary of Family History of Cardiovascular Risk Factors 
GSK Statistical Display Standard  
M12, EOS 
3.39. 
Safety 
SU1 
Summary of Substance Use 
GSK Statistical Display Standard  
M12, EOS 


TMF-14552026 
CONFIDENTIAL 
209493 
 
121 
Safety: Tables 
No. 
Population 
GSK 
Standard/ 
Example 
Shell 
Title  
Programming Notes 
Deliverable  
COVID-19 Adverse Events 
3.40. 
Safety 
PAN1 
Summary of COVID-19 Assessments for Subjects with 
COVID-19 Adverse Events 
GSK Statistical Display 
Standard, for EOS, use PAN1A 
shell and replace the first 
footnote with “[1] COVID-19 case 
diagnosis is based on WHO 
definition that was in effect at the 
time of diagnosis.” 
M12, EOS 
3.41. 
Safety 
PAN2 
Summary of COVID-19 Additional Assessments for 
Subjects with COVID-19 Adverse Events 
GSK Statistical Display 
Standard, for EOS, use PAN2A. 
M12, EOS 
3.42. 
Safety 
PAN3 
Summary of COVID-19 Symptoms for Subjects with 
COVID-19 Adverse Events 
GSK Statistical Display 
Standard, for EOS, use PAN3A. 
M12, EOS 
Adverse Events of Special Interest 
3.43. 
Safety 
201584/primar
y_27/T3.140 
Summary of Depression, Anxiety and Suicidal or Suicidal 
Ideation/Behaviour Adverse Events by System Organ 
Class, Maximum DAIDS Toxicity Grade, and History of 
Depression, Anxiety or Suicidal Ideation/Behaviour at 
Screening  
 
M12, EOS 
3.44. 
Safety 
201584/primar
y_07/T3.122 
Summary of Depression Adverse Events of Special 
Interest by System Organ Class and Preferred Term 
(Number of Subjects and Occurrences) 
 
M12, EOS 


TMF-14552026 
CONFIDENTIAL 
209493 
 
122 
Safety: Tables 
No. 
Population 
GSK 
Standard/ 
Example 
Shell 
Title  
Programming Notes 
Deliverable  
3.45. 
Safety 
201584/primar
y_07/T3.125 
Summary of Anxiety Adverse Events of Special Interest by 
System Organ Class and Preferred Term (Number of 
Subjects and Occurrences) 
 
M12, EOS 
3.46. 
Safety 
201584/primar
y_07/T3.128 
Summary of Suicidal Ideation/Behaviour Adverse Events of 
Special Interest by System Organ Class and Preferred 
Term (Number of Subjects and Occurrences) 
 
M12, EOS 
3.47. 
Safety 
201584/primar
y_07/T3.134 
Summary of Seizures Adverse Events of Special Interest 
by System Organ Class and Preferred Term (Number of 
Subjects and Occurrences) 
 
M12, EOS 
3.48. 
Safety 
201584/primar
y_07/T3.137 
Summary of Hepatic Safety Profile: Assessment of Risk of 
Hepatoxicity Adverse Events of Special Interest by System 
Organ Class and Preferred Term (Number of Subjects and 
Occurrences) 
 
M12, EOS 
3.49. 
Safety 
201584/primar
y_07/T3.140 
Summary of Hypersensitivity Reactions (HSR) Adverse 
Events of Special Interest by System Organ Class and 
Preferred Term (Number of Subjects and Occurrences) 
 
M12, EOS 
3.50. 
Safety 
201584/primar
y_07/T3.143 
Summary of Rash Adverse Events of Special Interest by 
System Organ Class and Preferred Term (Number of 
Subjects and Occurrences) 
 
M12, EOS 
3.51. 
Safety 
201584/primar
y_07/T3.146 
Summary of Prolongation of the Corrected QT Interval of 
the ECG in Supratherapeutic Doses Adverse Events of 
Special Interest by System Organ Class and Preferred 
Term (Number of Subjects and Occurrences) 
 
M12, EOS 


TMF-14552026 
CONFIDENTIAL 
209493 
 
123 
Safety: Tables 
No. 
Population 
GSK 
Standard/ 
Example 
Shell 
Title  
Programming Notes 
Deliverable  
3.52. 
Safety 
201584/primar
y_07/T3.149 
Summary of Bipolar Disorder Adverse Events of Special 
Interest by System Organ Class and Preferred Term 
(Number of Subjects and Occurrences) 
 
M12, EOS 
3.53. 
Safety 
201584/primar
y_07/T3.152 
Summary of Psychosis Adverse Events of Special Interest 
by System Organ Class and Preferred Term (Number of 
Subjects and Occurrences) 
 
M12, EOS 
3.54. 
Safety 
201584/primar
y_07/T3.155 
Summary of Mood Disorders Adverse Events of Special 
Interest by System Organ Class and Preferred Term 
(Number of Subjects and Occurrences) 
 
M12, EOS 
3.55. 
Safety 
201584/primar
y_07/T3.158 
Summary of Sleep Disorders Adverse Events of Special 
Interest by System Organ Class and Preferred Term 
(Number of Subjects and Occurrences) 
 
M12, EOS 
3.56. 
Safety 
201584/primar
y_07/T3.161 
Summary of Hyperglycaemia Adverse Events of Special 
Interest by System Organ Class and Preferred Term 
(Number of Subjects and Occurrences) 
 
M12, EOS 
3.57. 
Safety 
201584/primar
y_07/T3.161 
Summary of Weight Gain Adverse Events of Special 
Interest by System Organ Class and Preferred Term 
(Number of Subjects and Occurrences) 
 
M12, EOS 
3.58. 
Safety 
201584/primar
y_07/T3.164 
Summary of Rhabdomyolysis Adverse Events of Special 
Interest by System Organ Class and Preferred Term 
(Number of Subjects and Occurrences) 
 
M12, EOS 


TMF-14552026 
CONFIDENTIAL 
209493 
 
124 
Safety: Tables 
No. 
Population 
GSK 
Standard/ 
Example 
Shell 
Title  
Programming Notes 
Deliverable  
3.59. 
Safety 
201584/primar
y_07/T3.167 
Summary of Pancreatitis Adverse Events of Special 
Interest by System Organ Class and Preferred Term 
(Number of Subjects and Occurrences) 
 
M12, EOS 
3.60. 
Safety 
201584/primar
y_07/T3.170 
Summary of Impact on Creatinine Adverse Events of 
Special Interest by System Organ Class and Preferred 
Term (Number of Subjects and Occurrences) 
 
M12, EOS 
3.61. 
Safety 
201584/primar
y_07/T3.173 
Summary of Safety in Pregnancy Adverse Events of 
Special Interest by System Organ Class and Preferred 
Term (Number of Subjects and Occurrences) 
 
M12, EOS 
3.62. 
Safety 
207966/primar
y_15/T3.109 
Summary of Characteristics of Adverse Events of Special 
Interest  
 
M12, EOS 
 


TMF-14552026 
CONFIDENTIAL 
209493 
 
125 
13.13.8. 
Safety Figures 
Safety: Figures 
No. Population 
GSK Standard / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Adverse Events 
3.1. 
Safety 
201584/primary_07/F3.14 
Plot of Incidence of Intervention Phase Study Drug 
Injection Site Reaction Adverse Events by Visit 
(Overall and Common) – CAB and/or RPV 
For EOS, remove 
“Intervention Phase” from 
the title and include all ISRs 
from Intervention or 
Extension phase. 
M12, EOS 
3.2. 
Safety 
201584/primary_07/F3.17 
Plot of Incidence of Grade 3-5 Intervention Phase 
Study Drug Injection Site Reaction Adverse Events 
by Visit (Overall and Common) - CAB and/or RPV 
For EOS, remove 
“Intervention Phase” from 
the title and include all 
Grade 3-5 ISRs from 
Intervention or Extension 
phase. 
M12, EOS 
Laboratory 
3.3. 
Safety 
LIVER14 
Scatter Plot of Maximum vs. Baseline for ALT 
GSK Statistical Display 
Standard 
M12, EOS 
3.4. 
Safety 
LIVER9 
Scatter Plot of Maximum Total Bilirubin vs Maximum 
ALT – eDISH Plot 
GSK Statistical Display 
Standard  
M12, EOS 
 
 
 


TMF-14552026 
CONFIDENTIAL 
209493 
 
126 
13.13.9. 
Virology Tables 
No. Population 
GSK Standard / 
Example Shell 
Title  
Programming Notes 
Deliverable  
4.1. 
Safety 
201584/primary_17/T7.2 
Viral load, Genotypic and Phenotypic data for 
Subjects Who Met Confirmed Virologic Failure 
Criteria 
 
HL, M12, EOS 
4.2. 
Safety 
201584/primary_17/T7.4 Viral Load, Genotypic and Phenotypic Data for Non-
CVF Subjects 
Only include subjects with 
available genotypic or 
phenotypic data. 
M12, EOS 
 
 


TMF-14552026 
CONFIDENTIAL 
209493 
 
127 
13.13.10. Other Tables 
Study Visit Length 
No. 
Population 
GSK 
Standard / 
Example 
Shell 
Title  
Programming Notes 
Deliverable  
5.1. 
Safety 
OTR_T1 
Summary of Study Visit Length (minutes) by Visit and Site 
Type (Intervention Phase) 
 
HL, M12 
5.2. 
Safety 
OTR_T1 
Summary of Study Visit Length (minutes) by Visit and Site 
(Intervention Phase) 
 
HL, M12 
 
 
 


TMF-14552026 
CONFIDENTIAL 
209493 
 
128 
13.13.11. ICH Listings 
ICH: Listings 
No. Population 
GSK Standard / 
Example Shell 
Title  
Programming Notes 
Deliverable  
Subject Disposition 
1.  
Enrolled 
ES2 
Listing of Reasons for Study Withdrawal 
ICH E3 
Add column for Phase 
M12, EOS 
2.  
Enrolled 
SD2 
Listing of Reasons for Study Treatment 
Discontinuation 
ICH E3 
Add column for Phase 
HL, M12, 
EOS 
Protocol Deviations 
3.  
Enrolled 
DV2 
Listing of Important Protocol Deviations  
ICH E3 
Add column for Phase 
Add a column on the right for “COVID-
19 Related”. The possible values in this 
column are Y and N, where Y indicates 
the deviation is COVID-19 related and N 
indicates the deviation is non-COVID-19 
related. 
M12, EOS 
4.  
Enrolled 
DV2 
Listing of Protocol Deviations Related to 
COVID-19  
FDA Request 
Add column for Phase 
HL, M12, 
EOS 
5.  
Safety 
IE3 
Listing of Subjects with Inclusion/Exclusion 
Criteria Deviations 
ICH E3 
M12, EOS 
Populations Analysed 
6.  
Enrolled 
SP3 
Listing of Subjects Excluded from Safety 
Population 
ICH E3 
M12 


TMF-14552026 
CONFIDENTIAL 
209493 
129 
ICH: Listings 
No. Population 
GSK Standard / 
Example Shell 
Title 
Programming Notes 
Deliverable 
Demographic and Baseline Characteristics 
7. 
Safety 
DM2 
Listing of Demographic Characteristics 
ICH E3 
M12, EOS 
8. 
Safety 
DM9 
Listing of Race 
ICH E3 
M12, EOS 
Efficacy 
9. 
Safety 
SNAPSHOT11 
Listing of Qualitative and Quantitative Plasma 
HIV-1 RNA Data 
HL, M12, 
EOS 
10. 
Safety 
SNAPSHOT12 
Listing of Study Outcome (50 copies/mL 
cutoff) at Month 12 – Snapshot Analysis 
Include both original and LOCF imputed 
outcomes 
HL, M12 
11. 
Safety 
VF4 
Listing of Plasma HIV-1 RNA and CD4+ Cell 
Count for subjects with Confirmed Virologic 
Failure 
M12 
Exposure and Treatment Compliance 
12. 
Safety 
207966/primary_15/L12 Listing of Exposure Data 
ICH E3 
Remove Phase Day 
M12, EOS 
Adverse Events 
13. 
Safety 
AE8 
Listing of All Adverse Events 
ICH E3 
Add Phase/Period, Side/Drug, see 
gsk1265744/mid207966/primary_15/L19 
HL, M12, 
EOS 
14. 
Safety 
AE8 
Listing of Grade 3-5 Adverse Events 
Add Phase/Period, Side/Drug, see 
gsk1265744/mid207966/primary_15/L19 
M12 
15. 
Safety 
AE7 
Listing of Subject Numbers for Individual 
Adverse Events 
ICH E3 
M12, EOS 


TMF-14552026 
CONFIDENTIAL 
209493 
 
130 
ICH: Listings 
No. Population 
GSK Standard / 
Example Shell 
Title  
Programming Notes 
Deliverable  
16.  
Safety 
PSRAE1 
Listing of Possible Suicidality-Related 
Adverse Event Data: Event and Description 
(Section 1-Section 2) 
Add Phase 
M12 
17.  
Safety 
PSRAE3 
Listing of Possible Suicidality-Related 
Adverse Event Data: Possible Cause(s) 
(Section 3) 
Add Phase 
M12 
18.  
Safety 
PSRAE4 
Listing of Possible Suicidality-Related 
Adverse Event Data (Section 4) 
Add Phase 
M12 
19.  
Safety 
PSRAE5 
Listing of Possible Suicidality-Related 
Adverse Event Data (Section 5-Section 8) 
Add Phase 
M12 
20.  
Safety 
201584/primary_07/L22 Listing of Changes in Intensity/Grades of 
Study Drug Injection Site Adverse Events 
Remove phase treatment 
M12, EOS 
21.  
Safety 
AE8  
Listing of COVID-19 Adverse Events 
Add Phase/Period, Side/Drug, see 
gsk1265744/mid207966/primary_15/L19 
HL, M12, 
EOS 
22.  
Safety 
PAN12 
Listing of COVID-19 Assessments and 
Symptom Assessments 
 
M12, EOS 
23.  
Safety 
PAN5 
Country Level Listing of Start Dates of 
COVID-19 Pandemic Measures   
For EOS: change the title to be “Country 
Level Listing of Dates of Waves of 
COVID-19 Pandemic Measures” and 
use the PAN5A shell. 
M12, EOS 
Serious and Other Significant Adverse Events 
24.  
Safety 
AE8 
Listing of Fatal Serious Adverse Events 
ICH E3 
Add Phase/Period, Side/Drug 
M12, EOS 


TMF-14552026 
CONFIDENTIAL 
209493 
 
131 
ICH: Listings 
No. Population 
GSK Standard / 
Example Shell 
Title  
Programming Notes 
Deliverable  
25.  
Safety 
AE8 
Listing of Non-Fatal Serious Adverse Events 
ICH E3 
Add Phase/Period, Side/Drug 
M12, EOS 
26.  
Safety 
AE14 
Listing of Reasons for Considering as a 
Serious Adverse Event 
ICH E3 
M12, EOS 
27.  
Safety 
AE8  
Listing of Adverse Events Leading to 
Withdrawal from Study / Permanent 
Discontinuation of Study Treatment 
ICH E3 
Add Phase/Period, Side/Drug 
M12, EOS 
28.  
Safety 
AE8 
Listing of All Adverse Events with Completely 
Missing Onset Date, Missing Relationship to 
Study Treatment, Severity and/or Grade 
ICH E3 
Add Phase/Period, Side/Drug, see 
gsk1265744/mid207966/primary_15/L19 
M12 
Laboratory 
29.  
Safety 
UR2 
Listing of Urinalysis Data for Subjects with 
Any Value of Potential Clinical Importance 
ICH E3 
Include Grade 
Note: Potential Clinical Importance is 
defined as: 
1. Increase in Protein (dipstick) or 
Occult Blood (dipstick) post-baseline 
relative to baseline 
2. Increase in any DAIDS graded values 
for Protein, Occult Blood or Glucose 
relative to baseline  
3. If microscopy is performed. 
M12, EOS 
 
 


TMF-14552026 
CONFIDENTIAL 
209493 
 
132 
13.13.12. Non-ICH Listings 
Non-ICH: Listings 
No. 
Population 
GSK Standard GSK 
Statistical Display 
Standard / Example 
Shell 
Title  
Programming Notes 
Deliverable 
Subject Disposition  
30.  
Screened 
ES7 
Listing of Reasons for Screen Failure 
Journal Guidelines 
M12, EOS 
31.  
Screened 
ES9 
Listing of Subjects Who Were Rescreened 
 
M12, EOS 
32.  
Safety 
TA1 
Listing of Planned and Actual Treatments 
GSK Statistical Display 
Standard 
M12 
Prior and Concomitant Medications 
33.  
Safety 
207966/primary_15/Listing 
36 
Listing of Prior ART Medications 
Remove the column ‘Phase 
during Which Concomitant’ 
M12, EOS* 
34.  
Safety 
207966/primary_15/Listing 
37 
Listing of Concomitant ART Medications 
In case the same medication 
is concomitant during both 
intervention and extension 
phases, list each of them in 
two separate rows. Add a 
column “SOC Oral Bridging?” 
which has values of “Yes” 
and “No”. 
HL, M12, 
EOS 
35.  
Safety 
207966/primary_15/Listing 
38 
Listing of ART Medications Received during Long-
term Follow-up Phase 
Remove the column ‘Phase 
during Which Concomitant’ 
and “Start Date of the Long-
term Follow-up ART/Study 
Day”. 
M12, EOS 


TMF-14552026 
CONFIDENTIAL 
209493 
 
133 
Non-ICH: Listings 
No. 
Population 
GSK Standard GSK 
Statistical Display 
Standard / Example 
Shell 
Title  
Programming Notes 
Deliverable 
   51. 
Safety 
POP_L2 
Listing of COVID-19 Vaccine 
 
EOS 
Medical History 
36.  
Safety 
201584/primary_01/L43 
Listing of Medical History of Seizure 
 
M12, EOS* 
Transition to CAB + RPV LA Marketed Product Status 
52. 
Safety 
POP_L1 
Listing of Transition to CAB + RPV LA Marketed 
Product Status 
 
EOS 
Efficacy 
37.  
Safety 
CDC4 
Listing of CDC Classification of HIV-1 Infection at 
Baseline 
 
M12, EOS* 
38.  
Safety 
CDC5 
Listing of CDC Stage 3 HIV-1 Associated 
Conditions  
Add Phase 
EOS 
Hepatobiliary (Liver) 
39.  
Safety 
LIVER5 
Listing of Liver Monitoring/Stopping Event Reporting GSK Statistical Display 
Standard 
M12, EOS 
40.  
Safety 
LIVER15 
Liver Stopping Event Profile 
GSK Statistical Display 
Standard 
M12 
41.  
Safety 
LIVER13 
Listing of Subjects Meeting Hepatobiliary 
Laboratory Criteria Post-Baseline 
GSK Statistical Display 
Standard 
HL, M12, 
EOS 
42.  
Safety 
LB12 
Listing of ALT, AST, Bilirubin (including Total and 
Direct Bilirubin), INR, and ALP for Subjects Meeting 
Hepatobiliary Lab Abnormality Criteria 
Add Phase 
M12, EOS 


TMF-14552026 
CONFIDENTIAL 
209493 
 
134 
Non-ICH: Listings 
No. 
Population 
GSK Standard GSK 
Statistical Display 
Standard / Example 
Shell 
Title  
Programming Notes 
Deliverable 
ECG 
43.  
Safety 
EG3 
Listing of All ECG Values for Subjects with Any 
Value of Potential Clinical Importance 
GSK Statistical Display 
Standard 
By default, the definition of 
PCI is defined based on QTc 
value (e.g., QTcF Interval, 
Aggregate) where a subject 
has a QTc value >450 or a 
QTc increase of >30msec. 
M12, EOS 
44.  
Safety 
EG5 
Listing of All ECG Findings for Subjects with an 
Abnormal ECG Finding 
GSK Statistical Display 
Standard 
M12, EOS 
Other 
45.  
Safety 
207966/primary_15/L60 
Listing of Exposure Data for Subjects Receiving 
Oral Bridging 
Add column to identify 
COVID relatedness. 
HL, M12, 
EOS 
46.  
Safety 
207966/primary_15/L61 
Listing of Dosing Errors and IP Device Malfunctions 
Add Phase 
M12, EOS 
47.  
Safety 
PREG1 
Listing of Subjects or Partners Who Became 
Pregnant During the Study 
GSK Statistical Display 
Standard 
M12, EOS 
48.  
Safety 
201584/primary_17/L54 
Listing of Replication Capacity in IN and PR/RT 
Region 
Add Phase 
M12 
PK Endpoints 
49.  
Safety 
PK07 
Listing of Plasma CAB Pharmacokinetic 
Concentration-Time Data 
Add column ‘Reason for 
Collection” on the right. 
M12, EOS 


TMF-14552026 
CONFIDENTIAL 
209493 
 
135 
Non-ICH: Listings 
No. 
Population 
GSK Standard GSK 
Statistical Display 
Standard / Example 
Shell 
Title  
Programming Notes 
Deliverable 
50.  
Safety 
PK07 
Listing of Plasma RPV Pharmacokinetic 
Concentration-Time Data 
Add column ‘Reason for 
Collection” on the right. 
M12, EOS 
 
 
 


TMF-14552026 
CONFIDENTIAL 
209493 
136 
13.14. 
Appendix 14: Example Mock Shells for Data Displays 
Data Display Specification will be made available on request 


CONFIDENTIAL
The GlaxoSmithKline group of companies
209493
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for A qualitative hybrid III 
implementation study to identify and evaluate strategies for 
successful implementation of the cabotegravir + rilpivirine 
long-acting injectable regimen in the US
Compound Number :
GSK1265744
Clinical Study 
Identifier
:
209493
Effective Date 
:
29-OCT-2020
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 209493, specifically for clinical 
data. Any implementation science/health outcome analyses will be detailed in a 
separate Evidera SAP.

This RAP will be provided to the study team members to convey the content 
pertaining to clinical data for the Month 12 and End of Study (EOS) analyses.
RAP Author(s):
Author
Date
Lead
23-OCT-2020
Manager, Statistics
Copyright 2020 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0
PPD


CONFIDENTIAL
The GlaxoSmithKline group of companies
209493
2
RAP Team Reviews:
RAP Team Review Confirmations 
(Method: E-mail)
Reviewer 
Date
27-OCT-2020
(Clinical Scientists, Early 
Development, ViiV Healthcare)
28-OCT-2020
 Innovation and & Implementation Science (US Health 
Outcomes, ViiV Healthcare)
27-OCT-2020
(US Health Outcomes, ViiV Healthcare)
27-OCT-2020
Principal Programmer/Analyst (Dev Biostats Prog Dev)
Clinical Statistics and Clinical Programming Line Approvals:
Clinical Statistics & Clinical Programming Line Approvals 
(Method: Pharma TMF eSignature)
Approver
Date
29-OCT-2020
Statistics Leader (Dev Biostats Stats Dev)
29-OCT-2020
Programming Leader (Dev Biostats Prog Dev)
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL
209493
3
TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................6
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................6
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................6
2.2.
Study Objective(s) and Estimand(s) / Endpoint(s).........................................6
2.3.
Study Design ................................................................................................8
2.4.
Statistical Hypotheses / Statistical Analyses .................................................8
3.
PLANNED ANALYSES ............................................................................................9
3.1.
Interim Analyses ...........................................................................................9
3.2.
Final Analyses ..............................................................................................9
4.
ANALYSIS POPULATIONS ...................................................................................10
4.1.
Protocol Deviations.....................................................................................10
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................10
5.1.
Study Treatment & Sub-group Display Descriptors.....................................10
5.2.
Baseline Definitions ....................................................................................11
5.3.
Multicentre Studies .....................................................................................11
5.4.
Examination of Covariates, Other Strata and Subgroups............................11
5.4.1.
Covariates and Other Strata ........................................................11
5.4.2.
Examination of Subgroups...........................................................11
5.5.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................12
6.
STUDY POPULATION ANALYSES .......................................................................13
6.1.
Overview of Planned Study Population Analyses........................................13
7.
EFFICACY ANALYSES..........................................................................................13
7.1.
Secondary Efficacy Analyses......................................................................13
7.1.1.
Endpoint / Variables.....................................................................13
7.1.2.
Population of Interest...................................................................13
7.1.3.
Strategy for Intercurrent (Post-Randomization) Events ................13
7.1.4.
Statistical Analyses / Methods .....................................................14
7.1.4.1.
Statistical Methodology Specification..........................14
8.
SAFETY ANALYSES .............................................................................................14
8.1.
Adverse Events Analyses ...........................................................................14
8.1.1.
Injection Site Reaction Adverse Events .......................................15
8.2.
Adverse Events of Special Interest Analyses..............................................15
8.3.
Clinical Laboratory Analyses.......................................................................15
8.4.
Other Safety Analyses ................................................................................15
9.
PHARMACOKINETIC ANALYSES.........................................................................16
9.1.
Drug Concentration Measures ....................................................................16
10. VIROLOGY ............................................................................................................16
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
4
10.1.
Genotypic and Phenotypic Data..................................................................16
11. OTHER ANALYSES...............................................................................................16
11.1.
Study Visit Length.......................................................................................16
12. REFERENCES.......................................................................................................17
13. APPENDICES........................................................................................................18
13.1.
Appendix 1: Exclusions from Per Protocol Population.................................18
13.2.
Appendix 2: Schedule of Activities ..............................................................19
13.2.1.
Protocol Defined Schedule of Events...........................................19
13.2.1.1.
Schedule of Activities for Patient Study 
Participants (CAB LA + RPV LA Monthly 
Administration) ...........................................................19
13.2.1.2.
Schedule of Assessments Table for Staff Study 
Participants ................................................................24
13.2.1.3.
Schedule of Activities Table for Patient Study 
Participants (Long Term Follow Up) a .........................25
13.3.
Appendix 3: Assessment Windows .............................................................26
13.3.1.
Definitions of Assessment Windows for Analyses........................26
13.3.2.
Assessment Windows for PK Concentration Data........................30
13.4.
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................31
13.4.1.
Study Phases ..............................................................................31
13.4.2.
Treatment State...........................................................................33
13.4.3.
Oral Lead-in Period......................................................................33
13.5.
Appendix 5: Data Display Standards & Handling Conventions....................35
13.5.1.
Reporting Process .......................................................................35
13.5.2.
Reporting Standards....................................................................35
13.5.3.
Reporting Standards for Pharmacokinetic....................................36
13.6.
Appendix 6: Derived and Transformed Data ...............................................37
13.6.1.
General........................................................................................37
13.6.2.
Study Population..........................................................................38
13.6.3.
Efficacy........................................................................................39
13.6.4.
Safety ..........................................................................................40
13.6.5.
Virology .......................................................................................42
13.6.6.
Other Assessments .....................................................................44
13.7.
Appendix 7: Reporting Standards for Missing Data.....................................45
13.7.1.
Premature Withdrawals................................................................45
13.7.2.
Handling of Missing Data.............................................................45
13.7.2.1.
Handling of Missing and Partial Dates ........................45
13.7.2.2.
Handling of Missing Data for Statistical 
Analysis......................................................................47
13.8.
Appendix 8: Values of Potential Clinical Importance ...................................48
13.9.
Appendix 9: Snapshot Algorithm Details .....................................................49
13.10. Appendix 10: AESI identification.................................................................53
13.10.1. Hepatic Safety Profile ..................................................................53
13.10.2. Hyperglycaemia...........................................................................57
13.10.3. Hypersensitivity Reactions...........................................................59
13.10.4. Rash including severe cutaneous adverse reactions ...................60
13.10.5. Prolongation of the Corrected QT Interval of the ECG in 
Supra Therapeutic Doses ............................................................62
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
5
13.10.6. Suicidal Ideation/Behaviour .........................................................62
13.10.7. Depression ..................................................................................63
13.10.8. Bipolar Disorder...........................................................................64
13.10.9. Psychosis ....................................................................................65
13.10.10.Mood Disorders ...........................................................................68
13.10.11.Anxiety.........................................................................................69
13.10.12.Sleep Disorders ...........................................................................73
13.10.13.Injection site Reactions................................................................77
13.10.14.Seizures ......................................................................................77
13.10.15.Weight Gain.................................................................................80
13.10.16.Rhabdomyolysis ..........................................................................82
13.10.17.Pancreatitis..................................................................................82
13.10.18.Impact on Creatinine....................................................................83
13.10.19.Safety During Pregnancy.............................................................85
13.11. Appendix 11: Identification of COVID-19 Adverse Events...........................86
13.12. Appendix 12: Abbreviations & Trade Marks ................................................87
13.12.1. Abbreviations...............................................................................87
13.12.2. Trademarks .................................................................................88
13.13. Appendix 13: List of Data Displays..............................................................89
13.13.1. Data Display Numbering..............................................................89
13.13.2. Mock Example Shell Referencing ................................................89
13.13.3. Deliverables.................................................................................89
13.13.4. Study Population Tables..............................................................90
13.13.5. Efficacy Tables ............................................................................93
13.13.6. Efficacy Figures ...........................................................................94
13.13.7. Safety Tables...............................................................................96
13.13.8. Safety Figures ...........................................................................103
13.13.9. Virology Tables..........................................................................103
13.13.10.Other Tables..............................................................................104
13.13.11.ICH Listings ...............................................................................104
13.13.12.Non-ICH Listings........................................................................108
13.14. Appendix 14: Example Mock Shells for Data Displays ..............................111
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
6
1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol:
Revision Chronology:
2018N382441_00
02-JAN-2019
Original
2018N382441_01
02-APR-2019
Amendment No. 1
The reasons for this amendment include: addition of exclusion criterion regarding known major 
resistance mutations at Screening, clarification of timing for collection of visit length, removal of 
consent requirement for study staff, correction to allowable window around the Month 3 dosing 
visit, clarification of pregnancy testing requirements at Screening, clarification of wording to allow 
a single re-screen per subject, removal of color of vial stopper in product description to allow 
flexibility of packaging for cabotegravir and rilpivirine suspension, clarification of ECG collection 
during the study, clarification of wording to allow qualitative analyses to be performed by a CRO 
under GSK oversight.
2018N382441_02
15-MAY-2020
Amendment No.2
The purpose of this amendment is to include an Appendix related to COVID-19 Pandemic and 
Clinical Trial Continuity. This appendix will replace the previous Appendix 11, and “Protocol 
Amendment History,” will be included as Appendix 12.
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
There were no changes or deviations to the originally planned statistical analysis 
specified in protocol amendment 02 [(Dated: 15/May/2020)].
2.2.
Study Objective(s) and Estimand(s) / Endpoint(s)
Objectives
Estimands / Endpoints
Primary
Primary 

To evaluate acceptability, 
appropriateness, and feasibility of 
delivering CAB+RPV LA

Acceptability of Intervention Measure (AIM), Intervention 
Appropriateness Measure (IAM), and Feasibility of 
Intervention Measure (FIM). Assessed quantitatively by 
staff study participants at baseline- prior to any Month 1 
visits, after at least 4 monthly facilitation calls and upon 
completion of all Month 12 visits at that site.

Acceptability of Intervention Measure (AIM) and 
Intervention Appropriateness Measure (IAM). Assessed 
quantitatively by patient study participants at Month 1 
prior to first injection, Month 4 and Month 12
Secondary
Secondary 

To evaluate organizational facilitators 
and barriers

Facilitators/Barriers: Semi-Structured Interview (SSI) 
conducted with staff study participants at baseline- prior 
to any Month 1 visits, after at least 4 monthly facilitation 
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
7
Objectives
Estimands / Endpoints
calls and upon completion of at least 50% of Month 12 
visits at that site. 

Barriers, facilitators and best practice sharing amongst 
clinics assessed by short-term facilitation (coaching calls) 
for at least 6 months. These will be a combination of 
structured questions and open-ended questions.

Use of support materials/toolkit assessed via Survey 
responses of staff study participants prior to any Month 1 
visits, after at least 4 monthly facilitation calls and upon 
completion of all Month 12 visits at a site. 

Use of support materials/toolkit assessed via Survey 
responses of patient study participants via Survey 
responses at Month 1 and Month 4 and Month 12, as well 
as SSI responses prior to Month 1 and at Month 12.

Patient Facilitators and Barriers

Facilitators/Barriers: Semi-Structured Interviews (SSI) 
conducted with patient study participants prior to Month 1 
and at Month 12.

Implementation Fidelity

Injections occurring within target window from the 
expected injection date

Use of support materials/toolkit assessed through SSI of 
staff study participants at Day 1, after at least 4 monthly 
facilitation calls and upon completion of at least 50% of 
Month 12 visits at that site

Implementation Sustainability

Program Sustainability Assessment Tool (PSAT) 
assessed by staff study participants at Month 12

To measure patient satisfaction with 
process (timeliness of visits, length of 
visit, patient education)

Patient Survey responses at Month 1, Month 4 and Month 
12.

Patient SSI responses prior to Month 1 and at Month 12

Length of patient visit from arrival until departure from 
clinic at Month 1, Month 5 and Month 11

To evaluate the antiviral and 
immunologic effects, safety and 
tolerability, and viral resistance of 
CAB LA + RPV LA for all patients

Proportion of participants with plasma HIV-1 RNA <50 
c/mL over time

Proportion of participants with confirmed virologic failure 
(CVF) over time

Incidence of treatment emergent genotypic and 
phenotypic resistance to CAB and RPV in patients with 
CVF

Incidence and severity of AEs and laboratory 
abnormalities over time

Proportion of participants who discontinue treatment due 
to AEs over time

Reported injection site reactions over time

Absolute values and changes in laboratory parameters 
over time
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
8
2.3.
Study Design
Overview of Study Design and Key Features
N=115 patients; Open label with respect to treatment; patients randomized to CAB LA+RPV LA Interview: 
CAB LA + RPV LA Non-Interview
Design
Features

A qualitative hybrid III implementation study to identify and evaluate strategies for 
successful implementation of the cabotegravir + rilpivirine long-acting injectable 
regimen in the US

The CUSTOMIZE study comprises of screening phase (up to 21 days), Intervention 
Phase from Day 1 to Month 12, including Oral Lead-in, long term follow-up (LTFU) 
phase, and extension phase. During screening phase all clinical and laboratory 
assessments of eligibility must be performed and reviewed. Participants may be re-
screened once
Dosing

Intervention Phase is Open label with respect to treatment; 

Intervention Phase: randomized 1:3 to CAB LA+RPV LA Interview:CAB LA + RPV 
LA Non-Interview

Randomized at Day 1 (1:3) to receive CAB LA + RPV LA Interview or CAB LA + 
RPV LA Non-interview respectively

GSK Randall NG used to generate randomization schedule for interview group 
assignments
Time & 
Events

Refer to Appendix 2: Schedule of Activities
Treatment 
Assignment

CAB LA+RPV LA (N=115)
Interim 
Analysis

Analysis at Month 4 to provide preliminary data to inform planning for the initial 
commercial availability of the CAB LA + RPV LA regimen

Primary analysis will be conducted at Month 12
2.4.
Statistical Hypotheses / Statistical Analyses
No formal hypothesis testing is planned.
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
9
3.
PLANNED ANALYSES
This RAP describes standard analyses that will be applied to descriptively summarize 
clinical adverse events, laboratory evaluations, virologic parameters and other clinical 
safety and efficacy outcomes. 
Details pertaining to reporting of survey/interview data and health 
outcomes/effectiveness analyses will be described in a separate analysis plan provided by 
Evidera or other CRO partner under GSK’s oversight.
At least two analyses will be conducted to evaluate primary and secondary objectives of 
the protocol: an interim analysis at Month 4 and a primary analysis at Month 12. 
A final end-of-study (EOS) analysis will be conducted when all subjects have completed 
the study.
3.1.
Interim Analyses
One interim analysis at Month 4 was performed to provide preliminary data to inform 
planning for the initial commercial availability of the CAB + RPV LA regimen. No 
formal criteria for stopping or amending the study based on the interim analysis are 
envisioned. Analysis and reporting details can be found in the standalone Month 4 
interim analysis RAP.
3.2.
Final Analyses
The planned Month 12 primary analysis will be performed after the completion of the 
following sequential steps:
1.
All participants have completed Month 12 of the study as defined in the protocol.
2.
All required database cleaning activities have been completed and final database 
release (DBR), source data lock (SDL) and database freeze (DBF) have been 
declared by Data Management.
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
10
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Screened 

All participants who were screened for eligibility

Study Population
Enrolled

All participants who passed screening and entered 
the study (i.e. were administered study treatment).

Study Population
Safety

All participants who received at least one dose of 
study treatment.

Study Population, 
Safety, Efficacy, 
Virology, PK, Other 
Assessments
Refer to Appendix 13: List of Data Displays which details the population used for each display.
4.1.
Protocol Deviations
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed.
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan [Version 1.0,17-Jun-2019].
o Data will be reviewed prior to freezing the database to ensure all important 
deviations are captured and categorised on the protocol deviations dataset. 
o This dataset will be the basis for the summaries and listings of protocol 
deviations.
A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion 
page of the eCRF.
Protocol deviations related to the implementation process, and not the clinical conduct of 
the study will be reported separately. The identification and categorization of PDs as 
important may be different for implementation PDs vs those associated with the clinical 
conduct of the study.
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
Data Displays for Reporting 
Description
Order in TLF 
CAB LA +RPV LA
1
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
11
5.2.
Baseline Definitions
For all endpoints the baseline value will be the latest pre-treatment (See Table 10) 
assessment with a non-missing value, including those from unscheduled visits. If time is 
not collected, Day 1 assessments are assumed to be taken prior to first dose and used as 
baseline.
Electrocardiograms (ECGs) are to be performed in triplicate on Screening visit. The 
baseline value for an ECG parameter will be the mean of the last pre-treatment set of 
assessments from the same date so long as at least one of the triplicate assessments is 
available.
5.3.
Multicentre Studies
In this multicentre global study, enrolment will be presented by investigator and Site
type.
5.4.
Examination of Covariates, Other Strata and Subgroups
5.4.1.
Covariates and Other Strata
The list of covariates and other strata may be used in descriptive summaries and 
statistical analyses, some of which may also be used for subgroup analyses. Additional 
covariates and other strata of clinical interest may also be considered.
Category
Details
Covariates
Site Type
5.4.2.
Examination of Subgroups
The list of subgroups may be used in descriptive summaries and statistical analyses.
Additional subgroups of clinical interest may also be considered.

If the percentage of participants is small within a subgroup category, then the 
subgroup categories may be combined.
Subgroup
Categories 
Site Type
AIDS Healthcare Foundation, Federally Qualified Health Center, Health 
Maintenance Organization, Private Practice, University
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
12
5.5.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
13.3
Appendix 3: Assessment Windows
13.4
Appendix 4: Study Phases and Treatment Emergent Adverse Events
13.5
Appendix 5: Data Display Standards & Handling Conventions
13.6
Appendix 6: Derived and Transformed Data
13.7
Appendix 7: Reporting Standards for Missing Data
13.8
Appendix 8: Values of Potential Clinical Importance
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
13
6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the Safety population, unless otherwise 
specified.
Study population analyses including analyses of participant’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure and treatment compliance will be based on GSK Core Data Standards.  
Details of the planned displays are presented in Appendix 13: List of Data Displays.
7.
EFFICACY ANALYSES
Implementation Science/Health Outcomes endpoints will form the basis for the overall 
primary analysis of the study, and details of implementation science/health outcomes 
analyses are documented in a separate Evidera SAP.  Clinical efficacy endpoints are 
evaluated as secondary objectives for this study.
7.1.
Secondary Efficacy Analyses
7.1.1.
Endpoint / Variables

Proportion of participants with Plasma HIV-RNA < 50 copies/mL and plasma HIV-1 
RNA ≥ 50 c/mL, respectively, over time using the FDA Snapshot Algorithm. See 
Section 13.9 for Snapshot Algorithm details.
Other secondary efficacy endpoints:

Proportion of participants with confirmed virologic failure (CVF) over time

Absolute values and changes from Baseline CD4+ cell count over time
7.1.2.
Population of Interest 
Secondary efficacy analyses will be based on the Safety population, unless otherwise 
specified.
7.1.3.
Strategy for Intercurrent (Post-Randomization) Events

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 HIV-1 RNA < 50 c/mL.  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. 

Participants with last available HIV-1 RNA measurement greater or equal to 50 
copies/mL while the participant is on treatment within the analysis visit window of 
interest are classified as HIV-1 RNA ≥ 50 c/mL. Participants without evaluable HIV-
RNA data for the visit of interest and who discontinue treatment for reasons not 
related to adverse event while having HIV-1 RNA ≥50 copies/mL at time of 
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
14
discontinuation or who change study treatment not permitted per protocol before the 
analysis window are also classified as having HIV-RNA ≥50 copies/mL. 
Missing viral load values for reasons related to COVID-19 issues (e.g. participant is 
unable to have viral load assessed due to barriers in attending the clinic during the 
pandemic or COVID-19 related adverse events leading to treatment discontinuation) will 
be imputed using an LOCF approach in which the last on-treatment viral load value will 
be carried forward and used in place of missing values.
7.1.4.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 13: List of Data Displays and
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 7.1.1 will be
summarised using descriptive statistics, graphically presented (where appropriate) and
listed.
7.1.4.1.
Statistical Methodology Specification
Endpoint / Variables

Proportion of participants with plasma HIV-1 RNA < 50 c/mL over time using the FDA 
Snapshot algorithm (Safety population)

Proportion of participants with plasma HIV-1 RNA ≥50 c/mL over time using the FDA 
Snapshot algorithm (Safety population)
Results Presentation

The proportion of participants with HIV-1 RNA < 50 c/mL and HIV-1 RNA ≥50 c/mL, 
respectively, at each planned visit with corresponding 95% confidence intervals calculated 
using the Clopper-Pearson exact method.

The proportion of participants in each Snapshot study outcome category and sub-category 
will be summarized at Month 12, in which default sub-categories have been expanded to 
present COVID-19 vs. non COVID-19 related impact (as described in Section 13.9).
8.
SAFETY ANALYSES
The safety analyses will be based on the Safety population, unless otherwise specified.
For the Month 12 analysis, safety displays will summarize data across the combined   
Intervention + Extension Phases, unless otherwise specified in the display title presented 
in Appendix 13: List of Data Displays.
8.1.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs), 
COVID-19 AEs, and other significant AEs will be based on GSK Core Data Standards. 
The details of the planned displays are provided in Appendix 13: List of Data Displays.
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
15
8.1.1.
Injection Site Reaction Adverse Events
Injection Site Reaction (ISR) adverse events of interest are those from study drug 
injections. 
For the summary of Injection Site Reaction Adverse Events by Visit and Maximum 
Severity (Overall and by Common ISRs), ISRs will be assigned based on onset date to 
the most recent planned IM injection visit prior or equal to the AE onset date.  
Maximum grade at each visit will be derived as the maximum grade among ISRs 
assigned to the particular visit, with consideration for whether the summary applies to a 
particular preferred term (vs. across preferred terms), or drug-related associated to CAB 
and/or RPV.
Drug-related ISRs (based on investigator discretion) will be attributed to the causal agent 
(CAB vs. RPV) when this can be determined specifically based on the side of injection 
administration and the side of the reported ISR (as collected in the eCRF). If we are 
unable to determine the causal agent in those cases where both drugs are given on one 
side and the ISR is reported non-specifically, then the attribution to a specific causal 
agent will remain unknown.
Common study drug ISR adverse events are defined by MedDRA preferred terms 
including injection site pain, injection site induration, injection site nodules and preferred 
terms of any other ISR reported by ≥5% of participants overall.  
8.2.
Adverse Events of Special Interest Analyses
A comprehensive list of MedDRA terms based on clinical review will be used to identify 
Adverse Events of Special Interest (AESI). Changes to the MedDRA dictionary may 
occur between the start of the study and the time of reporting and/or emerging data from 
on-going studies may highlight additional adverse events of special interest, therefore the 
list of terms to be used for each event of interest and the specific events of interest will be 
based on the safety review team (SRT) agreements in place at the time of reporting. The 
details of the current planned grouping, including Standardized MedDRA Query (SMQ) 
values (as applicable), and planned displays are provided in Appendix 10: AESI
identification and Appendix 13: List of Data Displays.
8.3.
Clinical Laboratory Analyses
Laboratory evaluations will be based on GSK Core Data Standards. The details of the 
planned displays are in Appendix 13: List of Data Displays.
8.4.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. The details of the 
planned displays are presented in Appendix 13: List of Data Displays.
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
16
9.
PHARMACOKINETIC ANALYSES
9.1.
Drug Concentration Measures 
Available concentration-time data for CAB and RPV will be presented in listings as 
specified in Appendix 13: List of Data Displays and will be based on GSK Data
Standards and statistical principles.
Refer Appendix 5: Data Display Standards & Handling Conventions (Section 13.5.3
Reporting Standards for Pharmacokinetic).
10.
VIROLOGY
10.1.
Genotypic and Phenotypic Data
Available genotypic and phenotypic data at all collection timepoints will be presented by 
subject (separately for CVF and Non-CVF subjects), as specified in Appendix 13: List of
Data Displays.
11.
OTHER ANALYSES
11.1.
Study Visit Length
The details of the planned displays for study visit length data are in Appendix 13: List of
Data Displays and will be based on GSK Data Standards and statistical principles.
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
17
12.
REFERENCES
Wensing AM, et al. 2019 update of the drug resistance mutations in HIV-1. Topics in 
antiviral medicine. 2019;27:111-121. 
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
18
13.
APPENDICES
13.1.
Appendix 1: Exclusions from Per Protocol Population
Instream and final analysis population reviews as per SOP 130050 are not planned for 
this study because it does not include a Per-Protocol population.
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
19
13.2.
Appendix 2: Schedule of Activities
13.2.1.
Protocol Defined Schedule of Events
13.2.1.1.
Schedule of Activities for Patient Study Participants (CAB LA + RPV LA Monthly Administration)
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
20
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
21
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
22
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
23
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
24
13.2.1.2.
Schedule of Assessments Table for Staff Study Participants
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
25
13.2.1.3.
Schedule of Activities Table for Patient Study Participants (Long Term Follow Up) a
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
26
13.3.
Appendix 3: Assessment Windows
13.3.1.
Definitions of Assessment Windows for Analyses
Laboratory data, vital signs, ECGs, and genotypic/phenotypic data will be assigned to 
assessment windows according to actual dates rather than the nominal visit labels as 
recorded on the eCRF or in the laboratory database.
Prior to visit slotting, assessments are first assigned to a study phase (Screening, 
Intervention Phase, Extension, or Long Term Follow Up) as defined in Section 13.4.1.
According to the protocol, the nominal target study visit date will be based on the first 
injection, the Month 1 date. For instance, if Month 1 occurred on July 7th, all subsequent 
visits are expected to occur on the 7th of each month such that subsequent visits will be 
August 7th, September 7th, October 7th, etc. Since there are not >28 days in each month 
of the year, if the Month 1 injection occurred on the 29th, 30th, or 31st of the month, then 
the target study visit date for the remainder of the visits will be the 28th of the month.  
The nominal target study visit day is derived as

M1 Target Day = Date of Actual M1 Injection Visit Date – Date of First Oral lead-in 
Dose + 1, if subject receives M1 injection; else M1 Target Day = 30.

Mx Target Day = Mx Nominal Target Study Visit Date – Date of First Oral lead-in 
Dose + 1, for x=2,3, …
Assessment windows will be derived based on the midpoint between two consecutive 
planned target study visit dates. For the Snapshot efficacy data, the same approach will be 
used, except for Month 12, which will use a 6-week window around the projected 
target study visit date at Month 12.
For parameters which are not scheduled to be assessed at visits, the all-inclusive 
assessment windows will still be used; however, data summaries will only report 
scheduled visits. Assessments at unscheduled visits will be included in summaries of 
worst-case values across visit (e.g. during the intervention phase) and in data listings, as 
well any algorithms that make use of additional data (e.g., Snapshot).
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
27
Table 1
Assessment Windows for Screening, Intervention and Extension 
Phase Data (Excluding HIV-1 RNA and PK data)
Target
(Study 
Day) 
Analysis Window
Analysis 
Timepoint
Beginning Timepoint
Ending Timepoint
Day of 
earliest 
record
Assessment Study Day 1
Screening
For subjects discontinuing prior to receiving first injection:
30
Assessment Study Day = 2
Study Day of Last CAB/RPV 
Oral Dose+1
Month 1
Assessment Study Day > 
(Study Day of Last CAB/RPV Oral Lead-in Dose +1)
Follow-up
For subjects receiving first injection:
Day of First 
Injection
Study Day = 2
M1 target day + floor [(M2 
target day – M1 target day)/2]
Month 1
M2 
Target Day
M1 target day + floor [(M2 target day 
– M1 target day)/2] + 1
M2 target day + floor [(M4 
target day – M2 target day)/2]
Month 2
M4 
Target Day
M2 target day + floor [(M4 target day 
– M2 target day)/2] + 1
M4 target day + floor [(M6 
target day – M4 target day)/2] 
Month 4
M6 
Target Day
M4 target day + floor [(M6 target day 
– M4 target day)/2] + 1
M6 target day + floor [(M9 
target day – M6 target day)/2] 
Month 6
M9 
Target Day
M6 target day + floor [(M9 target day 
– M6 target day)/2] + 1
M9 target day + floor [(M12 
target day – M9 target day)/2] 
Month 9
M12 
Target Day
M9 target day + floor [(M12 target 
day – M9 target day)/2] + 1
M12 target day + floor [(M15 
target day – M12 target 
day)/2] 
Month 12
M15 
Target Day
M12 target day + floor [(M15 target 
day – M12 target day)/2] + 1
M15 target day + floor [(M18 
target day – M15 target 
day)/2] 
Month 15
M18 
Target Day
M15 target day + floor [(M18 target 
day – M15 target day)/2] + 1
M18 target day + floor [(M21 
target day – M18 target 
day)/2]
Month 18
Mx
Target Day
M(x-3) target day - floor [(Mx target 
day – M(x-3) target day)/2] + 1
Mx target day + floor [(M(x+3) 
target day – Mx target day)/2]
Month x
For x = 21, 
24, etc.
For subjects who permanently discontinue study treatment:
Assessment Study Day >
Max (Study Day of Last Dose of Oral Study Treatment (CAB+RPV or 
SOC Bridging) + 1, Study Day of Last CAB + RPV Injection + 35)
Follow-up
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
28
Table 2
Assessment Windows for Screening and Intervention Phase HIV-1 
RNA Data
Target
(Study Day) 
Analysis Window
Analysis 
Timepoint
Beginning Timepoint
Ending Timepoint
Day of earliest 
record
Assessment Study Day 1
Screening
For subjects discontinuing prior to receiving first injection:
28
Assessment Study Day = 2
Study Day of Last Oral Lead-in 
Dose +1
Month 1
Assessment Study Day >
(Study Day of Last CAB/RPV Oral Lead-in Dose +1)
Follow-up
For subjects receiving first injection:
Date of First 
Injection
Study Day = 2
M1 target day + floor [(M2 
target day – M1 target day)/2]
Month 1
M2 Target Day
M1 target day + floor [(M2 target 
day – M1 target day)/2] +1
M2 target day + floor [(M4 
target day – M2 target day)/2]
Month 2
M4 Target Day
M2 target day + floor [(M4 target 
day – M2 target day)/2] + 1
M4 target day + floor [(M6 
target day – M4 target day)/2]
Month 4
M6 Target Day
M4 target day + floor [(M6 target 
day – M4 target day + 1
M6 target day + floor [(M8 
target day – M6 target day)/2]
Month 6
M8 Target Day
M6 target day + floor [(M8 target 
day – M6 target day)/2] + 1
M8 target day + floor [(M10 
target day – M8 target day)/2]
Month 8
M10 Target 
Day
M8 target day + floor [(M10 
target day – M8 target day)/2] + 
1
M12 target day – 43
Month 10
M12 Target 
Day
M12 target day - 42
M12 target day + 42
Month 12
M13 Target 
Day
Assessment Study Day > M12 target day + 42
Month 13
For subjects who permanently discontinue study treatment during the Intervention Phase:
Assessment Study Day >
Max (Study Day of Last Dose of Oral Study Treatment (CAB+RPV 
or SOC Bridging) +1, Study Day of Last CAB + RPV Injection + 
35)
Follow-up
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
29
Table 3
Assessment Windows for Extension Phase HIV-1 RNA Data
Target
(Study Day) 
Analysis Window
Analysis 
Timepoi
nt
Beginning Timepoint
Ending Timepoint
M13 Target 
Day
Study Day of Nominal Week 13 
Visit
M13 target day - floor [(M15 
target day – M13 target day)/2] 
Month 13
M15 Target 
Day
M13 target day - floor [(M15 
target day – M13 target day)/2] 
+ 1
M15 target day + floor [(M17 
target day – M15 target day)/2]
Month 15
Mx Target Day
M(x-2) target day - floor [(Mx
target day – M(x-2) target 
day)/2] + 1
Mx target day + floor [(M(x+2) 
target day – Mx target day)/2]
Month x
For x
=17, 19 
etc.
For subjects who permanently discontinue study treatment during the Extension Phase:
Assessment Study Day >
Max (Study Day of Last Dose of Oral Study Treatment (CAB+RPV 
or SOC Bridging) +1, Study Day of Last CAB + RPV Injection + 35)
Follow-up
Table 4
Assessment Windows for Study Visit Length Data (Intervention and 
Extension Phase)
Target
(Study Day) 
Analysis Window
Analysis 
Timepoint
Beginning 
Timepoint
Ending Timepoint
Study Day of Actual M1 
Injection
Study Day of Actual M1 Injection
Month 1
Study Day of Actual M5 
Injection
Study Day of Actual M5 Injection
Month 5
Study Day of Actual M11 
Injection
Study Day of Actual M11 Injection
Month 11
Study Day of Actual M14 
Injection
Study Day of Actual M14 Injection
Month 14
Study Day of Actual Mx
Injection
Study Day of Actual Mx Injection
Month x
For x=17, 20, 
etc.
If none of the above, then
Analysis Timepoint = Other
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
30
Table 5
Assessment Windows for Summaries of Long-Term Follow-up 
Phase Data from Subjects who Received at Least One Injection of 
CAB+RPV and Permanently Discontinued from the Study
Day of Assessment
Assessment Window
Target LTFU Study Day of 
Window
1 ≤ LTFU Study Day ≤ 135
LTFU Month 3
90
136≤ LTFU Study Day ≤ 225
LTFU Month 6
180
226 ≤ LTFU Study Day ≤315
LTFU Month 9
270
316 ≤ LTFU Study Day ≤ 405
LTFU Month 12
360
(30*m-44) ≤ LTFU Study Day ≤ 
(30*m+45)
LTFU Month m 
M = 15, 18, 21
30*m

LTFU Study Day is defined in 13.6.1
13.3.2.
Assessment Windows for PK Concentration Data
PK data will be presented in data listings according to planned nominal visits (i.e. as 
collected in the eCRF), without additional assignment to assessment windows.
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
31
13.4.
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events
13.4.1.
Study Phases
AEs will be assigned to study phases as defined in Table 6. Laboratory data (efficacy, 
safety, and virology), HIV associated Conditions, health outcomes assessments, vital 
signs, and ECGs will be assigned to study phases as defined in Table 7.
Assessments/events are assigned to study phases sequentially, starting from the top of 
each table.
Table 6
Study Phases for AEs
Study Phase
Definition
Screen 
Date < Intervention Phase Treatment Start Date
Intervention
For subjects continuing into the Extension Phase:
Intervention Phase Treatment Start Date ≤ Date < Date of Nominal Month 13 Visit
For subjects not continuing into the Extension Phase:
Intervention Phase Treatment Start Date ≤ Date < LTFU ART Start Date [a]
For AEs leading to treatment withdrawal with start date equal to the LTFU ART 
Start Date, Intervention Phase instead of Long-term Follow-up Phase will be 
assigned.
Extension Phase
Date of Nominal Month 13 Injection ≤ Date < LTFU ART Start Date [a]
For AEs leading to treatment withdrawal with start date equal to the LTFU ART 
Start Date, Extension Phase instead of Long-Term Follow-up Phase will be 
assigned.
Long Term Follow-
Up
For subjects who receive at least one CAB/RPV injection and permanently 
discontinue study treatment:
AE Start Date LTFU ART Start Date
AEs with completely missing start date:

If AE end date is ≤Intervention Phase Treatment Start Date, then assign to Screening Phase;

Else if AE end date is completely missing or Intervention Phase Treatment Start Date < AE end 
date ≤Date of Nominal Month 13 Injection, then assign to Intervention Phase;

Else if AE end date > Date of Nominal Month 13 Injection, then assign to Extension Phase.
Date=AE Start Date 

[a] If participants have missing LFTU ART start date, only the lower bound will be considered in the derivation.
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
32
Table 7
Study Phases for Laboratory, PK, ECG, Vital Signs, HIV-1 
Associated Conditions, and Protocol Deviation Data
Study Phase
Definition
Screen
Date ≤ Study Treatment Start Date
Intervention
For subjects continuing into the Extension Phase:
Intervention Phase Treatment Start Date < Date < Date of Nominal Month 13 Visit
For subjects not continuing into the Extension Phase:
Intervention Phase Treatment Start Date < Date ≤ LTFU ART Start Date [a]  
Extension Phase
For subjects continuing into Extension Phase:
Date of Nominal Month 13 Visit ≤ Date ≤ LTFU ART Start Date [a]
Long Term Follow-
Up
For subjects who receive at least one CAB/RPV injection and permanently 
discontinue study treatment:
Assessment Date > LTFU ART Start Date 

Date = start or assessment date

[a] If participants have missing LFTU ART start date, only the lower bound will be considered in the derivation.
Study phase of discontinuation will be determined according to Table 8.
Table 8
Study Phases for Study Conclusion/IP Discontinuation
Study Phase
Definition
Intervention
Discontinuation Date is not missing, and no assessments collected at any 
extension phase nominal visits (i.e. Month 13, Month 15, Month 17 etc.).
Extension Phase
Discontinuation Date is not missing, and assessments collected at any extension 
phase nominal visits (i.e. Month 13, Month 15, Month 17 etc.).

Discontinuation Date = date of failure to complete study/date of IP discontinuation
Medication use will be classified as prior and concomitant with study treatment according 
to Table 9, noting that a medication can be assigned as “taken” during more than one 
study phase.
Table 9
Study Phases for Non-ART Medications/ART Medications
Definition
Prior 
Medication Taken < Intervention Treatment Start Date
Concomitant during 
Intervention Phase
For subjects continuing into Extension Phase:
Intervention Treatment Start Date[a] ≤ Medication Taken < Date of Nominal Month 
13 Visit 
For subjects not continuing into Extension Phase[b]:
Intervention Treatment Start Date[a] ≤ Medication Taken < LTFU ART Start Date
Concomitant during 
Extension Phase
For subjects continuing into Extension Phase[b]:
Date of Nominal Month 13 Visit ≤ Medication Taken < LTFU ART Start Date
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
33
Definition
Received during 
Long-term Follow-up
For subjects who received at least one CAB and/or RPV injection and have 
started LTFU ART:
Medication Taken ≥ LTFU ART Start Date
NOTES: 

Please refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and partial dates 
for medications. Use the rules in this table if medication date is completely missing.
a.
The ART medication stopped on start date of Intervention treatment will be considered a prior medication 
and will not be considered concomitant during the Intervention phase. If the stop date of ART medication is 
completely missing and this medication is recorded in eCRF as prior, it will be considered a prior medication 
and will not be considered concomitant during the intervention phase.
b.
If subjects have missing LFTU ART start date, only the lower bound will be considered in the derivation.
13.4.2.
Treatment State
Within each study phase (based on assignment of study phase described in Section 
13.4.1), only those events/assessments which occur within the ranges shown in Table 10
will be considered ‘on-treatment’ for the given phase.  No treatment states will be 
assigned to medications.
For adverse events, partial AE start date will use imputation as described in 13.7.2.1.
Table 10
Treatment State within Study Phases
Study Phase
State
Definition
Screen
Pre-Treatment
All assessments/events within phase
Intervention/Extension
On-treatment
Date ≤ max (Date of Last CAB LA +RPV LA IM Dose 
+ 35, Date of Last Dose of Oral Study Treatment 
(CAB+RPV or SOC Bridging) +1)
Post-Treatment
Date > max (Date of Last CAB LA +RPV LA IM Dose 
+ 35, Date of Last Dose of Oral Study Treatment 
(CAB+RPV or SOC Bridging) +1)
Long Term Follow-Up
Post-Treatment
All assessments/events within phase
NOTES:

Date = Assessment/Start Date
a.
Treatment State is determined after data has been assigned to the study phases as defined in Section 13.4.1.
b.
Last injection and/or last dose of oral study treatment (CAB+RPV or SOC bridging) are only applied to 
participants who permanently discontinued the study treatment. The assessments for participants who did not 
permanently discontinue the study treatment will be considered ‘On-treatment’. For participants continuing into 
extension phase, all data assigned to intervention phase per Section 13.4.1 will be considered ‘On-treatment’
13.4.3.
Oral Lead-in Period
Certain displays will be produced for data collected or events occurring during the oral-
lead-in period as defined in Table 11 and Table 12.
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
34
Table 11
Oral Lead-in Period for AEs
Study Period
Date Range
Oral Lead-in
For participants receiving at least one Injection:
Intervention Treatment Start Date ≤ Date [a] < Date of First IM Injection 
For participants withdrawing prior to first Injection:
Date Intervention Treatment Start Date
Note that the oral lead-in period is only applicable to the participants who received at 
least one dose of study treatment during the oral lead-in period in the study. Oral 
lead-in period is within the intervention phase.
[a] AEs with completely missing start date which have been assigned to the Intervention Phase based on Table 6
will not be assigned to the Oral Lead-in Period.
NOTES:

Date = AE Start date
Table 12
Oral Lead-in Period for Laboratory Data
Period
Date Range
Oral Lead-in
For participants receiving at least one Injection:
Intervention Treatment Start Date < Date ≤ Date of First IM Injection 
For participants withdrawing prior to first Injection:
Date > Intervention Treatment Start Date
Note that the oral lead-in period is only applicable to the participants 
who received at least one dose of study treatment during the oral lead-in 
period in the study. Oral lead-in period is within the intervention phase.
NOTES:

Date = Date of assessment
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
35
13.5.
Appendix 5: Data Display Standards & Handling 
Conventions
13.5.1.
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
us1salx00259
HARP Compound
  \ARPROD\GSK1265744\mid209493\primary_01
Analysis Datasets 

Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2 & ADaM IG 
Version 1.1).
Generation of RTF Files

RTF files will be generated for all reporting efforts described in the RAP.
13.5.2.
Reporting Standards
General

The current GSK Statistical Display Standards in the GSK Standards Library (IDSL) will be applied 
for reporting, unless otherwise stated (Library Location: 
https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 
Formats

GSK Statistical Display Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for 
reporting of data based on the raw data collected, unless otherwise stated.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the GSK Standard Statistical Display 
Principles but may be adjusted to a clinically interpretable number of DP’s. 
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled visit 
days on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to GSK 
Standard Statistical Display Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the participant’s listings. 
Unscheduled Visits

Unscheduled visits will be assigned to an analysis visit using the all-inclusive windows 
defined in Section 13.3.
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
36

However, data summaries will only report visits that are planned assessment time points for 
each parameter (according to the Schedule of Activities in Section 13.2.1).

Evaluable assessments at unscheduled visits will be used when categorizing values across 
visits, such as ‘maximum grade during the intervention phase’ or ‘at any time post-
baseline’, and for any algorithm that has specific rules for which observation to use (e.g. 
snapshot algorithm, LOCF or CVF identification).
Descriptive Summary Statistics
Continuous Data
Refer to GSK Standard Statistical Display Principle 6.06.1
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to GSK Standard Statistical Display Principals 7.01 to 7.13.
13.5.3.
Reporting Standards for Pharmacokinetic
Pharmacokinetic Concentration Data
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to the GSK Standard PK Display Standard.
Refer to the GSK Standard Statistical Display Principle 6.06.1.
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only. 
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
37
13.6.
Appendix 6: Derived and Transformed Data
13.6.1.
General
Multiple Measurements at One Analysis Time Point

If there are two values within a time window (as per Section 13.3.1) the value closest to the target 
day for that window will be used. If values are the same distance from the target, then the mean 
(geometric mean for HIV-1 RNA, arithmetic mean for all other measurement) will be taken.

Assessments not chosen for use in summary statistics by this algorithm will still appear in the 
associated listings. 

All applicable valid assessments, irrespective of proximity to the target study day, will be used when 
categorizing values across visits, such as ‘maximum grade during the intervention phase’ or ‘at any 
time post-baseline’, and for any algorithm that has specific rules for which observation to use (e.g. 
snapshot algorithm, LOCF or CVF identification).

Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance 
summary tables.
Treatment Start Date

Intervention Phase Treatment Start Date = Earliest date of CAB + RPV oral lead-in entered in the IP 
exposure eCRF form
Nominal Month 13 Visit Date

For participants who received Month 13 injection, the nominal Month 13 visit date is defined by the 
Month 13 injection date.

Otherwise, nominal Month 13 visit date is defined by the date of latest Month 13 assessment.

For participants who continued into Extension Phase but missed the Month 13 visit, the nominal 
Month 13 visit date is defined by the last contact date prior to the date of the first nominal extension 
phase visit (i.e. Month 15, Month 17, etc.).
Study Day

The Study Day of an event (e.g., lab assessment, vital sign, ECG, start date of AE or HIV associated 
condition) will be derived as the number of days between the date of the event and the Intervention 
Phase treatment start date as follows: 
o
If date of event ≥ start date of study treatment, then

Study Day = Date of Event - Intervention Phase Treatment Start Date +1
o
If date of event < start date of study treatment, then

Study Day = Date of Event - Intervention Phase Treatment Start Date

Note that the start date of intervention phase study treatment is on Study Day 1 and the day before 
this is Study Day -1; i.e., there is no Study Day 0.
Long Term Follow-up Study Day

The Long-Term Follow Up (LTFU) Study Day of an event (e.g., lab assessment, start date of AE or 
HIV associated condition) will be derived as the number of days between the date of the event and 
the end of IP treatment [i.e. max(Last IM Injection Date, Last Oral Bridging End Date)] as follows:
o
If the date of event falls in Long-term Follow up phase, then

LTFU Study Day = Date of event - End date of IP + 1
Study Treatment

Refers to CAB+RPV oral lead-in, CAB + RPV oral bridging, SOC bridging, CAB LA + RPV LA
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
38
13.6.2.
Study Population
Demographics
Age

Age, in whole years, will be calculated with respect to the subject’s Screening visit.

GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed as 
follows:

Any subject with a missing date and month will have this imputed as ‘30th June’.

Birth date will be presented in listings as ‘YYYY’.

Completely missing dates of birth will remain as missing, with no imputation applied. Consequently, 
the age of the subject will not be calculated and will remain missing.
Body Mass Index

Calculated as Weight (kg)/Height (m)²
Hepatitis Status

Hepatitis C status will be determined using antibody and/or hepatitis C virus (HCV) RNA 
assessments performed during screening or during the conduct of the study. 

If both antibody and virus RNA assessments are available, then the latter will take precedence and 
positive/negative status will be based on whether HCV RNA is detectable (i.e., ≥ limit of 
quantification) or not.

A participant will be considered positive for hepatitis B virus (HBV) if they have a positive surface 
antigen or detectable HBV DNA result. “HBV DNA DETECTED” in the lab comment takes 
precedence over HBV DNA test result for positive hepatitis B status; for example, if a participant has 
HBV DNA test result below level of detection and the lab comment shows that HBV DNA detected, 
this participant will be considered positive for hepatitis B. If HBV DNA result is available, it will be 
used to qualify hepatitis B status as positive or negative (positive if ≥ limit of quantification); 
otherwise Hepatitis B status will be determined using the surface antigen result.

Hepatitis status at entry will be based on the assessments prior to/on the start of the study treatment.
Adherence to CAB/RPV Injection Schedule

Timeliness of Injections relative to Date of Projected Dosing Visits are assessed by using "actual 
injection visit date - projected visit date from first injection". The injections of interest in adherence 
analysis are those after first injection at Month 1. (. Each injection visit is counted only once. 
Individual CAB and RPV injections administered at the same visit are not counted twice. "Extra" 
unscheduled injections are excluded from all derivations. For example, if during a scheduled visit a 
participant receives 1 ml of injection instead of 2 ml due to a dosing error, but this participant returns 
one week later for the remaining 1 ml injection, then the additional visit is excluded. If a participant 
receives an extra injection at an unscheduled visit by mistake, this visit will also be excluded.

The categories of Timeliness of Injections relative to Date of Projected Dosing Visits are listed below:

< -14 days

-14 to   - 8 days

-7   to   1

0

1 to 7 days 

8 to 14 days

>14 days

Missed Injection without Oral Bridging (COVID-19 related)

Missed Injection without Oral Bridging (Non COVID-19 related)

Missed Injection with Oral Bridging (COVID-19 related)
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
39

Missed Injection with Oral Bridging (non COVID-19 related)

Injection visits are expected monthly from Month 2 until the nominal month of a participant’s last 
injection visit during the phase(s) of interest.  For example:

If a participant discontinues study treatment with last injection visit occurring at nominal visit 
Month 6 (without oral bridging), then injection visits are expected at Month 2, Month 3, Month 4, 
Month 5 and Month 6.

Missed injections occurring during periods of on-going oral bridging (e.g. oral bridging is ongoing at 
the time of the data analysis cutoff or participant discontinues study treatment where last study 
treatment received is oral bridging) are not considered to be expected visits.
Site Type

AIDS Healthcare Foundation (Site Id.=
)

Federally Qualified Health Center (Site Id.=
)

Health Maintenance Organization (Site Id.=

Private Practice (Site Id.= 
) 

University (Site Id.=
)
13.6.3.
Efficacy
Efficacy
Snapshot

The Snapshot algorithm is intended to be primarily a virologic assessment of the endpoint, and as 
such follows a “virology first” hierarchy.

‘HIV-1 RNA < 50 c/mL’ or ‘HIV-1 RNA ≥ 50 c/mL’ within an analysis window (see Table 2 and Table 
3) is typically determined by the last available HIV-1 RNA measurement in that window while the 
participant is On-treatment in the Intervention Phase (as assigned based on Section 13.3).

When no HIV-1 RNA data is available within a window, a participant cannot be assigned to the 
category of ‘HIV-1 RNA < 50 c/mL’.  Depending on the reason for lack of data, the participant will be 
classified as ‘HIV-1 RNA ≥ 50 c/mL’ or reported as ‘No Virologic Data at Week X’; in the latter case, 
the algorithm further classifies the nature of the missing data. Typically, a participant withdrawn (i) 
due to AE or, (ii) for another reason yet was suppressed at the time, will be counted as ‘No Virologic 
Data at Week X’.  Should a participant withdraw for reasons other than AE and was not suppressed 
at the time, they will be categorized as ‘HIV-1 RNA ≥ 50 c/mL’.

Full details of the algorithm, including the handling of special cases, are included in Appendix 9:
Snapshot Algorithm Details.
Plasma HIV-1 RNA

For summaries and analyses which use HIV-1 RNA level as a continuous measure, the logarithm to 
base 10 of the value will be used.

HIV-1 RNA results may be provided as censored values, such as <40 or >9,999,999 c/mL. For the 
purposes of summary statistics, such values will be replaced by the next value beyond the limit of 
detection, e.g., 39 or 10,000,000 c/mL, respectively, for the given examples. Data listings will show 
the censored values as provided.
Confirmed Virologic Failure (CVF)

For the purposes of clinical management in this study, CVF is defined as: 
o
Rebound as indicated by two consecutive plasma HIV-1 RNA levels 200 c/mL.

The CVF definition is provided in the protocol Section 7.1.3
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL
209493
40
Efficacy

Only plasma HIV-1 RNA values determined by the central laboratory will be used to assess virologic 
failure.
CDC Classification for HIV-1 Infection (2014)

CDC HIV-1 Classification at Baseline is collected in eCRF and no derivation with be 
performed programmatically for analysis purposes. Please refer to study protocol for detail 
description of CDC HIV-1 Classification.
13.6.4.
Safety
Adverse Events
DAIDS Grading

Clinical adverse events will be graded based on the Division of AIDS Table for Grading the Severity 
of Adult and Pediatric Adverse Events Version 2.1, March 2017, as specified in the protocol 
Appendix 10.2.

If a grade value is expected per DAIDS but is missing in the eCRF, then the missing grade 
will be given an ordinal grade value of -1 for determining the maximum grade within and 
across preferred terms.  For example:

if a participant has two separate instances of the same preferred term, one with grade 2 
and one with missing grade, then the maximum grade for the preferred term will be set 
to grade 2.

if a participant reports two different AE preferred terms overall, one with grade 1 and 
one with missing grade (where a DAIDS grade is expected), then the maximum grade 
across preferred terms (i.e. in the ANY EVENT row) will be set to grade 1.

If a participant reports only one AE overall and this has a missing grade (where a DAIDS 
grade is expected), then this will be presented under a grade = missing category 
Days since First Dose (Days)

AE Start Date – Intervention Phase Treatment Start Date + 1
Days since Last Dose (Days)

AE Start Date – Date of Last Dose of Study Treatment (CAB+RPV, SOC bridging, CAB/RPV IM 
Injection) prior to/on the Start Date of AE + 1
Days since Phase Start

For AEs in Intervention/Extension Phase:
o
AE Start Date - Intervention Treatment Start Date + 1

For AEs in Long-term Follow-up Phase:
o
AE Start Date – Date of Last Dose of Study Treatment 
o
Date of Last Dose of Study Treatment = max (Last IM Injection Date, Last Oral 
Bridging End Date [CAB+RPV, SOC ART]), only applicable to participants who 
permanently discontinued study treatment.
Duration (Days)

AE Resolution Date – AE Start Date + 1
Drug-related

If relationship is marked ‘YES’ on Inform/eCRF

Injection site reactions will be considered as drug-related if the relationship to study drug value is 
missing in the eCRF.
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
41
Laboratory Parameters

If a laboratory value which is expected to have a numeric value for summary purposes, has a non-
detectable level reported in the database, where the numeric value is missing, but typically a 
character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the comment 
field) is present, the number of significant digits in the observed values will be used to determine how 
much to add or subtract in order to impute the corresponding numeric value. If a character value 
starting with “<=x”, then the numeric value will be x.
o
Example 1: 2 Significant Digits = ‘< x ‘becomes x – 0.01
o
Example 2: 1 Significant Digit = ‘> x’ or ‘>=x’ becomes x + 0.1
o
Example 3: 0 Significant Digits = ‘< x’ becomes x – 1
Lab Toxicities – DAIDS Grading 

Toxicities will be based on the Division of AIDS (DAIDS) grading system, Version 2.1, March 2.17, as 
specified in the protocol of Appendix 10.2 

Toxicity grades provided by the central laboratory do not distinguish between abnormally high or low 
criteria, when both are relevant for a particular parameter.

When summarizing toxicity grades for such parameters, they will be categorized as to whether they 
are above or below the midpoint of normal range.
Parameter
Below Midpoint for 
those ≥Grade 1
Above Midpoint for those 
≥Grade 1
Glucose
Hypoglycaemia
Hypoglycaemia
Sodium
Hyponatremia
Hyponatremia
Potassium
Hypokalaemia
Hypokalaemia
   
Other Safety Endpoints
Corrected QT (QTc)

When not entered directly in the eCRF, corrected QT intervals by Bazett’s (QTcB) and Fridericia’s 
(QTcF) formulas will be calculated, in msec, depending on the availability of other measurements.

If RR interval (in msec) is provided, then missing QTcB and/or QTcF will be derived as
1000
RR
QT
QTcB 
3
1000
RR
QT
QTcF 

where uncorrected QT interval is also measured in msec.

If RR interval is not provided directly and one of QTcB or QTcF has been entered, then RR interval 
can be obtained from the above formulas and used to calculate the other correction method value; 
i.e.,
QT
QTcF
QTcB
3

3
2
QTcB
QT
QTcF


Extent of Exposure

Exposure to CAB+RPV (oral lead-in or oral bridging) and CAB LA+RPV LA will be calculated from 
the IP eCRF pages.
For Intervention Phase:

Exposure to CAB+RPV Oral Lead-in = IP (oral lead-in) stop date - IP (oral lead-in) start date +1
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
42
Other Safety Endpoints

Exposure to CAB LA + RPV LA = Number of IP injection visits received during the Intervention 
Phase (up to but not including injections administered at Month 13)

Exposure to SOC oral bridging: Duration of the SOC ART medication taken as oral bridging during 
the Intervention Phase. If the SOC oral bridging is taken in different periods during the Intervention 
Phase, the duration will be calculated by the sum of non-overlapped periods. 

Exposure to CAB+RPV Oral Bridging (COVID-19 Related): Duration of the CAB+RPV taken as 
oral bridging for reasons related to COVID-19 during the Intervention Phase. If COVID-19 related
CAB+RPV oral bridging is taken in different periods during the Intervention Phase, the duration will 
be calculated by the sum of the non-overlapped periods.

Exposure to CAB+RPV Oral Bridging (Non COVID-19 Related): Duration of the CAB+RPV taken 
as oral bridging for reasons not related to COVID-19 during the Intervention Phase. If non COVID-19 
related CAB+RPV oral bridging is taken in different periods during the Intervention Phase, the 
duration will be calculated by the sum of the non-overlapped periods. 

Overall Exposure to Study Treatment: min [Date of Latest Intervention Phase Visit up to and 
including Month 13, max (Date of Last Injection + 35, Date of Last Dose of Oral CAB+RPV, Date of 
Last Dose of SOC Oral Bridging)] – min (Start Date for Oral lead-in CAB+RPV, Date of First 
CAB/RPV Injection) + 1
o
Note: Conditions in the above formula pertaining to Last Injection/Last Dose of Oral 
CAB+RPV/Last Dose of SOC Oral Bridging are only applicable to those who 
permanently discontinued study treatment.

Overall Exposure to CAB + RPV = Overall Exposure to Study Treatment – Exposure to SOC Oral 
Bridging
For Intervention Extension Phase:

Exposure to CAB LA + RPV LA = Number of IP injection visits received during Intervention Phase 
and Extension Phase

Exposure to SOC or CAB+RPV Oral Bridging during the Intervention and Extension Phase will be 
calculated similarly to that during the Intervention Phase except that the exposure includes both 
Intervention and Extension Phase. 

Overall Exposure to Study Treatment: min [Date of Latest Intervention/Extension Phase Visit, max 
(Date of Last Injection + 35, Date of Last Dose of Oral CAB+RPV, Date of Last Dose of SOC Oral 
Bridging)] – min (Start Date for Oral lead-in CAB+RPV, Date of First Study Injection) + 1
o
Note: Conditions in the above formula pertaining to Last Injection/Last Dose of Oral 
CAB+RPV/Last Dose of SOC Oral Bridging are only applicable to those who 
permanently discontinued study treatment.

Overall Exposure to IP = Overall Exposure to Study Treatment – Exposure to SOC Oral Bridging

Duration of dosing in participant years will be calculated as the sum of participant duration of dosing 
in days (across all participants)/365.25
13.6.5.
Virology
Genotype 
Amino Acid Changes

A mutation is considered present whenever the encoded amino acid residue differs from the amino 
acid that would have been encoded by the wild-type (e.g., HXB2, NL43) comparator gene; e.g., 
Q148K. 

If the encoded amino acid is seen as a mixture of wild-type and mutant amino acid, e.g., Q148Q/K, 
the mutated amino acid is considered present at the codon of interest. 
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
43

If the encoded amino acid is seen as a mixture of two or more amino acids, which may or may not 
include wild type, e.g., Q184K/H or Q184K/H/Q, etc., for the purposes of calculating the number of 
mutated amino acids, only one mutation is considered to be present at the codon of interest.
Representation of Amino Acid Changes 
Mutations
Amino Acid Change
T69S
Single mutation from amino acid 'T' (vendor reference) to 'S' (sample) at codon '69
Q148H/K/R
Mixture of amino acid mutations ‘H’, ‘K’ and ‘R’ (sample) from amino acid ‘Q 
(vendor reference) at codon ‘148’
_69_1T
First insertion of amino acid 'T' (sample) at codon '69'
_69_2S
Second insertion of amino acid 'S' (sample) at codon '69'
_69_3S/A
Third insertion of a mixture of amino acids 'S' and 'A' (sample) at codon '69'
L74L/-
Mixture of amino acid 'L' (sample) and a deletion at codon '74'
V75-
Single deletion of amino acid (sample) at codon '75'
Resistance Associated mutations
Known INI mutations associated with the development of resistance to Integrase Strand Transfer 
Inhibitors:
Amino Acids in 
HIV Integrase for 
Analysis
H51Y, T66A/I/K, L68V/I, L74I/M, E92Q/V/G, Q95K, T97A, G118R, F121Y, 
E138A/D/K/T, G140A/C/R/S, Y143C/H/R/K/S/G/A, P145S, Q146P, S147G, 
Q148H/K/R/N, V151/IL/A, S153F/Y, N155H/S/T, E157Q, G163R/K, G193E, 
S230R, R263K

Draft listing; may be modified in case of additional substantive data availability.

Based on the IAS-USA list of mutations associated with resistance to Bictegravir, Cabotegravir, 
Dolutegravir, Elvitegravir, or Raltegravir (IAS-USA 2019 resistance mutations update volume 27 issue 3, 
2019): T66A/I/K, L74M, E92Q/G, T97A, G118R, F121Y, E138A/K/T, G140A/C/R/S, Y143C/H/R, S147G, 
Q148H/K/R, S153F/Y, N155H, R263K) and observed mutations during in vitro passage of DTG or seen in a 
previous DTG study in INI-experienced subjects (study ING112574): H51Y, L74I, L68V/I, E92V, Q95K, 
E138D, Y143K/S/G/A, P145S, Q146P, V151I/L/A, N155S/T, E157Q, G163R/K, G193E, S230R. 

Major USA-IAS mutations associated with resistance to INSTI are bolded.

Major resistance mutations to other classes (i.e., NRTI, NNRTI, PI) as defined by the International 
Antiviral Society-USA (IAS-USA). The most up to date IAS-USA guidelines available at the time of 
DBF will be used in the analysis [Wensing, 2019].
Class
Mutations
NRTIs
M41L, A62V, K65R/E/N, D67N, 69 insert, K70E/R, L74V, V75I, F77L, Y115F, F116Y,
Q151M, M184V/I, L210W, T215Y/F, K219Q/E
NNRTIs
L100I, K101E/P, K103N/S, V106A/M, V108I, E138/A/G/K/Q/R, V179L,
Y181C/I/V, Y188C/L/H, G190S/A, H221Y, P225H, F227C, M230I/L
PIs
D30N, V32I, M46I/L, I47A/V, G48V, I50V/L, I54V/M/L, Q58E, T74P, L76V,
V82A/T/F/L/S, N83D, I84V, N88S, L90M

Draft listing; may be modified in case of additional substantive data availability.
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
44
13.6.6.
Other Assessments
Study Visit Length

Lead Time = Actual Start Time of Appointment – Arrival Time

Process Time = Actual End Time of Appointment – Actual Start Time of Appointment

Total Time = Actual End Time of Appointment – Arrival Time
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
45
13.7.
Appendix 7: Reporting Standards for Missing Data
13.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Withdrawn participants were not replaced in the study.

All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified. 

Withdrawal visits will be slotted according to Appendix 3: Assessment Windows
(excluding PK data)
13.7.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank fields 
on the collection instrument:
o
These data will be indicated by the use of a “blank” in participant listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such.
Outliers

Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
13.7.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in participant listing displays.

Where necessary, display macros may impute dates as temporary variables for sorting 
data in listings only. In addition, partial dates may be imputed for ‘slotting’ data to study 
phases or for specific analysis purposes as outlined below.

Imputed partial dates will not be used to derive study day, time to onset or duration 
(e.g., time to onset or duration of adverse events), or elapsed time variables (e.g., time 
since diagnosis). In addition, imputed dates are not used for deriving the last contact 
date in overall survival analysis dataset.
Adverse 
Events

Imputations in the adverse events dataset are used for slotting events to the 
appropriate study time periods and for sorting in data listings.

Partial dates for AEs recorded in the CRF will be imputed using the following 
conventions:
Missing start day

If study treatment start date is missing (i.e. participant did not 
start study treatment), then set start date = 1st of month.

Else if study treatment start date is not missing:
o
If month and year of start date = month and year of study 
treatment start date, then

If stop date contains a full date and stop date is 
earlier than study treatment start date, then set start 
date= 1st of month.

Else set start date = study treatment start date.
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
46
Element
Reporting Detail

Else 
o
For Non-ISR AEs: set start date = 1st of month
o
For ISR AEs: if oral bridging taken during the 
month and year, set start date = min(last day of 
the month, day of AE stop date if available, day 
of study treatment discontinuation if occurring 
during the month and year); else set start date = 
1st of month.
Missing start day 
and month

If study treatment start date is missing (i.e. participant did not 
start study treatment), then set start date = January 1.

Else if study treatment start date is not missing:
o
If year of start date = year of study treatment start date,
then

If stop date contains a full date and stop date is 
earlier than study treatment start date, then set start 
date = January 1.

Else set start date = study treatment start date.
o
Else set start date = January 1.
Missing stop day 
Last day of the month will be used.
Missing stop day 
and month
No Imputation
Completely missing 
start/end date
No imputation

Completely missing start or end dates will remain missing, with no imputation applied. 
Non-ART
Medications

Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention:
Missing start day

If study treatment start date is missing (i.e. participant did not 
start study treatment), then set start date = 1st of month.

Else if study treatment start date is not missing:
o
If month and year of start date = month and year of study 
treatment start date, then

If stop date contains a full date and stop date is earlier 
than study treatment start date, then set start date= 1st 
of month.

Else set start date = study treatment start date.
o
Else set start date = 1st of month.
Missing start day 
and month

If study treatment start date is missing (i.e. participant did not 
start study treatment), then set start date = January 1.

Else if study treatment start date is not missing:
o
If year of start date = year of study treatment start date,
then

If stop date contains a full date and stop date is earlier 
than study treatment start date, then set start date = 
January 1.

Else set start date = study treatment start date.      

Else set start date = January 1.
Missing end day
A '28/29/30/31' will be used for the day (dependent on the month 
and year) 
Missing end day and 
month
A '31' will be used for the day and 'Dec' will be used for the month.
Completely missing 
start/end date
No imputation
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
47
Element
Reporting Detail

The recorded partial date will be displayed in listings.
ART 
Medications

Partial dates recorded in the eCRF will be imputed using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will be 
used for the month.
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day (dependent 
on the month and year) and 'Dec' will be used for the month. If medications 
recorded in the PRIOR ART form of the eCRF, then the earlier date of the imputed 
and the day prior to the Intervention phase treatment start date will be used, i.e. 
min (imputed stop date, Intervention phase treatment start date - 1).

For medications with completely missing start date, they will be considered started prior 
to the Intervention phase treatment start date.

For medications with completely missing stop date, they will be considered ongoing 
unless recorded in the PRIOR ART form of the eCRF.

For ART booster medications, the start and stop dates are not recorded in the database 
(i.e. missing), the dates will be imputed to be the same as the dates of their parent 
medications. 

The recorded partial or missing date will be displayed in listings.
13.7.2.2.
Handling of Missing Data for Statistical Analysis
Element
Reporting Detail
Snapshot

In the Snapshot dataset, subjects without HIV – 1 RNA data in the 
assessment window for the visit of interest (due to missing data or 
discontinuation of IP prior to the visit window) do not belong to ‘HIV-1< 
50 c/mL (or 200 c/mL) The nature of this missing data will be further 
classified in Snapshot summaries as either ‘HIV-1 RNA≥50’ or ‘No 
Virologic Data at Week X’;

See Appendix 9: Snapshot Algorithm Details
LOCF (COVID-19 
Related)

Missing HIV-1 RNA values within an analysis visit for reasons related to 
COVID-19 will be imputed using the last on-treatment value from earlier 
analysis timepoints.

This approach will be used in the primary snapshot analysis to address 
missing data due to COVID-19.
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
48
13.8.
Appendix 8: Values of Potential Clinical Importance
ECG values of potential clinical importance are defined as QTc > 500 msec or increase 
from baseline in QTc ≥ 60 msec.
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
49
13.9.
Appendix 9: Snapshot Algorithm Details
Detailed Algorithm Steps

Consider an analysis visit window for Month X as defined in Table 2. 

The HIV-1 RNA threshold of 50 will be analysed,  in this study 

The COVID-19 pandemic presents significant logistical challenges for many clinical sites 
around the world, with variable restrictions being placed on site resources and operations, 
and on an individual participants ability to attend clinic visits. The snapshot algorithm is 
modified to allow for the presentation of full scope of COVID-19 relatedness. The analysis 
window for ‘Month 12’ and HIV-1 RNA threshold of ’50 c/mL’ are used for the purpose of 
illustration. A participant’s Snapshot response and reason at Month 12 are categorized as 
below.
o
HIV-1 RNA < 50 c/mL
o
HIV-1 RNA ≥ 50 c/mL
   Data in window not below 50
  Non-COVID-19 related 
Discontinued for lack of efficacy
Discontinued for other reason while not below 50
  COVID-19 related
Discontinued for lack of efficacy
Discontinued for other reason while not below 50
o
No Virologic Data at Month 12 Window
  Non-COVID-19 related
Discontinued study due to AE or death
Discontinued study for other reasons
On study but missing data in window
              COVID-19 related
Discontinued study due to AE or death 
Discontinued study for other reasons
On study but missing data in window
            Change in background therapy*
* Note: Use of CAB + RPV oral bridging and SOC oral bridging medication, where the latter is 
due to unavailability of CAB/RPV IM injections or oral CAB+RPV during the pandemic, will not 
be considered a “Change in background therapy” in the Snapshot algorithm.  All other 
permanent changes in ART are not permitted in this protocol.

The steps in determining response and reasons are indicated in the table below, in the order 
stated.

Background therapy is not given to participants while on study. The “change in background 
therapy” in detailed steps below refers to the “change in ART” in this study.
Detailed steps

Please note that the following scenarios will NOT be penalized in the Snapshot algorithm Oral bridging 
(CAB+RPV or SOC, where SOC oral bridging medication is permitted during COVID-19 pandemic due to 
the unavailability of the CAB/RPV IM injections and oral CAB+RPV) 
Condition (‘Month 12’ indicates Month 12 window)
Response 
Reasons
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
50
1.
If non-permitted change in background therapy prior 
to Month 12  
HIV-1 RNA ≥ 50
Change in 
background therapy
2.
If non-permitted change in background therapy during 
Month 12
Last on-treatment VL during Month 12 prior to/on 
the date of change ≥ 50 c/mL
HIV-1 RNA ≥ 50
Data in window not 
below 50
Last on-treatment VL during Month 12 prior to/on 
the date of change < 50 c/mL
HIV-1 RNA < 50
No VL during Month 12 prior to/on the date of 
change 
HIV-1 RNA ≥ 50
Change in 
background therapy 
3.
If none of the above conditions met
3.1. On-treatment VL available during Month 12

Last on-treatment VL during Month 12 ≥ 50 
c/mL
HIV-1 RNA ≥ 50
Data in window not 
below 50

Last on-treatment VL during Month 12 < 50 
c/mL
HIV-1 RNA < 50
3.2. No on-treatment VL during Month 12
3.2.1. If participants are still on study, i.e. a 
participant has not permanently 
discontinued the study treatment yet, or if a 
participant permanently discontinued the 
study treatment and the upper bound of 
analysis snapshot window is prior to the 
following date: 

Min[max(Date of last injection + 35, 
Date of Last  Dose of Oral Study 
Treatment (CAB+RPV, SOC Bridging) + 
1), LTFU ART Start Date]
3.2.1.1. If no on-treatment VL during Month 
12 is not due to COVID-19
No virologic 
data at Month 
12 Window
On study but missing 
data in window (Non-
COVID-19 related)
3.2.1.2. If no on-treatment VL during Month 
12 is due to COVID-19
No virologic 
data at Month 
12 Window
On study but missing 
data in window 
(COVID-19 related)
3.2.2. If participants withdraw before/during 
Month 12 due to
3.2.2.1. Non-COVID-19 related safety 
reasons (e.g. AE/death, liver 
chemistry stopping criteria, renal 
toxicity withdrawal criteria, QTc 
withdrawal criteria etc., as recorded 
in eCRF Conclusion form)
No virologic 
data at Month 
12 Window
Disc due to AE/death 
(Non-COVID-19 
related)
3.2.2.2. COVID-19 related safety reasons 
(e.g. AE/death, liver chemistry 
stopping criteria, renal toxicity 
withdrawal criteria, QTc withdrawal 
No virologic 
data at Month 
12 Window
Disc due to AE/death 
(COVID-19 related)
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
51
criteria etc., as recorded in eCRF 
Conclusion form)
3.2.2.3. Non-safety and Non-COVID-19 
related reasons (e.g. Lack of 
efficacy, protocol deviation, withdrew 
consent, loss to follow-up, study 
closed/terminated, investigator 
discretion etc., as recorded in eCRF
Treatment Discontinuation Form)
o
Last on-treatment VL <50 c/mL 
OR no on-treatment VL 
available during study  
No virologic 
Data at Month 
12 Window
Disc for other 
reasons (Non-
COVID-19 related)
o
Last on-treatment VL ≥ 50 
c/mL AND withdrawal due to 
Lack of efficacy
HIV-1 RNA ≥ 50
Disc. for lack of 
efficacy (Non-
COVID-19 related)
o
Last on-treatment VL ≥ 50 
c/mL AND withdrawal due to all 
other non-safety related 
reasons
HIV-1 RNA ≥ 50
Disc. for other 
reason while not 
below 50 (Non-
COVID-19 related)
3.2.2.4. Non-safety and COVID-19 related 
reasons (e.g. protocol deviation, 
withdrew consent, loss to follow-up, 
study closed/terminated, investigator 
discretion etc., as recorded in eCRF 
Conclusion Form)
o
Last on-treatment VL <50 c/mL 
OR no on-treatment VL 
available during study  
No virologic 
Data at Month 
12 Window
Disc for other 
reasons (COVID-19 
related)
o
Last on-treatment VL ≥ 50 
c/mL AND withdrawal due to 
Lack of efficacy
HIV-1 RNA ≥ 50
Disc. for lack of 
efficacy (COVID-19 
related)
o
Last on-treatment VL ≥ 50
c/mL AND withdrawal due to all 
other non-safety related 
reasons
HIV-1 RNA ≥ 50
Disc. for other 
reason while not 
below 50 (COVID-19 
related)
a.
Excluding permitted change in background therapy where change or decision to change is made prior to/on the 
first on-treatment viral result 
Examples from FDA guidance
Data in Window
Virologic outcome should be determined by the last available measurement while the patient is on 
treatment and continued on trial within the time window:

HIV-1 RNA = 580 c/mL at Day 336, HIV-1 RNA below 50 c/mL on Day 350. This should be categorized as 
HIV-1 RNA below 50 c/mL.
No Data in Window
Discontinued study due to Adverse Event or Death:
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
52

Any patient who discontinues because of an AE or death before the window should be classified as 
Discontinued due to AE or Death (as appropriate), regardless of the HIV-1 RNA result, even if the HIV-1 RNA 
is below 50 c/mL at the time of discontinuation. 

However, if a patient has an HIV-1 RNA value in the time window and also discontinues in the time window, 
the viral load data should be used to classify the patient’s response. This is the Virology First hierarchy:
a.
HIV-1 RNA below 50 c/mL at Day 336 and discontinues because of AE or even dies on Day 360 
— this person is categorized as having HIV-1 RNA below 50 c/mL. 
b.
HIV-1 RNA is 552 c/mL on Day 336 and the patient discontinues on Day 360, the patient is 
categorized as having HIV-1 RNA ≥ 50 c/mL.
Discontinued for Other Reasons:

Only patients who have achieved virologic suppression can be counted as Discontinued for Other Reasons.

If a patient discontinues the study before the time window because of lack of efficacy, then the patient should 
be included in the HIV-1 RNA ≥ 50 row and not in the Discontinued for Other Reasons row.

If a patient discontinues because participant withdrew consent and his or her HIV-1 RNA result at the time of 
discontinuation was equal to or above 50 c/mL, then he or she should be categorized as HIV-1 RNA ≥ 50 
and NOT as Discontinued for Other Reasons. 

If a patient discontinued because of Lost to Follow-Up and the last HIV-1 RNA result was 49 c/mL, then the 
patient can be categorized as Discontinued for Other Reasons.

If patients changed background treatment — not permitted by protocol— they should be considered an 
efficacy failure and captured in the HIV-1 RNA ≥ 50 c/mL row.
On study but missing data in window:

If there are no data during Days 294 to 377, but there is an HIV-1 RNA below 50 c/mL on Day 380, this 
patient should be considered On Study but Missing Data in Window.

If there are no data during Days 294 to 377, but there is an HIV-1 RNA equal to or above 50 c/mL on Day 
280, this patient also should be classified as On Study but Missing Data in Window.
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
53
13.10.
Appendix 10: AESI identification
SMQ and PT codes based on MedDRA dictionary version 23.0 for the Month 12 
analysis.
13.10.1.
Hepatic Safety Profile
Medical concept of hepatic failure and hepatitis. Sub- SMQs (1) 'Hepatic failure, fibrosis 
and cirrhosis and other liver damage-related conditions' and (2) 'Hepatitis, non-
infectious', both of parent SMQ 'Hepatic Disorders (SMQ code 20000005)'; only narrow 
terms selected from sub-SMQs. Some preferred terms, e.g. PT 'hepatitis fulminant' are 
duplicated.
SMQ: 'Hepatic Disorders'; SMQ Code: 20000005
Sub-SMQ: 'Hepatic failure, fibrosis and cirrhosis and other liver damage-related 
conditions'
Category: A
Scope: Narrow
Preferred Term
PT Code
Acquired hepatocerebral degeneration
10080860
Acute hepatic failure
10000804
Acute on chronic liver failure
10077305
Acute yellow liver atrophy
10070815
Ascites
10003445
Asterixis
10003547
Bacterascites
10068547
Biliary cirrhosis
10004659
Biliary fibrosis
10004664
Cardiohepatic syndrome
10082480
Cholestatic liver injury
10067969
Chronic hepatic failure
10057573
Coma hepatic
10010075
Cryptogenic cirrhosis
10063075
Diabetic hepatopathy
10071265
Drug-induced liver injury
10072268
Duodenal varices
10051010
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
54
Gallbladder varices
10072319
Gastric variceal injection
10076237
Gastric variceal ligation
10076238
Gastric varices
10051012
Gastric varices haemorrhage
10057572
Gastrooesophageal variceal haemorrhage prophylaxis
10066597
Hepatectomy
10061997
Hepatic atrophy
10019637
Hepatic calcification
10065274
Hepatic cirrhosis
10019641
Hepatic encephalopathy
10019660
Hepatic encephalopathy prophylaxis
10066599
Hepatic failure
10019663
Hepatic fibrosis
10019668
Hepatic hydrothorax
10067365
Hepatic infiltration eosinophilic
10064668
Hepatic lesion
10061998
Hepatic necrosis
10019692
Hepatic steato-fibrosis
10077215
Hepatic steatosis
10019708
Hepatitis fulminant
10019772
Hepatobiliary disease
10062000
Hepatocellular foamy cell syndrome
10053244
Hepatocellular injury
10019837
Hepatopulmonary syndrome
10052274
Hepatorenal failure
10019845
Hepatorenal syndrome
10019846
Hepatotoxicity
10019851
Immune-mediated cholangitis
10083406
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
55
Immune-mediated hepatic disorder
10083521
Intestinal varices
10071502
Intestinal varices haemorrhage
10078058
Liver dialysis
10076640
Liver disorder
10024670
Liver injury
10067125
Liver operation
10062040
Liver transplant
10024714
Lupoid hepatic cirrhosis
10025129
Minimal hepatic encephalopathy
10076204
Mixed liver injury
10066758
Nodular regenerative hyperplasia
10051081
Nonalcoholic fatty liver disease
10082249
Non-alcoholic steatohepatitis
10053219
Non-cirrhotic portal hypertension
10077259
Oedema due to hepatic disease
10049631
Oesophageal varices haemorrhage
10030210
Peripancreatic varices
10073215
Portal fibrosis
10074726
Portal hypertension
10036200
Portal hypertensive colopathy
10079446
Portal hypertensive enteropathy
10068923
Portal hypertensive gastropathy
10050897
Portal vein cavernous transformation
10073979
Portal vein dilatation
10073209
Portopulmonary hypertension
10067281
Primary biliary cholangitis
10080429
Regenerative siderotic hepatic nodule
10080679
Renal and liver transplant
10052279
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
56
Retrograde portal vein flow
10067338
Reye's syndrome
10039012
Reynold's syndrome
10070953
Splenic varices
10067823
Splenic varices haemorrhage
10068662
Steatohepatitis
10076331
Subacute hepatic failure
10056956
Sugiura procedure
10083010
Varices oesophageal
10056091
Varicose veins of abdominal wall
10072284
White nipple sign
10078438
SMQ: 'Hepatic Disorders'; SMQ Code: 20000005
Sub-SMQ: 'Hepatitis, non-infectious’
Category: A
Scope: Narrow
Preferred Term
PT Code
Acute graft versus host disease in liver
10066263
Allergic hepatitis
10071198
Alloimmune hepatitis
10080576
Autoimmune hepatitis
10003827
Chronic graft versus host disease in liver
10072160
Chronic hepatitis
10008909
Graft versus host disease in liver
10064676
Hepatitis
10019717
Hepatitis acute
10019727
Hepatitis cholestatic
10019754
Hepatitis chronic active
10019755
Hepatitis chronic persistent
10019759
Hepatitis fulminant
10019772
Hepatitis toxic
10019795
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
57
Immune-mediated hepatitis
10078962
Ischaemic hepatitis
10023025
Lupus hepatitis
10067737
Non-alcoholic steatohepatitis
10053219
Radiation hepatitis
10051015
Steatohepatitis
10076331
13.10.2.
Hyperglycaemia
Medical concept of Hyperglycaemia/new onset diabetes mellitus - SMQs (1) 
'Hyperglycaemia/new onset diabetes mellitus (SMQ) Narrow SMQ code 20000041.
SMQ: 'Hyperglycaemia/new onset diabetes mellitus '; SMQ Code: 20000041
Sub-SMQ: 'Hepatic failure, fibrosis and cirrhosis and other liver damage-related 
Category: A
Scope: Narrow
Preferred Term
PT Code
Acquired lipoatrophic diabetes
10073667
Blood 1,5-anhydroglucitol decreased
10065367
Blood glucose increased
10005557
Diabetes complicating pregnancy
10012596
Diabetes mellitus
10012601
Diabetes mellitus inadequate control
10012607
Diabetes with hyperosmolarity
10012631
Diabetic arteritis
10077357
Diabetic coma
10012650
Diabetic coronary microangiopathy
10080788
Diabetic hepatopathy
10071265
Diabetic hyperglycaemic coma
10012668
Diabetic hyperosmolar coma
10012669
Diabetic ketoacidosis
10012671
Diabetic ketoacidotic hyperglycaemic coma
10012672
Diabetic ketosis
10012673
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
58
Diabetic metabolic decompensation
10074309
Diabetic wound
10081558
Euglycaemic diabetic ketoacidosis
10080061
Fructosamine increased
10017395
Fulminant type 1 diabetes mellitus
10072628
Gestational diabetes
10018209
Glucose tolerance impaired
10018429
Glucose tolerance impaired in pregnancy
10018430
Glucose urine present
10018478
Glycated albumin increased
10082836
Glycosuria
10018473
Glycosuria during pregnancy
10018475
Glycosylated haemoglobin abnormal
10018481
Glycosylated haemoglobin increased
10018484
Hyperglycaemia
10020635
Hyperglycaemic hyperosmolar nonketotic syndrome
10063554
Hyperglycaemic seizure
10071394
Hyperglycaemic unconsciousness
10071286
Impaired fasting glucose
10056997
Insulin resistance
10022489
Insulin resistant diabetes
10022491
Insulin-requiring type 2 diabetes mellitus
10053247
Ketoacidosis
10023379
Ketonuria
10023388
Ketosis
10023391
Ketosis-prone diabetes mellitus
10023392
Latent autoimmune diabetes in adults
10066389
Monogenic diabetes
10075980
Neonatal diabetes mellitus
10028933
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
59
New onset diabetes after transplantation
10082630
Pancreatogenous diabetes
10033660
Steroid diabetes
10081755
Type 1 diabetes mellitus
10067584
Type 2 diabetes mellitus
10067585
Type 3 diabetes mellitus
10072659
Urine ketone body present
10057597
13.10.3.
Hypersensitivity Reactions 
Notes: Medical concept of hypersensitivity reactions/DRESS. Only narrow terms selected 
from Category A of SMQ 'Drug reaction with eosinophilia and systemic symptoms 
syndrome'. Algorithmic approach for this SMQ not used due to complexity in applying 
and poor specificity of remaining categories. Category A selected as PTs because more 
specific for concept (only narrow terms) and a pre-requisite for any combination in 
algorithmic search. Overlap of some preferred terms with SMQ 'Severe Cutaneous 
Adverse Reactions'. Plus additional preferred terms selected from HGLT 'Allergic 
conditions' under SOC 'Immune system disorders'.
SMQ: Drug reaction with eosinophilia and systemic symptoms syndrome 
SMQ Code: 20000225
Category: A
Scope: Narrow
Preferred Term
PT Code
Drug reaction with eosinophilia and systemic symptoms
10073508
Pseudolymphoma
10037127
Additional preferred terms selected from HLGT 'Allergic conditions' 
under SOC 'Immune system disorders'; HLGT code 10001708
Preferred Term
PT Code
Drug hypersensitivity
10013700
Hypersensitivity
10020751
Type IV Hypersensitivity reaction
10053613
Eosinophillia
10014950
Eye swelling
10015967
Eyelid oedema
10015993
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
60
Lip swelling
10024570
Angioedema
10002424
Circumoral oedema
10052250
Face oedema
10016029
Idiopathic angioedema
10073257
Lip oedema
10024558
Mouth swelling
10075203
Oedema mouth
10030110
Periorbital oedema
10034545
Swelling face
10042682
Periorbital swelling
10056647
Swelling of eyelid
10042690
13.10.4.
Rash including severe cutaneous adverse reactions
Medical concept of rash including severe cutaneous adverse reactions. Only narrow terms 
from SMQ 'Severe cutaneous adverse reactions' selected. Plus several additional 
preferred terms selected from HLTs 'Rashes, eruptions and exanthems NEC', 'Pruritus 
NEC', 'Pustular conditions', 'Dermatitis ascribed to specific agent' all under SOC 'Skin 
and subcutaneous tissue disorders'.
SMQ: Severe Cutaneous Adverse Reactions
SMQ Code: 20000020
Category: A
Scope: Narrow
SMQ
PT Code
Acute generalised exanthematous pustulosis
10048799
Bullous haemorrhagic dermatosis
10083809
Cutaneous vasculitis
10011686
Dermatitis bullous
10012441
Dermatitis exfoliative
10012455
Dermatitis exfoliative generalised
10012456
Drug reaction with eosinophilia and systemic symptoms
10073508
Epidermal necrosis
10059284
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
61
Erythema multiforme
10015218
Erythrodermic atopic dermatitis
10082985
Exfoliative rash
10064579
Oculomucocutaneous syndrome
10030081
SJS-TEN overlap
10083164
Skin necrosis
10040893
Stevens-Johnson syndrome
10042033
Target skin lesion
10081998
Toxic epidermal necrolysis
10044223
Toxic skin eruption
10057970
Addition selected preferred terms from HLTs 'Rashes, eruptions and 
exanthems NEC', HLT Code 1005266; 'Pruritus NEC', HLT Code 
10049293, 'Pustular conditions', HLT Code 10037573; 'Dermatitis 
ascribed to specific agent', HLT Code 10012437.
Preferred Term
PT Code
Eyelid rash
10074620
Genital rash
10018175
Mucocutaneous rash
10056671
Nodular rash
10075807
Perineal rash
10075364
Rash
10037844
Rash erythematous
10037855
Rash generalised
10037858
Rash macular
10037867
Rash maculo-papular
10037868
Rash maculovesicular
10050004
Rash morbilliform
10037870
Rash papular
10037876
Rash rubelliform
10057984
Rash scarlatiniform
10037890
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
62
Rash vesicular
10037898
Rash pruritic
10037884
Rash follicular
10037857
Rash pustular
10037888
Drug eruption
10013687
13.10.5.
Prolongation of the Corrected QT Interval of the ECG in Supra 
Therapeutic Doses
Medical concept of QT prolongation and complications. Only narrow terms from SMQ 
'Torsade de pointes/QT prolongation' selected plus one additional PT under HLT 'ECG 
investigations'.
SMQ: Torsade de pointes/QT prolongation
SMQ Code: 20000001
Category: A
Scope: Narrow
Preferred Term
PT Code
Electrocardiogram QT interval abnormal
10063748
Electrocardiogram QT prolonged
10014387
Long QT syndrome
10024803
Long QT syndrome congenital
10057926
Torsade de pointes
10044066
Ventricular tachycardia
10047302
Additional selected preferred terms from HLT 'ECG investigations', HLT 
Code 10053104.
Preferred Term
PT Code
Electrocardiogram repolarisation abnormality
10052464
13.10.6.
Suicidal Ideation/Behaviour 
Medical concept of suicidal ideation and behaviour. Sub-SMQ 'Suicide/self-injury' 
(SMQ) from parent SMQ of 'Depression and Suicide/Self Injury (SMQ Code 20000035)'. 
Only narrow terms from the sub-SMQ selected.
SMQ: 'Depression and Suicide/Self Injury'
SMQ Code: 20000035
Sub-SMQ: 'Suicide/self-injury'
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
63
Category: A
Scope: Narrow
Preferred Term
PT Code
Assisted suicide
10079105
Columbia suicide severity rating scale abnormal
10075616
Completed suicide
10010144
Depression suicidal
10012397
Intentional overdose
10022523
Intentional self-injury
10022524
Poisoning deliberate
10036000
Self-injurious ideation
10051154
Suicidal behaviour
10065604
Suicidal ideation
10042458
Suicide attempt
10042464
Suicide threat
10077417
Suspected suicide
10082458
Suspected suicide attempt
10081704
13.10.7.
Depression 
Medical concept of Depression. Sub-SMQ 'Depression (excl suicide and self-injury)' 
(SMQ) from parent SMQ of 'Depression and Suicide/Self Injury'. Only narrow terms 
from the sub-SMQ selected.
SMQ: ‘'Depression and Suicide/Self Injury'
SMQ Code: 20000035
Sub-SMQ: 'Depression (excl suicide and self-injury)' 
Category: A
Scope: Narrow
Preferred Term
PT Code
Activation syndrome
10066817
Adjustment disorder with depressed mood
10001297
Adjustment disorder with mixed anxiety and depressed mood
10001299
Agitated depression
10001496
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
64
Anhedonia
10002511
Antidepressant therapy
10054976
Childhood depression
10068631
Decreased interest
10011971
Depressed mood
10012374
Depression
10012378
Depression postoperative
10012390
Depressive symptom
10054089
Dysphoria
10013954
Electroconvulsive therapy
10014404
Feeling guilty
10049708
Feeling of despair
10016344
Feelings of worthlessness
10016374
Helplessness
10077169
Major depression
10057840
Menopausal depression
10067371
Mixed anxiety and depressive disorder
10080836
Perinatal depression
10078366
Persistent depressive disorder
10077804
Post stroke depression
10070606
Postictal depression
10071324
13.10.8.
Bipolar Disorder
Medical concept of bipolar disorder. All preferred terms from HLGT ‘Manic and Bipolar 
mood disorders and disturbances’ under SOC “Psychiatric disorders”; HLGT Code 
10026753.
Preferred Term
PT Code
Bipolar I disorder
10004939
Bipolar II disorder
10004940
Bipolar disorder
10057667
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
65
Preferred Term
PT Code
Cyclothymic disorder
10011724
Hypomania
10021030
Mania
10026749
13.10.9.
Psychosis
Medical concept of psychosis. Only narrow terms from SMQ 'Psychosis and psychotic 
disorders' selected.
SMQ: 'Psychosis and psychotic disorders'
SMQ Code: 20000117
Category: A
Scope: Narrow
Preferred Term
PT Code
Acute psychosis
10001022
Alcoholic psychosis
10001632
Alice in wonderland syndrome
10001666
Brief psychotic disorder with marked stressors
10048549
Brief psychotic disorder without marked stressors
10056395
Brief psychotic disorder, with postpartum onset
10006362
Charles Bonnet syndrome
10063354
Childhood psychosis
10061040
Clang associations
10009232
Cotard's syndrome
10059591
Delusion
10012239
Delusion of grandeur
10012241
Delusion of parasitosis
10012242
Delusion of reference
10012244
Delusion of replacement
10012245
Delusion of theft
10084030
Delusional disorder, erotomanic type
10012249
Delusional disorder, grandiose type
10012250
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
66
Delusional disorder, jealous type
10012251
Delusional disorder, mixed type
10012252
Delusional disorder, persecutory type
10053195
Delusional disorder, somatic type
10012254
Delusional disorder, unspecified type
10012255
Delusional perception
10012258
Dementia of the Alzheimer's type, with delusions
10012295
Depressive delusion
10063033
Derailment
10012411
Epileptic psychosis
10059232
Erotomanic delusion
10015134
Flight of ideas
10016777
Hallucination
10019063
Hallucination, auditory
10019070
Hallucination, gustatory
10019071
Hallucination, olfactory
10019072
Hallucination, synaesthetic
10062824
Hallucination, tactile
10019074
Hallucination, visual
10019075
Hallucinations, mixed
10019079
Hypnagogic hallucination
10020927
Hypnopompic hallucination
10020928
Hysterical psychosis
10062645
Ideas of reference
10021212
Illusion
10021403
Jealous delusion
10023164
Loose associations
10024825
Mixed delusion
10076429
Neologism
10028916
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
67
Neuroleptic-induced deficit syndrome
10075295
Paranoia
10033864
Paranoid personality disorder
10033869
Parkinson's disease psychosis
10074835
Paroxysmal perceptual alteration
10063117
Persecutory delusion
10034702
Postictal psychosis
10070669
Post-injection delirium sedation syndrome
10072851
Posturing
10036437
Psychosis postoperative
10065617
Psychotic behaviour
10037249
Psychotic disorder
10061920
Psychotic disorder due to a general medical condition
10061921
Reactive psychosis
10053632
Rebound psychosis
10074833
Schizoaffective disorder
10039621
Schizoaffective disorder bipolar type
10068889
Schizoaffective disorder depressive type
10068890
Schizophrenia
10039626
Schizophreniform disorder
10039647
Schizotypal personality disorder
10039651
Senile psychosis
10039987
Shared psychotic disorder
10040535
Somatic delusion
10041317
Somatic hallucination
10062684
Substance-induced psychotic disorder
10072388
Tangentiality
10043114
Thought blocking
10043495
Thought broadcasting
10052214
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
68
Thought insertion
10043496
Thought withdrawal
10043497
Transient psychosis
10056326
Waxy flexibility
10047853
13.10.10. Mood Disorders
Medical concept of mood disorders. All preferred terms from HLGT 'Mood disorders and 
disturbances NEC', under SOC 'Psychiatric disorders'; HLGT Code 10027946.
Preferred Term
PT Code
Affect lability
10054196
Affective ambivalence
10077173
Affective disorder
10001443
Alexithymia
10077719
Anger
10002368
Apathy
10002942
Blunted affect
10005885
Boredom
10048909
Constricted affect
10010778
Crying
10011469
Diencephalic syndrome of infancy
10012774
Dysphoria
10013954
Emotional disorder
10014551
Emotional distress
10049119
Emotional poverty
10014557
Euphoric mood
10015535
Flat affect
10016759
Frustration tolerance decreased
10077753
Inappropriate affect
10021588
Irritability
10022998
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
69
Laziness
10051602
Lethargy
10024264
Listless
10024642
Moaning
10027783
Mood altered
10027940
Mood disorder due to a general medical condition
10027944
Mood swings
10027951
Morose
10027977
Neuroleptic-induced deficit syndrome
10075295
Premenstrual dysphoric disorder
10051537
Premenstrual syndrome
10036618
Screaming
10039740
Seasonal affective disorder
10039775
Steroid withdrawal syndrome
10042028
Substance-induced mood disorder
10072387
13.10.11. Anxiety
Notes: Medical concept of anxiety disorders. All preferred terms from HLGT “Anxiety 
disorders and symptoms”, under SOC “Psychiatric disorders”; HLGT Code 10002861.
Preferred Terms
PT Code
Acrophobia
10000605
Activation syndrome
10066817
Acute stress disorder
10001084
Aerophobia
10080300
Agitation
10001497
Agitation postoperative
10049989
Agoraphobia
10001502
Akathisia
10001540
Algophobia
10078056
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
70
Animal phobia
10002518
Anniversary reaction
10074066
Anticipatory anxiety
10002758
Anxiety
10002855
Anxiety disorder
10057666
Anxiety disorder due to a general medical condition
10002859
Arachnophobia
10051408
Astraphobia
10078372
Autophobia
10071070
Body dysmorphic disorder
10052793
Burnout syndrome
10065369
Catastrophic reaction
10082329
Cibophobia
10082413
Claustrophobia
10009244
Compulsions
10010219
Compulsive cheek biting
10076510
Compulsive handwashing
10071263
Compulsive hoarding
10068007
Compulsive lip biting
10066241
Compulsive shopping
10067948
Cryophobia
10082662
Dermatillomania
10065701
Dysmorphophobia
10049096
Emetophobia
10070637
Fear
10016275
Fear of animals
10016276
Fear of closed spaces
10016277
Fear of crowded places
10050365
Fear of death
10066392
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
71
Fear of disease
10016278
Fear of eating
10050366
Fear of falling
10048744
Fear of injection
10073753
Fear of open spaces
10016279
Fear of pregnancy
10067035
Fear of weight gain
10016280
Fear-related avoidance of activities
10080136
Generalised anxiety disorder
10018075
Glossophobia
10080077
Haemophobia
10073458
Haphephobia
10067580
Herpetophobia
10081809
Hydrophobia
10053317
Hyperarousal
10080831
Immunisation anxiety related reaction
10075205
Kinesiophobia
10078430
Limited symptom panic attack
10024511
Mysophobia
10078769
Nail picking
10066779
Nervousness
10029216
Neurosis
10029333
Noctiphobia
10057946
Nocturnal fear
10057948
Nosocomephobia
10083993
Nosophobia
10063546
Obsessive need for symmetry
10077179
Obsessive rumination
10056264
Obsessive thoughts
10029897
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
72
Obsessive-compulsive disorder
10029898
Obsessive-compulsive symptom
10077894
Ochlophobia
10050095
Osmophobia
10060765
Paediatric autoimmune neuropsychiatric disorders associated with 
streptococcal infection
10072147
Panic attack
10033664
Panic disorder
10033666
Panic reaction
10033670
Paruresis
10069024
Performance fear
10034432
Phagophobia
10050096
Pharmacophobia
10069423
Phobia
10034912
Phobia of driving
10056676
Phobia of exams
10034913
Phobic avoidance
10034918
Phonophobia
10054956
Photaugiaphobia
10064420
Postpartum anxiety
10082233
Postpartum neurosis
10036419
Postpartum stress disorder
10056394
Post-traumatic stress disorder
10036316
Procedural anxiety
10075204
Pseudoangina
10056610
Selective mutism
10039917
Separation anxiety disorder
10040045
Sitophobia
10080170
Social anxiety disorder
10041242
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
73
Social fear
10041247
Stress
10042209
Tension
10043268
Terminal agitation
10077416
Thanatophobia
10064723
Thermophobia
10075147
Trichotemnomania
10072752
Trichotillomania
10044629
13.10.12. Sleep Disorders
Medical concept of sleep disorders. All preferred terms from (1) HLGT 'Sleep Disorders 
and Disturbances', 'Psychiatric disorders' SOC plus (2) HLGT 'Sleep disturbances (incl 
subtypes)', 'Nervous system' SOC. Numerous duplicated preferred terms e.g. middle 
insomnia.
HLGT Sleep Disorders and Disturbances, HLGT Code 10040991
Preferred Term
PT Code
Abnormal dreams
10000125
Abnormal sleep-related event
10061613
Advanced sleep phase
10001423
Behavioural induced insufficient sleep syndrome
10081938
Behavioural insomnia of childhood
10072072
Breathing-related sleep disorder
10006344
Cataplexy
10007737
Circadian rhythm sleep disorder
10009191
Confusional arousal
10067494
Delayed sleep phase
10012209
Dyssomnia
10061827
Exploding head syndrome
10080684
Hypersomnia
10020765
Hypersomnia related to another mental condition
10020767
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
74
Hypersomnia-bulimia syndrome
10053712
Hypnagogic hallucination
10020927
Hypnopompic hallucination
10020928
Hyposomnia
10067530
Initial insomnia
10022035
Insomnia
10022437
Insomnia related to another mental condition
10022443
Irregular sleep phase
10022995
Irregular sleep wake rhythm disorder
10080301
Loss of dreaming
10065085
Middle insomnia
10027590
Narcolepsy
10028713
Nightmare
10029412
Non-24-hour sleep-wake disorder
10078086
Parasomnia
10061910
Paradoxical insomnia
10083337
Periodic limb movement disorder
10064600
Pickwickian syndrome
10035004
Poor quality sleep
10062519
Rapid eye movement sleep behaviour disorder
10077299
Rapid eye movements sleep abnormal
10037841
Shift work disorder
10078088
Sleep apnoea syndrome
10040979
Sleep attacks
10040981
Sleep disorder
10040984
Sleep disorder due to a general medical condition
10063910
Sleep disorder due to general medical condition, hypersomnia type
10040985
Sleep disorder due to general medical condition, insomnia type
10040986
Sleep disorder due to general medical condition, mixed type
10040987
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
75
Sleep disorder due to general medical condition, parasomnia type
10040988
Sleep inertia
10067493
Sleep paralysis
10041002
Sleep sex
10067492
Sleep talking
10041009
Sleep terror
10041010
Sleep-related eating disorder
10067315
Somnambulism
10041347
Somnolence
10041349
Somnolence neonatal
10041350
Sopor
10058709
Stupor
10042264
Terminal insomnia
10068932
Upper airway resistance syndrome
10063968
HLGT Sleep disturbances (incl subtypes), HLGT code 10040998
Abnormal dreams
10000125
Abnormal sleep-related event
10061613
Advanced sleep phase
10001423
Behavioural induced insufficient sleep syndrome
10081938
Behavioural insomnia of childhood
10072072
Breathing-related sleep disorder
10006344
Cataplexy
10007737
Central-alveolar hypoventilation
10007982
Circadian rhythm sleep disorder
10009191
Confusional arousal
10067494
Delayed sleep phase
10012209
Dyssomnia
10061827
Fatal familial insomnia
10072077
Hypersomnia
10020765
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
76
Hyposomnia
10067530
Initial insomnia
10022035
Insomnia
10022437
Irregular sleep phase
10022995
Irregular sleep wake rhythm disorder
10080301
Loss of dreaming
10065085
Microsleep
10076954
Middle insomnia
10027590
Narcolepsy
10028713
Non-24-hour sleep-wake disorder
10078086
Periodic limb movement disorder
10064600
Pickwickian syndrome
10035004
Poor quality sleep
10062519
Rapid eye movement sleep behaviour disorder
10077299
Rapid eye movements sleep abnormal
10037841
Shift work disorder
10078088
Sleep apnoea syndrome
10040979
Sleep deficit
10080881
Sleep inertia
10067493
Sleep paralysis
10041002
Sleep sex
10067492
Sleep talking
10041009
Sleep terror
10041010
Sleep-related eating disorder
10067315
Somnambulism
10041347
Sudden onset of sleep
10050014
Terminal insomnia
10068932
Upper airway resistance syndrome
10063968
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
77
13.10.13. Injection site Reactions
Use eCRF terms for ISR.
13.10.14. Seizures 
Medical concept of seizures. Only narrow terms from SMQ 'Convulsions' selected plus 
selected PTs of possible seizure events from HLT 'Disturbances in consciousness NEC' 
under SOC 'Nervous systems disorders' and HLT 'Confusion and disorientation' under 
SOC 'Psychiatric disorders'.
SMQ: ‘Convulsions’ 
SMQ Code: 20000079
Category: A
Scope: Narrow
Preferred Term
PT Code
1p36 deletion syndrome
10082398
2-Hydroxyglutaric aciduria
10078971
Acquired epileptic aphasia
10052075
Acute encephalitis with refractory, repetitive partial seizures
10076948
Alcoholic seizure
10056347
Alpers disease
10083857
Aspartate-glutamate-transporter deficiency
10079140
Atonic seizures
10003628
Atypical benign partial epilepsy
10056699
Automatism epileptic
10003831
Autonomic seizure
10049612
Baltic myoclonic epilepsy
10054895
Benign familial neonatal convulsions
10067866
Benign rolandic epilepsy
10070530
Biotinidase deficiency
10071434
CEC syndrome
10083749
CDKL5 deficiency disorder
10083005
Change in seizure presentation
10075606
Clonic convulsion
10053398
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
78
Congenital bilateral perisylvian syndrome
10082716
Convulsion in childhood
10052391
Convulsions local
10010920
Convulsive threshold lowered
10010927
CSWS syndrome
10078827
Deja vu
10012177
Double cortex syndrome
10073490
Dreamy state
10013634
Drug withdrawal convulsions
10013752
Early infantile epileptic encephalopathy with burst-suppression
10071545
Eclampsia
10014129
Epilepsy
10015037
Epilepsy surgery
10079824
Epilepsy with myoclonic-atonic seizures
10081179
Epileptic aura
10015049
Epileptic psychosis
10059232
Febrile convulsion
10016284
Febrile infection-related epilepsy syndrome
10079438
Focal dyscognitive seizures
10079424
Frontal lobe epilepsy
10049424
Gelastic seizure
10082918
Generalised onset non-motor seizure
10083376
Generalised tonic-clonic seizure
10018100
Glucose transporter type 1 deficiency syndrome
10078727
GM2 gangliosidosis
10083933
Grey matter heterotopia
10082084
Hemimegalencephaly
10078100
Hyperglycaemic seizure
10071394
Hypocalcaemic seizure
10072456
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
79
Hypoglycaemic seizure
10048803
Hyponatraemic seizure
10073183
Idiopathic generalised epilepsy
10071081
Infantile spasms
10021750
Juvenile myoclonic epilepsy
10071082
Lafora's myoclonic epilepsy
10054030
Lennox-Gastaut syndrome
10048816
Migraine-triggered seizure
10076676
Molybdenum cofactor deficiency
10069687
Multiple subpial transection
10079825
Myoclonic epilepsy
10054859
Myoclonic epilepsy and ragged-red fibres
10069825
Neonatal epileptic seizure
10082068
Neonatal seizure
10082067
Partial seizures
10061334
Partial seizures with secondary generalisation
10056209
Petit mal epilepsy
10034759
Polymicrogyria
10073489
Post stroke epilepsy
10076982
Post stroke seizure
10076981
Postictal headache
10052470
Postictal paralysis
10052469
Postictal psychosis
10070669
Postictal state
10048727
Post-traumatic epilepsy
10036312
Schizencephaly
10073487
Seizure
10039906
Seizure anoxic
10039907
Seizure cluster
10071350
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
80
Seizure like phenomena
10071048
Severe myoclonic epilepsy of infancy
10073677
Simple partial seizures
10040703
Status epilepticus
10041962
Sudden unexplained death in epilepsy
10063894
Temporal lobe epilepsy
10043209
Tonic clonic movements
10051171
Tonic convulsion
10043994
Tonic posturing
10075125
Topectomy
10073488
Transient epileptic amnesia
10081728
Tuberous sclerosis complex
10080584
Uncinate fits
10045476
Additional selected preferred terms from HLT Disturbances in 
consciousness NEC, HLT code 10013509 and HLT Confusion and 
disorientation, HLT code 10010301.
Preferred Term
PT Code
Confusional state
10010305
Loss of consciousness
10024855
Syncope
10042772
Sopor
10058709
Stupor
10042264
Altered state of consciousness
10050093
Depressed level of consciousness
10012373
Consciousness fluctuating
10050093
13.10.15. Weight Gain
Medical concept of weight gain. Selected PTs from HLT 'General nutritional disorders 
NEC', under SOC 'Metabolism and nutrition disorders', and HLT 'Physical examination 
procedures and organ system status', under SOC 'Investigations' and HLT 'General signs 
and symptoms NEC', under SOC 'General disorders and administration site conditions'.
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
81
PTs (Select) from HLT General nutritional disorders NEC, HLT code 10018067
Preferred Term
PT Code
Abdominal fat apron
10077983
Overweight
10033307
Abnormal weight gain
10000188
Central obesity
10065941
Obesity
10029883
Abdominal fat apron
10077983
Overweight
10033307
Abnormal weight gain
10000188
Central obesity
10065941
Obesity
10029883
PTs (Select) from HLT Physical examination procedures and organ system status, 
HLT Code 10071941
Preferred Term
PT Code
Weight abnormal
10056814
Weight increased
10047899
Waist circumference increased
10064863
Body mass index abnormal
10074506
Body mass index increased
10005897
PTs (Select) from HLT General signs and symptoms NEC, HLT Code 10018072
Preferred Term
PT Code
Fat tissue increased
10016251
Sarcopenic obesity
10083992
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
82
13.10.16. Rhabdomyolysis
Medical concept of rhabdomyolysis. Only narrow terms only for SMQ 
'Rhabdomyolysis/myopathy' plus 2 additional preferred terms selected from HGLT 
'muscle disorders' under SOC 'Musculoskeletal and connective tissue disorders'.
SMQ: 'Rhabdomyolysis/myopathy'
SMQ Code: 20000002
Category: A
Scope: Narrow
Preferred Term
PT Code
Muscle necrosis
10028320
Myoglobin blood increased
10028625
Myoglobin blood present
10059888
Myoglobin urine present
10028631
Myoglobinaemia
10058735
Myoglobinuria
10028629
Myopathy
10028641
Myopathy toxic
10028648
Necrotising myositis
10074769
Rhabdomyolysis
10039020
Thyrotoxic myopathy
10081524
PTs (Select) from HGLT muscle disorders, HLGT Code 10028302
Preferred Term
PT Code
Myalgia
10028411
Myositis
10028653
13.10.17. Pancreatitis 
Medical concept of acute pancreatitis. Only narrow terms of SMQ 'Acute pancreatitis' 
selected. Algorithmic approach for this SMQ not used due to complexity in applying and 
poor specificity of remaining categories. Category A selected as PTs because more 
specific for concept (only narrow terms).
SMQ: 'Acute pancreatitis' 
SMQ Code: 20000022 
Category: A
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
83
Scope: Narrow
Preferred Term
PT Code
Cullen's sign
10059029
Grey Turner's sign
10075426
Haemorrhagic necrotic pancreatitis
10076058
Hereditary pancreatitis
10056976
Immune-mediated pancreatitis
10083072
Ischaemic pancreatitis
10066127
Oedematous pancreatitis
10052400
Pancreatic abscess
10048984
Pancreatic cyst drainage
10082531
Pancreatic haemorrhage
10033625
Pancreatic necrosis
10058096
Pancreatic phlegmon
10056975
Pancreatic pseudoaneurysm
10081762
Pancreatic pseudocyst
10033635
Pancreatic pseudocyst drainage
10033636
Pancreatic pseudocyst haemorrhage
10083813
Pancreatic pseudocyst rupture
10083811
Pancreatitis
10033645
Pancreatitis acute
10033647
Pancreatitis haemorrhagic
10033650
Pancreatitis necrotising
10033654
Pancreatitis relapsing
10033657
Pancreatorenal syndrome
10056277
13.10.18. Impact on Creatinine
Medical concept of worsening renal function/renal failure in the context of impact on 
creatinine. Only narrow terms from SMQ 'Acute renal failure' plus all PTs from HLT 
'Renal failure and impairment', under SOC 'Renal and urinary disorders'. Numerous 
duplicated preferred terms e.g. renal failure
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
84
SMQ: ‘Acute renal failure’
SMQ Code: 20000003
Category: A
Scope: Narrow
Preferred Term
PT Code
Acute kidney injury
10069339
Acute phosphate nephropathy
10069688
Anuria
10002847
Azotaemia
10003885
Continuous haemodiafiltration
10066338
Dialysis
10061105
Foetal renal impairment
10078987
Haemodialysis
10018875
Haemofiltration
10053090
Neonatal anuria
10049778
Nephropathy toxic
10029155
Oliguria
10030302
Peritoneal dialysis
10034660
Prerenal failure
10072370
Renal failure
10038435
Renal failure neonatal
10038447
Renal impairment
10062237
Renal impairment neonatal
10049776
Subacute kidney injury
10081980
Renal Failure and Impairment HLT, HLT Code 10038443
Preferred Term
PT Code
Acute Kidney injury
10069339
Anuria
10002847
Atypical haemolytic uraemic syndrome
10079840
Cardiorenal syndrome
10068230
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
85
Chronic kidney disease
10064848
Crush syndrome
10050702
Diabetic end stage renal disease
10012660
End stage renal disease
10077512
Foetal renal impairment
10078987
Haemolytic uraemic syndrome
10018932
Hepatorenal failure
10019845
Hepatorenal syndrome
10019846
Nail-patella syndrome
10063431
Neonatal anuria
10049778
Oliguria
10030302
Pancreatorenal syndrome
10056277
Postoperative renal failure
10056675
Postrenal failure
10059345
Prerenal failure
10072370
Propofol infusion syndrome
10063181
Renal failure
10038435
Renal failure neonatal
10038447
Renal impairment
10062237
Renal impairment neonatal
10049776
Renal injury
10061481
Scleroderma renal crisis
10062553
Traumatic anuria
10044501
13.10.19. Safety During Pregnancy
Use AE terms co-reported in pregnancy exposures to CAB.
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
86
13.11.
Appendix 11: Identification of COVID-19 Adverse Events
COVID-19 adverse events are identified based on MedDRA coded values and/or AE 
referenced in the COVID-19 Coronavirus Infection assessment. The Lowest Level Terms 
(LLTs) and codes, Preferred Terms (PTs), High Level Terms (HLTs), High Level Group 
Terms (HLGTs), and System Organ Classes (SOCs), below are from MedDRA 23.0. In 
case there is a change to the version of MedDRA at time of reporting, the coded values 
based on the MedDRA version at the time of reporting will be used. The additional 
events may also be added based on the blinded review of AE data collected on study prior 
to the database freeze.
SOC: Infections and infestations
LLT code
LLT
PT
HLT
HLGT
10084459
Asymptomatic COVID-19
Asymptomatic 
COVID-19
Coronavirus 
infections
Viral infectious 
disorders
10084467
Asymptomatic SARS-
CoV-2 infection
Asymptomatic 
COVID-19
Coronavirus 
infections
Viral infectious 
disorders
10053983
Corona virus infection
Coronavirus 
infection
Coronavirus 
infections
Viral infectious 
disorders
10051905
Coronavirus infection
Coronavirus 
infection
Coronavirus 
infections
Viral infectious 
disorders
10084382
Coronavirus disease 
2019
COVID-19
Coronavirus 
infections
Viral infectious 
disorders
10084268
COVID-19
COVID-19
Coronavirus 
infections
Viral infectious 
disorders
10084401
COVID-19 respiratory 
infection
COVID-19
Coronavirus 
infections
Viral infectious 
disorders
10084270
SARS-CoV-2 acute 
respiratory disease
COVID-19
Coronavirus 
infections
Viral infectious 
disorders
10084272
SARS-CoV-2 infection
COVID-19
Coronavirus 
infections
Viral infectious 
disorders
10084381
Coronavirus pneumonia
COVID-19 
pneumonia
Coronavirus 
infections
Viral infectious 
disorders
10084380
COVID-19 pneumonia
COVID-19 
pneumonia
Coronavirus 
infections
Viral infectious 
disorders
10084383
Novel COVID-19-
infected pneumonia
COVID-19 
pneumonia
Coronavirus 
infections
Viral infectious 
disorders
10084451
Suspected COVID-19
Suspected 
COVID-19
Coronavirus 
infections
Viral infectious 
disorders
10084452
Suspected SARS-CoV-2 
infection
Suspected 
COVID-19
Coronavirus 
infections
Viral infectious 
disorders
10084461
SARS-CoV-2 carrier
SARS-CoV-2 
carrier
Infectious 
disorders carrier
Ancillary infectious 
topics
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
87
13.12.
Appendix 12: Abbreviations & Trade Marks
13.12.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
AIC
Akaike's Information Criteria
A&R
Analysis and Reporting 
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CPMS
Clinical Pharmacology Modelling & Simulation
CS
Clinical Statistics
CSR
Clinical Study Report
CTR
Clinical Trial Register
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
DBF
Database Freeze
DBR
Database Release
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Record Form
EEP
Efficacy Evaluable Population
EMA
European Medicines Agency
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
GSK
GlaxoSmithKline
IA
Interim Analysis
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System
IP
Investigational Product
ITT
Intent-To-Treat
MMRM
Mixed Model Repeated Measures
PBMC
Peripheral Blood Mononuclear Cells
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PP
Per Protocol
PopPK
Population PK
QC
Quality Control
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RAMOS
Randomization & Medication Ordering System 
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
88
Abbreviation
Description
SAC
Statistical Analysis Complete
SDSP
Study Data Standardization Plan
SDTM
Study Data Tabulation Model
SOP
Standard Operation Procedure
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
13.12.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
NONE
SAS
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
89
13.13.
Appendix 13: List of Data Displays
All data displays will use the term “subject” rather than “participant” in accordance with 
CDSIC and GSK Statistical Display Standards.
Where applicable, all summary displays will present data across both the Intervention and 
Extension phases unless explicitly stated otherwise in the display title.
13.13.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.n
1.1 to 1.n
Efficacy
2.1 to 2.n
2.1 to 2.n
Safety
3.1 to 3.n
3.1 to 3.n
Pharmacokinetic
4.1 to 4.n
4.1 to 4.n
Virology
5.1 to 5.n
5.1 to 4.n
Other
6.1 to 6.n
6.1 to 6.n
Section
Listings
ICH Listings
1 to x
Other Listings
y to z
13.13.2.
Mock Example Shell Referencing
Nonstandard specifications will be referenced as indicated below (where a study specific 
mock shell is available) or the location of a similar display produced for a different study 
in the HARP reporting environment will be provided as reference.  If required example 
mock-up displays provided in Appendix 14: Example Mock Shells for Data Displays.  
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Efficacy
EFF_Fn
EFF_Tn
EFF_Ln
Safety
SAF_Fn
SAF_Tn
SAF_Ln
Pharmacokinetic
PK_Fn
PK_Tn
PK_Ln
Virology
VIR_Fn
VIR_Tn
VIR_Ln
Other
OTR_Tn
OTR_Fn
OTR_Ln
13.13.3.
Deliverables
Delivery
Description
HL
Month 12 Headline
M12
Month 12 Analysis
EOS
End of Study Analysis
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
90
13.13.4.
Study Population Tables
Study Population Tables
No.
Population
GSK Standard / 
Example Shell
Title
Programming Notes
Deliverable
Subject Disposition
1.1.
Safety
ES1
Summary of Subject Disposition for the Subject Conclusion 
Record
ICH E3, FDAAA, EudraCT
HL, M12, EOS
1.2.
Safety
SD1
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment
ICH E3
M12, EOS
1.3.
Safety
ES4
Summary of Subject Disposition at Each Study Phase
ICH E3
Intervention/Extension phase: status 
and reason for withdrawal based on 
date and reason collected in the study 
treatment discontinuation form.
Long term Follow-up: 
completion/withdrawal based on data 
collected in the Study Conclusion form.
M12, EOS
1.4.
Safety
ES5
Summary of Reason for Withdrawal at Each Study Phase
FDAAA, EudraCT
HL, M12, EOS
1.5.
Safety
ES11
Summary of Outcome of Adverse Events Which Led to Study 
Withdrawal/Treatment Discontinuation at Each Study Phase
EudraCT
M12, EOS
1.6.
Screened
ES6
Summary of Screening Status and Reasons for Screen Failure
Journal Requirements
M12, EOS
1.7.
Enrolled
NS1
Summary of Number of Subjects by Country and Site ID
EudraCT/Clinical Operations
M12, EOS
1.8.
Screened
NS1
Summary of Number of Subjects by Site Type and Site ID
Replace Country with Site Type
Add column for Investigator Name
M12, EOS
Protocol Deviation
1.9.
Enrolled
DV1
Summary of Important Protocol Deviations 
ICH E3
M12, EOS
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
91
Study Population Tables
No.
Population
GSK Standard / 
Example Shell
Title
Programming Notes
Deliverable
1.10.
Enrolled
DV1
Summary of Important COVID-19 Related Protocol Deviations 
Update the label for the first row to be 
“ANY IMPORTANT COVID-19 
RELATED PROTOCOL DEVIATIONS”
M12, EOS
1.11.
Enrolled
DV1
Summary of Important Non-COVID-19 Protocol Deviations 
Update the label for the first row to be 
“ANY IMPORTANT NON-COVID-19 
RELATED PROTOCOL DEVIATIONS”
M12, EOS
1.12.
Enrolled
DV1
Summary of All COVID-19 Protocol Deviations by Site
Update the label for the first row to be 
“ANY COVID-19 RELATED 
PROTOCOL DEVIATIONS”.
Summary for each site and ‘Total’
across sites.
HL, M12, EOS
1.13.
Enrolled
DV1
Summary of All Implementation Protocol Deviations by Site
Update the label for the first row to be 
“ANY IMPLEMENTATION RELATED 
PROTOCOL DEVIATIONS”
Summary for each site and ‘Total’
across sites.
HL, M12, EOS
Population Analysed
1.14.
Screened
SP1
Summary of Study Populations 
GSK Statistical Display Standard
M12, EOS
1.15.
Enrolled
SP2
Summary of Exclusions from the Safety Population
GSK Statistical Display Standard
M12, EOS
Demographic and Baseline Characteristics
1.16.
Safety
DM1
Summary of Demographic Characteristics
ICH E3, FDAAA, EudraCT
HL, M12, EOS
1.17.
Enrolled
DM11
Summary of Age Ranges
EudraCT
M12, EOS
1.18.
Safety
DM6
Summary of Race and Racial Combinations
ICH E3, FDA, FDAAA, EudraCT
M12, EOS
1.19.
Safety
BASELINE2
Distribution of CD4+ Cell Count Results at Screening and 
Baseline
M12, EOS
1.20.
Safety
BASELINE3
Summary of Hepatitis Status at Entry
M12, EOS
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
92
Study Population Tables
No.
Population
GSK Standard / 
Example Shell
Title
Programming Notes
Deliverable
1.21.
Safety
CDC1
Summary of CDC Classification of HIV-1 Infection at Baseline
M12, EOS
Prior and Concomitant Medications
1.22.
Safety
MH1
Summary of Past Medical Conditions
ICH E3
M12, EOS
1.23.
Safety
MH4
Summary of Past Cardiac, Gastrointestinal, Metabolism and 
Nutrition, Psychiatric, Renal and Urinary, Nervous System 
Conditions, and Hepatobiliary Disorders
ICH E3
M12, EOS
1.24.
Safety
MH1
Summary of Current Medical Conditions
ICH E3
M12, EOS
1.25.
Safety
MH4
Summary of Current Cardiac, Gastrointestinal, Metabolism and 
Nutrition, Psychiatric, Renal and Urinary, Nervous System 
Conditions, and Hepatobiliary Disorders
ICH E3
M12, EOS
1.26.
Safety
CM9
Summary of Concomitant Medications by Ingredient 
Combinations
ICH E3
See GSK Statistical Display Standard
Multi-ingredient medications will be 
labelled according to the sum of their 
ingredients, i.e., Generic Term.
M12, EOS
1.27.
Safety
207966/primary_
15/T1.30
Summary of Prior Antiretroviral Therapy Medications
Remove the footnote. Follow definitions 
in Section 13.4.1 to determine the prior 
ART medications.
M12, EOS
1.28.
Safety
201585/primary_
02/T1.30
Summary of Antiretroviral Therapy Taken During Screening by 
Baseline Third Agent Class
Like Example shell but stratified by 
Baseline Third Agent Class (NNRTI, 
INI, PI); add ‘Any’ row under each 
class.
M12, EOS
1.29.
Safety
RF1
Summary of HIV Risk Factors
M12, EOS
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
93
13.13.5.
Efficacy Tables
Efficacy: Tables
No.
Population
GSK Standard/ 
Example Shell
Title
Programming Notes
Deliverable
Snapshot
2.1.
Safety
EFF_T1
See Section 
13.14
Summary of Study Outcomes (50 c/mL cutoff) at Month 12 
(Intervention Phase) – Modified Snapshot Analysis with COVID-
19 related LOCF
Missing HIV-1 RNA due to COVID-19 
are imputing using last post baseline 
value carried forward.
HL, M12
2.2.
Safety
EFF_T2
See Section
13.14
Summary of Study Outcomes (50 c/mL cutoff) at Month 12 
(Intervention Phase) –Snapshot Analysis
With expanded COVID-19 related/Non-
related categories
HL, M12
2.3.
Safety
SNAPSHOT4
Proportion of Subjects with Plasma HIV-1 RNA ≥ 50 c/mL Over 
Time (Intervention Phase) – Modified Snapshot Analysis with 
COVID-19 related LOCF
Missing HIV-1 RNA due to COVID-19 
are imputing using last post baseline 
value carried forward.
Use Exact (Clopper-Pearson) method 
for 95% confidence Intervals.
M12
2.4.
Safety
SNAPSHOT4
Proportion of Subjects with Plasma HIV-1 RNA < 50 c/mL Over 
Time (Intervention Phase) – Modified Snapshot Analysis with 
COVID-19 related LOCF
Missing HIV-1 RNA due to COVID-19 
are imputing using last post baseline 
value carried forward.
Use Exact (Clopper-Pearson) method 
for 95% confidence Intervals.
M12
2.5.
Safety
SNAPSHOT7
Summary of Study Outcomes (50 c/mL cutoff) at Month 12 by 
Site Type (Intervention Phase) – Modified Snapshot Analysis
with COVID-19 related LOCF
Missing HIV-1 RNA due to COVID-19 
are imputing using last post baseline 
value carried forward.
M12
CVF
2.6.
Safety
VF1
Cumulative Proportion of Subjects Meeting Confirmed Virologic 
Failure Criteria Over Time (Intervention Phase)
HL, M12
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
94
Efficacy: Tables
No.
Population
GSK Standard/ 
Example Shell
Title
Programming Notes
Deliverable
2.7.
Safety
VF2
Proportion of Subjects Meeting Confirmed Virologic Failure 
Criteria Over Time
M12, EOS
CD4
2.8.
Safety
LB1
Summary of CD4+ Cell Count (cells/mm^3) by Visit
M12, EOS
2.9.
Safety
LB1
Summary of Change from Baseline in CD4+ Cell Count 
(cells/mm^3) by Visit
M12, EOS
HIV Associated Conditions
2.10.
Safety
CDC2
Summary of Post-Baseline CDC Stage 3 HIV-1 Associated 
Conditions Including Recurrences 
M12, EOS
2.11.
Safety
CDC2
Summary of Post-Baseline CDC Stage 3 HIV-1 Associated 
Conditions Excluding Recurrences 
M12, EOS
13.13.6.
Efficacy Figures
Efficacy: Figures
No.
Population
GSK Standard
/ Example 
Shell
Title
Programming Notes
Deliverable 
2.1.
Safety
SNAPSHOT8
Percent (95% CI) of Subjects with Plasma HIV-1 RNA ≥ 50 
copies/mL Over Time (Intervention Phase) – Modified Snapshot 
Analysis with COVID-19 related LOCF
Missing HIV-1 RNA due to COVID-19 
are imputing using last post baseline 
value carried forward.
Use Exact (Clopper-Pearson) method 
for 95% confidence Intervals.
M12, EOS
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
95
Efficacy: Figures
No.
Population
GSK Standard
/ Example 
Shell
Title
Programming Notes
Deliverable 
2.2.
Safety
SNAPSHOT8
Percent (95% CI) of Subjects with Plasma HIV-1 RNA < 50 
copies/mL Over Time (Intervention Phase) – Modified Snapshot 
Analysis with COVID-19 related LOCF
Missing HIV-1 RNA due to COVID-19 
are imputing using last post baseline 
value carried forward.
Use Exact (Clopper-Pearson) method 
for 95% confidence Intervals.
M12, EOS
2.3.
Safety
SNAPSHOT10
Individual Plasma HIV-1 RNA for Subjects Snapshot Algorithm 
Plasma HIV-1 RNA >= 50 copies/mL at Month 12 – Modified 
Snapshot Analysis with COVID-19 related LOCF
The 1st vertical line indicates start of 
study treatment at Intervention Phase. 
The second vertical reference line 
indicates last IP on-treatment study 
day.  i.e. min (last IP injection dose+35 
days, LTFU HAART start date, date of 
last oral CAB+RPV+1). This vertical line 
is only for subjects who withdraw from 
Intervention Phase/Extension phase.
M12
2.4.
Safety
SNAPSHOT10
Individual Plasma HIV-1 RNA for Subjects with Confirmed 
Virologic Failure
The 1st vertical line indicates start of 
study treatment at Intervention Phase. 
The second vertical reference line 
indicates last IP on-treatment study 
day.  i.e. min (last IP injection dose+35 
days, LTFU HAART start date, date of 
last oral CAB+RPV+1). This vertical line 
is only for subjects who withdraw from 
Intervention Phase/Extension phase.
M12, EOS
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
96
13.13.7.
Safety Tables
Safety: Tables
No.
Population
GSK Standard/
Example Shell
Title
Programming Notes
Deliverable 
Exposure
3.1.
Safety
207966/primary
_15/T3.1
Summary of Exposure to Study Treatment (Intervention Phase)
M12
3.2.
Safety
207966/primary
_15/T3.1
Summary of Exposure to Study Treatment
M12, EOS
3.3.
Safety
SAF_T1
See Section 
13.14
Summary of Adherence to CAB LA + RPV LA Dosing Schedule 
by Visit, Site Type and COVID-19 Impact /Non-Impact 
(Intervention Phase)
COVID Impact refers to missed or out 
of window injections for COVID-19 
related reasons (as captured as 
COVID-19 related protocol deviations)
HL, M12
3.4.
Safety
SAF_T2
See Section 
13.14
Summary of Adherence to CAB LA + RPV LA Dosing Schedule 
by Visit, Site ID and COVID-19 Impact /Non-Impact (Intervention 
Phase)
COVID Impact refers to missed or out 
of window injections for COVID-19 
related reasons (as captured as 
COVID-19 related protocol deviations)
HL, M12
3.5.
Safety
SAF_T1
See Section 
13.14
Summary of Adherence to CAB LA + RPV LA Dosing Schedule 
by Visit, Site Type and COVID-19 Impact /Non-Impact
COVID Impact refers to missed or out 
of window injections for COVID-19 
related reasons (as captured as 
COVID-19 related protocol deviations)
EOS
3.6.
Safety
SAF_T2
See Section 
13.14
Summary of Adherence to CAB LA + RPV LA Dosing Schedule 
by Visit, Site ID and COVID-19 Impact /Non-Impact
COVID Impact refers to missed or out 
of window injections for COVID-19 
related reasons (as captured as 
COVID-19 related protocol deviations)
EOS
Adverse Events (AEs)
3.7.
Safety
AE3
Summary of Adverse Events by Overall Frequency
ICH E3
M12, EOS
3.8.
Safety
AE5B
Summary of Adverse Events by System Organ Class and 
Maximum Grade
ICH E3
HL, M12, EOS
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
97
Safety: Tables
No.
Population
GSK Standard/
Example Shell
Title
Programming Notes
Deliverable 
3.9.
Safety
AE5B
Summary of Adverse Events by System Organ Class and 
Maximum Grade — Excluding Study Drug Injection Site 
Reactions 
M12, EOS
3.10.
Safety
AE5B
Summary of Adverse Events by System Organ Class and 
Maximum Grade (Oral Lead-in Period) 
M12, EOS
3.11.
Safety
AE3
Summary of Common (>=5%) Adverse Events by Overall 
Frequency
ICH E3
M12, EOS
3.12.
Safety
AE3
Summary of Common (>=1%) Grade 2-5 Adverse Events by 
Overall Frequency
ICH E3
M12, EOS
3.13.
Safety
AE3
Summary Drug-Related Adverse Events by Overall Frequency
ICH E3
M12, EOS
3.14.
Safety
AE5B
Summary of Drug-Related Adverse Events by System Organ 
Class and Maximum Grade
ICH E3
HL, M12, EOS
3.15.
Safety
AE5B
Summary of Drug-Related Adverse Events by System Organ 
Class and Maximum Grade — Excluding Study Drug Injection 
Site Reactions
M12, EOS
3.16.
Safety
AE15
Summary of Common (>=5%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Subjects 
and Occurrences)
FDAAA, EudraCT
M12, EOS
3.17.
Safety
AE3
Summary of Common (>=1%) Drug-Related Grade 2-5 Adverse 
Events by Overall Frequency
ICH E3
M12, EOS
3.18.
Safety
AE3
Summary of Non-Serious Drug-Related Adverse Events by 
Overall Frequency
Plain Language Summary 
requirements.
M12, EOS
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
98
Safety: Tables
No.
Population
GSK Standard/
Example Shell
Title
Programming Notes
Deliverable 
Serious and Other Significant Adverse Events
3.19.
Safety
AE5B
Summary of Serious Adverse Events by System Organ Class 
and Maximum Grade
ICH E3
HL, M12, EOS
3.20.
Safety
AE16
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Subjects and Occurrences)
FDAAA, EudraCT
M12, EOS
3.21.
Safety
AE1
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study by 
System Organ Class and Preferred Term
GSK Statistical Display Standard
HL, M12, EOS
3.22.
Safety
AE20
Summary of Serious Fatal and Non-Fatal Drug-Related Adverse 
Events by Overall Frequency
Plain Language Summary 
requirements.
M12, EOS
Injection Site Reaction Adverse Events  
3.23.
Safety
201584/primary_
7/T3.40
Summary of Study Drug Injection Site Reaction Adverse Events 
(Event-level Summary)
HL, M12, EOS
3.24.
Safety
201584/primary_
7/T3.43
Summary of Subject-level Characteristics of Study Drug 
Injection Site Reaction Adverse Events – Overall and Common
HL, M12, EOS
3.25.
Safety
201584/primary_
7/T3.46
Summary of Study Drug Injection Site Reaction Adverse Events 
by Visit and Maximum Severity – Overall and Common
HL, M12, EOS
Laboratory: Chemistry 
3.26.
Safety
LB1
Summary of Chemistry Values 
Includes pre-specified parameters 
repeated in conventional units.
Includes baseline values
M12, EOS
3.27.
Safety
LB1
Summary of Chemistry Changes from Baseline 
ICH E3
M12, EOS
3.28.
Safety
LB16
Summary of Chemistry Results by Maximum Grade Increase 
Post-Baseline Relative to Baseline
ICH E3
HL, M12, EOS
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
99
Safety: Tables
No.
Population
GSK Standard/
Example Shell
Title
Programming Notes
Deliverable 
3.29.
Safety
LB16
Summary of Chemistry Results by Maximum Grade Increase
Post-Baseline Relative to Baseline (Oral Lead-in Period)
ICH E3
M12, EOS
Laboratory: Hematology
3.30.
Safety
LB1
Summary of Hematology Values 
Includes pre-specified parameters 
repeated in conventional units.
M12, EOS
3.31.
Safety
LB1
Summary of Hematology Changes from Baseline
Includes pre-specified parameters 
repeated in conventional units.
Includes baseline values
M12, EOS
3.32.
Safety
LB16
Summary of Hematology Results by Maximum Grade Increase 
Post-Baseline Relative to Baseline
ICH E3
M12, EOS
3.33.
Safety
LB16
Summary of Hematology Results by Maximum Grade Increase 
Post-Baseline Relative to Baseline (Oral Lead-in Period)
ICH E3
M12, EOS
Laboratory: Hepatobiliary (Liver)
3.34.
Safety
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting
GSK Statistical Display Standard
M12, EOS
3.35.
Safety
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities
GSK Statistical Display Standard 
HL, M12, EOS
3.36.
Safety
LIVER11
Summary of Liver Restart/Re-Challenges
GSK Statistical Display Standard 
M12, EOS
Vital Signs
3.37.
Safety
VS1
Summary of Change from Baseline in Vital Signs
ICH E3
Include Baseline values
M12, EOS
Cardiovascular Risk Factors
3.38.
Safety
FH1
Summary of Family History of Cardiovascular Risk Factors
GSK Statistical Display Standard 
M12, EOS
3.39.
Safety
SU1
Summary of Substance Use
GSK Statistical Display Standard 
M12, EOS
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
100
Safety: Tables
No.
Population
GSK Standard/
Example Shell
Title
Programming Notes
Deliverable 
COVID-19 Adverse Events
3.40.
Safety
PAN1
Summary of COVID-19 Assessments for Subjects with COVID-
19 Adverse Events
GSK Statistical Display Standard
M12, EOS
3.41.
Safety
PAN2
Summary of COVID-19 Additional Assessments for Subjects 
with COVID-19 Adverse Events
GSK Statistical Display Standard
M12, EOS
3.42.
Safety
PAN3
Summary of COVID-19 Symptoms for Subjects with COVID-19 
Adverse Events
GSK Statistical Display Standard
M12, EOS
Adverse Events of Special Interest
3.43.
Safety
201584/primary_
27/T3.140
Summary of Depression, Anxiety and Suicidal or Suicidal 
Ideation/Behaviour Adverse Events by System Organ Class, 
Maximum DAIDS Toxicity Grade, and History of Depression, 
Anxiety or Suicidal Ideation/Behaviour at Screening 
M12, EOS
3.44.
Safety
201584/primary_
07/T3.122
Summary of Depression Adverse Events of Special Interest by 
System Organ Class and Preferred Term (Number of Subjects 
and Occurrences)
M12, EOS
3.45.
Safety
201584/primary_
07/T3.125
Summary of Anxiety Adverse Events of Special Interest by 
System Organ Class and Preferred Term (Number of Subjects 
and Occurrences)
M12, EOS
3.46.
Safety
201584/primary_
07/T3.128
Summary of Suicidal Ideation/Behaviour Adverse Events of 
Special Interest by System Organ Class and Preferred Term 
(Number of Subjects and Occurrences)
M12, EOS
3.47.
Safety
201584/primary_
07/T3.134
Summary of Seizures Adverse Events of Special Interest by 
System Organ Class and Preferred Term (Number of Subjects 
and Occurrences)
M12, EOS
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
101
Safety: Tables
No.
Population
GSK Standard/
Example Shell
Title
Programming Notes
Deliverable 
3.48.
Safety
201584/primary_
07/T3.137
Summary of Hepatic Safety Profile: Assessment of Risk of 
Hepatoxicity Adverse Events of Special Interest by System 
Organ Class and Preferred Term (Number of Subjects and 
Occurrences)
M12, EOS
3.49.
Safety
201584/primary_
07/T3.140
Summary of Hypersensitivity Reactions (HSR) Adverse Events 
of Special Interest by System Organ Class and Preferred Term 
(Number of Subjects and Occurrences)
M12, EOS
3.50.
Safety
201584/primary_
07/T3.143
Summary of Rash Adverse Events of Special Interest by System 
Organ Class and Preferred Term (Number of Subjects and 
Occurrences)
M12, EOS
3.51.
Safety
201584/primary_
07/T3.146
Summary of Prolongation of the Corrected QT Interval of the 
ECG in Supratherapeutic Doses Adverse Events of Special 
Interest by System Organ Class and Preferred Term (Number of 
Subjects and Occurrences)
M12, EOS
3.52.
Safety
201584/primary_
07/T3.149
Summary of Bipolar Disorder Adverse Events of Special Interest 
by System Organ Class and Preferred Term (Number of 
Subjects and Occurrences)
M12, EOS
3.53.
Safety
201584/primary_
07/T3.152
Summary of Psychosis Adverse Events of Special Interest by 
System Organ Class and Preferred Term (Number of Subjects 
and Occurrences)
M12, EOS
3.54.
Safety
201584/primary_
07/T3.155
Summary of Mood Disorders Adverse Events of Special Interest 
by System Organ Class and Preferred Term (Number of 
Subjects and Occurrences)
M12, EOS
3.55.
Safety
201584/primary_
07/T3.158
Summary of Sleep Disorders Adverse Events of Special Interest 
by System Organ Class and Preferred Term (Number of 
Subjects and Occurrences)
M12, EOS
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
102
Safety: Tables
No.
Population
GSK Standard/
Example Shell
Title
Programming Notes
Deliverable 
3.56.
Safety
201584/primary_
07/T3.161
Summary of Hyperglycaemia Adverse Events of Special Interest 
by System Organ Class and Preferred Term (Number of 
Subjects and Occurrences)
M12, EOS
3.57.
Safety
201584/primary_
07/T3.161
Summary of Weight Gain Adverse Events of Special Interest by 
System Organ Class and Preferred Term (Number of Subjects 
and Occurrences)
M12, EOS
3.58.
Safety
201584/primary_
07/T3.164
Summary of Rhabdomyolysis Adverse Events of Special Interest 
by System Organ Class and Preferred Term (Number of 
Subjects and Occurrences)
M12, EOS
3.59.
Safety
201584/primary_
07/T3.167
Summary of Pancreatitis Adverse Events of Special Interest by 
System Organ Class and Preferred Term (Number of Subjects 
and Occurrences)
M12, EOS
3.60.
Safety
201584/primary_
07/T3.170
Summary of Impact on Creatinine Adverse Events of Special 
Interest by System Organ Class and Preferred Term (Number of 
Subjects and Occurrences)
M12, EOS
3.61.
Safety
201584/primary_
07/T3.173
Summary of Safety in Pregnancy Adverse Events of Special 
Interest by System Organ Class and Preferred Term (Number of 
Subjects and Occurrences)
M12, EOS
3.62.
Safety
207966/primary_
15/T3.109
Summary of Characteristics of Adverse Events of Special 
Interest 
M12, EOS
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
103
13.13.8.
Safety Figures
Safety: Figures
No.
Population
GSK Standard / 
Example Shell
Title
Programming Notes
Deliverable
Adverse Events
3.1.
Safety
201584/primary_07/F3.14
Plot of Incidence of Intervention Phase Study Drug Injection 
Site Reaction Adverse Events by Visit (Overall and 
Common) – CAB and/or RPV
M12, EOS
3.2.
Safety
201584/primary_07/F3.17
Plot of Incidence of Grade 3-5 Intervention Phase Study 
Drug Injection Site Reaction Adverse Events by Visit 
(Overall and Common) - CAB and/or RPV
M12, EOS
Laboratory
3.3.
Safety
LIVER14
Scatter Plot of Maximum vs. Baseline for ALT
GSK Statistical Display Standard
M12, EOS
3.4.
Safety
LIVER9
Scatter Plot of Maximum Total Bilirubin vs Maximum ALT –
eDISH Plot
GSK Statistical Display Standard 
M12, EOS
13.13.9.
Virology Tables
No.
Population
GSK Standard /
Example Shell
Title
Programming Notes
Deliverable 
4.1.
Safety
20184/primary_17/T7.2
Viral load, Genotypic and Phenotypic data for Subjects Who 
Met Confirmed Virologic Failure Criteria
HL, M12, EOS
4.2.
Safety
20184/primary_17/T7.4
Viral Load, Genotypic and Phenotypic Data for Non-CVF 
Subjects
Only include subjects with available 
genotypic or phenotypic data.
M12, EOS
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
104
13.13.10. Other Tables
Study Visit Length
No.
Population
GSK Standard
/ Example 
Shell
Title
Programming Notes
Deliverable 
5.1.
Safety
OTR_T1
Summary of Study Visit Length (minutes) by Visit and Site 
Type (Intervention Phase)
HL, M12, EOS
5.2.
Safety
OTR_T1
Summary of Study Visit Length (minutes) by Visit and Site 
(Intervention Phase)
HL, M12, EOS
13.13.11. ICH Listings
ICH: Listings
No.
Population
GSK Standard / 
Example Shell
Title
Programming Notes
Deliverable 
Subject Disposition
1.
Enrolled
ES2
Listing of Reasons for Study Withdrawal
ICH E3
Add column for Phase
M12, EOS
2.
Enrolled
SD2
Listing of Reasons for Study Treatment Discontinuation
ICH E3
Add column for Phase
HL, M12, EOS
Protocol Deviations
3.
Enrolled
DV2
Listing of Important Protocol Deviations 
ICH E3
Add column for Phase
M12, EOS
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
105
ICH: Listings
No.
Population
GSK Standard / 
Example Shell
Title
Programming Notes
Deliverable 
Add a column on the right for “COVID-
19 Related”. The possible values in this 
column are Y and N, where Y indicates 
the deviation is COVID-19 related and N 
indicates the deviation is non-COVID-19 
related.
4.
Enrolled
DV2
Listing of Protocol Deviations Related to COVID-19 
FDA Request
Add column for Phase
HL, M12, EOS
5.
Safety
IE3
Listing of Subjects with Inclusion/Exclusion Criteria 
Deviations
ICH E3
M12, EOS
Populations Analysed
6.
Enrolled
SP3
Listing of Subjects Excluded from Safety Population
ICH E3
M12, EOS
Demographic and Baseline Characteristics
7.
Safety
DM2
Listing of Demographic Characteristics
ICH E3
M12, EOS
8.
Safety
DM9
Listing of Race
ICH E3
M12, EOS
Efficacy
9.
Safety
SNAPSHOT11
Listing of Qualitative and Quantitative Plasma HIV-1 RNA 
Data
HL, M12, EOS
10.
Safety
SNAPSHOT12
Listing of Study Outcome (50 copies/mL cutoff) at Month 
12 – Snapshot Analysis
Include both original and LOCF imputed 
outcomes
HL, M12, EOS
11.
Safety
VF4
Listing of Plasma HIV-1 RNA and CD4+ Cell Count for 
subjects with Confirmed Virologic Failure
M12, EOS
Exposure and Treatment Compliance
12.
Safety
207966/primary_15/L12
Listing of Exposure Data
ICH E3
Remove Phase Day
M12, EOS
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
106
ICH: Listings
No.
Population
GSK Standard / 
Example Shell
Title
Programming Notes
Deliverable 
Adverse Events
13.
Safety
AE8 
Listing of All Adverse Events
ICH E3
Add Phase/Period, Side/Drug, see 
gsk1265744/mid207966/primary_15/L19
HL, M12, EOS
14.
Safety
AE8 
Listing of Grade 3-5 Adverse Events
Add Phase/Period, Side/Drug, see 
gsk1265744/mid207966/primary_15/L19
M12, EOS
15.
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events
ICH E3
M12, EOS
16.
Safety
PSRAE1
Listing of Possible Suicidality-Related Adverse Event 
Data: Event and Description (Section 1-Section 2)
Add Phase
M12, EOS
17.
Safety
PSRAE3
Listing of Possible Suicidality-Related Adverse Event 
Data: Possible Cause(s) (Section 3)
Add Phase
M12, EOS
18.
Safety
PSRAE4
Listing of Possible Suicidality-Related Adverse Event Data 
(Section 4)
Add Phase
M12, EOS
19.
Safety
PSRAE5
Listing of Possible Suicidality-Related Adverse Event Data 
(Section 5-Section 8)
Add Phase
M12, EOS
20.
Safety
201584/primary_07/L22
Listing of Changes in Intensity/Grades of Study Drug 
Injection Site Adverse Events
Remove phase treatment
M12, EOS
21.
Safety
AE8 
Listing of COVID-19 Adverse Events
Add Phase/Period, Side/Drug, see 
gsk1265744/mid207966/primary_15/L19
HL, M12, EOS
22.
Safety
PAN12
Listing of COVID-19 Assessments and Symptom 
Assessments
M12, EOS
23.
Safety
PAN5
Country Level Listing of Start Dates of COVID-19 
Pandemic Measures  
M12, EOS
Serious and Other Significant Adverse Events
24.
Safety
AE8
Listing of Fatal Serious Adverse Events
ICH E3
M12, EOS
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
107
ICH: Listings
No.
Population
GSK Standard / 
Example Shell
Title
Programming Notes
Deliverable 
Add Phase/Period, Side/Drug
25.
Safety
AE8
Listing of Non-Fatal Serious Adverse Events
ICH E3
Add Phase/Period, Side/Drug
M12, EOS
26.
Safety
AE14
Listing of Reasons for Considering as a Serious Adverse 
Event
ICH E3
M12, EOS
27.
Safety
AE8 
Listing of Adverse Events Leading to Withdrawal from 
Study / Permanent Discontinuation of Study Treatment
ICH E3
Add Phase/Period, Side/Drug
M12, EOS
28.
Safety
AE8
Listing of All Adverse Events with Completely Missing 
Onset Date, Missing Relationship to Study Treatment, 
Severity and/or Grade
ICH E3
Add Phase/Period, Side/Drug, see 
gsk1265744/mid207966/primary_15/L19
M12, EOS
Laboratory
29.
Safety
UR2
Listing of Urinalysis Data for Subjects with Any Value of 
Potential Clinical Importance
ICH E3
Include Grade
Note: Potential Clinical Importance is 
defined as:
1. Increase in Protein (dipstick) or 
Occult Blood (dipstick) post-baseline 
relative to baseline
2. Increase in any DAIDS graded values 
for Protein, Occult Blood or Glucose 
relative to baseline 
3. If microscopy is performed.
M12, EOS
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
108
13.13.12. Non-ICH Listings
Non-ICH: Listings
No.
Population
GSK Standard GSK 
Statistical Display 
Standard / Example 
Shell
Title
Programming Notes
Deliverable
Subject Disposition
30.
Screened
ES7
Listing of Reasons for Screen Failure
Journal Guidelines
M12, EOS
31.
Screened
ES9
Listing of Subjects Who Were Rescreened
M12, EOS
32.
Safety
TA1
Listing of Planned and Actual Treatments
GSK Statistical Display Standard
M12, EOS
Prior and Concomitant Medications
33.
Safety
207966/primary_15/Listing 
36
Listing of Prior ART Medications
Remove the column ‘Phase during 
Which Concomitant’
M12, EOS
34.
Safety
207966/primary_15/Listing 
37
Listing of Concomitant ART Medications
In case the same medication is 
concomitant during both intervention
and extension phases, list each of 
them in two separate rows. Add a 
column “SOC Oral Bridging?” which 
has values of “Yes” and “No”.
HL, M12, 
EOS
35.
Safety
207966/primary_15/Listing 
38
Listing of ART Medications Received during Long-term 
Follow-up Phase
Remove the column ‘Phase during 
Which Concomitant’ and “Start Date 
of the Long-term Follow-up 
ART/Study Day”.
M12, EOS
Medical History
36.
Safety
201584/primary_01/L43
Listing of Medical History of Seizure
M12, EOS
Efficacy
37.
Safety
CDC4
Listing of CDC Classification of HIV-1 Infection at 
Baseline
Add Phase
M12, EOS
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
109
Non-ICH: Listings
No.
Population
GSK Standard GSK 
Statistical Display 
Standard / Example 
Shell
Title
Programming Notes
Deliverable
38.
Safety
CDC5
Listing of CDC Stage 3 HIV-1 Associated Conditions 
Add Phase
Hepatobiliary (Liver)
39.
Safety
LIVER5
Listing of Liver Monitoring/Stopping Event Reporting
GSK Statistical Display Standard
M12, EOS
40.
Safety
LIVER15
Liver Stopping Event Profile
GSK Statistical Display Standard
M12, EOS
41.
Safety
LIVER13
Listing of Subjects Meeting Hepatobiliary Laboratory 
Criteria Post-Baseline
GSK Statistical Display Standard
HL, M12, 
EOS
42.
Safety
LB12
Listing of ALT, AST, Bilirubin (including Total and Direct 
Bilirubin), INR, and ALP for Subjects Meeting 
Hepatobiliary Lab Abnormality Criteria
Add Phase
M12, EOS
ECG
43.
Safety
EG3
Listing of All ECG Values for Subjects with Any Value of 
Potential Clinical Importance
GSK Statistical Display Standard
By default, the definition of PCI is 
defined based on QTc value (e.g., 
QTcF Interval, Aggregate) where a 
subject has a QTc value >450 or a 
QTc increase of >30msec.
M12, EOS
44.
Safety
EG5
Listing of All ECG Findings for Subjects with an Abnormal 
ECG Finding
GSK Statistical Display Standard
M12, EOS
Other
45.
Safety
207966/primary_15/L60
Listing of Exposure Data for Subjects Receiving Oral 
Bridging
Add column to identify COVID 
relatedness.
HL, M12, 
EOS
46.
Safety
207966/primary_15/L61
Listing of Dosing Errors and IP Device Malfunctions
Add Phase
M12, EOS
47.
Safety
PREG1
Listing of Subjects or Partners Who Became Pregnant 
During the Study
GSK Statistical Display Standard
Add Phase/Period
M12, EOS
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
110
Non-ICH: Listings
No.
Population
GSK Standard GSK 
Statistical Display 
Standard / Example 
Shell
Title
Programming Notes
Deliverable
48.
Safety
201584/primary_17/L54
Listing of Replication Capacity in IN and PR/RT Region
Add Phase
M12, EOS
PK Endpoints
49.
Safety
PK07
Listing of Plasma CAB Pharmacokinetic Concentration-
Time Data
M12, EOS
50.
Safety
PK07
Listing of Plasma RPV Pharmacokinetic Concentration-
Time Data
M12, EOS
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0


CONFIDENTIAL
209493
111
13.14.
Appendix 14: Example Mock Shells for Data Displays
Data Display Specification will be made available on request
209493 | Statistical Analysis Plan  RAP 29 Oct 2020 | TMF-9963918 | 2.0

Prot_000.pdf: 
2018N382441_03
CONFIDENTIAL
ViiV Healthcare group of companies
209493
1
TITLE PAGE
Protocol Title: A qualitative hybrid III implementation study to identify and evaluate 
strategies for successful implementation of the cabotegravir + rilpivirine long-acting 
injectable regimen in the US
Protocol Number
209493/ Amendment 03
Compound Number
GSK1265744
Study Phase
Phase 3
Approval Date
16-NOV-2020
Short Title: Study to Identify and Determine Best Implementation Practices for 
Injectable CAB + RPV in the US
This study is sponsored by ViiV Healthcare. GlaxoSmithKline is implementing and 
managing all aspects of this study on behalf of ViiV Healthcare. 
Author (s):
 
 
US IND Sponsor Legal Registered Address:
ViiV Healthcare 
Five Moore Drive
P.O. 13398
Research Triangle Park, NC 27709-3398, USA
Telephone: 
Sponsor Legal Registered Address (excluding US): 
ViiV Healthcare
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
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
Medical Monitor Name and Contact Information can be found in the Study 
Reference Manual
Copyright 2020 ViiV Healthcare group of companies. All rights reserved.  Unauthorised 
copying or use of this information is prohibited.
PPD
PPD


2018N382441_03
CONFIDENTIAL
ViiV Healthcare group of companies
209493
2
MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Primary Medical Monitor/SAE Contact Information:
ViiV Healthcare
Research Triangle Park
Five Moore Drive, Research Triangle Park, NC 27709 (USA)
Mobile: 
Office Telephone: +same as mobile
e-mail:
Secondary Medical Monitor:
, DO, MSc
ViiV Healthcare
Research Triangle Park
Five Moore Drive, Research Triangle Park, NC 27709 (USA)
Mobile: 
Office Telephone:
Fax:
e-mail:
Sponsor Serious Adverse Events (SAE) Contact Information:
ViiV Healthcare
Research Triangle Park
Five Moore Drive, Research Triangle Park, NC 27709 (USA)
Mobile:
Office Telephone: +same as mobile
e-mail:
Regulatory Agency Identifying Number(s):
IND: 109,678
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


2018N382441_03 
CONFIDENTIAL 
 
 
 
209493 
3 
 
SPONSOR SIGNATORY: 
 
 
 
 
 
Sherene Shakib Min, MD, MPH  
VP, Head of Clinical Development 
ViiV Healthcare 
 
Date 
 
 


2018N382441_03
CONFIDENTIAL
209493
4
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
DNG Number
Amendment No. 3
16-Nov-2020
2018N382441_03
Amendment No. 2
15-May-2020
2018N382441_02
Amendment No. 1
02-Apr-2019
2018N382441_01
Original
02-Jan-2019
2018N382441_00
Amendment 3: 16-NOV-2020
Overall Rationale for the Amendment: The primary purpose of this amendment is to 
allow participants who become pregnant while in the study to remain in the study and not 
be withdrawn as a result of the pregnancy. Allowing pregnant participants to continue in 
the study will negate any subsequent fetal exposures to new antiretrovirals agents that 
would occur if the pregnant participant was withdrawn from study and placed on an oral 
SOC regimen. An Appendix, “Information and Guidance for Managing Pregnant 
Participants” was inserted as Appendix 8 and all subsequent appendices were renumbered 
accordingly.
Minor additional edits were made which were previously addressed with a note to file 
(NTF), for clarity and/or correction.
Section # and Name
Description of Change
Brief Rationale
Medical Monitor/ 
Sponsor Information 
Page
Updated name and contact 
information for primary 
and secondary medical 
monitors, Sponsor Serious 
Adverse Events (SAE) 
Contact Information, and 
sponsor signatory details
Change in study medical monitor
General Change 
throughout the 
document
Women of Childbearing 
Potential (WCBP) has been 
changed to Females of 
Reproductive Potential
Where appropriate, women 
has been change to females
Changed for consistency in 
terminology throughout
Section 1.2: 
Outcomes/Endpoints 
Table
Verbiage modified for 
clarity (previously 
addressed in NTF)
To address inconsistency in 
wording regarding the collection 
time for Month 12 subject 
interviews
Section 1.5: Schedule 
Additional PK assessment 
Reminder for additional 


2018N382441_03
CONFIDENTIAL
209493
5
Section # and Name
Description of Change
Brief Rationale
of Activities Table 3 
(CAB LA + RPV LA 
Monthly 
Administration)
instructions added before 
the table title
Footnote “b” added for 
requirement for specific 
pregnancy ICF addendum; 
subsequent footnotes 
renumbered
Footnote “h” edited
Footnote “j” added for 
additional PK sample 
collection; subsequent 
footnotes renumbered
Footnote “k” (now footnote 
“m”) verbiage modified for 
clarity (previously 
addressed in NTF)
assessments for pregnant 
participants remaining in the study 
and directing to Appendix 8.
Pregnant participants who remain 
in the study will need to sign a 
specific pregnancy ICF addendum
Pregnant participants who remain 
in the study have additional 
assessments required, and do not 
need pregnancy testing performed 
for the duration of their pregnancy
Pregnant participants who remain 
in the study will have additional 
PK samples collected
To address inconsistency in 
wording regarding the collection 
time for Month 12 subject 
interviews
Section 1.5: Schedule 
of Activities Table 5 
(Long Term Follow-
Up)
Footnote “c” added for for 
additional PK sample 
collection; subsequent 
footnotes renumbered
Footnote “d” edited to 
reflect pregnancy testing is 
not needed during the 
study for pregnant 
participants. 
Pregnant participants who remain 
in the study will have additional 
PK samples collected, and do not 
need pregnancy testing performed 
for the duration of their pregnancy
Section 2.3.1 Risk 
Assessment 
Oral CAB and CAB 
LA 
(GSK1265744/GSK12
65744 LA) Risk 
Assessment Table: 
Summary of 
Data/Rationale for Risk
Effects in pregnancy seen 
in non-clinical studies
Mitigation Strategy
Late stage removed, as 
Verbiage changed to indicate 
pregnant females are not enrolled 
in the study, but may participate, if 
they become pregnant during the 
course of the study. Additional 
language added to include the 
requirement for an additional 


2018N382441_03
CONFIDENTIAL
209493
6
Section # and Name
Description of Change
Brief Rationale
additional non-clinical data 
was added to describe 
effects of cabotegravir in 
animals
Potential effects in females
exposed to dolutegravir 
during conception and 
early pregnancy
pregnancy specific ICF addendum, 
and directing the reader to 
Appendix 8 for management of 
pregnant participants. Language 
added to clarify that pregnant 
participants who remain in the 
study do not need pregnancy 
testing for the duration of the 
pregnancy
Updated to reflect most recent 
DTG data regarding NTDs in 
pregnancy. 
Verbiage changed to indicate 
pregnant females are not enrolled 
in the study, but may participate, if 
they become pregnant during the 
course of the study. Additional 
language added to include the 
requirement for an additional 
pregnancy specific ICF addendum, 
and directing the reader to 
Appendix 8 for management of 
pregnant participants. Language 
added to clarify that pregnant 
participants who remain in the 
study do not need pregnancy 
testing for the duration of the 
pregnancy
Section 6.5.2 
Prohibited 
Medications and Non-
Drug Therapies
Wording changed to clarify 
permitted Hepatitis C 
therapy vs what is 
prohibited
Existing language interpreted as 
contradictory
Section 7
Discontinuation of 
Study Intervention and 
Participant 
Discontinuation/Withd
rawal
Deleted bullet: Pregnancy 
(intrauterine), regardless of 
termination status of 
pregnancy.
Participants may remain in the 
study, if they become pregnant 
during the course of the study, and 
are not required to be withdrawn
Section 8.4.1 Clinical 
Bullets discussing 
pregnancy testing updated 
Participants may remain in the 
study, if they become pregnant 


2018N382441_03
CONFIDENTIAL
209493
7
Section # and Name
Description of Change
Brief Rationale
Evaluations
to include language 
regarding pregnant 
participants being 
permitted to remain in the 
study Language added to 
clarify that pregnant 
participants who remain in 
the study do not need 
pregnancy testing for the 
duration of the pregnancy
during the course of the study. 
Additional language was needed to 
include the requirement for an 
additional pregnancy specific ICF 
addendum, and directing the 
reader to Appendix 8 for 
management of pregnant 
participants. Pregnant participants 
who remain in the study do not 
need pregnancy testing during the 
study
Section 8.4.5 Clinical 
Safety Assessments
Bullet “f” added to the 
table footnote
Inadvertently omitted in the 
previous protocol version
Section 8.5.5 
Pregnancy (including 
subsections 8.5.5.1, 
8.5.5.2, 8.5.5.3)
Entire section edited. 
Directs the reader 
throughout to reference the 
Pregnancy appendix
8.5.5 - Added general 
instructions for first steps 
in the event that a 
participant in the study gets 
pregnant. Language 
regarding withdrawal in the 
event of pregnancy was 
removed. Language added 
to clarify that pregnant 
participants who remain in 
the study do not need 
pregnancy testing for the 
duration of the pregnancy
8.5.5.1 - New section 
added, providing general 
risk/benefit information 
regarding continued use in 
pregnancy
8.5.5.2 – Instructions 
Pregnant participants are no longer 
required to be withdrawn from the 
study and may remain the study. 
The addition and updating of 
information/instructions was also 
necessary. Some repetitive 
information or information that 
was not/no longer relevant for this 
section was removed. Pregnant 
participants who remain in the 
study do not need pregnancy 
testing during the study


2018N382441_03
CONFIDENTIAL
209493
8
Section # and Name
Description of Change
Brief Rationale
updated to include 
information for pregnant 
participants remaining in 
the study. Language 
around continued use of 
contraception removed.
8.5.5.3 - Instructions 
updated to include 
information for any 
participant who becomes 
pregnant while in the 
study, including those 
participants who chose to 
withdraw (and enter 
LTFU), or those who chose 
to remain in the study. 
Instructions removed 
regarding cord blood 
and/or breast milk 
collection.
Section 8.6 
Pharmacokinetics
Language added for PK 
collection of pregnant 
participants
Pregnant participants remaining in 
the study will have additional PK 
samples drawn at regularly 
scheduled visits, throughout the 
course of the pregnancy
Section 10.1.3
Informed Consent 
Process
Language added for 
pregnancy specific ICF 
addendum
Participants who become pregnant 
while in the study and who elect to 
continue to receive CAB + RPV 
LA injections must sign the 
pregnancy specific ICF addendum.
Section 10.7 Appendix 
7, Table 15
Table 15: Removed 
footnote “b” that was 
inadvertently added and 
was not required.
Both long-acting reversible 
contraception (LARC) and 
progestogen only injectable 
contraception (POIC) are 
considered highly effective forms 
of contraception and are allowed 
as single agents Therefore, the 
footnote in the table requiring a 
second form of contraception was 
not accurate.


2018N382441_03
CONFIDENTIAL
209493
9
Section # and Name
Description of Change
Brief Rationale
Pregnancy Testing –
Added bullet to refer to 
Appendix 8
Collection of Pregnancy 
Information – Updated 
with general information; 
details deleted and moved 
to Appendix 8.  Removed 
statements regarding 
withdrawal of participants 
who become pregnant 
while in the study and 
pregnancy testing for 
pregnant participants
Participants may remain in the 
study, if they become pregnant 
during the course of the study,
provided that the pregnancy 
specific ICF addendum is signed.  
Reader is directed to Appendix 8 
for details regarding management 
of pregnant participants.
Language added to clarify that 
pregnant participants who remain 
in the study do not need pregnancy 
testing for the duration of the 
pregnancy
Section 10.8 –
Appendix 8: 
Information and 
Guidance for 
Managing Pregnant 
Participants
New Appendix added; all 
subsequent sections 
renumbered.
Participants may remain in the 
study, if they become pregnant 
during the course of the study. 
Because the number of 
participants who become pregnant 
in the study is expected to be very 
small, and the information doesn’t 
pertain to most of the study 
population, the decision was made 
to include this information in an 
Appendix, rather than in the full 
protocol.
For managing participants who 
become pregnant while in the 
study, the Reader is directed to 
Appendix 8, where all details are 
available.
Section 10.8 Appendix 
8: Abbreviations and 
Trademarks
Now Section 10.9
Appendix 9: Abbreviations 
and Trademarks
Abbreviations APR, 
MTCT, NTF added. 
Trademark CABENUVA 
added
New Appendix 8 added; all 
subsequent sections renumbered
New information included the use 
of new terms, and the mention of 
CABENUVA


2018N382441_03
CONFIDENTIAL
209493
10
Section # and Name
Description of Change
Brief Rationale
Section 10.9 Appendix 
9: Patient Study 
Participant Surveys
Section 10.10 
Appendix 10: Staff 
Study Participant 
Survey
Section 10.11 
Appendix 11: COVID-
19 Pandemic and 
Clinical Trial 
Continuity
Now Section 10.10
Appendix 10: Patient Study 
Participant Surveys
Now Section 10.11
Appendix 11: Staff Study 
Participant Survey
Now Section 10.12 
Appendix 12: COVID-19 
Pandemic and Clinical 
Trial Continuity
New Appendix 8 added; all 
subsequent sections renumbered.
Section 10.12 
Appendix 12: Protocol 
Amendment History
Now Section 10.13 
Appendix 13: Protocol 
Amendment History. 
Amendment 2 information 
added to Appendix


2018N382441_03
CONFIDENTIAL
209493
11
TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................4
1.
PROTOCOL SUMMARY........................................................................................16
1.1.
Synopsis.....................................................................................................16
1.2.
Objectives and Endpoints: ..........................................................................17
1.3.
Overall Design: ...........................................................................................19
1.4.
Schema ......................................................................................................27
1.5.
Schedule of Activities (SoA)........................................................................28
2.
INTRODUCTION....................................................................................................35
2.1.
Study Rationale ..........................................................................................35
2.2.
Background ................................................................................................35
2.3.
Benefit/Risk Assessment ............................................................................42
2.3.1.
Risk Assessment .........................................................................42
2.3.1.1.
Other Clinically Relevant Information..........................53
2.3.2.
Benefit Assessment.....................................................................53
2.3.3.
Overall Benefit: Risk Conclusion..................................................53
3.
OBJECTIVES AND ENDPOINTS...........................................................................54
4.
STUDY DESIGN ....................................................................................................56
4.1.
Overall Design ............................................................................................56
4.2.
Scientific Rationale for Study Design ..........................................................56
4.3.
Justification for Dose ..................................................................................56
4.3.1.
Oral Lead-In Phase......................................................................56
4.3.2.
Long Acting Injectable Phase.......................................................59
4.3.3.
RPV LA Pharmacokinetics...........................................................63
4.4.
End of Study Definition ...............................................................................66
4.4.1.
Study Completion ........................................................................66
5.
STUDY POPULATION...........................................................................................67
5.1.
Inclusion Criteria.........................................................................................67
5.2.
Exclusion Criteria........................................................................................70
5.2.1.
Additional Eligibility Criteria..........................................................73
5.3.
Lifestyle Considerations..............................................................................73
5.4.
Screen Failures...........................................................................................73
6.
STUDY INTERVENTION........................................................................................73
6.1.
Study Intervention(s) Administered .............................................................73
6.1.1.
Formulations of CAB + RPV ........................................................74
6.1.1.1.
Cabotegravir Tablets (CAB)........................................74
6.1.1.2.
Rilpivirine Tablets (RPV).............................................75
6.1.1.3.
Cabotegravir Injectable Suspension (CAB LA) ...........75
6.1.1.4.
Rilpivirine Injectable Suspension (RPV LA) ................75
6.1.1.5.
CAB + RPV LA Packs.................................................76
6.2.
Preparation/Handling/Storage/Accountability..............................................76
6.2.1.
Dosing Considerations for CAB LA + RPV LA..............................77
6.3.
Measures to Minimize Bias: Randomization and Blinding ...........................78


2018N382441_03
CONFIDENTIAL
209493
12
6.4.
Study Intervention Compliance ...................................................................78
6.5.
Concomitant Therapy..................................................................................78
6.5.1.
Permitted Medications and Non-Drug Therapies..........................79
6.5.2.
Prohibited Medications and Non-Drug Therapies.........................80
6.5.2.1.
Concurrent with CAB and/or RPV...............................81
6.5.2.2.
Concurrent with oral RPV ...........................................81
6.5.2.3.
Concurrent with either CAB LA or RPV LA .................81
6.5.2.4.
Prohibited Medications for Participants 
Receiving HAART during the Long-Term 
Follow-Up Phase ........................................................81
6.6.
Dose Modification .......................................................................................82
6.6.1.
Protocol Permitted Substitutions..................................................82
6.6.1.1.
Oral Bridging ..............................................................82
6.6.2.
IM Dosing ....................................................................................82
6.6.2.1.
IM injections every 1 month:.......................................83
6.6.3.
Oral Dosing..................................................................................83
6.7.
Intervention after the End of the Study........................................................83
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.....................................................................83
7.1.
Discontinuation of Study Intervention..........................................................86
7.1.1.
QTc Stopping Criteria ..................................................................86
7.1.2.
Virologic Failure...........................................................................86
7.1.3.
Definition of Protocol-Defined Confirmed Virologic Failure...........86
7.1.4.
Managing Virologic Failure ..........................................................86
7.1.4.1.
HIV-1 RNA Blips.........................................................87
7.1.4.2.
Suspected Virologic Failure........................................87
7.1.4.3.
Confirmed Virologic Failure ........................................88
7.2.
Participant Discontinuation/Withdrawal from the Study ...............................88
7.3.
Lost to Follow Up........................................................................................89
8.
STUDY ASSESSMENTS AND PROCEDURES .....................................................90
8.1.
Screening Assessments .............................................................................90
8.2.
Baseline Assessments................................................................................91
8.2.1.
Patient Study Participants............................................................91
8.2.2.
Staff Study Participants................................................................92
8.3.
Efficacy Assessments- Patient Study Participants ......................................92
8.3.1.
Plasma HIV-1 RNA......................................................................92
8.3.2.
Lymphocyte Subsets, CD4+ and CD8+ .......................................92
8.3.3.
HIV Associated Conditions ..........................................................92
8.4.
Safety Assessments- Patient Study Participants.........................................92
8.4.1.
Clinical Evaluations......................................................................92
8.4.2.
Physical Examinations.................................................................94
8.4.3.
Vital Signs....................................................................................94
8.4.4.
Electrocardiograms......................................................................94
8.4.5.
Clinical Safety Laboratory Assessments ......................................95
8.4.6.
Suicidal Ideation and Behaviour Risk Monitoring .........................95
8.5.
Adverse Events and Serious Adverse Events.............................................96
8.5.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................96
8.5.2.
Method of Detecting AEs and SAEs.............................................97
8.5.3.
Follow-up of AEs and SAEs.........................................................97


2018N382441_03
CONFIDENTIAL
209493
13
8.5.4.
Regulatory Reporting Requirements for SAEs .............................97
8.5.5.
Pregnancy ...................................................................................97
8.5.5.1.
Rationale for Continued Use in Pregnancy.................98
8.5.5.2.
Time Period for Collecting Pregnancy 
Information .................................................................98
8.5.5.3.
Action to be Taken if Pregnancy Occurs.....................99
8.5.6.
Cardiovascular and Death Events................................................99
8.5.7.
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as SAEs.............................................100
8.6.
Pharmacokinetics .....................................................................................101
8.7.
Pharmacodynamics ..................................................................................101
8.8.
Genetics ...................................................................................................101
8.9.
Biomarkers ...............................................................................................101
8.10.
Health Economics.....................................................................................101
9.
STATISTICAL CONSIDERATIONS......................................................................101
9.1.
Statistical Hypotheses...............................................................................101
9.2.
Sample Size Determination ......................................................................101
9.3.
Populations for Analyses ..........................................................................102
9.4.
Statistical Analyses...................................................................................102
9.4.1.
Health Outcomes Analyses (Effectiveness Analyses) ................103
9.4.2.
Efficacy Analyses.......................................................................104
9.4.3.
Safety Analyses.........................................................................104
9.4.4.
Other Analyses ..........................................................................104
9.5.
Interim Analyses .......................................................................................104
10. SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS.............................................................................................105
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations..........................................................................................105
10.1.1.
Regulatory and Ethical Considerations ......................................105
10.1.2.
Financial Disclosure...................................................................105
10.1.3.
Informed Consent Process ........................................................106
10.1.4.
Data Protection..........................................................................106
10.1.5.
Quality Control (Study Monitoring) .............................................106
10.1.6.
Dissemination of Clinical Study Data .........................................107
10.1.7.
Data Quality Assurance .............................................................108
10.1.8.
Source Documents ....................................................................108
10.1.9.
Study and Site Closure ..............................................................109
10.2.
Appendix 2: Division of AIDS Table for Grading the Severity of Adult 
and Pediatric Adverse Events Version 2.1, March 2017............................110
10.3.
Appendix 3: Liver Safety – Study Treatment Restart or Rechallenge 
Guidelines.................................................................................................134
10.3.1.
VSLC Guidelines for Drug Restart or Rechallenge after 
stop for Liver criteria ..................................................................134
10.3.2.
VSLC Decision Process for Drug Rechallenge Approval or 
Disapproval................................................................................135
10.3.3.
VSLC Decision Process for Drug Restart Approval or 
Disapproval................................................................................138
10.3.4.
Medical monitor, GCSP Physician and PI actions for 
Restart or Rechallenge following VSLC decision .......................139
10.3.5.
Medical Monitor and GCSP Physician Actions...........................139


2018N382441_03
CONFIDENTIAL
209493
14
10.3.6.
PI Actions: .................................................................................140
10.4.
Appendix 4: CDC Classification for HIV-1 Infection (2014)........................141
10.5.
Appendix 5: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events.............................................143
10.5.1.
Definition of Adverse Events......................................................143
10.5.2.
Definition of Serious Adverse Events.........................................144
10.5.3.
Definition of Cardiovascular Events ...........................................145
10.5.4.
Recording of AEs and SAEs ......................................................146
10.5.5.
Evaluating AEs and SAEs..........................................................146
10.5.6.
Reporting of SAEs to GSK.........................................................148
10.6.
Appendix 6: Toxicity Management ............................................................149
10.6.1.
Treatment Interruption Due to an Adverse Event .......................149
10.6.2.
Liver Chemistry Stopping and Follow-up Criteria .......................149
10.6.3.
Grade 1 or Grade 2 Toxicity/Adverse Event...............................150
10.6.4.
Grade 3 Toxicity/Adverse Event.................................................150
10.6.5.
Grade 4 Toxicity/Adverse Event.................................................151
10.6.6.
Adverse Event Management......................................................152
10.6.6.1.
Diarrhea ...................................................................152
10.6.6.2.
Hypertriglyceridemia/ Hypercholesterolemia.............152
10.6.6.3.
Seizures ...................................................................153
10.6.6.4.
Creatine Phosphokinase (CPK) Elevation ................153
10.6.6.5.
Lipase Elevations and Pancreatitis...........................154
10.6.6.6.
Decline in Renal Function.........................................154
10.6.6.6.1.
Proximal Renal Tubule 
Dysfunctions (PRTD)............................155
10.6.6.7.
Proteinuria................................................................155
10.6.6.8.
QTc Prolongation .....................................................155
10.6.6.9.
Injection Site Reactions (ISRs) .................................156
10.6.6.10. Allergic reaction........................................................156
10.6.6.10.1. Rash Without HSR Symptoms..............156
10.7.
Appendix 7: Contraceptive Guidance and Collection of Pregnancy 
Information................................................................................................158
10.8.
Appendix 8: Information and Guidance for Managing Pregnant 
Participants...............................................................................................161
10.8.1.
Collection of Pregnancy Information ..........................................162
10.8.2.
Introduction................................................................................162
10.8.3.
Background ...............................................................................163
10.8.4.
Benefit/Risk Assessment ...........................................................163
10.8.4.1.
Cabotegravir.............................................................164
10.8.4.2.
Rilpivirine..................................................................165
10.8.5.
Clinical Considerations ..............................................................166
10.8.5.1.
Exposure..................................................................166
10.8.5.2.
Use of Supplements with CAB + RPV LA .................168
10.8.5.2.1.
Oral Cabotegravir Only.........................168
10.8.5.3.
Overall Benefit:Risk Conclusion................................168
10.8.6.
Study Assessments and Procedures: specific 
assessments for pregnant participants.......................................169
10.8.6.1.
Safety Assessments.................................................169
10.8.6.2.
Pharmacokinetics .....................................................169
10.8.7.
References ................................................................................170
10.9.
Appendix 9: Abbreviations and Trademarks..............................................171
10.10. Appendix 10: Patient Study Participant Surveys .......................................174


2018N382441_03
CONFIDENTIAL
209493
15
10.11. Appendix 11: Staff Study Participant Survey.............................................175
10.12. Appendix 12: COVID-19 Pandemic and Clinical Trial Continuity...............176
10.12.1. Changes to Study Visits and Study Procedures.........................176
10.12.2. Changes to Informed Consent ...................................................177
10.12.3. Permissible Use of Antiretroviral Therapy ..................................177
10.12.4. Direct-To-Patient (DTP) Shipment of Oral Study IP ...................179
10.12.5. COVID-19 Experimental Agents ................................................180
10.12.6. COVID-19 Specific Data Capture...............................................180
10.12.6.1. Capturing COVID-19 Specific Protocol 
Deviations ................................................................180
10.12.6.2. Capturing COVID-19 Specific AEs and SAEs...........180
10.13. Appendix 13: Protocol Amendment History...............................................183
11. REFERENCES.....................................................................................................186


2018N382441_03
CONFIDENTIAL
209493
16
1.
PROTOCOL SUMMARY
1.1.
Synopsis
Protocol Title: A qualitative hybrid III implementation study to identify and evaluate 
strategies for successful implementation of the cabotegravir + rilpivirine long-acting 
injectable regimen in the US
Short Title: Study to Identify and Determine Best Implementation Practices for 
Injectable CAB + RPV in the US
Rationale:
CAB + RPV LA is an investigational HIV treatment regimen of long-acting cabotegravir 
plus long-acting rilpivirine administered as two individual intramuscular injections every 
month (CAB + RPV LA following an oral lead-in [OLI] period). This new HIV treatment 
will require changes to the current standard of prescribing oral antiretroviral therapies, 
including the logistics of delivering a complete antiretroviral treatment regimen as long 
acting (LA) injectable therapy. This new treatment option will require patients to receive 
injections from a provider every month and will require greater staff and logistical 
resources to administer the injections. As this is a promising new treatment modality for 
people living with HIV (PLHIV), it is important to understand how to optimize the 
delivery of CAB + RPV LA injectable from a PLHIV, HCP and healthcare system 
perspective in order to fully realize this benefit. In preparation for national 
implementation following regulatory approval, there is a need to understand what level of 
clinic training and staff support that will be needed to effectively deliver this regimen to 
patients. Therefore, the current study aims to identify and evaluate strategies for 
successful implementation of this injectable regimen. In this study, investigational sites 
will have access to a suite of training and implementation tools as well as short-term 
intensive facilitation calls; the study will evaluate both qualitative and quantitative 
measures across a range of clinic types to determine the most effective strategies and to
identify barriers and facilitators (including solutions) for successful implementation of 
the CAB + RPV long-acting injectable regimen.


2018N382441_03
CONFIDENTIAL
209493
17
1.2.
Objectives and Endpoints:
Objectives
Endpoints
Primary
To evaluate acceptability, appropriateness, and 
feasibility of delivering CAB+RPV LA 
Acceptability of Intervention Measure (AIM),
Intervention Appropriateness Measure (IAM),
and Feasibility of Intervention Measure (FIM). 
Assessed quantitatively by staff study 
participants at baseline- prior to any Month 1 
visits, after at least 4 monthly facilitation calls 
and upon completion of all Month 12 visits at 
that site.
Acceptability of Intervention Measure (AIM) and 
Intervention Appropriateness Measure (IAM). 
Assessed quantitatively by patient study 
participants at Month 1 prior to first injection, 
Month 4 and Month 12
Secondary
To evaluate organizational facilitators and 
barriers
Facilitators/Barriers: Semi-Structured Interview 
(SSI) conducted with staff study participants at 
baseline- prior to any Month 1 visits, after at 
least 4 monthly facilitation calls and upon 
completion of at least 50% of Month 12 visits at 
that site. 
Barriers, facilitators and best practice sharing 
amongst clinics assessed by short-term 
facilitation (coaching calls) for at least 6 months. 
These will be a combination of structured 
questions and open-ended questions.
Use of support materials/toolkit assessed via 
Survey responses of staff study participants 
prior to any Month 1 visits, after at least 4 
monthly facilitation calls and upon completion of 
all Month 12 visits at a site. 
Use of support materials/toolkit assessed via 
Survey responses of patient study participants
via Survey responses at Month 1 and Month 4 
and Month 12, as well as SSI responses prior to 
Month 1 and at Month 12.


2018N382441_03
CONFIDENTIAL
209493
18
Objectives
Endpoints
Patient Facilitators and Barriers
Facilitators/Barriers: Semi-structured interviews 
conducted with patient study participants prior 
to month 1 and within 4 weeks of their Month 12 
study visit
Implementation Fidelity
Injections occurring within target window from 
the expected injection date
Use of support materials/toolkit assessed 
through SSI of staff study participants at Day 1, 
after at least 4 monthly facilitation calls and 
upon completion of at least 50% of Month 12 
visits at that site.
Implementation Sustainability
Program Sustainability Assessment Tool 
(PSAT) assessed by staff study participants at 
Month 12.
To measure patient satisfaction with process 
(timeliness of visits, length of visit, patient 
education)
Patient Survey responses at Month 1, Month 4
and Month 12.
Patient SSI responses prior to Month 1 and at 
Month 12
Length of patient visit from arrival until 
departure from clinic at Month 1, Month 5 and 
Month 11
Evaluate safety and efficacy measures of 
CAB+RPV LA
Proportion of participants with plasma HIV-1 
RNA <50 c/mL over time
Proportion of participants with confirmed 
virologic failure (CVF) over time
Incidence of treatment emergent genotypic and 
phenotypic resistance to CAB and RPV in 
patients with CVF
Incidence and severity of AEs and laboratory 
abnormalities over time
Proportion of participants who discontinue 
treatment due to AEs over time
Reported injection site reactions over time
Absolute values and changes in laboratory 


2018N382441_03
CONFIDENTIAL
209493
19
Objectives
Endpoints
parameters over time
1.3.
Overall Design:
This study is an evaluation of implementation strategies on the degree of acceptability, 
appropriateness, feasibility, fidelity, and sustainability of clinic practices to deliver the 
CAB+RPV LA regimen to appropriate HIV-infected patients. The study will use an 
implementation science approach to understand the barriers and facilitators for both 
patients and providers, including best practices for delivering CAB + RPV LA within an 
interventional clinical trial where the CAB + RPV LA regimen is delivered to HIV-
infected, virologically-suppressed patients.
Staff Study Participants & Patient Study Participants:
Staff study participants will include lead HIV care providers (HCPs), Nurses/staff 
performing CAB + RPV LA injections, and administrators/clinic managers. Patient Study 
Participants are HIV-infected patients recruited at each study site. Patient study 
participants will receive CAB LA + RPV LA and clinical assessments throughout the 
study per the Schedule of Activities (SoA), Section 1.5. Additionally, data will be 
collected from staff study participants and patient study participants per Table 1.
Table 1
Implementation Science Data Collection Plans
Patient 
Schedule
HIV-infected 
participants
Staff Study 
Participant 
Schedule
Lead HIV 
provider
Nurse or 
person giving 
injection 
(Injector)
Administrators 
/ Clinic 
Manager 
(Admin)
Month 1, 
prior to 
receiving 
injection
After 
Baseline, 
Prior to 
First 
Injection
Survey 
(100% of 
patient study 
participants)
Semi-
structured 
Interviews 
(up to 4 
patient study 
participants 
per site)
Baseline: 
(prior to first 
subject Month 
1 visit at the 
site)
Survey of 
lead HIV 
provider
Semi-
structured 
Interviews of 
lead HIV 
provider
Short-term 
facilitation*
Survey of 
nurse/person 
delivering CAB 
+ RPV LA 
injections
Semi-structured 
Interviews of 
nurse/person 
delivering CAB 
+ RPV LA 
injections
Short-term 
facilitation*
Survey of clinic 
administrator/ 
manager
Semi-structured 
Interviews of 
clinic 
administrator/ 
manager
Short-term 
facilitation*
Month 4
Survey 
(100% of 
patient study 
participants)
After 4th 
Monthly 
Facilitation 
Call
Survey of 
lead HIV 
provider
Survey of 
nurse/person 
delivering CAB 
+ RPV LA 
Survey of clinic 
administrator/ 
manager


2018N382441_03
CONFIDENTIAL
209493
20
Patient 
Schedule
HIV-infected 
participants
Staff Study 
Participant 
Schedule
Lead HIV 
provider
Nurse or 
person giving 
injection 
(Injector)
Administrators 
/ Clinic 
Manager 
(Admin)
Semi-
structured 
Interview of 
lead HIV 
provider
Short-term 
facilitationa
injections
Semi-structured 
Interview of 
nurse/person 
delivering CAB 
+ RPV LA 
injections
Short-term 
facilitation*
Semi-structured 
Interview of 
clinic 
administrator/ 
manager
Short-term 
facilitation*
Month 
12/End of 
Study 
Survey 
(100% of 
patient study 
participants)
Semi-
structured 
Interview (up 
to 4 patient 
study 
participants 
per site)b
End of Studyc
Survey of 
lead HIV 
provider
Semi-
structured 
Interview of 
lead HIV 
provider
Survey of 
nurse/person 
delivering CAB 
+ RPV LA 
injections
Semi-structured 
Interview of 
nurse/person 
delivering CAB 
+ RPV LA 
injections
Survey of clinic 
administrator/ 
manager
Semi-structured 
Interview of 
clinic 
administrator/ 
manager
a) Short-term facilitation calls with the staff study participants (Investigator, nurse and clinic 
manager are expected to attend each call, but at least one person from each site must be 
present) will occur monthly for at least 6 months. Facilitation calls will begin after sites 
begin enrolling patient study participants. Facilitation calls will continue during the 
enrollment period until the last enrolled subject achieves their Month 6 study visit.
b) Semi-structured interviews for patient study participants should be conducted within 
approximately 4 weeks of their Month 12 study visit.
c)
Surveys should occur within approximately 4 weeks of the last patient study participant 
visit at each site and interviews of staff study participants should occur after at least 50% 
of Month 12 patient study participant visits at each site.
All patient study participants enrolled in this study will switch from their pre-entry oral 
HAART regimen to the CAB + RPV LA regimen (single arm switch study) for at least 
12 months, including a one-month safety lead-in period with oral cabotegravir and oral 
rilpivirine (Edurant) dosed once-daily. Patients who successfully complete the Month 12
visit and assessments will have completed the study and will need to obtain ongoing HIV 
treatment outside of the study. Patients who discontinue the CAB + RPV LA regimen 
after receiving 1 injection of cabotegravir and/or rilpivirine will enter a long-term 


2018N382441_03
CONFIDENTIAL
209493
21
follow-up period with safety and efficacy/virology evaluated on a quarterly basis for 1 
year.
Site/Clinic Selection: Investigational sites that have not previously delivered the CAB + 
RPV LA regimen will be targeted for inclusion in the study and screened based upon 
objective criteria of their ability to perform the assessments required in the study within 
GCP requirements. Sites will be identified as either university/hospital, private or public 
health clinic based upon their own determination (Principal Investigator determination). 
Clinics that include participants from multiple categories (public/private) will be 
categorized based on the principal investigator’s determination of the majority of their 
patient base. In order to create a representative sample, sites will be chosen not only to 
represent all three categories of clinic type, but also based upon geographic and 
demographic representation (rural, suburban, urban), as much as possible within practical 
limitations.
Enrollment of Staff Study Participants: Investigational sites will be selected and staff 
study participants (lead HIV care providers (HCPs), Nurses/staff performing CAB + RPV 
LA injections, and administrators/clinic managers) will be identified prior to study 
commencement. Upon study initiation, clinical sites will have up to 2 months to engage 
and enrol up to 15 patient study participants into this study. Key objectives of this study 
relate to the delivery of the CAB + RPV LA regimen at a clinic, including the learning 
process clinic staff will undergo for this paradigm-changing regimen. One of the goals is 
to facilitate shared learnings across clinics in order to drive successful implementation,
and this will be conducted through the short-term facilitation calls with study personnel.
Thus, it is necessary for participating sites to initiate and complete enrolment 
concurrently within a short time frame. A limited enrolment period of up to 2 months is 
proposed with a goal to have approximately 80% of participating clinics fully prepared to 
enrol at the time of study commencement. Adjustments to this time frame will be 
considered by the sponsor study team based upon study progress and may include an 
extension of the enrolment period for up to a maximum of 4 months; if the enrolment 
period is extended beyond 2 months, enrolment caps at individual sites may be raised 
beyond 15, up to the study maximum of 135 patient study participants.
All lead investigators, nurses/injectors, and/or administrators responsible for 
implementation will attend an in-person investigator meeting prior to study start. The 
purpose of this meeting is to educate healthcare staff on the CAB + RPV LA regimen, 
including the proper administration of the regimen, protocol requirements for all study 
participants, data collection methods and an overview of available support tools (toolkit). 
Additionally, an overview of the key protocol objectives and relevant implementation 
science elements will be reviewed.
Upon study initiation, investigational sites will begin enrolment of eligible patient study 
participants into the study. Patient study participant enrolment is expected to continue for 
approximately 2 months. During the period after enrolment commences, patients will be 
screened and sites will begin to deliver the CAB + RPV LA regimen. Continuing through 
the last enrolled patient study participant achieving their Month 6 visit in the study CAB 
+ RPV LA, staff study participants will receive short-term facilitation calls in addition to 
the available support tools (toolkit). The core component of the facilitation includes


2018N382441_03
CONFIDENTIAL
209493
22
structured monthly group coaching calls (inclusive of all participating clinics) facilitated 
through the study team/ CRO partners. The purpose of the monthly group 
facilitation/coaching calls is to share best practices, discuss alternative work flows, 
discuss support tools, and help identify barriers and facilitators to the successful delivery 
of the CAB + RPV LA regimen. After the last enrolled patient study participant achieves 
the Month 6 visit, the short-term facilitation calls will be discontinued. Following an 
additional 6 months during which no external facilitation occurs (Month 6 to Month 12),
sustainment of implementation strategies will be assessed via surveys and semi-structured 
interviews of staff study participants as well as patient study participants. During the 
course of the study, staff study participants will be asked about their utilization of each 
element of the toolkit. For example, if they found the injection training video useful, 
which tools they used, for how long, and if they used any clinic-developed 
implementation strategies (not part of the study “toolkit”) to facilitate successful 
utilization and sustainment of CAB + RPV LA. This data will be captured in the surveys 
and semi-structured interviews.
While a “toolkit” of supporting elements will be provided in this study, clinical sites will 
be allowed to choose how they will implement CAB + RPV LA delivery in their clinical 
setting (i.e. nurse visit during clinic hours, pre-post clinic hours, weekend hours, 
Tues/Thursday clinics, etc.) as well as to create and use their own clinic-developed
resources. The delivery models chosen will be tracked by study staff and captured in the 
surveys and semi-structured interviews. Modifications made to the implementation 
process or approach during the study i.e. who administers the injection, timing of delivery 
of the injection, use of support materials, etc are permissible and encouraged in order to 
facilitate successful delivery of the CAB + RPV LA regimen. Investigators will inform 
the study team of their change and document the reasons why (step change).
Key informant interviews: Key informant interviews will be conducted with staff study 
participants and a subset (up to 4 patients per site) of patient study participants to assess 
whether acceptability, appropriateness, fidelity, and sustainability are achievable in the 
clinic settings. Interviews will also probe for multilevel barriers to, and facilitators of 
CAB + RPV LA implementation and sustainability. Key stakeholder interviews are an 
ideal method for the proposed research as they elicit in-depth, detailed information from a 
relatively small number of individuals with first-hand knowledge of the factors 
influencing local CAB + RPV LA implementation programs as well as contextual factors 
that impact implementation and sustainment. The interviews will be guided by a semi-
structured interview guide with open-ended questions and prompts to elicit organic 
feedback. The interview guides will be included in the Study Reference Manual.
Interview questions are based on the CFIR framework (described in Table 2), with a 
focus on characteristics of the patient needs and resources, readiness for implementation, 
available resources, champions, reflection and evaluation. The interview will elicit the 
characteristics that may enable or inhibit implementation and sustainability in order to 
inform future implementation efforts. Interviews will be conducted with 3 key 
stakeholders of various disciplines in each clinic relevant to the implementation of CAB 
+ RPV LA (HIV care provider, nurse/person administering the injections, and clinic 
administrator/ manager). These interviews will be conducted at three time-points: at the 
start of the study (following the Investigator Meeting but prior to the first patient at each 
site receiving their first injection), after the 4th facilitation call, and after at least 50% of


2018N382441_03
CONFIDENTIAL
209493
23
patient study participants have completed Month 12. Because this study will employ
qualitative methodology as a primary objective, there is no equivalent to power 
calculations to determine the number of interviews needed to address research questions. 
Rather, the objective is to conduct enough interviews to reach thematic “saturation” (i.e., 
no more themes emerge from the data). Interviews will be audio recorded, transcribed 
verbatim and coded.
Study “Toolkit”
A suite of educational items, training aids, treatment and planning tools, electronic 
reminders and patient-directed support items/ options will be made available as part of 
this study. These items and tools will be directed both towards HCPs (staff study 
participants, SSP) as well as patients (patient study participants, PSP) and will comprise 
the study “toolkit.” Toolkit items are noted in the table below and are optional for use by 
both SSPs and PSPs. However, items in the toolkit will be offered to SSPs and PSPs 
throughout the study and, at a minimum, at the timepoints outlined in the table. Use of 
toolkit items will be evaluated in the study through survey and qualitative interviews and 
will consist of (i) Educational Materials; (ii) Operationalization Tools and (iii) 
Appointment Reminders.
Table 2
Study Toolkit Items
Material
Objective
Offered to
Timepoints when 
offered
CAB + RPV LA
Factsheet
Overview of CAB + RPV 
LA regimen expectations 
and administration
SSP
Investigator Meeting, 
Site Initiation and per 
site preference
CAB + RPV LA
Injection Video
Educational video of how 
to prepare and administer 
CAB + RPV LA
SSP
Investigator Meeting, 
Site Initiation and per 
site preference
Web-based 
Treatment Planner
Electronic tool to assist 
staff in managing patient 
work flow
SSP
Investigator Meeting, 
Site Initiation and per 
site preference
Patient Reminder 
System
App that can be used as a 
reminder service for 
future appointments (text, 
email, SMS)
SSP, PSP
Investigator Meeting, 
Site Initiation, Day 1, 
Month 1 and per site 
preference
Hot and cold packs
To be used to alleviate 
pain and potential ISR 
due to the CAB + RPV 
LA injection
PSP
At each study visit
where a CAB + RPV 
LA injection occurs.
Injection flash card
Educational card about 
“What to expect” with 
CAB + RPV LA regimen
PSP
Screening, Day 1, 
Month 1 and per site 
preference
FAQ
Educational Question and 
Answer about the CAB + 
PSP
Screening, Day 1,
Month 1 and per site 


2018N382441_03
CONFIDENTIAL
209493
24
Material
Objective
Offered to
Timepoints when 
offered
RPV LA regimen
preference
“What to expect” 
video
Educational video about 
the CAB + RPV LA
regimen
PSP
Screening, Day 1, 
Month 1 and per site 
preference
Unintended Consequences
Unintended consequences refer to outcomes that are not anticipated and intended at the 
time of intervention implementation; they can be both positive (e.g. improved job 
satisfaction) and negative (e.g. increased workload for healthcare professional). During 
the semi-structured stakeholder interviews, we will ask if there were any unintended 
consequences that were not anticipated (i.e. Yes or No), if they were positive or negative 
and specifically what were they.
Disclosure Statement: This is a single group, open-label, interventional treatment study 
to assess the implementation of a new therapeutic strategy for HIV infection.
Number of Participants:
Approximately 9 sites will be included in this study and will be allowed two months to
enrol up to 15 patient study participants each. Additional time for recruitment of patient 
study participants (up to an additional two months) may be allowed depending upon the 
site activation and enrollment rate. Fifteen patient study participants per site is intended 
as a reasonable number to provide clinic staff adequate exposure to implement the CAB + 
RPV LA regimen so that they can describe the challenges and practical limitations
experienced during initial implementation of CAB + RPV LA. Fifteen patient study 
participants per site may also yield enough recurring office visits at clinics to necessitate 
alternate approaches to successful injection implementation beyond typical clinic 
practice. Therefore, the maximum number of patients included in this study is anticipated 
to be approximately 135.
Staff study participants from each site (physician/ PCP, nurse/medication administration 
personnel, administrator/clinic manager) will also take part in this study, including 
participation in surveys, interviews and facilitation calls.
Intervention Groups and Duration:
Informed consent must be obtained prior to any study procedures, including any Day 1 
assessment.
Patient study participants
All patient study participants will complete the screening phase of up to 21 days prior to 
Day 1 during which all clinical and laboratory assessments of eligibility must be 
performed and reviewed. Participants may be re-screened twice. Participants who are 


2018N382441_03
CONFIDENTIAL
209493
25
enrolled into the trial and subsequently withdrawn from the study, for any reason, may 
not be re-screened. Participants may be enrolled as soon as all eligibility requirements 
have been confirmed at the site. Patient study participants with an undetectable HIV-1 
RNA (<50 c/mL) at Screen are eligible to enter this study. A single repeat viral load to 
determine eligibility may be allowed ONLY after consultation with the medical monitor. 
Should a participant be allowed a repeat, results of this repeat must be available prior to 
Day 1 of this study, therefore the time needed for scheduling the Day 1 visit, lab draws 
and lab analysis should be considered.  
HIV-infected participants who meet all eligibility criteria will be switched at Day 1 from 
their pre-baseline regimen to an oral regimen for one month (CAB 30 mg + RPV 25 mg). 
Participants will return to the clinic, and if laboratory and clinical evaluations continue to 
support progression into the LA portion of the study, will take the last dose of their oral
regimen (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). All subsequent 
injections (CAB LA 400 mg + RPV LA 600 mg) will occur every month thereafter. Note: 
Patient study participants with Grade 1 LFTs at screening and or day 1 must be 
discussed with the Medical Monitor prior to initiation of LA dosing; continuation in the 
study or progression onto LA dosing may require additional evaluations, including labs 
drawn after a period of oral dosing with CAB + RPV.
The dosing window for the second and third injection (Month 2 and Month 3) will be +0 /
-7 days from the projected dosing visit; All subsequent injection windows (beginning at 
Month 4) will be +7/-7 days from the projected date of the visit. Doses outside of the 
window may be allowed with prior Medical Monitor approval.
Participants will continue CAB LA + RPV LA until: 

study intervention is locally approved and commercially available, 

the participant no longer derives clinical benefit, 

the participant meets a protocol-defined reason for discontinuation  

the development of either CAB LA or RPV LA is terminated

participant withdraws consent

investigator discretion

participant or investigator non-compliance

termination of the study by the Sponsor.
Safety and efficacy assessments will be conducted as per the Schedule of Assessments.
Dosing will occur according to the selected regimen. 
If the intramuscular (IM) dosing regimen is discontinued as a result of an independent 
data monitoring committee (IDMC) review from the ongoing Phase 3 studies, any 
subsequent analysis, or any other programmatic analysis, those participants who have not 
met any clinical management criteria for discontinuation will be discontinued 
permanently from the study and will enter into the LTFU Phase of the study.


2018N382441_03
CONFIDENTIAL
209493
26
LTFU Phase –Following the 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 during the period of declining drug exposures 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 monthly injection, however if withdrawn due to virologic failure, 
HAART should be initiated as soon as virologic failure is confirmed. Discuss with 
medical monitor. The Long-Term Follow Up period (LTFU) will begin the day of the 
last CAB LA and/or RPV LA dose and continue for 52 weeks. These participants will not 
complete a Withdrawal visit, but will instead move directly into the LTFU as per the
Schedule of Activities, Section 1.5. 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 for the entire year of follow up.
In order to assure that participants have access to HAART during the LTFU, ViiV 
Healthcare may supply HAART or reimbursement may 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, end of study timings, etc.
Staff study participants
Staff study participants will include HIV care providers (HCPs), nurses/ staff performing 
CAB + RPV LA injections, and administrators/clinic managers at each investigational 
site. Staff study participants will provide input through the use of surveys, semi-
structured interviews (SSI) and via the monthly facilitation calls, per the Schedule of 
Assessments Table.
Should there be turnover in staff study participants over the course of the study, the 
replacement staff member will undergo study training per site standard practice, and 
provide input through surveys, SSI and monthly facilitation calls as per the Schedule of 
Activities Table, Section 1.5.
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.


2018N382441_03
CONFIDENTIAL
209493
27
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). The SPM will provide 
the site personnel with administrative and detailed technical information.
Data Monitoring Committee:
A Data Monitoring Committee will not be used in this study.
1.4.
Schema


2018N382441_03
CONFIDENTIAL
209493
28
1.5.
Schedule of Activities (SoA)
There are additional PK assessments for any pregnant participants who are remaining in the study. See Appendix 8
Table 3
Schedule of Activities for Patient Study Participants (CAB LA + RPV LA Monthly Administration)
Procedures
Screeninga
Intervention Period
WDo
Day 1
Month 1
Month 2
Month 3
Month 4
Month 5
Month 6
Month 7
Month 8
Month 9
Month 10c
Month 11c
Month 12c
Written 
Informed 
Consent b
X
Demography
X
Eligibility 
Verification
X
Physical Exam
X
Medical 
History
X
Center for 
Disease 
Control and 
Prevention 
(CDC) 
Classification
X
Randomization 
for interviews
X
Rapid Plasma 
Reagin (RPR)
X


2018N382441_03
CONFIDENTIAL
209493
29
Procedures
Screeninga
Intervention Period
WDo
Day 1
Month 1
Month 2
Month 3
Month 4
Month 5
Month 6
Month 7
Month 8
Month 9
Month 10c
Month 11c
Month 12c
Symptom 
Directed 
Physical Exam 
and Medical 
Assessmentd
X
X
X
X
X
X
X
X
X
X
Injection site 
reaction (ISR) 
assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs
(temperature, 
blood pressure 
[BP], heart 
rate [HR])e
X
X
X
X
X
X
X
X
X
Weight, 
Height & body 
mass index 
(BMI)f
X
X
X
X
X
X
HIV 
Associated 
Conditions, 
AE and serious 
adverse event 
(SAE) 
Assessments& 
Con Meds
X
X
X
X
X
X
X
X
X
X
12-Lead ECGg
X
X


2018N382441_03
CONFIDENTIAL
209493
30
Procedures
Screeninga
Intervention Period
WDo
Day 1
Month 1
Month 2
Month 3
Month 4
Month 5
Month 6
Month 7
Month 8
Month 9
Month 10c
Month 11c
Month 12c
Clinical and 
Hematology
X
X
X
X
X
X
X
Pregnancy 
Testing 
(U)rine or 
(S)erumh
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
HIV-1 RNA
X
X
X
X
X
X
X
X
X
X
Plasma sample 
for storagei,j
X
X
X
X
X
X
X
X
X
CD4+cell 
counts
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
Glucose
X
Prothrombin 
time (PT)/ 
partial 
thromboplastin 
time (PTT)/ 
international 
normalized 
ratio (INR)
X
X
Oral study 
product 
dispensation
X


2018N382441_03
CONFIDENTIAL
209493
31
Procedures
Screeninga
Intervention Period
WDo
Day 1
Month 1
Month 2
Month 3
Month 4
Month 5
Month 6
Month 7
Month 8
Month 9
Month 10c
Month 11c
Month 12c
LA study 
product 
administrationk
Xn
X
X
X
X
X
X
X
X
X
X
X
Participant 
Visit 
Reminder 
Contact
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Participant 
Contact Detail 
Confirmation
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Record study
visit lengthl
X
X
X
Patient 
Questionnaire
X
X
X
Selected 
Patient 
Interviews 
(SSI)m
X
X
See footnote “c” for continuation of visit schedule after Month 12, if required. Subjects will continue on study until the CAB + RPV LA regimen is either locally approved and commercially 
available, the participant no longer derives clinical benefit or meets a protocol-defined reason for discontinuation or until development is terminated.
a.
A screening visit will be conducted within 21 days of Day 1.  However, it is preferred for Day 1 to be conducted as soon as practical after all screening results are available.
b.
After discussion of risk:benefit, a pregnancy specific ICF addendum must be signed by pregnant participants who wish to remain in the study 
c.
Continue this pattern for visits for the remainder of the study if needed, until commercial CAB + RPV LA is available. For example, Month 13 will be conducted as per Month 10, Month 14
will be conducted as per Month 11, Month 15 will be conducted as per Month 12, Month 16 will be conducted as per Month 10, and so on. The exception to this pattern is that no 
questionnaires, study visit length collection, or patient interviews will be conducted after the Month 12 visit.
d.
Physical exams should be conducted as part of normal routine clinical care but data will not be collected in the electronic case report form (eCRF). Medical assessments include any 
decisions the study staff must make for participant management.
e.
Measure vital signs after about 5 minutes of rest in a semi-supine position.


2018N382441_03
CONFIDENTIAL
209493
32
f.
Height collected at Day 1 only.
g.
At Screening, ECGs should be performed in triplicate at least 5 minutes apart and following 5 minutes of rest in a semi-supine position. ECG evaluations performed at subsequent visits 
should be obtained after dosing, preferably 2-4 hours post dosing. ECG at Withdrawal should be performed following 5 minutes of rest in a semi-supine position.
h.
A (-) urine pregnancy test is required prior to any injection and as required by medical monitor after a treatment interruption. A (+) urine test should be confirmed with a stat serum test. A 
Serum pregnancy test should be performed at any time pregnancy is suspected by the Investigator and may be used in place of a urine test at the discretion of the investigator. Pregnant 
participants who remain in the study do not need pregnancy testing during the study, for the duration of their pregnancy. Pregnant participants remaining in the study have additional 
assessments required, as described in Appendix 8
i.
Plasma for storage samples are collected for possible future analyses, back-up in cases of loss/damage in transit, geno/pheno analyses for virologic failures or PK in the event of 
maladministration or virologic failure.
j.
Participants who get pregnant while in study will have additional PK samples for CAB and RPV obtained. See Appendix 8
k.
Monthly injections are 1 x CAB LA 600 mg IM + 1 x RPV LA 900 mg IM at Month 1.  Subsequent injections beginning at Month 2 are 1 x CAB LA 400 mg IM + 1 x RPV LA 600 mg IM. If 
possible, injections should be spaced approximately 2 cm from one another and from the site of any previous injection and/or any injection site reaction. Bring RPV LA to approximately 
room temperature prior to injecting. Time and location of injection (right or left) as well as needle length used will be collected in the eCRF. IM dosing is expected to occur during the 
month in which the participant’s projected visit falls (as according to the Day 1 visit). A dosing window of +0 / -7 days from date of projected visit is stipulated for IM dosing at 
Month 2 and Month 3. A (+ or -) 7 day window from date of projected visit is stipulated for IM dosing beginning at Month 4. All decisions regarding dose interruption/ 
resumption must be discussed with the medical monitor in advance.
l.
Length of study visit from arrival until departure from clinic will be evaluated. Time of arrival, time of appointment, and departure times will be recorded in the eCRF.
m.
The first semi-structured interview will be scheduled between Day 1 and prior to Month 1 visit. The end of study SSI will be scheduled within approximately within approximately 4 
weeks of their Month 12 study visit.
n.
Note: Patient study participants with Grade 1 LFTs at screening and or day 1 must be discussed with the Medical Monitor prior to initiation of LA dosing; continuation in the 
study or progression onto LA dosing may require additional evaluations, including labs drawn after a period of oral dosing with CAB + RPV.
o.
Follow Up Visit - Conduct ~4 weeks after the last dose of investigational product (IP) if not entering Long-Term Follow Up and only if the participant has ongoing AEs or lab abnormalities at 
the last on-study visit. May be conducted by telephone.


2018N382441_03
CONFIDENTIAL
209493
33
Table 4
Schedule of Assessments Table for Staff Study Participants
a.
Questionnaire and interview should be conducted prior to the first patient receiving their first CAB + RPV LA injection at that site.
b.
Questionnaire and interview should be conducted within approximately 4 weeks of the targeted subject visit at each site for Month 4 and after at least 50% 
of patient study participant visits at Month 12.
c.
Facilitation calls will continue during the enrollment period until the last enrolled subject achieves their Month 6 study visit.
Procedures
Prior to 
Enrollment
Intervention Period (Month)
Day 1
1
2
3
4
5
6
7
8
9
12
Staff Study Participant 
Questionnaire
Xa
Xb
Xb
Staff Study Participant 
Interviews (SSI)
Xa
Xb
Xb
Staff Study Participant 
Monthly Facilitation 
Callsc
X
X
X
X
X
X
X
X
X
X


2018N382441_03
CONFIDENTIAL
209493
34
Table 5
Schedule of Activities Table for Patient Study Participants (Long Term Follow Up)a
Procedures for Long-Term Follow Upa
Month 3
Month 6
Month 9
Month 12
WD
Notes
HIV Associated Conditions, AE and SAE 
Assessments, Con Meds
X
X
X
X
X
Every effort should be made to enter participants into the Long-Term 
Follow Up if they withdraw from or discontinue the study after receiving 
at least one dose of CAB LA and / or RPV LA.
a.
The start of the 52-week follow-up period begins the day of the last 
CAB LA and/or RPV LA dose.
b.
A PK sample for storage should be collected in the event of 
virologic failure during the LTFU phase
c.
Participants who get pregnant while in study will have additional PK 
samples for CAB and RPV obtained, see Appendix 8
d.
FRP only. U=urine; pregnant participants who remain in the study 
do not need pregnancy testing during the study, for the duration of 
their pregnancy
e.
FRP should continue to receive counselling on the need to use 
adequate contraception for the entirety of the Long-Term Follow-Up 
Period.
f.
Investigators must discuss choice of HAART regimen and timing of 
initiation with the medical monitor before initiating
HIV-1 RNA
X
X
X
X
X
CD4+ cell counts
X
X
X
X
X
Plasma for Storage
X
X
X
X
X
PK Sample for Storageb,c
Clinical Chemistry and Hematology
X
X
X
X
X
Pregnancy Testingd
U
U
U
U
U
Urinalysis
X
X
PT/PTT/INR
X
X
Contraception Counsellinge
X
X
X
X
X
HAART Dispensationf
X
X
X
X
X


2018N382441_03
CONFIDENTIAL
209493
35
2.
INTRODUCTION
While advances in the development of new anti-retroviral therapies (ART) provide 
extensive insights into the management of human immunodeficiency virus (HIV)-
infected individuals, chronic HIV infection in adults continues to be characterized by 
increased development of resistant virus, increasing transmission of resistant virus and 
issues associated with the long-term toxicity of ART. The current paradigm in the 
treatment of HIV involves life-long therapy with multiple antiretrovirals. There is an 
enduring need to develop new agents and combinations with improved dosing schedules, 
and robust efficacy, safety and resistance profiles for both antiretroviral treatment-naive 
and treatment-experienced participants.
2.1.
Study Rationale
CAB + RPV LA is an investigational HIV treatment regimen of long-acting cabotegravir 
plus long-acting rilpivirine administered as two concurrent intramuscular injections every 
month. This new HIV regimen will require changes to the current standard of care, which 
involves the prescription of oral antiretroviral therapies. Such changes will include 
managing the logistics of delivering a complete antiretroviral treatment regimen as long 
acting (LA) injectable therapy. This new treatment option will require patients to receive 
injections from a provider every month and require staffing resources and logistical 
arrangements for administration of the injections. It is therefore important to understand 
how to optimize the delivery of CAB + RPV LA from a PLHIV, HCP and healthcare 
system perspective in order to ensure equal and easy access for patients. In preparation 
for national implementation following regulatory approval, there is a need to understand 
what level of clinic training and support will be needed to effectively deliver this 
regimen. In this study, investigational sites will have access to a suite of training and 
implementation tools as well as short-term intensive counseling. The study will evaluate 
both qualitative and quantitative measures across a range of clinic types to determine the 
most effective strategies, identify barriers and facilitators for successful implementation 
of the CAB + RPV LA regimen.
The CAB + RPV LA regimen is also being studied for use once every two months in the 
ATLAS-2M study. If successful, a two-monthly regimen may become available after 
initial approval; while two-monthly dosing would reduce the frequency of injection visits
for patients, it would require similar strategies for successful implementation, thus the 
learnings from this study are expected to be applicable to a two-monthly dosing regimen
as well.
2.2.
Background
The treatment of HIV-1 infection has advanced since the first oral antiretroviral agent 
(AZT) was approved for the treatment of HIV-1 infected individuals in 1987. Newer 
antiretrovirals are more potent, better tolerated and have enabled the formulation of 
multiple regimens that can provide viral suppression with a single tablet once daily. 
Moreover, clinic visits for laboratory monitoring have become less frequent; current 
standard of care for virally suppressed patients is a clinic visit with laboratory every 3-6 
months. While there have been major advances in the field of HIV therapeutics, 


2018N382441_03
CONFIDENTIAL
209493
36
tolerability, long term safety concerns and adherence remain significant limitations to 
treatment success. Consistent lifetime daily adherence is difficult for many patients, 
reducing effectiveness of these treatments [DHHS, 2018]. Moreover, intermittent 
compliance can result in HIV drug resistance, with subsequent regimens being more 
complicated to construct.
Long acting injectable versions of drugs are being developed to enable therapy with 
infrequent dosing injection. These therapeutic options hold great promise for future 
treatment and represent an emerging paradigm for the treatment of HIV infection. 
Cabotegravir (CAB) is a potent integrase inhibitor that possesses attributes that allow 
formulation and delivery as a long-acting (LA) parenteral product. Rilpivirine (RPV), 
also formulated as a LA product, is a diarylpyrimidine derivative and a potent non-
nucleoside reverse transcriptase inhibitor (NNRTI) with in vitro activity against wild type 
HIV-1 and select NNRTI-resistant mutants. A two-drug regimen with CAB LA plus RPV 
LA (CAB + RPV LA) offers many potential advantages over daily oral regimens 
including infrequent dosing that decreases the daily reminder to patients of their HIV 
status, better tolerability, less likely to develop viral resistance due to intermittent 
compliance with oral agents that can lead to sub-therapeutic concentration of 
antiretroviral medication and emergence of resistance, and improved adherence and 
overall treatment satisfaction in virologically suppressed patients. Results to date have 
demonstrated the efficacy of a two-drug regimen of CAB + RPV LA as maintenance 
therapy with several on-going Phase 2 and 3 studies including LATTE-2, ATLAS, 
FLAIR, and ATLAS 2M currently underway. [Margolis, 2017]
This new treatment paradigm will require changes to the current standard of care of
prescribing oral antiretroviral therapies including the logistics of delivering a complete 
antiretroviral treatment regimen as LA injectable therapy. This new treatment paradigm 
will require more frequent visits by patients to see a provider and receive injections, as 
well as potentially require greater resources in the clinical setting to administer the 
injection. As this is a promising new treatment modality for people living with HIV 
(PLHIV), it is important to understand how to optimize the delivery of CAB + RPV LA
from a PLHIV, HCP and healthcare system perspective. Previous focus groups convened 
in the United States have provided some insights into the mixed reactions of how CAB + 
RPV LA will be implemented in the clinical setting. Concerns raised about chronic 
dosing injections include overburdening the health care system, CAB + RPV LA more 
frequent patient encounters and concerns that patients will not want, or not remember to 
come to clinic for scheduled monthly injections, with the potential to lead to inadequate 
ART coverage and the development of viral resistance.
The need for pragmatic data and experience is essential to fully understand the barriers 
and enablers for delivery of this evidence-based treatment. As this is a new and novel 
treatment in the field of HIV therapeutics, it is critical to understand “how” to effectively 
implement this treatment paradigm to ensure optimal impacts on healthcare service 
system- and patient-level outcomes. In preparation for national implementation following 
FDA approval, it is important to understand what level of support and preparation will be 
needed to ensure that clinics are well prepared for administering and incorporating this 
new and more frequent directly observed injectable therapy in the clinic setting. This 
study will explore a suite of training and implementation tools as well as short-term 


2018N382441_03
CONFIDENTIAL
209493
37
intensive facilitation, to determine what will be effective in preparing clinics to deliver 
CAB + RPV LA across diverse clinical settings. Therefore, this study will aim to collect 
insights regarding clinical settings, context, barriers and facilitators from a patient, 
healthcare provider and healthcare system perspective in order to effectively implement 
the CAB + RPV LA regimen at the time of FDA approval.
Implementation Rationale/Theory of Change: 
Lippitt, Watson, and Westley created a seven-step theory that focuses more on the role 
and responsibility of the change agent than on the evolution of the innovation itself. 
Information is continuously exchanged throughout the process. Infectious Disease/HIV 
providers were queried on their plan and ability to implement CAB + RPV LA effectively 
into their clinical settings. Mixed responses suggested that some sites might require more 
support and some sites many require less support to implement this new intervention 
well. Based on Powell’s list of most effective intervention strategies, ViiV Healthcare is 
proposing to test a complex implementation strategy with external facilitation as a core 
component of this study [Powell, 2015] to help elucidate the level of support, best 
practices, and required tools needed to implement this novel evidenced-based 
intervention into a variety of clinical settings.
The seven steps of this theory are: 1. Understand the new change or innovation. 2. Assess 
the motivation and capacity for change. 3. Assess the resources and motivation to support 
the innovation. 4. Choose progressive change strategies. 5. Implement a clear 
intervention. 6. Maintain the change. 7. Gradually terminate from the helping 
relationship. The change agent should gradually withdraw from their role over time. This 
will occur when the change becomes part of the organizational culture (Lippitt, Watson 
and Westley).
The implementation strategy for this study was constructed based on Lippitt, Watson and 
Westley’s theory of change but also took into consideration feedback from numerous 
focus groups and advisory boards conducted by ViiV Healthcare.
Implementation Questions:
How prepared are healthcare settings to incorporate a high volume of patients receiving 
the CAB + RPV LA regimen into their clinical flow across three different clinical settings 
in the US while also identifying multi-level barriers to and facilitators for successful 
implementation? In order to answer this fundamental question, the study will focus on the 
following four aims.
Study Aims:
Aim 1: Evaluate the degree of acceptability, appropriateness, feasibility, fidelity, and 
sustainability achieved for CAB + RPV LA;
Aim 2: Identify multi-level barriers and facilitators to implement and sustain the 
intervention (CAB + RPV LA);


2018N382441_03
CONFIDENTIAL
209493
38
Aim 3: To identify the optimized complex implementation strategy required for 
successful implementation of CAB + RPV LA in various clinical settings and contexts;
Aim 4: To measure patient satisfaction with the process (timeliness of visits, length of 
visit, and patient education).
Implementation Stage of Research Project:
Initial implementation stage: the first use of an evidence-based intervention (i.e., CAB + 
RPV LA) by healthcare professionals and patients/service users in pragmatic clinical care 
settings and learning how to support successful implementation into routine care. 
The LATTE and LATTE-2 studies have demonstrated the efficacy of maintaining viral 
load suppression in participants who initiated a three drug ARV regimen prior to 
switching to the two-drug CAB + RPV regimen. Specifically, phase 2b studies including 
LATTE and LATTE-2 provided a proof of concept for a two-drug regimen in patients
initially suppressed on three drugs. The LATTE study provided valuable information on 
both the optimal dose of oral CAB and the importance of an induction/maintenance 
approach to HIV therapy. The LATTE-2 study demonstrated the ability of a 2-drug 
maintenance therapy of LA CAB and LA RPV to maintain virologic suppression in 
patients who initiated on a triple antiretroviral oral based regimen
Several larger, phase 3 studies are currently underway (ATLAS, ATLAS-2M, and 
FLAIR) that will test the effectiveness of CAB + RPV LA in maintaining viral load 
suppression in patients initially suppressed on a three-drug regimen.
Design of Implementation Research:
Hybrid III: The primary focus of this study is implementation of mostly provider-
focused implementation strategies (suite of training and implementation tools as well as 
short-term intensive facilitation); The secondary focus is on the clinical efficacy of this 
novel approach to antiretroviral therapy for the treatment of HIV infection (CAB + RPV 
LA). Implementation research outcomes are different than clinical outcomes more 
commonly incorporated into clinical trial research and design. In Implementation 
Science, research outcomes are typically provider and/or system behaviours rather than 
patient clinical outcomes. For example, outcomes can include levels and rates of 
acceptability, adoption, and fidelity to the clinical intervention [Proctor, 2011]. 
In addition, implementation research focuses on addressing the question ‘what works 
where and why.’ In other words, implementation research focuses on identifying 
factors/processes that negatively and positively impact implementation outcomes so that 
these issues can be effectively addressed in subsequent implementation efforts. The 
proposed research will allow us to tailor implementation strategies and clinical support 
materials to match the specific needs of different clinical settings. This proposal is thus 
guided by frameworks that are appropriate to the proposed stage of implementation 
research, including a determinants framework and an outcomes taxonomy, that is highly 
sensitive to features of the context in which the implementation efforts are to occur when 
CAB + RPV LA goes to scale. Additionally, this study will clinically monitor all patients 
enrolled and will collect routine HIV laboratory testing including basic safety analysis, 


2018N382441_03
CONFIDENTIAL
209493
39
HIV RNA and CD4 measurements and physical assessments that will be obtained 
throughout the study to ensure clinical safety, tolerability and efficacy (Section 1.5).
Frameworks:
In this study, a combination of two complementary frameworks will guide the 
implementation evaluation. [Proctor, 2011] put forth a taxonomy of 8 distinct 
implementation outcomes that are key indicators of implementation success as well as 
proximal indicators of implementation processes. As this is a Phase III study with an 
investigational drug that is not registered or available commercially, the focus for initial 
implementation evaluation is on 5 key implementation outcomes: (1) acceptability, (2) 
appropriateness, (3) feasibility, (4) fidelity, and (5) sustainability (see Table 6 below for 
definitions). According to [Proctor, 2011], these represent key intermediate outcomes in 
relation to service system outcomes or clinical outcomes in treatment effectiveness and 
quality of care research. [Proctor, 2011]
Table 6
Primary Implementation Outcomes
Acceptability: Perception amongst implementation stakeholders (providers, administrators, and 
patients) that the new intervention is agreeable, palatable and satisfactory
Appropriateness: The perceived fit, relevance, or compatibility of the innovation or evidence-
based practice for a given practice setting, provider, or consumer; and/or perceived fit of the 
innovation to address a particular issue or problem.
Feasibility: Extent to which an intervention can be successfully used or carried out in a given 
setting
Fidelity: Extent to which an intervention gets applied as originally designed/intended. Will the 
new intervention be administered as intended.
Sustainability: Extent to which the intervention becomes routinely available/maintained post 
introduction
For the purposes of this study we will quantitively assess (1) Acceptability (2) 
Appropriateness, (3) Feasibility, and (4) Sustainability. These will be conducted in short 
validated off the shelf surveys which take approximately 15 minutes per survey. By 
measuring acceptability, appropriateness and feasibility, these can act as surrogate 
markers for adoption (and can be extrapolated to real-world adoption outside of a clinical 
trial environment). (See Section 10.10 , Section 10.11, for a summary of elements to be 
evaluated in the surveys)
As the effectiveness of CAB + RPV LA has been documented in several Phase IIb 
studies with several larger Phase III studies (ATLAS, ATLAS-2M and FLAIR) nearing 
completion, it is therefore assumed that successful implementation of CAB + RPV LA
will have a positive impact on patient-level outcomes.
In addition, this study requires rigorous application of a determinants implementation 
framework to identify and assess the factors—across multiple system levels and at the 
clinic and individual provider levels—that explain why the implementation of CAB + 
RPV LA is or is not successful across contexts and clinical settings. We know there are 
many different perceptions of the additional burden that regular injections may place on 
the healthcare system. However, because of the lack of real-world experience, we will be 


2018N382441_03
CONFIDENTIAL
209493
40
exploring within this study what the pragmatic facilitators and barriers may be at clinic 
types where this study will be implemented.
Many implementation frameworks exist; each has advantages and disadvantages, with 
relative advantage conferred on those that are (a) highly specified operationally and (b) 
widely used in implementation evaluations. The Consolidated Framework for 
Implementation Research (CFIR) framework [Andrade, 2009; CDC, 2014; Damschroder, 
2009] meets each of these criteria while emphasizing the central role of context and 
identification of multi-level barriers. The application of the CFIR framework will enable 
us to fully characterize and explain the ways in which implementation strategies and 
service system processes have and have not been successful across contexts and settings 
(Aims 1 and 2). These findings will inform the tailoring of implementation strategies to 
enhance the implementation effectiveness of CAB + RPV LA once approved and ready 
to be taken to scale in the US. We therefore propose to use the Consolidated Framework 
for Implementation Research (CFIR), a well-established, comprehensive, and widely 
used framework that is used to assess existing and potential barriers and facilitators to 
successful implementation and sustainment. CFIR is comprised of 39 constructs 
organized into five domains. It is not practical or necessary to assess all 39 constructs and 
therefore the focus will be on a subset of 14 key CFIR constructs that are most relevant to 
the implementation of CAB + RPV LA (Table 7).
Table 7
CFIR Constructs Guiding the Evaluation of Multi-Level Barriers to 
and Facilitators of CAB + RPV LA Implementation and Sustainment
CFIR Framework -
CONSTRUCTS
SHORT DESCRIPTION
II. Outer Setting
Patient needs and resources
The extent to which patient needs, as well as barriers and 
facilitators to meet those needs, are accurately known and 
prioritized by the organization
III. Inner Setting
Readiness for Implementation –
Leadership Engagement
Tangible and immediate indicators of organizational 
commitment to implement an intervention
Readiness for Implementation -
Available resources
The level of resources dedicated for implementation and 
on-going operations, including money, training, education, 
physical space, and time
Readiness for Implementation –
Access to Knowledge and 
Information
Ease of access to digestible information and knowledge 
about the intervention and how to incorporate it into work 
tasks.
Structural Characteristics
The social architecture, age, maturity, and size of an 
organization
Networks & Communications
The nature and quality of webs of social networks and the 
nature and quality of formal and informal communications 
within an organization
Implementation Climate
The absorptive capacity for change, shared receptivity of 
involved individuals to an intervention, and the extent to 
which use of that intervention will be rewarded, supported
and expected within the organization


2018N382441_03
CONFIDENTIAL
209493
41
CFIR Framework -
CONSTRUCTS
SHORT DESCRIPTION
Tension for Change
The degree to which stakeholders perceive the current 
situation as intolerable or needing to change
Compatibility
The degree of tangible fit between meaning and values 
attached to the intervention by involved individuals, how 
those align with individuals’ own norms, values and 
perceived risks and needs, and how the intervention fits 
with existing workflows and systems
Learning Climate
A climate which a) leaders express their own fallibility and 
need for team members’ assistance and input; b) team 
members feel that they are essential, valued, and 
knowledgeable partners in the change process; c) 
individuals feel psychologically safe to try new methods; d) 
there is sufficient time and space for reflective thinking and 
evaluation
IV. Characteristics of Individuals (e.g. Patients, Providers, Injectors, Administrators etc)
Individual Stage of Change
Characterization of the phase an individual is in, as he or 
she progresses toward skilled, enthusiastic, and sustained 
use of the intervention
IV. Process
Planning
The degree to which a scheme or method of behaviour and 
tasks for implementing an intervention re developed in 
advance, and the quality of those schemes or methods
Engaging Champions
Individuals who dedicate themselves to supporting, 
marketing, and ‘driving through’ an implementation, 
overcoming indifference or resistance that the intervention 
may provoke in an organization
Key Stakeholder
Individuals who are affiliated with an outside entity who 
formally influence or facilitate intervention decisions in a 
desirable direction
Executing
Carrying out or accomplishing the implementation 
according to plan


2018N382441_03
CONFIDENTIAL
209493
42
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 (2017 CAB IB:  
GlaxoSmithKline Document Number RH2009/00003/07; Rilpivirine Clinical Investigator 
Brochure, 2018).
Oral RPV is an approved medicinal product and detailed information on its benefit/risk 
profile together with any risk mitigation measures are described in product labelling. 
(Edurant Prescribing Information, 2018)
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 investigator’s 
brochure (IB).


2018N382441_03
CONFIDENTIAL
209493
43
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 
>3100 participants) 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 participants with suspected DILI identified to date were receiving oral CAB.  

Exclusion criteria as described in Section 5.2 will prohibit 
participation of PLWHIV who have 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. 

Liver transaminases (ALT and AST) will be monitored 
throughout this study (refer to Schedule of Activities
Table, Section 1.5) and the liver chemistry stopping 
criteria will be adopted as described in Section 10.6.2 of 
this protocol. Participants will be withdrawn from CAB 
treatment where no compelling alternative cause is 
identified, and DILI is suspected.

Participants who develop ALT ≥3 times the upper limit of 
normal (ULN) while on study must consult with Medical 
Monitor prior to initiation or continuation of CAB LA + RPV 
LA.  
Injection Site Reactions 
(ISRs)
Clinical, experience to date has demonstrated ISRs occur in the majority of 
exposed participants treated with CAB LA but are generally mild (Grade 1) or 
moderate (Grade 2) and include events of pain, tenderness, erythema, or 
nodule formation of several days duration (median duration for individual events 
<1 week).
ISRs may occur more than once in an individual participant receiving multiple 
injections. Although some Grade 3 ISRs have been reported, overall ISRs 
appear tolerable and have not to date been associated with an excess of 
participants’ withdrawal.

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,


2018N382441_03
CONFIDENTIAL
209493
44
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 (INI), 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. 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 
receiving the injection who develop suspected HSR would 
not receive further injections. During oral (oral bridge) and 
IM CAB treatment, any HSR reactions that occur would 
be managed supportively.
Effects in pregnancy seen 
in non-clinical studies
In animal reproduction studies, CAB when administered to rats at > 30 times the 
systemic exposure at the maximum recommended oral human dose (MRHD) of 
30 mg during organogenesis through delivery, had adverse effects on labor and 
delivery that may be related to a delay in the onset of parturition, resulting in 
increased fetal mortality (stillbirths) and neonatal deaths immediately after birth.
A delay in the onset of parturition and increased stillbirths and neonatal deaths 
were observed in a rat pre- and postnatal development study at greater than 28 
times the exposure at the recommended human dose (RHD). No evidence of 
adverse developmental outcomes was observed with oral cabotegravir in rats or 
rabbits (greater than 28 times or similar to the exposure at the RHD, 
respectively) given during organogenesis.
The clinical significance of these finding in humans is unknown.
For pregnant participants remaining in the study, refer to Appendix 8 for 

Pregnant females are excluded from enrollment in this 
study and females of reproductive potential (FRP) are 
required to adopt highly reliable means of contraception 
during participation and 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. Pregnant participants 
who remain in the study do not need pregnancy testing 
for the duration of the pregnancy

Participants who become pregnant during the study may 
remain in the study provided all protocol defined 
pregnancy related assessments, procedures and 
documentation are completed, and a pregnancy specific 
ICF addendum is signed by the participant. Details 
regarding management of pregnant participants are found 


2018N382441_03
CONFIDENTIAL
209493
45
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
additional data regarding CAB and pregnancy.
in Appendix 8
Potential effects in females
exposed to dolutegravir 
during conception and 
early pregnancy
A preliminary analysis of an ongoing birth outcome surveillance study in 
Botswana involving women exposed to dolutegravir (DTG) a different molecule 
in the same integrase class of medications as CAB, identified four cases (as of 
May 2018) of neural tube defects in 426 infants born to mothers who were 
exposed to DTG-containing regimens from the time of conception. In the same 
study, no infant born to a woman who started DTG during pregnancy had a 
neural tube defect, out of 2,824 women. A causal relationship of these events to 
the use of DTG has not been established. The incidence of neural tube defects 
in the general population ranges from 0.5-1 case per 1,000 live births. As neural 
tube defects occur within the first 4 weeks of fetal development (at which time 
the neural tubes are sealed) this potential risk would concern women exposed 
to DTG at the time of conception and in early pregnancy. Recently updated data 
(April 2020) for this birth outcome study showed that among women who were 
on DTG when they got pregnant, 7/3591 neural tube defects (NTD) occurred 
(0.19%). In comparison, NTDs were identified in 21/19,361 (.11%) women 
delivering on any non-DTG antiretrovirals. There was not a significant difference 
in the number of neural tube defects between births to women taking DTG and 
those taking other non-DTG antiretroviral treatments (0.09% difference).
The clinical relevance of either of these findings in relation to CAB use is 
unknown

Pregnant females are excluded from enrollment in clinical 
trials of CAB at this time and females of reproductive 
potential (FRP) are required to adopt highly reliable 
means of contraception during participation and 
throughout long term follow up phases of studies after 
exposure to CAB LA.

FRP potential also undergo regular pregnancy testing 
throughout study conduct. Pregnant participants who 
remain in the study do not need pregnancy testing for the 
duration of the pregnancy It should be noted that CAB 
concentration could remain for prolonged periods despite 
discontinuation of CAB LA

Participants who become pregnant during the study may 
remain in the study, provided all protocol defined 
pregnancy related assessments, procedures and 
documentation are completed and a pregnancy specific 
ICF addendum is signed by the participant. Details 
regarding management of pregnant participants is found 
in Appendix 8
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 participants 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 highly active 
antiretroviral therapy (HAART) regimens will be 
prescribed within 4 weeks after the last monthly dose, 
and following consultation with the medical monitor. This 
would be anticipated to result in continued suppression or 
rapid re-suppression 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.


2018N382441_03
CONFIDENTIAL
209493
46
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 6.5.
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 UDP-glucuronosyltransferase (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 drug-drug 
interactions (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.
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 accidental intravenous administration of 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 may be obtained at a few 


2018N382441_03
CONFIDENTIAL
209493
47
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
early timepoints for determination of CAB concentration 
and possible pharmacokinetic correlation with safety 
parameters such as ECG changes and virologic 
response.


2018N382441_03
CONFIDENTIAL
209493
48
Oral RPV
For safety and risk mitigation for oral RPV refer to the RPV local prescribing information 
[Edurant Prescribing Information, 2018]
RPV LA
Information about the clinical experience to date and possible risks associated with 
treatment using RPV LA can be found in the Summary of Data and Guidance for the 
Investigator section of the IB. Beyond what has already been identified with oral RPV, no 
new systemic adverse reactions to RPV LA (same active moiety) have been observed.
The following risks are considered to be of specific clinical relevance in the context of 
IM use.


2018N382441_03
CONFIDENTIAL
209493
49
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Injection Site Reactions
Clinical, experience to date has demonstrated ISRs occur in the majority of 
exposed participants treated with RPV LA but are generally mild (Grade 1) or 
moderate (Grade 2) and include events of pain, tenderness, erythema, or 
nodule formation of several days duration (median duration for individual 
events <1 week). ISRs may occur more than once in an individual participant 
receiving multiple injections. Although some Grade 3 ISRs were reported, 
overall ISRs have been well tolerated and have not to date been associated 
with an excess of participants’ withdrawal due to ISRs.
None of the ISRs was serious and no clinical significant complications were 
reported

Administration advice to minimize risk of poor 
administration technique giving rise to injection site 
reactions. Advice on care, monitoring, natural course, and 
treatment of ISRs given in study documentation 

Advice to participants on care of injection site on day/days 
immediately post administration, use of analgesia, 
compresses where appropriate.

Participants will be closely monitored for ISRs particularly 
for signs of pain, tenderness, infections, erythema, 
swelling, induration, or nodules (granulomas or cysts) 
throughout the study. 

Complications of ISRs such as infections (abscess, 
cellulitis) and collections of fluid requiring drainage will be 
monitored 

Significant ISRs may be photographed and referred to a 
dermatologist for specialist advice.
Rash
Some observations of rash with oral RPV have been reported in clinical studies 
executed to date (the majority are mild). 
Severe skin and hypersensitivity reactions have been reported during the 
postmarketing experience, including cases of Drug Reaction with Eosinophilia 
and Systemic Symptoms (DRESS), with oral RPV-containing regimens.  While 
some skin reactions were accompanied by constitutional symptoms such as 
fever, other skin reactions were associated with organ dysfunctions, including 
elevations in hepatic serum biochemistries.

Participants 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 antiretroviral (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 
10.6.6.10.1 for additional guidance on management of 
rash.


2018N382441_03
CONFIDENTIAL
209493
50
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 
participants)
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 one month after the last monthly dose, 
and following consultation with the medical monitor. This 
would be anticipated to result in rapid re-suppression of 
HIV-1 RNA thus minimizing the risk of emergent resistance

The Sponsor will continue to monitor participants in this 
study who discontinue the 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 6.5.
RPV LA should not be co-administered with the following medicinal products, 
as significant decreases in RPV plasma concentrations may occur (due to 
CYP3A enzyme induction), which may result in loss of therapeutic effect of 
RPV LA.
-
the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, 
phenytoin
-
the antimycobacterials rifampicin, rifapentine, rifabutin
-
the glucocorticoid systemic dexamethasone, except as a single dose 
treatment
-
St John’s wort (Hypericum perforatum).
Of note, evidence to date indicates that clinically relevant DDIs with RPV LA 
and other antiretrovirals are unlikely to occur. 
Oral RPV administration only:  
-
Antacid products containing divalent cations (e.g., aluminum, calcium, 

All participants will be informed of prohibited medications 
throughout the study and updates provided as needed via 
informed consent.


2018N382441_03
CONFIDENTIAL
209493
51
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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;
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 
intravenous [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. 
Overall 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
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 


2018N382441_03
CONFIDENTIAL
209493
52
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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.
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.
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.

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 as needed during the 
injection Phase for determination of CAB and RPV 
concentration and possible pharmacokinetic correlation 
with virologic response.


2018N382441_03
CONFIDENTIAL
53
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. Refer to ‘Summary of data and guidance 
for the investigator’.
Seizure
Several cases of seizure have occurred during the cabotegravir program. These cases 
have had alternative explanations for their occurrence. Overall, there is not convincing 
evidence that cabotegravir exposure may be causally associated with seizure or with 
reduction of seizure threshold, due to the low frequency of reports, the confounders 
present in the cases received to date and lack of any pre-clinical signal or identified 
plausible mechanism. However, seizure and seizure-like events are considered as AEs of 
special interest for CAB. Subjects with an unstable or poorly controlled seizure disorder 
will be excluded from study participation. Report any cases of seizure or seizure like 
events immediately.
2.3.2.
Benefit Assessment
The antiviral activity against HIV-1 of CAB has been well established through in vitro 
and clinical studies. RPV is an established antiviral agent against HIV-1 in treatment 
naive participants, with long term durability (>96 weeks in Phase 3 and >240 weeks in 
Phase IIb).
2.3.3.
Overall Benefit: Risk Conclusion 
Participants receiving CAB LA + RPV LA are anticipated to benefit from maintenance of 
virological suppression using LA agents. Participants who receive CAB LA+ RPV LA as 
monthly dosing will not need to take concomitant daily oral antiretroviral 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 (Margolis, 2018).
Taking into account the measures taken to minimize risk to participants participating in 
this study, the potential risks identified in association with the CAB LA and RPV LA 
regimen and the study as a whole are justified by the anticipated benefits that may be 
afforded to virologically suppressed, treatment-experienced participants with HIV-1 
infection.
The questionnaires and interviews to be administered to clinical staff and study 
participants are not associated with additional risk.


2018N382441_03
CONFIDENTIAL
54
3.
OBJECTIVES AND ENDPOINTS
Objective
Endpoint
Primary
To evaluate acceptability, appropriateness, 
and feasibility of delivering CAB+RPV LA 
Acceptability of Intervention Measure (AIM), 
Intervention Appropriateness Measure (IAM),
and Feasibility of Intervention Measure (FIM). 
Assessed quantitatively by staff study 
participants at baseline- prior to any Month 1 
visits, after at least 4 monthly facilitation calls 
and upon completion of all Month 12 visits at 
that site.
Acceptability of Intervention Measure (AIM) 
and Intervention Appropriateness Measure 
(IAM). Assessed quantitatively by patient 
study participants at Month 1 prior to first 
injection, Month 4 and Month 12
Secondary
To evaluate organizational facilitators and 
barriers
Facilitators/Barriers: Semi-Structured 
Interview (SSI) conducted with staff study 
participants at baseline- prior to any Month 1 
visits, after at least 4 monthly facilitation calls 
and upon completion of at least 50% of Month 
12 visits at that site. 
Barriers, facilitators and best practice sharing 
amongst clinics assessed by short-term 
facilitation (coaching calls) for at least 6 
months. These will be a combination of 
structured questions and open-ended 
questions.
Use of support materials/toolkit assessed via 
Survey responses of staff study participants 
prior to any Month 1 visits, after at least 4 
monthly facilitation calls and upon completion 
of all Month 12 visits at a site. 
Use of support materials/toolkit assessed via 
Survey responses of patient study
participants via Survey responses at Month 1 
and Month 4 and Month 12, as well as SSI 
responses prior to Month 1 and at Month 12.


2018N382441_03
CONFIDENTIAL
55
Objective
Endpoint
Patient Facilitators and Barriers
Facilitators/Barriers: Semi-Structured 
Interviews (SSI) conducted with patient study 
participants prior to Month 1 and at Month 12
Implementation Fidelity
Injections occurring within target window from 
the expected injection date
Use of support materials/toolkit assessed 
through SSI of staff study participants at Day 
1, after at least 4 monthly facilitation calls and 
upon completion of at least 50% of Month 12 
visits at that site.
Implementation Sustainability
Program Sustainability Assessment Tool 
(PSAT) assessed by staff study participants 
at Month 12.
To measure patient satisfaction with process 
(timeliness of visits, length of visit, patient 
education)
Patient Survey responses at Month 1, Month 
4 and Month 12.
Patient SSI responses prior to Month 1 and at 
Month 12
Length of patient visit from arrival until 
departure from clinic at Month 1, Month 5 and 
Month 11
Evaluate safety and efficacy measures of 
CAB+RPV LA
Proportion of participants with plasma HIV-1 
RNA <50 c/mL over time
Proportion of participants with confirmed 
virologic failure (CVF) over time
Incidence of treatment emergent genotypic 
and phenotypic resistance to CAB and RPV in 
patients with CVF
Incidence and severity of AEs and laboratory 
abnormalities over time
Proportion of participants who discontinue 
treatment due to AEs over time
Reported injection site reactions over time
Absolute values and changes in laboratory 
parameters over time


2018N382441_03
CONFIDENTIAL
56
4.
STUDY DESIGN
4.1.
Overall Design
This study is a single-arm, multicenter, one-year evaluation of the effect of an 
implementation strategy on the degree of acceptability, appropriateness, feasibility, 
fidelity, and sustainability of clinic practices to deliver the CAB + RPV LA regimen to 
appropriate HIV-infected patients. The study will use an implementation study approach 
at various clinic types (university/hospital, private clinic or public health) to develop a 
site-specific framework for delivering the CAB + RPV LA regimen which could be 
adapted for broad utilization upon commercial availability of this regimen.
4.2.
Scientific Rationale for Study Design
This time-sensitive proposal will evaluate the implementation of CAB + RPV LA for 
HIV treatment into University/Hospital, public health clinics, and private practices clinic 
settings through an implementation Hybrid Type III evaluation. This will be a phase IIIb, 
qualitative, multicentre study design to evaluate intervention strategies (suite of training 
and implementation tools as well as short-term facilitation). The clinical effectiveness of 
CAB + RPV LA will be also captured as a secondary endpoint. A mixed methods 
approach is proposed where quantitative (surveys) and qualitative (key informant 
interviews) implementation outcomes are collected, as well as quantitative data to assess 
clinical effectiveness outcomes. Summative implementation outcome data will be 
analysed using the Proctor framework and survey questionnaires. The barriers, 
facilitators, sustainment, fidelity, use of implementation tools, training and patient 
satisfaction will be analysed using semi-structured interviews from the validated CFIR 
framework. Sharing best practices and key learnings will be analysed by short-term 
facilitation calls.
4.3.
Justification for Dose
4.3.1.
Oral Lead-In Phase
Participants in 209493 will enter the study virologically-suppressed on an oral SOC 
regimen and will receive oral CAB 30 mg + RPV 25 mg once daily during the oral lead-
in phase to confirm tolerability prior to receiving CAB LA + RPV LA injectable 
treatment.
Oral CAB has been co-administered with oral RPV in several studies. No clinically 
relevant drug-drug interaction following repeat oral administration of CAB with RPV 
was observed in healthy subjects in LAI116181 [GlaxoSmithKline Document Number 
2011N130484_00]. Oral RPV 25 mg once daily, the approved oral dose of RPV, was 
administered in combination with oral CAB to HIV-infected participants in the dose-
ranging Phase 2b study LAI116482 [(LATTE, (CAB 10, 30, or 60 mg once daily)); 
GlaxoSmithKline Document Number 2014N216014_00] and 200056 [LATTE-2]
(GlaxoSmithKline Document Number 2013N168152_05) with CAB 30mg once daily 
during the ~4 week oral lead-in phase and in Phase 3 studies 201585 [ATLAS] and 
201584 [FLAIR] which are evaluating Q4W dosing of CAB LA + RPV LA.


2018N382441_03
CONFIDENTIAL
57
LAI116482 (LATTE), a Phase 2b, dose-ranging study (randomized 1:1:1: to CAB 10 mg, 
30 mg, or 60 mg) evaluated the long-term efficacy and safety of a two-drug, two-class, 
once-daily combination of CAB + RPV in HIV-infected, treatment-naïve adult 
participants. Following a 24-week phase of induction of virologic suppression using CAB 
+ 2 NRTIs, the regimen was simplified to a dual regimen, where subjects continued their 
randomized oral dose of CAB with RPV 25 mg once daily for an additional 72-weeks 
(total comparative study duration of 96 weeks; [Margolis, 2018], after which one oral 
CAB dose was selected for progression into the Extension Phase with RPV 25 mg once 
daily. 
Across all dose arms, CAB achieved similar efficacy when co-administered with 2 
NRTIs at Weeks 16 and 24, and on dual treatment with RPV at Weeks 48 and 96, 
respectively (Table 8). Rates of virologic suppression through Week 96 (Maintenance) 
were numerically higher than the EFV-based comparator regimen.
Table 8
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
+2 NRTIs
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
+ 2 NRTIs
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
+ RPV
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
+ RPV
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.
Overall, the efficacy and safety data from the LATTE study, CAB exposure following 
LA administration, and limited drug-drug interaction potential, supported 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 studies with CAB LA and RPV LA. Select 


2018N382441_03
CONFIDENTIAL
58
plasma CAB PK parameters observed following oral administration with oral RPV, 
including following the oral lead-in for LATTE-2, are summarized in Table 9.
Table 9
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)
AUC(0-)
(g.h/mL)
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)]
---
median (range)
n=57
n=50
n=53
n=51
n=55
n=49


2018N382441_03
CONFIDENTIAL
59
4.3.2.
Long Acting Injectable Phase
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 Oral Phase (16 weeks of 
oral CAB + 2 NRTIs, 4 weeks of CAB + 2 NRTIs + oral RPV) to induce suppression of 
HIV and assess for tolerability to CAB and RPV prior to receiving LA injections. 
Participants who were eligible to continue into the Injection Phase were then randomized 
(2:2:1) to receive IM 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 oral triple ART regimen.
Both Q4W and Q8W regimens were continued throughout the Injection Phase as 
planned, and Week 96 results (Table 10) were supportive of further evaluation both the 
Q4W regimen in ATLAS and FLAIR as well as the Q8W regimen in the ATLAS-2M 
study. Subjects completing the 96-week Injection Phase remained 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.
At week 160, 90% of patients receiving intramuscular CAB + RPV every eight weeks 
and 83% of patients receiving the same regimen every four weeks remained virally 
suppressed. Of the patients that switched from the comparator regimen of oral CAB + 
abacavir(ABC)/lamivudine(3TC) to the intramuscular regimen following week 96, 98% 
remained suppressed through to week 160. (Margolis, 2018)
Approximately 86% of patients reported an injection site reaction (ISR), of which 85% 
were mild and 14% were moderate. 87% of ISRs resolved within 7 days. Excluding site 
ISRs, the most common adverse events (AEs) were nasopharyngitis (38%), diarrhea 
(22%), and headache (22%). 21% and 25% of patients dosed every 8 or 4 weeks, 
respectively, reported AEs grade 3 or above, of which 2% and 5% reported grade 3 drug-
related AEs. 3% and 5% of patients had AEs leading to withdrawal or permeant 
discontinuation of the intramuscular CAB + RPV regimen. 15% and 18% of patients 
reported serious adverse events, and 1 patient had a serious adverse event that was 
reported as drug related.
Only two patients originally randomised to the LA dosing regimens had ISRs leading to 
discontinuation and none after week 24. Of the patients who switched to IM therapy 
following Week 96, 1/44 patients had an ISR leading to discontinuation. The overall ISR 
discontinuation rate was very low 3/274 (1%), and suggests good tolerability to CAB + 


2018N382441_03
CONFIDENTIAL
60
RPV injections for up to 3 years. No serious ISRs were reported and the majority were 
mild/moderate pain and discomfort with <1% of ISRs classified as severe (grade 3).
Table 10
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 1
and summarized in Table 11.
Figure 1
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)
Both predose and 2h post injection concentrations are shown at Time Zero, Week 32, and 
Week 48.


2018N382441_03
CONFIDENTIAL
61
Table 11
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)


2018N382441_03
CONFIDENTIAL
62
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 predicted CAB profile for the Q4W regimen based on population PK modelling is 
shown in Figure 2.
Figure 2
Simulated* Median (90% Prediction Interval [PI]) CAB Plasma 
Concentrations versus Time for the CAB LA Q4W Regimen (600 mg 
IM Day 1, then 400 mg IM Q4W thereafter)
* Note: current simulations based on interim plasma concentration dataset
^Study schedule of activities include a 4 week oral lead in.  Therefore, Day 1 = day of first injections (Week 4b 
study visit); Week 4 = second injections (Week 8 study visit)
Medium dashed line at 1.35 g/mL corresponds to the geometric mean Ctrough concentration following oral CAB 
10 mg once daily (LATTE) and is equivalent to 8x PA-IC90 
Dotted line at 0.664 g/mL corresponds to 4x PA-IC90 


2018N382441_03
CONFIDENTIAL
63
4.3.3.
RPV LA Pharmacokinetics
Observed PK data for both RPV LA Q4W and Q8W regimens in LATTE-2 are presented 
in Figure 3 and Table 12. The RPV LA population PK model has been updated to include 
data from LATTE-2 and from Phase 1 studies in healthy volunteers.
Figure 3
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
Both predose and 2 hr post injection concentrations are shown at Time Zero, Week 32, 
and Week 48.


2018N382441_03
CONFIDENTIAL
64
Table 12
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 
Interva
l
(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)
AUC(0- ) 
(g•h/mL)
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


2018N382441_03
CONFIDENTIAL
65
The predicted RPV profile for the Q4W regimen based on population PK modelling is 
shown in Figure 4.
Figure 4
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 schedule of activities include a 4 week oral lead in. Therefore, Day 1 = day of first injections (Week 4b study 
visit); Week 4 = second injections (Week 8 study visit) 
Horizontal line at 72 ng/mL corresponds to median Cfollowing oral RPV 25mg once daily in LATTE-2 (oral lead-in) 
and is similar to median RPV Cin other studies in HIV-infected patients (LATTE, ECHO/THRIVE)


2018N382441_03
CONFIDENTIAL
66
4.4.
End of Study Definition
4.4.1.
Study Completion
Patient Study Participants
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the patient study participant’s medical condition. 
Patient study participants are considered to have completed the study if they remain on 
therapy (i.e., have not permanently discontinued study intervention) and satisfy the 
following:

Have completed all Month 12 evaluations

remaining on study until commercial supplies of the CAB LA + RPV LA regimen 
becomes locally available, or initiates alternate antiretroviral therapy at the discretion 
of their HIV care provider, or 

development of CAB LA + RPV LA is terminated;
Upon completion of the above, patient study participants will exit the study and transition 
to commercial supplies of CAB LA + RPV LA, or alternate antiretroviral therapy at the 
discretion of their HIV HCP.
Until meeting the definition for study completion, participants will continue in the study
until: 

the participant no longer derives clinical benefit, 

the participant meets a protocol-defined reason for discontinuation  
Participants who withdraw from CAB LA + RPV LA and go into the LTFU Phase will be 
considered to have prematurely withdrawn from the study intervention.
Patient study participants will complete the 52-week Follow-Up phase required for 
participants who receive one or more injections with CAB LA or RPV LA. Assessments 
at the Follow-up visits 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.
Study Staff Participants
Study Staff participants will have completed the study upon completion of all surveys 
and qualitative interviews after Month 12 evaluations have been completed at their site,
per the Schedule of Activities (Section 1.5).


2018N382441_03
CONFIDENTIAL
67
5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the investigational regimen or other study intervention 
that may impact participant eligibility is provided in the current Investigator’s Brochures 
(IB) for CAB (GlaxoSmithKline Document Number RH2009/00003/07 and Rilpivirine 
Clinical Investigator Brochure, 2018, and Edurant Prescribing Information, 2018.
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 lab results can be reviewed and approved 
by the Medical Monitor for consideration of participant eligibility. A repeat sample to the 
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 enrolment. Source documents from other medical 
facilities must be located/received during the 21-day screening phase and under no 
circumstances may the participant be enrolled in the absence of source documentation. 


2018N382441_03
CONFIDENTIAL
68
All Participants eligible for enrolment in the study must meet all of the following 
criteria:
AGE
1. Aged 18 years or older at the time of signing the informed consent.
TYPE OF PARTICIPANT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. HIV-1 infected and must be on an active HAART (2 or 3 drug) 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 ≥200 c/mL). 
Acceptable stable 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)

Any suppressed participants on a triple ART regimen for at least 6 months who 
had their regimen switched to a 2DR of DTG/RPV
3. Documented evidence of at least two plasma HIV-1 RNA measurements <50 
c/mL in the 12 months prior to Screening: at least one within 6 months prior to 
Screening; 
4. Plasma HIV-1 RNA <50 c/mL at Screening; 
SEX
5. A female participant is eligible to participate if she is not pregnant (as confirmed 
by a negative urine human chorionic gonadotrophin (hCG) test at screen and at 
Day 1), 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


2018N382441_03
CONFIDENTIAL
69

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) (Section 10.7, Appendix 7) from 30 days prior to the first dose of study 
medication, throughout the study, and for at least 30 days after discontinuation of all oral 
study medications and for at least 52 weeks after discontinuation of CAB LA and RPV 
LA. 
The investigator is responsible for ensuring that participants understand how to properly 
use these methods of contraception.
INFORMED CONSENT
Capable of giving signed informed consent, which includes compliance with the 
requirements and restrictions listed in the consent form and in this protocol. Eligible 
participants or their legal guardians (and next of kin when locally required), must sign a 
written Informed Consent Form before any protocol-specified assessments are conducted. 
Enrolment of participants who are unable to provide direct informed consent is optional 
and will be based on local legal/regulatory requirements and site feasibility to conduct 
protocol procedures.
ALL participants in the study should be counseled on safer sexual practices including 
the use and benefit/risk of effective barrier methods (e.g., male condom) and on the risk 
of HIV transmission to an uninfected partner.


2018N382441_03
CONFIDENTIAL
70
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:
HIV-1 RNA
1. Within 6 months prior to Screening, plasma HIV-1 RNA measurement 50 c/mL;
2. During the previous 12 months, any confirmed HIV-1 RNA measurement 
200 c/mL
Exclusionary medical conditions
3. Women who are pregnant, breastfeeding, or plan to become pregnant or 
breastfeed during the study.
4. 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..
5. 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.
6. 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.
7. Participants who, in the investigator's judgment, pose a significant suicide risk. 
Participant’s recent history of suicidal behavior and/or suicidal ideation should be 
considered when evaluating for suicide risk
8. The participant has a tattoo or other dermatological condition overlying the 
gluteus region which may interfere with interpretation of injection site reactions
9. Evidence of Hepatitis B virus (HBV) infection based on the results of testing 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.
10. Participants who are anticipated to require HCV treatment within 12 months must 


2018N382441_03
CONFIDENTIAL
71
be excluded. Asymptomatic individuals with chronic hepatitis C virus (HCV) 
infection will not be excluded; investigators must carefully assess if therapy 
specific for HCV infection is required. (HCV treatment on study may be 
permitted, following consultation and approval of the DAA based therapy being 
considered with the medical monitor)
11. 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.  
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 ])
12. 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)
13. History of liver cirrhosis with or without hepatitis viral co-infection.
14. Ongoing or clinically relevant pancreatitis
15. Clinically significant cardiovascular disease, as defined by history/evidence of 
congestive heart failure, symptomatic arrhythmia, angina/ischemia, coronary 
artery bypass grafting (CABG) surgery or percutaneous transluminal coronary 
angioplasty (PTCA) or any clinically significant cardiac disease
16. 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 inclusion
17. 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
18. History or presence of allergy or intolerance to the study drugs or their 
components or drugs of their class.


2018N382441_03
CONFIDENTIAL
72
19. Current or anticipated need for chronic anti-coagulation with the exception of the 
use of low dose acetylsalicylic acid (≤325 mg per day) or hereditary coagulation 
and platelet disorders such as haemophilia or Von Willebrand Disease.
20. Corrected QT interval (QTc (Bazett)) >450 msec or QTc (Bazett) >480 msec for 
subjects with bundle branch block).
Exclusionary Laboratory Values or Clinical Assessments (a single repeat to determine 
eligibility is allowed)
21. Any evidence of primary resistance based on the presence of any major known 
INI or NNRTI resistance-associated mutation, except for K103N, (International 
AIDS Society [IAS]-USA) by any historical resistance test result (Wensing, 2017)
22. Alanine aminotransferase (ALT) 5 × ULN or ALT 3xULN and bilirubin 
1.5xULN (with >35% direct bilirubin) over the last 6 months
23. Any verified Grade 4 laboratory abnormality. A single repeat test is allowed 
during the Screening phase to verify a result
24. Participant has estimated creatinine clearance <50 mL/min/1.73m2 via the 
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation 
(Levey, 2009).
Concomitant Medications
25. Exposure to an experimental drug or experimental vaccine within either 28 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;
26. Treatment with any of the following agents within 28 days of Day 1:

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. 
27. Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of 
Screening.
28. Use of medications which are associated with Torsade de Pointes must be 
discussed with the Medical Monitor to determine eligibility. (See SPM for a list of 
relevant medications)
29. 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 


2018N382441_03
CONFIDENTIAL
73
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
5.2.1.
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.
Note: Patient study participants with Grade 1 LFTs at screening and or day 1 
must be discussed with the Medical Monitor prior to initiation of LA dosing; 
continuation in the study or progression onto LA dosing may require additional 
evaluations, including labs drawn after a period of oral dosing with CAB + RPV.
5.3.
Lifestyle Considerations
No restrictions are required.
5.4.
Screen Failures
Screen failures are defined as patient study participants who consent to participate in the 
clinical study but are not subsequently entered in the study. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure 
participants to meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any 
serious adverse events (SAEs).
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened one time within 4 weeks of the original screening; informed consent 
will need to be reviewed and re-signed for each rescreen. Subjects will be issued a new 
subject number for every screening/re-screening event. 
Staff study participants will not be captured for screen failure reporting.
6.
STUDY INTERVENTION
6.1.
Study Intervention(s) Administered
The term ‘study intervention’ is used throughout the protocol to describe any 
combination of products received by the participant as per the protocol design. Study 
intervention 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 intervention may therefore refer to the individual 
study interventions or the combination of those study interventions.


2018N382441_03
CONFIDENTIAL
74
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.
Dosing and Administration
Day 1 to End of Study+
CAB + RPV LA Oral Lead-In
Day 1 to Month 1
(two once daily tablets taken 
with food)

Take one tablet of CAB 30 mg + RPV 25 mg once daily
CAB + RPV LA
First Injections (Loading Doses) – Month 1
Month 1

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 one month following Loading Dose at Month 1
Month 2 to End of Study+
(two 2 mL injections every 
month)

Receive CAB LA 400 mg given as 1 X 2 mL IM injection

Receive RPV LA 600 mg given as 1 X 2 mL IM injection
+Until locally approved and commercially available, the participant no longer derives clinical benefit, the participant 
meets a protocol-defined reason for discontinuation or until development of CAB LA or RPV LA is terminated
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 


2018N382441_03
CONFIDENTIAL
75
available to support the use of pill boxes. The recommended storage conditions, and 
expiry date where required, are stated on the product label.
CAB Tablet is composed of cabotegravir sodium, lactose monohydrate, microcrystalline 
cellulose, hypromellose, sodium starch glycolate, magnesium stearate, and white film-
coating. The white film-coating contains hypromellose, titanium dioxide and 
polyethylene glycol.
6.1.1.2.
Rilpivirine Tablets (RPV)
RPV 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. The recommended storage conditions, and expiry 
date where required, are stated on the product label.
Each tablet contains 27.5 mg of rilpivirine hydrochloride, which is equivalent to 25 mg of
RPV. Each tablet also contains the inactive ingredients croscarmellose sodium, lactose 
monohydrate, magnesium stearate, polysorbate 20, povidone K30 and silicified 
microcrystalline cellulose. The tablet coating contains hypromellose 2910 6 mPa.s, 
lactose monohydrate, PEG 3000, titanium dioxide and triacetin.
6.1.1.3.
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 stopper and aluminum seal. Each vial is for single-dose use containing a 
withdrawable volume of 2.0 mL (400 mg) or 3.0 mL (600 mg) and does not require 
dilution prior to administration. The recommended storage conditions, and expiry date 
where required, are stated on the product label.
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 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. The recommended storage conditions, and expiry 
date where required, are stated on the product label.


2018N382441_03
CONFIDENTIAL
76
RPV LA is composed of RPV free base, poloxamer 338, sodium dihydrogen phosphate 
monohydrate, citric acid monohydrate, glucose monohydrate, sodium hydroxide, water 
for injection.
6.1.1.5.
CAB + RPV LA Packs
CAB + RPV LA will be packaged in a pharmacy pack. In addition to the CAB + RPV LA 
vials, the pharmacy pack will contain:

Vial adapters, used to draw IP out of the vials into the injection syringes

Syringes 

Needles (23ga, 1.5 inch)

Printed instructions for use
The CAB + RPV LA packs will be available with both vials including a 3mL fill of CAB 
LA and RPV LA (for Loading dose use) and vials including a 2mL fill, for use during 
Maintenance dosing.
6.2.
Preparation/Handling/Storage/Accountability

The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention.

Only participants enrolled in the study may receive study intervention and only
authorized site staff may supply or administer study intervention. All study 
interventions 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 
intervention 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 
intervention are provided in the Study Reference Manual. 

Under normal conditions of handling and administration, study intervention 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.


2018N382441_03
CONFIDENTIAL
77

Product accountability records must be maintained throughout the course of the 
study.
IP accountability will be evaluated using pill counts of unused IP for participants 
receiving oral treatment (oral CAB and oral RPV). This assessment will be conducted 
each time the participant receives a new (refill) supply of IP through the withdrawal or 
study completion.
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.
Please refer to Section 10.12, Appendix 12 in for study management information during 
the COVID-19 pandemic.
6.2.1.
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(s) 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 or provided vial adapter to withdraw the required volume of 
suspension for IM injection.
All injections must be given intramuscularly in the gluteus medius. Sites may use their 
discretion as to where in the gluteus muscle each injection is given according to 
individual participant circumstance. If possible, injections should be spaced 
approximately 2 cm from one another, from the site of any previous injection or any 
injection site reaction. The time and location of injection will be captured in the eCRF.
Intermuscular 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 Day 1 visit, participants transitioning from oral CAB + RPV 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 


2018N382441_03
CONFIDENTIAL
78
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.
6.3.
Measures to Minimize Bias: Randomization and Blinding
This will be an open-label, single-arm study and therefore no blinding will be performed.
6.4.
Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention 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 
intervention 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 
intervention.
When participants self-administer oral study interventions 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 + RPV tablets). This assessment will be 
conducted each time the participant receives a new (refill) supply of oral study 
medication or any oral bridging phase. A record of the number of CAB + RPV tablets 
dispensed to and taken by each participant must be maintained and reconciled with study 
intervention and compliance records. Treatment start and stop dates will also be recorded 
in the eCRF.
Due to the long acting nature of the CAB LA and RPV LA it will be imperative that the 
participant is compliant with dosing instructions. As part of the screening and participant 
selection process, it is imperative that Investigators discuss with potential participants the 
long-term commitments for the trial, and the importance of adhering to treatment 
regimens. Sites are to have plans in place for adherence counselling for both treatment 
arms of the study for the duration of the study including the LTFU Phase. In addition, 
Investigators must have plans in place to verify the participant’s contact information at 
each visit. Investigators should contact participants directly in the event that a participant
misses any scheduled visit.
6.5.
Concomitant Therapy
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 6.5.2 and should be administered only as medically necessary during the study. 
All concomitant medication, blood products, and vaccines taken during the study will be 


2018N382441_03
CONFIDENTIAL
79
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.
6.5.1.
Permitted Medications and Non-Drug Therapies
Chemoprophylaxis for HIV-associated conditions is encouraged, if appropriate, at the 
discretion of the participant and their physician. All concomitant medications, blood 
products, and vaccines taken during the study will be recorded in the eCRF with dates of 
administration.
Because non-HIV vaccines may cause a temporary increase in the level of plasma HIV-1 
RNA, it is recommended that a vaccine, if necessary, be given during or immediately 
after a scheduled visit after all laboratory tests have been drawn. This approach will 
minimize the risk of non-specific increases in the level of plasma HIV-1 RNA at the next 
scheduled assessment.
Other IM injectables (with exceptions below) are permitted but must be administered 
away from the site of IP administration (should be spaced 2 cm or more away from site of 
IP injection).
Antacid and H2 Antagonist Use:
The most restrictive dosing requirements must be taken into consideration to account for 
the co-administration of oral CAB and RPV. The marketed approved recommendation for 
administration of antacids and H2 antagonists with the FDC of DTG + RPV incorporates 
the most restrictive dosing requirements and should be used when antacids and H2 
antagonists are co-administered with oral CAB + RPV.
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 


2018N382441_03
CONFIDENTIAL
80
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).
6.5.2.
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, Section 5.2). 

Systemically administered immunomodulators (such as interleukin and 
interferon agents) are prohibited (a list of examples is provided in the SPM). 
This includes topical agents with substantial systemic exposure and systemic 
effects. Use of topical imiquimod is permitted.

Acetaminophen (paracetamol) cannot be used in participants with acute viral 
hepatitis (James, 2009).

Chronic use of systemic (oral or parenteral) glucocorticoids must be avoided 
due to 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.

Direct acting antivirals (DAA) against Hepatitis C infection is allowed, 
provided there are no DDIs associated the DAA being considered for 
treatment. 

Interferon-based HCV therapy is prohibited throughout the entire study, 
partly because as an immunomodulator, Interferon is a prohibited medication.
For information on concurrent therapies and interactions suspected to be relevant to other 
antiretroviral therapy in the regimen, please consult the local prescribing information.


2018N382441_03
CONFIDENTIAL
81
6.5.2.1.
Concurrent with CAB and/or RPV 
For participants receiving either formulation of CAB and 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)
6.5.2.2.
Concurrent with oral RPV
In addition to the medications listed in Section 6.5.2, participants must discontinue the 
following (or change to an allowable alternative) while receiving treatment with oral 
RPV:

proton pump inhibitors, such as esomeprazole, lansoprazole, omeprazole, 
pantoprazole, rabeprazole;

systemic dexamethasone (more than a single dose)
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.
6.5.2.3.
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.
6.5.2.4.
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.


2018N382441_03
CONFIDENTIAL
82
6.6.
Dose Modification
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.
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM). The SPM will provide 
the site personnel with administrative and detailed technical information.
6.6.1.
Protocol Permitted Substitutions
6.6.1.1.
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 (3 months) “bridging” strategy for 
participants who have begun CAB LA + RPV LA. In certain circumstances (e.g., prior to 
steady state dosing and following a >8 weeks since last injection) 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.
Please refer to Section 10.12, Appendix 12 in for study management information during 
the COVID-19 pandemic.
6.6.2.
IM Dosing
Participants receiving CAB LA and/or RPV LA are anticipated to be at risk for 
development of virologic resistance if ART is interrupted. The time period during which 
participants are at risk for development of virologic resistance may be determined by the 
period between when drug levels fall below therapeutic values and when they fall below 
levels which exert selective pressure on HIV. This time period will vary by ART agent 
and is dependent upon effective concentration, inhibitory concentration, and half-life.  
Plasma concentrations of both LA drugs may be measurable for more than one year 
following IM injections. Any interruption in IM dosing should be discussed with the 
Medical Monitor. Investigators should ensure that the participant initiates alternative 
highly active ART to minimize the risk of developing resistance as concentrations of 
CAB and RPV decline over time.
IM dosing is expected to occur during the week in which the participant’s projected visit 
falls (as according to the date of the first injection).
Since the first injection visit (Month 1) 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.).


2018N382441_03
CONFIDENTIAL
83
CAB LA + RPV LA dosing for participants transitioning from oral CAB + RPV is 
as follows:
All injections should be planned as single injections per drug.
6.6.2.1.
IM injections every 1 month:
On Day 1, participants 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 second injection will be administered at Month 2 (CAB LA 400 mg + RPV LA 
600 mg, with all subsequent injections (CAB LA 400 mg + RPV LA 600 mg) occurring 
every 1 month thereafter. The dosing window for the second and third injections allow
administration between -7 days of the proposed injection visit date but preferably not 
later than the target date (-7 days/ +0 days around the proposed visit date). Beginning on 
Month 4, a dosing window (7 days) for injections is stipulated. The Medical Monitor 
must be contacted to discuss individual participant case management if a dose must be 
administered outside of the window.
6.6.3.
Oral Dosing
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.
6.7.
Intervention 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 intervention. Participants who have successfully completed IM dosing 
for 12 months will continue to have access to both CAB LA and RPV LA until study 
intervention 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.
7.
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
Participants permanently discontinuing study treatments prior to the Month 12 visit are 
considered to be withdrawn from the study treatments. Participants permanently 
discontinuing study treatments prior to the commercial availability of CAB LA + RPV 
LA visit are not considered to be withdrawn from the study because they will enter the 
long-term Follow-up Phase.


2018N382441_03
CONFIDENTIAL
84
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). 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 will be asked for additional 
information to establish the reason for withdrawal.
Participants are not obligated to state the reason for withdrawal. However, the reasons for 
withdrawal, or failure to provide a reason, must be documented by the Investigator on the 
Completion/Withdrawal section of the electronic case report form (eCRF). Every effort 
should be made by the Investigator to follow-up participants who withdraw from the 
study.
Participants may have a temporary interruption to their study intervention for 
management of toxicities.
Participants may be prematurely discontinued from the study intervention 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;

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 intervention for any of the following 
reasons:

Virologic withdrawal criteria as specified in Section 7.1.3 are met;

Participant requires substitution of ART; 

Participant requires substitution or dose reduction of CAB LA, 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 10.6.2);


2018N382441_03
CONFIDENTIAL
85

Renal toxicity is met and no compelling alternate cause is identified;

Corrected QT interval (QTc) >550 msec from three or more tracings separated by at 
least 5 minutes and considered causally related to IP.  Note: ECGs are not routinely 
conducted in this study.

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.

Participant withdrew consent
Safety data for all participants who receive any amount of study drug, including 
participants who withdraw from the study, will be included in evaluations of safety.
If a participant is prematurely or permanently withdrawn from the study, the procedures 
described in the Schedule of Activities Table, Section 1.5, for the in-clinic Withdrawal 
visit are to be performed. An in-clinic Follow-Up visit will be conducted 4 weeks after 
the last dose of study medication for participants with ongoing AEs, and serious adverse 
events (SAEs) related & not related to study drug and also any laboratory abnormalities 
that are considered to be AEs or potentially harmful to the participant, at the last on-study 
visit. 
All data from the Withdrawal visit will be recorded, as they comprise an essential 
evaluation that should be done prior to discharging any participant from the study.
The following actions must be taken and documented 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. 
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 intervention 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.


2018N382441_03
CONFIDENTIAL
86
7.1.
Discontinuation of Study Intervention
Participants unable to manage drug toxicity or tolerate investigational product (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 an additional 52 weeks of follow up.
7.1.1.
QTc Stopping Criteria
A participant who has a QTc interval >550 msec considered causally related to IP will be 
withdrawn from the study. The QTc should be based on averaged QTc values of 
triplicate electrocardiograms obtained over a brief (e.g., 5 to 10 minute) recording 
period.
If an alternative cause of the QT prolongation is determined (e.g., participant receiving 
drug known to cause prolonged QT or TdP), the IP may be restarted (or continued) after 
consultation and agreement with the Medical Monitor. RPV and RPV LA should not be 
administered to participants 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.
7.1.2.
Virologic Failure
Only plasma HIV-1 RNA values determined by the central laboratory will be used to 
assess virologic failure. 
7.1.3.
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.
7.1.4.
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.


2018N382441_03
CONFIDENTIAL
87
Inadequate adherence or maladministration may be a 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 
(SVF), the Investigator should query the participant regarding intercurrent illness, recent 
immunization, or interruption of oral therapy.
7.1.4.1.
HIV-1 RNA Blips
HIV-1 RNA “blips” are not usually associated with subsequent virologic failure [DHHS, 
2018]. Although the implications of persistent HIV-1 RNA levels between the lower 
level of detection and <200 c/mL are unclear, the risk of emerging resistance is believed 
to be relatively low.
Participants with transient increases in HIV-1 RNA (‘blips’ HIV-1 RNA <200 c/mL) are 
not considered suspected virologic failures and do not require a change in therapy.
Participants who have a HIV-1 RNA ≥50 c/mL at the key analysis timepoints (Month 12, 
End of Study visit) should return for a repeat HIV-1 RNA as soon as possible but no later 
than 4 weeks after the date of the Month 12 or End of study visit, respectively 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.
7.1.4.2.
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.


2018N382441_03
CONFIDENTIAL
88

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.
7.1.4.3.
Confirmed Virologic Failure
Participants with 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 intervention.
If a participant is prematurely discontinued from the study intervention, the investigator 
must make every effort to perform the Withdrawal Visit evaluations outlined in the 
Schedule of Activities Table, Section 1.5. These data will be recorded as they comprise 
essential evaluations needed to be done before discharging any participant from the 
study.
7.2.
Participant Discontinuation/Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, 
or may be withdrawn at any time at the discretion of the investigator for safety, 


2018N382441_03
CONFIDENTIAL
89
behavioral, compliance or administrative reasons. This is expected to be 
uncommon.

At the time of discontinuing from the study, if possible, an early discontinuation 
visit should be conducted, as shown in the Schedule of Activities, Section 1.5. 
See SoA, Section 1.5 for data to be collected at the time of study discontinuation 
and follow-up and for any further evaluations that need to be completed.

The participant will be permanently discontinued both from the study 
intervention and from the study at that time.

If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent.

If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records.
7.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and 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.

Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole are handled as part of Section 
10.1.


2018N382441_03
CONFIDENTIAL
90
8.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of urgent actions to 
address immediate safety concerns. Therefore, adherence to the study design 
requirements, including those specified in the Schedule of Activities Table, Section 1.5, 
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 Schedule of Activities, Section 1.5.
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
•The IRB/independent ethics committee (IEC) will be informed of any safety issues that 
require alteration of the safety monitoring scheme or amendment of the Informed 
Consent Form.
Please refer to Section 10.12, Appendix 12 in for study management information during 
the COVID-19 pandemic.
8.1.
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 enrolled 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 21 days prior to Baseline (Day 1) during which all 
clinical and laboratory assessments of eligibility must be performed and reviewed. All 
Screening results must be available prior to enrollment.
All information about the participant’s current regimen must be available for 
review by the Principal Investigator or designee prior to enrollment. Source 
documents from other medical facilities must be located/received during the 21 day
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.


2018N382441_03
CONFIDENTIAL
91
Participants who meet all entry criteria and are enrolled will be 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 one time within 4 weeks and receive a new participant 
number. Participants who are enrolled into the trial and subsequently withdrawn from the 
study for any reason may not be rescreened.
8.2.
Baseline Assessments
8.2.1.
Patient Study Participants
At Day 1, any changes to the eligibility parameters must be assessed and any results 
required prior to enrollment (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 5.1.
Baseline information to be collected at Day 1 includes general medical history and 
current medical conditions. Laboratory 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.
In addition to a full routine medical history at Baseline, more detailed information will be 
collected for some disease processes such as:

Cardiovascular medical history/risk factors (as detailed in the eCRF) will be 
assessed at Baseline and assessments will include height, weight, blood pressure, 
smoking status and history, pertinent medical conditions (e.g., hypertension, 
diabetes mellitus), and family history of premature cardiovascular disease. In 
addition, medical history/risk factors for renal disease such as nephropathy, renal 
failure, and nephrolithiasis will be assessed.

history of illicit drug use [e.g., cocaine, heroin, and methamphetamine use]);

intravenous drug use history;

gastrointestinal disease (e.g., gastrointestinal [GI] bleeding, peptic ulcer disease 
[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 


2018N382441_03
CONFIDENTIAL
92
utilized for 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.
8.2.2.
Staff Study Participants
Surveys and Questionnaires for staff study participants should be performed/ collected
prior to the first Patient Study Participant CAB + RPV LA injection, but may be 
conducted after Patient Study Participant screening or Day 1 visits.
8.3.
Efficacy Assessments- Patient Study Participants
8.3.1.
Plasma HIV-1 RNA
Plasma for quantitative HIV-1 RNA will be collected according to the Schedule of 
Activities (Section 1.5). 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.
8.3.2.
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 the Schedule of Activities (Section 1.5).
8.3.3.
HIV Associated Conditions
HIV-associated conditions will be recorded and will be assessed according to the 2014 
CDC Revised Classification System for HIV Infection.
8.4.
Safety Assessments- Patient Study Participants
8.4.1.
Clinical Evaluations
The following clinical evaluations will be performed according to the schedule of 
activities:

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 
1.5.

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.


2018N382441_03
CONFIDENTIAL
93

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. At Screening, ECGs should be performed in triplicate. 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, glucose and lipids 
(parameters to be tested listed below).

Pregnancy testing.  A negative urine pregnancy test is required prior to initiation 
of IP, any dose of CAB LA or RPV LA or as required by the Medical Monitor 
following a treatment interruption(s). If serum testing is required locally, the 
results should be available prior to the visit where urine testing is indicated per the
Schedule of Activities, Section 1.5.
o
Participants who are enrolled in the study and have a positive pregnancy 
test during the course of the study, will be allowed to remain in the study,
provided a pregnancy specific ICF addendum is signed by the participant. 
No IP can be continued (oral or LA) in any pregnant participant until the 
benefit/risk assessment is discussed with the participant and the pregnancy 
specific ICF addendum has been signed. See details in Appendix 8.
o
Pregnant participants who remain in the study do not need pregnancy 
testing during the study, for the duration of their pregnancy.

Evaluation and documentation of all concomitant medications and blood products.

Injection Site Reactions (ISRs) will be assessed clinically during the study 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.
Any appropriately qualified site personnel (e.g., Investigator, sub-Investigator, or study 
coordinator/nurse) can perform assessments.


2018N382441_03
CONFIDENTIAL
94
8.4.2.
Physical Examinations
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 Schedule of 
Activities (Section 1.5).

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.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.4.3.
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 Schedule of Activities (Section 1.5).
8.4.4.
Electrocardiograms
A 12-lead ECG will be performed in a semi-supine position. ECGs should be performed 
in triplicate at Screening. Refer to Section 7.1.1 for [QTc] withdrawal criteria and 
additional [QTc] readings that may be necessary.


2018N382441_03
CONFIDENTIAL
95
8.4.5.
Clinical 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
Other Tests
Plasma HIV-1 RNAd
CD4+ and CD8+ cell counts [CD4/CD8 ratio]e
Peripheral Blood Mononuclear Cells (PBMCs): Day 1 and Withdrawal only
Rapid Plasma Reagin (RPR)
Prothrombin Time (PT)/International Normalized Ratio (INR)/ Partial Thromboplastin Time (PTT)
Pregnancy test for FRPf
Urinalysis, urine albumin/creatinine ratio, and urine protein/creatinine ratio, urine phosphate
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, 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)
Screening glucose test will be done in a non-fasting state.
d)
For participants meeting virologic withdrawal criteria, plasma samples will be analyzed in attempt to obtain 
genotype/phenotype data.
e)
CD8+ cells will only be reported at Baseline and end of the study.
f)
Urine pregnancy test/ serum pregnancy test will be performed according to the Schedule of Activities (Section
1.5).
8.4.6.
Suicidal Ideation and Behaviour Risk Monitoring
Participants with HIV infection may occasionally present with symptoms of depression 
and/or suicidal ideation or behavior. In addition, there have been some reports of 
depression, suicidal ideation and behavior (particularly in participants with a pre-existing 
history of depression or psychiatric illness) in some participants being treated with INIs 
including DTG. 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.


2018N382441_03
CONFIDENTIAL
96
The investigator will collect information using the Possible Suicidality-Related AE 
(PSRAE) eCRF form in addition to the Adverse Event (non-serious or Serious Adverse 
Events) eCRF form on any participant that experiences a possible suicidality-related 
adverse event while participating in this study. This may include, but is not limited to, an 
event that involves suicidal ideation, a preparatory act toward imminent suicidal 
behavior, a suicide attempt, or a completed suicide. The investigator will exercise his or 
her medical and scientific judgment in deciding whether an event is possibly suicide
related. PSRAE forms should be completed and reported to ViiV/GSK within one week 
of the investigator diagnosing a possible suicidality-related adverse event. All sites 
should have a plan in place for managing possible risks for suicide related events.
8.5.
Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Section 10.5, Appendix 5.
The investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or the 
study, or that caused the participant to discontinue IP. (see Section 7). 
Please refer to Section 10.12, Appendix 12 in for study management information during 
the COVID-19 pandemic.
8.5.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the signing of the informed consent form until 
the follow-up visit at the time points specified in the SoA (Section 1.5).  

All AEs will be collected from Day 1 until the follow-up visit at the time points 
specified in the SoA (Section 1.5).

Medical occurrences that begin before the start of study intervention but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the case report form (CRF) not the AE section.

All SAEs will be recorded and reported to the sponsor or designee immediately 
and under no circumstance should this exceed 24 hours, as indicated in Section 
10.5.6. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available.

Investigators are not obligated to actively seek AEs or SAEs after the conclusion 
of the study participation. 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 to be reasonably related to the study 
intervention or study participation, the investigator must promptly notify the 
sponsor.


2018N382441_03
CONFIDENTIAL
97
8.5.2.
Method of Detecting AEs and SAEs

The method of recording, evaluating, and assessing causality of AEs and SAEs 
and the procedures for completing and transmitting SAE reports are provided in
Section 10.5.6.

Care will be taken not to introduce bias when detecting AE and/or SAE. Open-
ended and non-leading verbal questioning of the participant is the preferred 
method to inquire about AE occurrence.
8.5.3.
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, will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up. Further 
information on follow-up procedures is given in Section 10.5, Appendix 5.
8.5.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention 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 study intervention
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or 
other specific safety information e.g., summary or listing of SAE) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.
8.5.5.
Pregnancy
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 Schedule of 
Activities (Section 1.5) and at any time during the trial when pregnancy is suspected.
Pregnant participants who remain in the study do not need pregnancy testing during the 
study, for the duration of their pregnancy.

Additionally, the Medical Monitor may request that a urine pregnancy test be 
performed in the event of a treatment interruption greater than 7 days.


2018N382441_03
CONFIDENTIAL
98

Details of all pregnancies in female participants will be collected after the start of 
study intervention and until the last follow-up assessment. This includes the entirety 
of the long-term follow-up period.

If a pregnancy is reported, the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Section 10.7, 
Appendix 7.

If pregnancy is confirmed, a discussion with the pregnant study participant assessing 
the benefit/risk assessment of continuing in the study will be undertaken. If, after this 
discussion, the participant would like to continue in the study, this will be allowed,
provided the pregnant participant signs the pregnancy specific ICF addendum. See 
Appendix 8 for details.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
8.5.5.1.
Rationale for Continued Use in Pregnancy
Additional data regarding the use of CAB + RPV LA during pregnancy, and management 
of pregnant participants remaining in the study are found in Appendix 8
The use of CAB + RPV LA during pregnancy may offer unique benefits. It is well 
documented that treatment adherence challenges to oral therapy exists both in the peri-
partum and post-partum periods with LA dosing offering a unique opportunity to 
overcome such adherence challenges. LA therapy may also help with nausea (50 % mild 
to moderate) or hyperemesis (2%) that is frequently seen, especially during the first 
trimester of gestation.
Participants on LA dosing who become pregnant will have exposures throughout 
pregnancy due to the long half-life and PK tail of CAB/RPV. Prior to this protocol
amendment, pregnant participants would have been withdrawn from the study, and 
initiated on an alternative oral ART regimen. Alternative regimens consist of either 2 or 3 
antiretrovirals to protect the life of the mother and for the prevention of MTCT. This 
regimen, combined with the long half-life and PK tail of CAB/RPV, would potentially 
expose the fetus to additional ARVs during gestation (in some cases upwards of 5 
antiretrovirals).
Given the risk/benefit ratio for cabotegravir and rilpivirine LA dosing in FRP, coupled 
with concerns of increasing fetal exposure to several additional antiretrovirals upon 
participant withdrawal, this amendment to the protocol will allow pregnant participants to 
remain in the study after a pregnancy specific ICF addendum is signed by the participant.
8.5.5.2.
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.
Pregnant study participants who consent to remain in the study during pregnancy will 
continue to have all clinical assessments performed as per the SoA, Table 3, including the 
collection of additional PK samples for CAB and RPV. See Appendix 8 for details.


2018N382441_03
CONFIDENTIAL
99
Pregnant participants who have received at least one dose of CAB LA or RPV LA and 
decide NOT to continue in the study during pregnancy will be transitioned to the LTFU 
phase of the study and will be monitored for 52 weeks after the last LA dose. Moreover,
an alternative oral ARV regimen will be initiated, at the discretion of the PI and in 
discussion with the medical monitor.
8.5.5.3.
Action to be Taken if Pregnancy Occurs
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form. The investigator should inform GSK within 24 hours of learning of 
the pregnancy and should follow the procedures outlined in Appendix 8.
Pregnant participants who elect to continue with CAB + RPV LA must sign a pregnancy 
specific ICF addendum. Cabotegravir and rilpivirine are detected in systemic circulation 
for up to 12 months or longer after discontinuing injections of CAB + RPV LA;
therefore, consideration should be given to the potential for fetal exposure during 
pregnancy and should be discussed between the study participant and the study PI. 
All participants who become pregnant and who received at least one dose of LA therapy
during the study, whether they elect to continue with CAB + RPV LA injections or
transition to LTFU, will have additional PK samples collected to monitor cabotegravir 
and rilpivirine exposure levels throughout the pregnancy (see Appendix 8).
The pregnancy must be followed up to determine outcome (including premature 
termination) and status of mother and child(ren). Pregnancy complications and elective 
terminations for medical reasons must be reported as an AE or SAE. Abnormal 
pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAE.
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 intervention, 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.
8.5.6.
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 and QT prolongation-related adverse events

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack


2018N382441_03
CONFIDENTIAL
100

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularisation
For any cardiovascular events detailed above and all deaths, whether or not they are 
considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF 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 CRF within one week of receipt of a CV Event data query prompting its completion.
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.
8.5.7.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
Disease related events (DREs) or outcomes listed in the CDC Classification System for 
HIV-1 Infections (Section 10.4, 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 10.5.2), or

The event is, in the investigator’s opinion, of greater intensity, frequency, 
or duration than expected for the individual participant, or

The investigator considers that there is a reasonable possibility that the 
event was related to treatment with the investigational product, or

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 10.5.2) to GSK.


2018N382441_03
CONFIDENTIAL
101
8.6.
Pharmacokinetics
Pharmacokinetic samples will be collected in subjects who experience virologic failure in 
order to determine drug levels at the time of viral rebounds.
Pregnant participants will have additional PK samples collected during the duration of the 
pregnancy. See Appendix 8 for details.
8.7.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.8.
Genetics
Genetics are not evaluated in this study.
8.9.
Biomarkers
Biomarkers are not evaluated in this study.
8.10.
Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study.
9.
STATISTICAL CONSIDERATIONS
9.1.
Statistical Hypotheses
No formal hypothesis testing is planned.
9.2.
Sample Size Determination
As described above, the study size is based on practical considerations in terms of 
feasibility of enrolling an adequate number of sites on each intervention balanced with 
the desire to have interventions tested across several types of investigative sites: 
University Setting, Private Practice and Ryan White Clinic.
The primary consideration for study sizing is to obtain in-depth qualitative site level 
feedback via interviews of site personnel (treating clinician, nurses, administrators).
Additionally, this study is a single arm, open label interventional study, whereby patients 
at each site will receive the same intervention of the CAB + RPV LA ARV regimen and 
additional site facilitation to support the implementation of this regimen in their practice 
setting.
The primary endpoint is change from baseline to the study Month 12 injection visit in site 
survey responses for acceptability, appropriateness and feasibility, as described above 
(cross-reference and provide published citation). This survey includes a likert scale of 


2018N382441_03
CONFIDENTIAL
102
response ranging from 1 to 5, with higher values representing better outcomes. Although 
adequate prior information on expected responses are unavailable, it is expected that the 
standard deviation of change from baseline is 0.50.
9 sites will allow for estimation of paired mean change from baseline of 0.55 (half-width 
of the 95% confidence interval) using a two-sided confidence interval based on the 
normal distribution and assumed standard deviation of 1.
For subject level outcomes, the primary outcome will also be survey responses as 
described above (reference surveys). 135 subject pairs (average of 15 per site) will allow 
for estimation of paired mean change from baseline of 0.17 (half-width of the 95% 
confidence interval) using a two-sided confidence interval based on the normal 
distribution and assumed standard deviation of 1.
9.3.
Populations for Analyses
Analysis populations will be defined as follows:
Population
Definition/Criteria
Intent to 
Treat Site 
(ITTS)
All sites enrolled and who have administered at least one dose of CAB LA + 
RPV LA
Intent to 
Treat Patient 
(ITTP)
All patients enrolled and who have administered at least one dose of CAB LA 
+ RPV LA
Safety 
Population
All patients enrolled and who received at least one dose of CAB LA + RPV LA
9.4.
Statistical Analyses
As mentioned above, this study has both site- and subject-level outcomes and each 
outcome will be analyzed and summarized accordingly.


2018N382441_03
CONFIDENTIAL
103
Survey Data:
Qualitative interview data will be summarized by Evidera and reported as part of the 
overall study results (CSR). Details of these analyses will be described in a separate 
analysis plan provided by Evidera or other CRO partner under GSK’s oversight.
Randomization will be used to assign patients from the PSP to qualitative interview 
group or to no interview group. 
Quantitative data (site and subject level) will be summarized using descriptive statistics 
including 95% confidence intervals for primary and secondary endpoints, as appropriate.  
ata will be summarized by month of study/injection visit as actual values and change 
from baseline.
Responses will be summarized overall and by site type. Exploratory analyses will be 
undertaken to assess the variability of responses by factors including but not limited to 
site type, setting (urban, suburban, rural) and for subject level outcomes markers of 
demographic and baseline characteristics.
Clinical Safety and Efficacy data:
Given that this is an interventional clinical trial of an unapproved investigational product, 
standard analyses will be applied to summarize descriptively clinical adverse events, 
laboratory evaluations, virologic parameters and other outcomes.
All analyses performed will be described in the study Reporting and Analysis Plan which 
will be finalized and approved prior to database lock.
One interim analysis will be timed to provide preliminary data to inform the initial 
commercial availability of the CAB + RPV LA regimen. No formal criteria for stopping 
or amending the study based on the interim analysis are envisioned.
9.4.1.
Health Outcomes Analyses (Effectiveness Analyses)
Endpoint
Statistical Analysis Methods
Primary
Change from baseline at Month 12 in Acceptability of Intervention Measure (AIM), 
Intervention Appropriateness Measure (IAM), and Feasibility of Intervention 
Measure (FIM).
Secondary
Change from baseline at Month 12 in Acceptability of Intervention Measure (AIM), 
Intervention Appropriateness Measure (IAM), and Feasibility of Intervention 
Measure (FIM) by visit.


2018N382441_03
CONFIDENTIAL
104
9.4.2.
Efficacy Analyses
Endpoint
Statistical Analysis Methods
Secondary
Proportion of participants with plasma HIV-1 RNA <50 c/mL over time
Secondary
Proportion of participants with confirmed virologic failure (CVF) over time
Secondary
Incidence of treatment emergent genotypic and phenotypic resistance to CAB and 
RPV in patients with CVF
9.4.3.
Safety Analyses
All safety analyses will be performed on the Safety Population. 
Endpoint
Statistical Analysis Methods
Secondary
Incidence and severity of Adverse Events
Secondary
Incidence and severity of laboratory abnormalities over time
Secondary
Proportion of participants who discontinue treatment due to AEs over time
Secondary
Absolute values and changes in laboratory parameters over time
9.4.4.
Other Analyses
The impact of demographic parameters including, but not limited to, age, sex, race, as 
potential predictors of inter- and intra-participant variability for acceptability, adoption, 
appropriateness, and sustainability may be explored if sufficient data are available.
9.5.
Interim Analyses
One interim analysis will be timed to provide preliminary data to inform planning for the 
initial commercial availability of the CAB + RPV LA regimen. No formal criteria for 
stopping or amending the study based on the interim analysis are envisioned. The 
Reporting and Analysis Plan will describe the planned interim analyses in greater detail.


2018N382441_03
CONFIDENTIAL
105
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1.
Regulatory and Ethical Considerations
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.

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
10.1.2.
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. 


2018N382441_03
CONFIDENTIAL
106
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
10.1.3.
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.

Participants who become pregnant while in the study and who elect to continue 
to receive CAB + RPV LA injections must sign the pregnancy specific ICF
addendum.
10.1.4.
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.
10.1.5.
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 


2018N382441_03
CONFIDENTIAL
107
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.
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.
10.1.6.
Dissemination of Clinical Study Data

Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report.  The investigator 
will be provided reasonable access to statistical tables, figures, and relevant 
reports and will have the opportunity to review the complete study results at a 
GSK site or other mutually agreeable location.

GSK will also provide the investigator with the full summary of the study 
results.  The investigator is encouraged to share the summary results with the 
study subjects, as appropriate.

The procedures and timing for public disclosure of the protocol and results 
summary and for development of a manuscript for publication for this study will 
be in accordance with GSK Policy.

GSK intends to make anonymized patient-level data from this trial available to 
external researchers for scientific analyses or to conduct further research that 


2018N382441_03
CONFIDENTIAL
108
can help advance medical science or improve patient care. This helps ensure the 
data provided by trial participants are used to maximum effect in the creation of 
knowledge and understanding
10.1.7.
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. 

Monitoring details describing strategy (e.g., risk-based initiatives in operations 
and quality such as Risk Management and Mitigation Strategies and Analytical 
Risk-Based Monitoring), methods, responsibilities and requirements, including 
handling of noncompliance issues and monitoring techniques (central, remote, 
or on-site monitoring) are provided in the study data monitoring plan.

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

The sponsor assumes accountability for actions delegated to other individuals 
(e.g., Contract Research Organizations).

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 
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.
10.1.8.
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 


2018N382441_03
CONFIDENTIAL
109
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.
10.1.9.
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 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.


2018N382441_03
CONFIDENTIAL
110
10.2.
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.


2018N382441_03
CONFIDENTIAL
111


2018N382441_03
CONFIDENTIAL
112


2018N382441_03
CONFIDENTIAL
113


2018N382441_03
CONFIDENTIAL
114


2018N382441_03
CONFIDENTIAL
115


2018N382441_03
CONFIDENTIAL
116


2018N382441_03
CONFIDENTIAL
117


2018N382441_03
CONFIDENTIAL
118


2018N382441_03
CONFIDENTIAL
119


2018N382441_03
CONFIDENTIAL
120


2018N382441_03
CONFIDENTIAL
121


2018N382441_03
CONFIDENTIAL
122


2018N382441_03
CONFIDENTIAL
123


2018N382441_03
CONFIDENTIAL
124


2018N382441_03
CONFIDENTIAL
125


2018N382441_03
CONFIDENTIAL
126


2018N382441_03
CONFIDENTIAL
127


2018N382441_03
CONFIDENTIAL
128


2018N382441_03
CONFIDENTIAL
129


2018N382441_03
CONFIDENTIAL
130


2018N382441_03
CONFIDENTIAL
131


2018N382441_03
CONFIDENTIAL
132


2018N382441_03
CONFIDENTIAL
133
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


2018N382441_03
CONFIDENTIAL
134
10.3.
Appendix 3: Liver Safety – Study Treatment Restart or 
Rechallenge Guidelines
10.3.1.
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 13, Figure 5).
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 14; Figure 6).
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])


2018N382441_03
CONFIDENTIAL
135
10.3.2.
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 13).

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


2018N382441_03
CONFIDENTIAL
136
Table 13
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


2018N382441_03
CONFIDENTIAL
137
Figure 5
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.


2018N382441_03
CONFIDENTIAL
138
10.3.3.
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 14).
–
must present source data defining the patient’s current resistance profile 
with documented evidence of extensive drug resistance and previous drug 
history.

The local operating company (LOC) medical director should be informed that 
study drug restart is under consideration and of the final decision, whether or not 
to proceed.

Relevant physicians (listed below) must review and agree on action to be taken 
regarding request for drug restart:

Safety Review Team Leader, Safety Development Leader, or Senior Safety 
Physician

MDL and PPL

Request is taken to VSLC for final decision
Table 14
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


2018N382441_03
CONFIDENTIAL
139
Figure 6
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
10.3.4.
Medical monitor, GCSP Physician and PI actions for Restart or 
Rechallenge following VSLC decision
10.3.5.
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 


2018N382441_03
CONFIDENTIAL
140
Chair, VP Global Medical Strategy and EU Qualified Person for 
Pharmacovigilance. 
10.3.6.
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


2018N382441_03
CONFIDENTIAL
141
10.4.
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


2018N382441_03
CONFIDENTIAL
142

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.


2018N382441_03
CONFIDENTIAL
143
10.5.
Appendix 5: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
10.5.1.
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.
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 


2018N382441_03
CONFIDENTIAL
144
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.
10.5.2.
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 
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.


2018N382441_03
CONFIDENTIAL
145

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.
10.5.3.
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


2018N382441_03
CONFIDENTIAL
146

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
10.5.4.
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.
10.5.5.
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.


2018N382441_03
CONFIDENTIAL
147
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.
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.


2018N382441_03
CONFIDENTIAL
148
10.5.6.
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.
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.


2018N382441_03
CONFIDENTIAL
149
10.6.
Appendix 6: Toxicity Management
10.6.1.
Treatment Interruption Due to an Adverse Event
IP may be interrupted at the discretion of the Investigator and according to the severity of 
the AE. If one or more antiretroviral medications is held due to toxicity or adverse events, 
all antiretroviral medications must be held to reduce the risk of development of resistance 
taking into account both the length of the planned interruption and the pharmacokinetic 
half-life of each antiretroviral of the regimen, in a way to minimize the risk of 
development of resistance.
No toxicity-related dose reductions of IP will be allowed. IP should be restarted as soon 
as medically appropriate; in general, for oral dosing, this should be no longer than 14 
days after discontinuation (unless Grade 3 or 4 toxicities persist). Any interruption in 
therapy during the Maintenance Phase, oral dosing, of greater than 7 consecutive days 
must be discussed with and agreed by the Medical Monitor prior to resumption of 
therapy. The Medical Monitor must be contacted upon becoming aware of resumption in 
therapy, if therapy was resumed without prior approval. IM dosing is expected to occur 
during the week in which the participant’s projected visit falls (as according to the 
date of the first injection visit [Month 1]). A +0 / -7 day window is stipulated around 
the projected dosing date for dosing injections at Month 2 and Month 3. A +7 / -
7 day window, from the projected visit date, is allowable from the fourth injections 
forward for IM dosing but not preferred. Any interruption outside of this guidance 
MUST be discussed with the Medical Monitor prior to reinitiating IM IP.
Guidance is provided below on general participant management and IP interruptions 
based on the severity of the AE. All changes in the IP regimen must be accurately 
recorded in the participant’s eCRF.
10.6.2.
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 (See also Section 10.3, Appendix 3). 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.
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.


2018N382441_03
CONFIDENTIAL
150
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 10.2, Appendix 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 10.3.3: Liver Safety – Study Treatment Restart Guidelines for further 
details.
10.6.3.
Grade 1 or Grade 2 Toxicity/Adverse Event
Participants who develop a Grade 1 or Grade 2 AE or toxicity may continue IP at the 
discretion of the Investigator. (NOTE: See Section 10.6 Appendix 6, Specific 
Toxicities/Adverse Event Management” for exceptions to this guideline). Participants 
who choose to withdraw from study due to a Grade 1 or 2 AE should have study 
withdrawal and follow-up evaluations completed.
Participants who develop ALT ≥3 times ULN while on study must consult with 
Medical Monitor prior to initiation or continuation of CAB LA and RPV LA.
10.6.4.
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. 


2018N382441_03
CONFIDENTIAL
151

Participants experiencing Grade 3 AEs requiring permanent discontinuation of IP 
should be followed weekly until resolution of the AE and to have withdrawal 
study evaluations completed. A follow-up visit should be performed 4 weeks after 
the last dose of IP.  Any participant receiving at least one dose of CAB LA and /or 
RPV LA who discontinue IP / Withdraw will initiate treatment with HAART and 
enter the Long-Term Follow-Up Phase for 52 weeks of follow up. 

Participants with Grade 3 asymptomatic laboratory abnormalities should be 
investigated for all potential non-drug related causes, and, following discussion 
with the Medical Monitor, may continue IP if the Investigator has compelling 
evidence that the toxicity is not related to IP, with the exception of liver chemistry 
stopping criteria (See Section 10.6.2). Isolated Grade 3 lipid abnormalities do not 
require withdrawal of IP.
10.6.5.
Grade 4 Toxicity/Adverse Event

Participants who develop a Grade 4 AE or toxicity must have IP permanently 
discontinued.  However, if the Investigator has compelling evidence that the AE is 
not causally related to the IP, dosing may continue after discussion with and 
assent from the Medical Monitor.  Participants should be rechecked each week 
until the AE returns to Grade 2.

Participants experiencing Grade 4 AEs requiring permanent discontinuation of IP 
should be followed weekly until resolution of the AE and encouraged to complete 
the withdrawal and follow-up study evaluations as noted above.  Any participant 
receiving at least one dose of CAB LA and /or RPV LA who discontinue IP / 
Withdraw will initiate treatment with HAART and enter the Long-Term Follow-
Up Phase for 52 weeks of follow up. 

Participants with Grade 4 asymptomatic laboratory abnormalities should be 
investigated for all potential non-drug related causes, and, following discussion 
with the Medical Monitor, may continue therapy if the Investigator has 
compelling evidence that the toxicity is not related to IP, with the exception of 
liver chemistry stopping criteria. 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.
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.


2018N382441_03
CONFIDENTIAL
152
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 10.2 Appendix 2).
However, if the etiology of the rash has been definitively diagnosed as being unrelated to 
study drug and due to a specific medical event or a concomitant infection or a 
concomitant non-study medication, routine management should be performed and 
documentation of the diagnosis provided.  In this situation, the study drug should be 
continued. 
Participants in the 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 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.
10.6.6.
Adverse Event Management
10.6.6.1.
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.
10.6.6.2.
Hypertriglyceridemia/ Hypercholesterolemia
Samples for lipid measurements must be obtained in a fasted state according to the
Schedule of Activities, Section 1.5. 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 


2018N382441_03
CONFIDENTIAL
153
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 [for full discussion of management of hyperlipidemia in the context 
of HIV therapy.
10.6.6.3.
Seizures
Several cases of seizure have occurred during the cabotegravir program. These cases 
have alternate explanations for their occurrence. ViiV Healthcare has reviewed these 
cases in detail and does not believe they constitute a reasonable likelihood of causation 
associated with CAB. This assessment is supported by the lack of preclinical signal, class 
effect or known CNS mechanism, the relatively low frequency of seizures relative to 
expected rates in both healthy and HIV positive participants and clinical confounders in 
each case. The Sponsor considers the risk of developing seizures on the study as being no 
higher than that of the rest of the HIV-1 infected population.  
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 studies. Subjects 
with an unstable or poorly controlled seizure disorder will be excluded from study 
participation.
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.
10.6.6.4.
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. 


2018N382441_03
CONFIDENTIAL
154
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.
10.6.6.5.
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.
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.
10.6.6.6.
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 
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 


2018N382441_03
CONFIDENTIAL
155
medications, dehydration, concurrent conditions) should be taken into account, and a 
nephrology consult may be obtained.  
10.6.6.6.1. 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.
10.6.6.7.
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. 
10.6.6.8.
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 


2018N382441_03
CONFIDENTIAL
156
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. 
10.6.6.9.
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.
10.6.6.10. 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.
10.6.6.10.1.
Rash Without 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.


2018N382441_03
CONFIDENTIAL
157
As many products 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 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 10 weeks of 
treatment, rarely require interruptions or discontinuations of therapy and tend to resolve 
within two to three weeks.  No instances of serious skin reaction, including SJS, 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 RH2009/00003/07].
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 2 weeks), if there is any worsening of 
the rash, if any systemic signs or allergic symptoms develop, or if mucosal involvement 
develops.


2018N382441_03
CONFIDENTIAL
158
10.7.
Appendix 7: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Females of Reproductive Potential (FRP)
A female is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)
Females in the following categories are not considered FRP
Premenarchal
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.
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 15. 


2018N382441_03
CONFIDENTIAL
159
Table 15
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulation

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the FRP 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.
Pregnancy Testing
o
FRP 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 Schedule of 
Activities Table, Section 1.5. Pregnant participants who remain in the study do 
not need pregnancy testing during the study, for the duration of their pregnancy.


2018N382441_03
CONFIDENTIAL
160
o
Pregnancy testing will be performed whenever a menstrual cycle is missed or 
when pregnancy is otherwise suspected 
o
Pregnancy testing will be performed and assayed in the central laboratory OR 
using the test kit provided by the central laboratory / provided by the sponsor 
/approved by the sponsor and in accordance with instructions provided in its 
package insert.
o
If pregnancy is confirmed, please see Appendix 8 for details regarding allowing 
pregnant participants to remain in the study
Collection of Pregnancy Information
The Investigator will collect pregnancy information on any participant who becomes 
pregnant while participating in this study. See Appendix 8 and Section 10.8.1for 
information to be collected for participants who become pregnant while participating in 
this study.
Participants who become pregnant while in the study may remain in study and continue 
scheduled dosing with CAB + RPV LA, once a pregnancy specific ICF addendum is 
signed by the participant. See Appendix 8 for additional data and information regarding 
the management of participants who remain in the study while pregnant.


2018N382441_03
CONFIDENTIAL
161
10.8.
Appendix 8: Information and Guidance for Managing 
Pregnant Participants
TABLE OF CONTENTS
PAGE
10.8.
Appendix 8: Information and Guidance for Managing Pregnant 
Participants...............................................................................................161
10.8.1.
Collection of Pregnancy Information ..........................................162
10.8.2.
Introduction................................................................................162
10.8.3.
Background ...............................................................................163
10.8.4.
Benefit/Risk Assessment ...........................................................163
10.8.4.1.
Cabotegravir.............................................................164
10.8.4.2.
Rilpivirine..................................................................165
10.8.5.
Clinical Considerations ..............................................................166
10.8.5.1.
Exposure..................................................................166
10.8.5.2.
Use of Supplements with CAB + RPV LA .................168
10.8.5.2.1.
Oral Cabotegravir Only.........................168
10.8.5.3.
Overall Benefit:Risk Conclusion................................168
10.8.6.
Study Assessments and Procedures: specific 
assessments for pregnant participants.......................................169
10.8.6.1.
Safety Assessments.................................................169
10.8.6.2.
Pharmacokinetics .....................................................169
10.8.7.
References ................................................................................170


2018N382441_03
CONFIDENTIAL
209493
162
10.8.1.
Collection of Pregnancy Information
The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy.

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on mother and infant, which will be 
forwarded to GSK.  Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in the protocol in Section 10.5.6, Appendix 5.  While the investigator is 
not obligated to actively seek this information in former study participants, he or she 
may learn of an SAE through spontaneous reporting.

Females who become pregnant while in the study may remain in study, and continue 
scheduled dosing with CAB + RPV LA, once a pregnancy ICF addendum is signed 
by the participant.
10.8.2.
Introduction
Pregnancy increases the risk of HIV progression, while HIV increases the risk for 
maternal complications from pregnancy and poses the risk of perinatal HIV transmission 
to the unborn fetus.  Mother to child transmission (MTCT) of HIV can occur during 
pregnancy, labor, delivery or postpartum through breastfeeding.  In the absence of any 
interventions, vertical HIV transmission rates approximate 35%, but fall below 5% with 
effective interventions [WHO, 2010].  In the United States and other developed countries, 
the risk of perinatal infection has decreased from 25% without intervention to less than 
2% with intervention [WHO, 2012].  The HIV-infected mother who breastfeeds her 
infant while taking ARVs herself or giving ARVs to her infant reduces the risk of 
transmission to about 2% after 6 months of breastfeeding, or 4% over 12 months 
[UNAIDS, 2011].
The 2013 WHO Guidelines thus recommend (strong recommendation, moderate-quality 
evidence) all pregnant and breastfeeding women with HIV should initiate triple ARVs 
(ART), which should be maintained at least for the duration of mother-to-child 
transmission risk. Women meeting treatment eligibility criteria should continue lifelong 


2018N382441_03
CONFIDENTIAL
209493
163
ART [WHO, 2013]. The global benefits anticipated from ART in pregnant women who 
are eligible for treatment include treatment of the mother’s underlying HIV disease, 
eliminating pediatric transmission/infection and reducing sexual transmission of HIV
Recent recommendation updates to treatment guidelines have included objectives to 
increase HIV screening of patients, including pregnant women (noting the importance of 
adopting HIV screening to be a part of prenatal care).
The ART recommendation for pregnant females prioritizes the health of women over 
potential risks and increased cost.  For females who are on ARV therapy at the time that 
they become pregnant, the World Health Organization recommends that they continue 
such therapy if they are responding to the ARV.
In line with this recommendation, this study will allow those females participating in 
209493 who are receiving CAB + RPV LA but become pregnant on study, to continue in 
the study in order to maintain their effective regimen with minimal disruption.  The PK of 
CAB + RPV LA, characterization of the safety of CAB + RPV LA administered during 
pregnancy, and characterization of maternal, birth and infant outcomes following 
treatment with CAB + RPV LA will be examined.
10.8.3.
Background
At the time of finalizing this protocol, there have been 25 pregnancies reported during the 
CAB/RPV LA P3 development program (including 6 during PK tail and 5 during OLI) 
with 8 pregnancies leading to live births (including 3 pregnancies exposed during the PK 
tail of treatment and 1 pregnancy exposure occurring during CAB oral lead-in) and 5 on-
going pregnancies.

A total of 12 pregnancy losses (11 of these occurring during the first trimester)

Missed abortions: 2 (one of these was a twin anembryonic pregnancy)

Elective abortions (no medical indication): 5

Elective abortion for nausea and vomiting: 1

Spontaneous abortions: 4 (one late spontaneous abortion at 23/40; severe IUGR, 
placental insufficiency; presence of risk factors)
No reported congenital anomalies
10.8.4.
Benefit/Risk Assessment
Discuss with pregnant participant the benefit-risk of continuing in the study and 
continuing to receive CAB + RPV LA injections, or being withdrawn from study, as a 
result of her pregnancy. All participants who chose to stay in the study during pregnancy, 
and who choose to continue to receive CAB + RPV LA injections will need to sign a 
pregnancy specific ICF addendum.
There is a pregnancy exposure registry that monitors pregnancy outcomes in women 
exposed to CAB + RPV LA (CABENUVA) during pregnancy. Healthcare providers are 


2018N382441_03
CONFIDENTIAL
209493
164
encouraged to register all pregnant study participants, whether or not they choose to 
remain in the study, by calling the Antiretroviral Pregnancy Registry [Antiretroviral 
Pregnancy Registry (APR) Steering Committee] at 1-800-258-4263.
10.8.4.1.
Cabotegravir
Cabotegravir use in pregnant females has not been evaluated and there are insufficient 
human data on the use of during pregnancy to adequately assess a drug-associated risk of 
birth defects and miscarriage. 
The rate of miscarriage is not reported in the APR. The background risk for major birth 
defects and miscarriage for the indicated population is unknown. The background rate for 
major birth defects in a U.S. reference population of the Metropolitan Atlanta Congenital 
Defects Program (MACDP) is 2.7%. The estimated background rate of miscarriage in 
clinically recognized pregnancies in the U.S. general population is 15% to 20%. The APR 
uses the MACDP as the U.S. reference population for birth defects in the general 
population. The MACDP evaluates women and infants from a limited geographic area 
and does not include outcomes for births that occurred at less than 20 weeks’ gestation.
Animal Data (pre-clinical) 
Cabotegravir was administered orally to pregnant rats at 0, 0.5, 5, or 1,000 mg/kg/day 
from 15 days before cohabitation, during cohabitation, and from Gestation Days 0 to 17. 
There were no effects on fetal viability when fetuses were delivered by caesarean 
although a minor decrease in fetal body weight was observed at 1,000 mg/kg/day (greater 
than 28 times the exposure in humans at the RHD). No drug-related fetal toxicities were 
observed at 5 mg/kg/day (approximately 13 times the exposure in humans at the RHD) 
and no drug-related fetal malformations were observed at any dose.
Cabotegravir was administered orally to pregnant rabbits at 0, 30, 500, or 2,000 
mg/kg/day from Gestation Days 7 to 19. No drug-related fetal toxicities were observed at 
2,000 mg/kg/day (approximately 0.7 times the exposure in humans at the RHD).
In a rat pre- and postnatal development study, cabotegravir was administered orally to 
pregnant rats at 0, 0.5, 5, or 1,000 mg/kg/day from Gestation Day 6 to Lactation Day 21. 
A delay in the onset of parturition and increases in the number of stillbirths and neonatal 
deaths by Lactation Day 4 were observed at 1,000 mg/kg/day (greater than 28 times the 
exposure in humans at the RHD); there were no alterations to growth and development of 
surviving offspring. In a cross-fostering study, similar incidences of stillbirths and early 
postnatal deaths were observed when rat pups born to cabotegravir-treated mothers were 
nursed from birth by control mothers. There was no effect on neonatal survival of control 
pups nursed from birth by cabotegravir-treated mothers. A lower dose of 5 mg/kg/day (13 
times the exposure at the RHD) was not associated with delayed parturition or neonatal 
mortality in rats. Studies in pregnant rats showed that cabotegravir crosses the placenta 
and can be detected in fetal tissue.
During the pre-clinical development of CAB, there were no positive genotox findings. 
Embryo-fetal studies also showed no adverse findings including neural tube defects.  In a 
pre and postnatal study, there were some test article-related decreases in F1 pup survival 


2018N382441_03
CONFIDENTIAL
209493
165
(87.4% vs 98.9% in control) in the highest dose (1000mg/kg/day) during postnatal days 
1-4.  No findings in the 0, 0.5 and 5 mg/kg/day doses). 
The clinical significance of these finding in humans is unknown.
Human Data 
Cabotegravir use in pregnant females has not been evaluated and there are insufficient 
human data on the use of CAB + RPV LA during pregnancy to adequately assess a drug-
associated risk of birth defects and miscarriage. 
While there are insufficient human data to assess the risk of neural tube defects (NTDs) 
with exposure to CAB + RPV LA during pregnancy, NTDs were associated with 
dolutegravir, another integrase inhibitor. A preliminary analysis of an ongoing birth 
outcome surveillance study in Botswana involving women exposed to DTG, a different 
molecule in the same integrase class of medications as CAB, identified four cases (as of 
May 2018) of neural tube defects in 426 infants born to mothers who were exposed to 
DTG-containing regimens from the time of conception. In the same study, no infant born 
to a woman who started DTG during pregnancy had a neural tube defect, out of 2,824 
women.  More recently, data from the Tsepamo study was updated.  In April 2020, the 
Tsepamo study team provided interim data from the study, which included available data 
through to 29 February 2020. Subsequently, the study team presented an updated 
analysis, including data through to 30 April 2020, at the 23rd International AIDS Society 
(IAS) Meeting [Zash, 2020]. 
The latest data from the Tsepamo study included additional data accrued between 1 April 
2019 (the cut-off for the last formal analysis) and 30 April 2020. Over this 13-month 
period, 39,200 additional births were recorded, including 1908 additional exposures to 
DTG at conception. Two additional NTDs were detected in 1908 (0.10%) deliveries to 
mothers taking DTG at conception, compared with six NTDs in 4569 (0.13%) deliveries 
in mothers taking non-DTG regimens at conception, of which five NTDs in 2999 (0.17%) 
deliveries were to mothers taking efavirenz at conception. The incidence in HIV negative 
mothers over the 13-month period was 17/30,258 (0.06%). 
A causal relationship of these events to the use of DTG has not been established. 
The incidence of neural tube defects in the general population ranges from 0.5-1 case per 
1,000 live births. There are insufficient human data on the use of CAB + RPV LA during 
pregnancy to adequately assess a drug-associated risk of miscarriage or birth defects, 
including NTDs.
10.8.4.2.
Rilpivirine
Animal Data 
Rilpivirine was administered orally to pregnant rats (40, 120, or 400 mg/kg/day) and 
rabbits (5, 10, or 20 mg/kg/day) through organogenesis (on Gestation Days 6 through 17,
and 6 through 19, respectively). No significant toxicological effects were observed in
embryo-fetal toxicity studies performed with rilpivirine in rats and rabbits at exposures 


2018N382441_03
CONFIDENTIAL
209493
166
15 (rats) and 70 (rabbits) times the exposure in humans at the RHD. In a pre- and 
postnatal development study, rilpivirine was administered orally up to 400 mg/kg/day 
through lactation. No adverse effects were noted in the offspring at maternal exposures 
up to 63 times the exposure in humans at the RHD
Human Data 
Based on prospective reports to the APR of over 390 exposures to oral rilpivirine-
containing regimens during the first trimester of pregnancy and over 170 during 
second/third trimester of pregnancy, the prevalence of birth defects in live births was 
1.3% (95% CI: 0.4% to 3.0%) and 1.1% (95% CI: 0.1% to 4.0%) following first and 
second/third trimester exposures.
Available data from the APR show no difference in the overall risk of birth defects for 
rilpivirine compared with the background rate for major birth defects of 2.7% in a U.S. 
reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP)
In a clinical trial, total oral rilpivirine exposures were generally lower during pregnancy 
compared with the postpartum period. Refer to Edurant Prescribing Information, 2018 for 
additional information on rilpivirine.
10.8.5.
Clinical Considerations
10.8.5.1.
Exposure
Lower exposures with oral rilpivirine were observed during pregnancy. Cabotegravir and 
rilpivirine are detected in systemic circulation for up to 12 months or longer after 
discontinuing injections of CAB + RPV LA; therefore, consideration should be given to 
the potential for fetal exposure during pregnancy.
With the change in volume of distribution associated with pregnancy, drug concentrations 
of CAB and RPV during pregnancy will be assessed in pregnant participants who 
contiune to receive LA therapy while on study. For these participants, PK samples will be
collected up to 4 times throughout the duration of the pregnancy. Additionally, all other 
scheduled assessments, including viral load monitoring, will continue as reflected in as 
described in the protocol in the SoA, Section 1.5, Table 3).


2018N382441_03
CONFIDENTIAL
209493
167
Figure 7
LTFU PK in Female and Pregnant Participants
(LATTE-2, ATLAS)
Weeks Post Final Injection
0
12
24
36
48
60
Plasma CAB (g/mL)
0.01
0.1
1
10
L2 512
A 5911
L2 592
A 5487 (+HCG)
A 5485 (-HCG)
A 7224 (-HCG)
A 6595 (-HCG)


2018N382441_03
CONFIDENTIAL
209493
168
10.8.5.2.
Use of Supplements with CAB + RPV LA
During pregnancy, additional supplements including vitamins, minerals and other 
mediations including OTC meds may be prescribed to the pregnant woman. It is 
important for all female participants who remain in the study to be aware of any potential 
DDIs that may occur with study medications and other agents used during pregnancy.
10.8.5.2.1. Oral Cabotegravir Only
Antacid products containing divalent cations (e.g., aluminium, calcium and 
magnesium) must be taken at least 2 hours before or at least 4 hours after CAB.
Concurrent administration of multivitamins is acceptable.
10.8.5.3.
Overall Benefit:Risk Conclusion 
All medications have AE profiles that must be assessed prior to use, allowing for an 
appropriate risk/benefit assessment.  Additional considerations when using CAB + RPV 
LA can be found in the protocol in Section 2.3
There is limited data regarding the use of CAB + RPV LA in pregnant females. Based on 
animal data, the use of CAB + RPV LA is not anticipated to increase the risk of adverse 
developmental or reproductive outcomes in humans.  Available data from the APR show 
no difference in the overall risk of birth defects for rilpivirine compared with the 
background rate for major birth defects of 2.7% in a U.S. reference population of the 
Metropolitan Atlanta Congenital Defects Program (MACDP).
Refer to Section 10.8.4.1 for additional data.
The use of CAB + RPV LA during pregnancy may offer unique benefits. It is well 
documented that treatment adherence challenges to oral therapy exists both in the peri-
partum and post-partum periods with LA dosing offering an opportunity to overcome 
such adherence challenges. LA therapy may also help with nausea (50 % mild to 
moderate) or hyperemesis (2%). Female participants on LA dosing who become pregnant 
will have exposures throughout pregnancy due to the long half-life and PK tail of 
CAB/RPV. Pregnant participants who are withdrawn from study and are initiated on an 
alternative oral ART regimen consisting of either 2 or 3 antiretrovirals to protect the life 
of the mother and for the prevention of MTCT, potentially expose the fetus to additional 
ARVs during gestation (in some cases upwards of 5 antiretrovirals).
In summary, taking into account the measures taken to minimize risk to participants 
participating in this study, the potential risks identified in association with CAB + RPV 
LA are justified by the anticipated benefits that may be afforded to pregnant participants
with HIV infection.
Given the risk/benefit ratio for CAB + RPV LA dosing in FRP, coupled with concerns of 
increasing fetal exposure to several additional antiretrovirals upon participant withdrawal, 
pregnant participants will be allowed to remain in the study and continue to receive CAB 


2018N382441_03
CONFIDENTIAL
209493
169
+ RPV LA injections, once the new pregnancy ICF addendum is signed by the 
participant. 
10.8.6.
Study Assessments and Procedures: specific assessments for 
pregnant participants
Participants who become pregnant while in the study, and who sign the informed consent 
pregnancy addendum may remain in the study and continue to receive CAB + RPV LA. 
Please note: The HIV provider is responsible for HIV care and will collaborate and share 
information with the subject’s obstetric care provider, discuss the subject’s participation 
in this study, the necessary procedures at delivery, to share HIV information, and to 
collect birth and infant outcomes from the subject’s obstetric care provider and/or the 
pediatric health provider for the infant.
Because obstetric and/or pediatric care will not be specifically provided via this study, the 
subject must also establish appropriate obstetric and pediatric care (including prenatal 
care) per local standard of care (SoC) in parallel.  It will be necessary for the subject to 
provide a release of medical information to facilitate collection of pregnancy and 
pregnancy outcomes by the investigator
All assessments will be conducted in accordance with the protocol, Section 8, and as 
described in the SoA, Section 1.5, Table 3).
10.8.6.1.
Safety Assessments
Pregnancy related complications and diagnoses, and outcomes will be captured as AEs 
and SAEs as outlined in the protocol in Section 8.5.
Pregnancy complications (e.g., preeclampsia or eclampsia, prolonged hospitalization after 
delivery, for wound infections etc, seizures) and elective terminations for medical reasons 
must be reported as an AE or SAE.  Spontaneous abortions must be reported as an SAE.
In the event of a pregnancy loss, after the loss is confirmed the subject may continue to 
receive CAB + RPV LA unless they meet the criteria for confirmed virologic withdrawal.  
They may continue to CAB + RPV LA until study medications are locally approved and 
commercially available or until they no longer receive benefit.  In this case the subject 
must agree to use contraception to avoid a ‘new’ pregnancy (See Appendix 7).
Any SAE occurring in association with the pregnancy brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
possibly related to the study treatment, must be promptly reported to GSK
10.8.6.2.
Pharmacokinetics
Refer to Section 8.6 in the protocol.
All pregnant participants who elect to remain in the study will have additional PK 
sampling obtained. Blood samples for evaluation of plasma concentrations of 
cabotegravir and rilpivirine will be collected prior to each LA injection  throughout the 


2018N382441_03
CONFIDENTIAL
209493
170
pregnancy. A final PK sample for cabotegravir and rilpivirine concentrations will 
obtained at the first postpartum LA visit. All PK samples will be trough levels and will be 
collected prior to the scheduled LA injection. The pre-dose trough PK sample is to be 
collected within 15 minutes prior to the LA dose, on the day of the study visit. 
Please refer to the SPM for PK sample collection, processing, and shipping instructions.
The actual date and time of each PK sample collection will be recorded in the eCRF.
10.8.7.
References
Antiretroviral Pregnancy Registry (APR) Steering Committee. Antiretroviral Pregnancy 
Registry International Interim Report for 1 January 1989 through 31 January 2013. 
Wilmington, NC: Registry Coordinating Center; 2013. Available from URL: 
www.APRegistry.com.
Edurant Prescribing Information, February 2018
UNAIDS (2011) Reference Group on Estimates, Modelling and Projections. Working 
Paper on Mother-to-Child HIV Transmission Rates for use in Spectrum, 6 June 2011. 
Available online at http://www.epidem.org/Publications/MTCTratesworkingpaper.pdf.
World Health Organization (WHO) (2010). Antiretroviral drugs for treating pregnant 
women and preventing HIV infection in infants: Recommendations for a public health 
approach.  Available online at: 
http://whqlibdoc.who.int/publications/2010/9789241599818_eng.pdf, accessed 6 Feb 
2013.
World Health Organization (WHO) (2012). Antiretroviral Treatment as Prevention 
(TasP) of HIV and TB:  2012 Update.  June 2012, Available online at: 
http://www.who.int/hiv/pub/mtct/programmatic_update_tasp/en/index.html
World Health Organization (WHO) (2013). Consolidated Guidelines on the Use of 
Antiretroviral Drugs for Treating and Preventing HIV Infection. 30 June 2013.  Available 
online at: http://www.who.int/hiv/pub/guidelines/arv2013/download/en/index.html
Zash R, Holmes L, Diseko M, Jacobson D, Mayondi G. Update on neural tube defects 
with antiretroviral exposure in the Tsepamo study, Botswana. JAIDS 2020


2018N382441_03
CONFIDENTIAL
209493
171
10.9.
Appendix 9: Abbreviations and Trademarks
Abbreviations
ADR
Adverse drug reaction
AE
Adverse event
AIDS
Acquired immunodeficiency syndrome
AIM
Acceptability of intervention measure
ALT
Alanine aminotransferase
Anti-HBc
Hepatitis B core Antibody
Anti-HbsAg
Antibodies against Hepatitis B surface Antigen
APR
Antiviral Pregnancy Registry
ARV
Antiretroviral
ART
Antiretroviral therapy
AST
Aspartate aminotransferase
AUC
Area under the curve
AUC(0-)
Area under the concentration curve from 0 hours to the time 
of next dosing
AZT
Azidothymidine (zidovudine)
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
CFIR
Consolidated framework for implementation research
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
Cmax
Maximum concentration
ConART
Concomitant Antiretroviral Therapy
CONSORT
Consolidated Standards of Reporting Trials
CPK
Creatine phosphokinase
CPMS
Clinical Pharmacology Modelling and Simulation
CRO
Contract research organization
CSR
Clinical Study Report
CV
Cardiovascular
CVF
Confirmed Virologic Failure
DAIDS
Division of Acquired Immunodeficiency Syndrome
DILI
Drug-induced liver injury
DNA
Deoxyribonucleic acid
DRE
Disease-Related Events
DVT
Deep vein thrombosis
ECG
Electrocardiogram
eCRF
Electronic case report form


2018N382441_03
CONFIDENTIAL
209493
172
FIM
Feasibility of intervention measure
FDA
Food and Drug Administration
FRP
Female of Reproductive Potential
GCP
Good Clinical Practice
GSK
GlaxoSmithKline
HAART
Highly active antiretroviral therapy
HbsAg
Hepatitis B surface Antigen
HBV
Hepatitis B virus
HCG
human chorionic gonadotrophin
HCP
Healthcare practitioner
HCV
Hepatitis C virus
HDPE
High density polyethylene
HIV
Human immunodeficiency virus 
HLA
Human leukocyte antigen
HSR
Hypersensitivity reaction
IAM
Intervention appropriateness measure
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IDMC
Independent data monitoring committee
IEC
Independent Ethics Committee
IgM
Immunoglobulin M
IM
Intramuscular
INI
Integrase inhibitor
INR
International normalized ratio
INSTI
Integrase strand transfer inhibitor
IP
Investigational Product
IRB
Institutional Review Board
ITT-E
Intent-to-treat exposed
IUD
Intrauterine device
ISR
Injection Site Reaction
LA
Long Acting
LDL 
Low density lipoprotein
LFTs
Liver function tests
LTFU
Long-Term Follow-UP
MTCT
Mother-to-Child Transmission
MCV
Mean corpuscular volume
MedDRA
Medical dictionary for regulatory activities
Mg
Milligram
Mg/dL
Milligram per deciliter
NNRTI
Non-nucleoside reverse transcriptase inhibitor
NRS
Numeric Rating Scale
NRTI
Nucleoside reverse transcriptase inhibitor
NTF
Note to File
OLI
Oral lead-in
PK
Pharmacokinetic
PLHIV
Persons living with HIV


2018N382441_03
CONFIDENTIAL
209493
173
PP
Per-protocol
PRO
Protease
PRTD
Proximal Renal Tubule Dysfunction
PSAT
Program sustainability assessment tool
PSP
Patient study participant
PSRAE
Possible suicidality-related adverse event
QTc
Corrected QT interval 
Q8W
Every 8 weeks
Q4W
Every 4 weeks
RAP
Reporting and Analysis Plan
RBC
Red blood cell
RNA
Ribonucleic acid
RPR
Rapid plasma reagin
RPV
Rilpivirine, Edurant
RPV LA
Rilpivirine long-acting
RT
Reverse transcriptase
SAE
Serious adverse event
SJS
Stevens-Johnson syndrome
SoA
Schedule of activities
SOC
Standard of Care
SPM
Study Procedures Manual
SSI
Semi-structured interview
SSP
Staff study participants
TEN
Toxic epidermal necrolysis
TMC278
Tibotec Medicinal Compound 278
ULN
Upper limit of normal
US
United States
VAPI
Vaccines’ Perception of Injection
VSLC
ViiV Safety and Labeling Committee
WBC
White blood cell
Trademark Information
Trademarks of ViiV Healthcare
Trademarks not owned by ViiV 
Healthcare
CABENUVA
Edurant
Evidera
Genosure
InForm
MedDRA
Monogram Biosciences
PhenoSense


2018N382441_03
CONFIDENTIAL
209493
174
10.10.
Appendix 10: Patient Study Participant Surveys
A survey will be administered to the patient study participants at three timepoints:

Month 1 visit- at the end of the oral dosing period, prior to receiving the 
CAB+RPV injection.  

Month 4 visit

Month 12/ End of Study
Each of the patient surveys will include approximately 40-50 questions and will take 
about 15 minutes to complete. Patients will be asked to answer the questions at Month 1 
based on their current expectations of receiving the CAB+RPV injection, and at the 
Month 4 and 12 timepoints, based on the current experience receiving the injection.  
The following concepts are measured in the patient study participant surveys:

Acceptability of the CAB+RPV injection (AIM)

Appropriateness of the CAB+RPV injection (IAM)

Facilitators and barriers to implementation of the CAB+RPV injection

Utility of patient specific toolkit resources

Patient satisfaction with current treatment (HIV-TSQs, HIV-TSQc)
Acceptability and appropriateness will be measured by the Acceptability of Intervention 
Measure (AIM) and Intervention Appropriateness Measure (IAM), which are constructs 
validated from the Proctor Framework. Reponses are measured using a 5-point Likert 
scale. (Weiner, 2017)
Additional questions are included to evaluate facilitators and barriers from the patient 
perspective, and to evaluate the usefulness of the patient specific toolkit resources. 
Patient satisfaction will be measured using the validated HIV Treatment Satisfaction 
Questionnaire (HIV-TSQ), status version (HIV-TSQs), which measures satisfaction with 
the treatment used in the previous few weeks, and the HIV-TSQ change version (HIV-
TSQc), which measures change in satisfaction over time. The HIV-TSQs will be included 
at all 3 timepoints, while the HIV-TSQc is only measured at Month 12/End of study. 
(Woodcock, 2006)


2018N382441_03
CONFIDENTIAL
209493
175
10.11.
Appendix 11: Staff Study Participant Survey 
A survey will be administered to the staff study participants at three timepoints:

Month 1 – following the investigator meeting, but prior to any patients at the site 
receiving the CAB+RPV injection  

After the 4th monthly facilitation call

Month 12/ End of Study
The first two surveys will include approximately 55 questions and will take about 15
minutes to complete. The final survey will include approximately 100 questions and will 
take about 25 minutes to complete. Staff study participants will be asked to answer the 
questions at Month 1 based on their current expectations of administering the CAB+RPV 
injection, and at the following timepoints based on their current experience administering 
the injection.
The following concepts are measured in the staff study participant surveys:

Acceptability of the CAB+RPV injection (AIM)

Appropriateness of the CAB+RPV injection (IAM) 

Feasibility of the CAB+RPV injection (FIM)

Facilitators and barriers to implementation of the CAB+RPV injection

Utility of toolkit and study resources

Experiences and attitudes about the CAB+RPV injection

Sustainability of the CAB+RPV injection (PSAT) (Month 12 only)
Acceptability, appropriateness and feasibility will be measured by the Acceptability of 
Intervention Measure (AIM), the Intervention Appropriateness Measure (IAM) and the 
Feasibility Appropriateness Measure (FIM), which are constructs validated from the 
Proctor Framework. Reponses are measured using a 5-point Likert scale. (Weiner, 2017)
Additional questions are included to evaluate facilitators and barriers from the site 
perspective.  A series of questions are also included to evaluate the usefulness of toolkit 
resources, and about staff study participant experiences and attitudes towards 
implementing the CAB+RPV injection.
Sustainability is measured by the Program Sustainability Assessment Tool (PSAT). The 
PSAT evaluates the capability of clinics to maintain processes developed to administer 
CAB+RPV injection in routine clinical settings after the conclusion of this study. (Luke, 
2014)


2018N382441_03
CONFIDENTIAL
209493
176
10.12.
Appendix 12: COVID-19 Pandemic and Clinical Trial 
Continuity
Background
The COVID-19 pandemic presents significant logistical challenges for many clinical sites 
around the world, with variable restrictions being placed on site resources and operations, 
and on an individual participants ability to attend clinic visits.  In some places, medical 
visits are occurring, and in others, research clinics are operating with only emergency 
staff.
Based on these challenges, it may be necessary to adopt additional measures and 
procedures to protect participant safety, and to ensure that there are no gaps in HIV-1 
treatment for participants enrolled in this clinical study, through continuous access to 
antiretroviral therapy.
In order to maintain the scientific integrity of the study, and adhere to updated guidance 
from regulators, procedures have also been put into place to ensure that the actions taken 
to mitigate against any impact of COVID-19 are well documented in the trial database.
A “Memo to Investigators” was issued on March 18th, 2020 and served as a record of 
approved emergency actions being taken within this clinical trial to manage issues related 
to COVID-19.  That memo continues to serve as record of approved actions which can be 
fully implemented by Investigators, in advance of this protocol guidance.  This appendix 
will remain consistent with the guidance provided within the “Memo to Investigators” 
and will also serve to provide additional protocol documentation requirements and 
procedures.
This appendix outlines the measures which are approved for implementation within this 
clinical trial, to protect patient safety and to ensure the integrity of the clinical trial, as a 
result of COVID-19 only. These measures may be implemented in accordance with any 
requirements and expectations set out by local Independent Review Boards/Independent 
Ethics Committees and National Competent Authorities, as necessary.
This appendix does not apply to participant management issues that are unrelated to a 
specific, and documented, impact from COVID-19. 
10.12.1.
Changes to Study Visits and Study Procedures

Where site staff resource is constrained due to COVID-19, IM dosing visits may 
proceed with limited or no other protocol-defined assessments (e.g. lab tests, 
questionnaires, etc.). If lab tests will be missed for more than one consecutive 
visit, the medical monitor must be contacted, to provide guidance for safety 
monitoring. 

For FRP, point of care pregnancy testing should be performed, prior to IM dosing.

If central laboratory testing cannot be performed at a particular visit, and 
monitoring for safety is required, tests may be performed at an appropriately 
authorised/accredited local laboratory (or other relevant clinical facility), if this 


2018N382441_03
CONFIDENTIAL
209493
177
can be done within local restrictions on physical distancing. The site should 
proactively inform the sponsor about such instances. Local laboratory results may 
be used to inform safety decisions. Results should be retained in source records.

When on-site visits are reduced, it is important that the investigator continue 
collecting relevant clinical information, including adverse events, from the 
participant through alternative means, e.g. by telephone contact.

There may be cases where the current principal investigator (PI) of a site is 
indisposed for a period and may need to delegate parts of his/her duties 
temporarily, e.g. to a sub-investigator. Any such changes should be documented 
in the site’s source records. Any permanent changes in PI should be 
communicated to the sponsor.

There may also be circumstances where immediate actions are required by the 
sponsor and/or investigator, outside of what is contemplated in the protocol, in 
order to protect a study participant from immediate hazard. Any such measures 
will be carefully documented and conducted in accordance with the National 
Competent Authority (NCA)/IRB/IEC regulations.
10.12.2.
Changes to Informed Consent
Informed consent should continue per normal procedure and as described in the main 
body of the protocol, to the extent possible. However, there may be circumstances where 
re-consent of participants is needed, and a physical signature on site is not possible. In 
these cases, alternative ways of obtaining such re-consent should be considered, such as 
the participant sending a picture of his/her written consent to the investigator, or the 
investigator contacting the participant by telephone or video call and obtaining verbal 
consent, supplemented with email confirmation.  
Any updated informed consent form or other subject-facing materials should be provided 
to participants by e-mail, mail or courier before re-consent is obtained. Any consent 
obtained this way should be documented in source records and confirmed by way of 
normal consent procedure at the earliest opportunity when participants attend their next 
on-site study visit.
Any alternative informed consent procedure must be undertaken only after site 
IRB/Ethics Committee agreement and approval.
10.12.3.
Permissible Use of Antiretroviral Therapy
In order to minimize the risk of gaps in HIV-1 antiretroviral therapy (ART) for 
participants impacted by COVID-19 in the clinical trial, the following options can be 
considered with regards to ART dosing, in order of preference:


2018N382441_03
CONFIDENTIAL
209493
178
1. Where possible, and safe to do, please continue to prioritize IM dosing visits in 
order to keep the participants on the protocol-defined regimen
a.
Qualified healthcare professionals (HCPs) trained on study procedures can 
administer IM injections outside of the study clinic setting (e.g. home, 
nursing facility, hospital), assuming this can be done safely, without 
compromising investigational product 
preparation/handling/storage/accountability requirements and done in 
accordance with local requirements. Please seek approval by the study 
team on a case-by-case basis.
2. If a participant is not able to attend an IM injection visit due to COVID-19 related 
restrictions, the gap in IM dosing should be covered with oral ART, until IM 
dosing can resume. Participants should be reminded of the importance of adhering 
with daily oral dosing. Two options can be approved for oral bridging therapy in 
consultation with the Medical Monitor, listed in order of preference:
a.
Oral CAB + RPV 
i. Investigator should request availability of oral CAB + RPV supplies, 
prior to pursuing option b.
b. Oral standard of care (SOC) commercial ART (prescribed locally)
Oral bridging with CAB + RPV
The protocol permits oral bridging to cover planned missed injections with oral CAB + 
RPV, only until IM dosing can be resumed.  The start date of oral bridging should be 
within the dosing window for the missed IM dosing visit. This recommendation can be 
used to accommodate requests for oral dosing due to COVID-19. Oral bridging 
recommendations should be followed as per protocol Section 6.6.1.1. The process and 
required information for requesting oral bridging can be found in your Study 
Reference/Procedure Manual.  Please continue to reach out to your study medical 
monitor for approval of oral bridging, in order to document use and to ensure expeditious 
shipment of oral CAB + RPV to your site. 
Participants who use oral CAB + RPV as short-term oral bridging are permitted to return 
to IM dosing, on protocol, once the COVID-19 conditions permit resumption of site 
activities. 
The investigator should reach out to the medical monitor to confirm IM restart 
instructions, and to ensure the participant remains appropriate for resumption of IM 
dosing. If oral bridging with CAB/RPV is anticipated to continue for >2 months, 
additional approval and guidance should be obtained from the medical monitor to 
continue with oral bridging therapy. Loading/Re-initiation doses of CAB + RPV IM may 
be required, depending on the length of oral bridging.


2018N382441_03
CONFIDENTIAL
209493
179
Oral bridging with Standard of Care Antiretroviral Therapy (SOC ART)
For participants impacted by COVID-19, where the participant is unable to receive IM 
injections, and oral CAB + RPV is not available for use, oral bridging with any 
commercially available, guideline-recommended, SOC ART regimen is permitted. The 
start date of oral bridging should be within the dosing window for the missed IM dosing 
visit.  Please reach out to your study medical monitor for approval of SOC ART as oral 
bridging, in order to document the use of commercially available SOC ART within the 
study.
Participants who use oral SOC ART as short-term oral bridging as a result of COVID-19 
will not be considered formally withdrawn insofar as they wish to continue on the study.  
Individuals who bridge with SOC ART will be permitted to return to IM dosing, on 
study, once the COVID-19 conditions permit resumption of site activities.  
The investigator should reach out to the medical monitor to confirm IM restart 
instructions, and to ensure the participant remains appropriate for resumption of IM 
dosing. If oral bridging with SOC ART is anticipated to continue for >2 months, 
additional approval and guidance should be obtained from the medical monitor to 
continue with oral bridging therapy.  Loading/Re-initiation doses of CAB + RPV IM may 
be required, depending on the length of oral bridging.
10.12.4.
Direct-To-Patient (DTP) Shipment of Oral Study IP 
If a participant is unable to travel to the clinic, either to receive IM injections or to be 
dispensed oral bridging, sites are encouraged to consider DTP shipments of drug, from 
the site, to the participant, to ensure access to medicines. 

If the study site is considering DTP shipment of oral CAB + RPV investigational 
product (IP), the site must first verify if DTP IP dispensing by 
investigators/hospital pharmacies is locally permitted and whether it requires 
regulatory and/or local ethics pre-approval, or post-hoc notification.

The study participant should express his/her agreement for DTP shipment and the 
sharing of their personal information with any third-party couriers (as applicable), 
in accordance with local requirements.  This agreement should be documented in 
source records.

Oral CAB + RPV IP can be shipped at ambient temperatures via ground transport 
without a temperature monitoring device, with low risk of temperature excursions. 
Sites are encouraged to use discretion in determining the need for in-transit 
temperature monitoring based on the labelled storage requirements and the 
planned mode of transport and apply this as appropriate.  Shipment of oral CAB + 
RPV via air courier continues to require appropriate temperature monitoring.  For 
shipment conditions of oral medications other than oral CAB + RPV, please 
consult the product labelling.

In all cases IP accountability must be maintained, and all DTP dispensing 
documentation should be reflected in source records and dispensing logs per GCP.


2018N382441_03
CONFIDENTIAL
209493
180

Please refer to your CRA or local study manager for support with the DTP 
process, ensuring reference to current sponsor guidance and arrangement of a 
courier that can support shipment of IMP directly to participants.
10.12.5.
COVID-19 Experimental Agents
If any treatments for COVID-19 are planned for a study participant, please consult with 
the study medical monitor to ensure that relevant drug interactions are considered and to 
ensure that continued study participation remains appropriate.
10.12.6.
COVID-19 Specific Data Capture
10.12.6.1. Capturing COVID-19 Specific Protocol Deviations
In order to summarise the impact of COVID-19 in a systematic way and in line with 
regulatory authorities’ recommendations, any study-level impact around COVID-19 will 
be documented as a protocol deviation. This will include the permissible actions 
summarized in this Appendix, which are taken to protect patient safety, including the use 
of CAB + RPV or SOC ART as oral bridging as well as missed visits and assessments as 
a result of logistical challenges resulting from COVID-19.
Although the conduct of remote visits and the continuity of antiretroviral therapy, via oral 
bridging, are being utilized to protect patient safety, these events fall outside of the intent 
of the original protocol design, may have an impact on data interpretation, and thus will 
be characterized as protocol deviations for the purposes of data summary and analysis.
Any protocol deviations resulting from COVID-19 will be clearly identified as such 
within the protocol deviation description and summarised separately.
Please refer to your study procedure manual for specific details on capturing protocol 
deviations as a result of COVID-19.
10.12.6.2. Capturing COVID-19 Specific AEs and SAEs
It is important for the study team to describe COVID-19 related adverse events/serious 
adverse and their impact on study data and outcomes. Standardization of case definitions 
will facilitate future data analysis. 
Please use the following guidance: 
1. AEs should continue to be evaluated as to whether they meet SAE criteria as 
defined in the protocol, and if so, submitted according to established SAE 
reporting requirements. SAEs and AEs should be submitted following usual 
study procedures and timelines. 
2. When an in-person clinic visit is not possible, please conduct a remote telehealth 
visit to assess for, and document any AEs/SAEs.


2018N382441_03
CONFIDENTIAL
209493
181
3. Investigators should use the WHO definition to classify COVID-19 cases. The 
definition below, released March 20, 2020, represents a time point for 
standardized collection. We recognize definitions are likely to continue to 
evolve. When reporting both serious and non- serious adverse events (related 
to COVID-19 infection, investigators should use the following Verbatim 
terms: 
a) Suspected COVID-19 infection; or 
b) Probable COVID-19 infection; or 
c) Confirmed COVID-19 infection 
4. Sites should contact the study Medical Monitor for questions related to definitions 
and reporting, and decisions around impact to study drug continuation. 
5. A new COVID-19 infection Case Report Form will be added to the eCRF to 
collect additional details about the reported COVID-19 AE or SAE data. It is 
important to collect the correct information from each participant reporting a 
COVID-19 AE or SAE.  Therefore, please use the CRF templates to help you 
collect this information, once available.
WHO Case Definition - March 20, 2020 Version (https://www.who.int/publications-
detail/global-surveillance-for-human-infection-with-novel-coronavirus-(2019-ncov))
: 
Suspected case: 
A. A patient with acute respiratory illness (fever and at least one sign/symptom of 
respiratory disease, e.g., cough, shortness of breath), AND a history of travel to or 
residence in a location reporting community transmission of COVID-19 disease 
during the 14 days prior to symptom onset; 
OR 
B. A patient with any acute respiratory illness AND in contact (see definition of 
“contact” below) with a confirmed or probable COVID-19 case (see definition of 
contact) in the last 14 days prior to symptom onset; 
OR 
C. A patient with severe acute respiratory illness (fever and at least one 
sign/symptom of respiratory disease, e.g., cough, shortness of breath; AND 
requiring hospitalization) AND in the absence of an alternative diagnosis that 
fully explains the clinical presentation. 


2018N382441_03
CONFIDENTIAL
209493
182
Probable case: 
A. A suspect case for whom testing for the COVID-19 virus is inconclusive 
(Inconclusive being the result of the test reported by the laboratory). 
OR 
B. A suspect case for whom testing could not be performed for any reason. 
Confirmed case: 
A person with laboratory confirmation of COVID-19 infection, irrespective of 
clinical signs and symptoms. 
Covid-19 Contact:
A contact is a person who experienced any one of the following exposures during the 2 
days before and the 14 days after the onset of symptoms of a probable or confirmed case: 
1. Face-to-face contact with a probable or confirmed case within 1 meter and for 
more than 15 minutes; 
2. Direct physical contact with a probable or confirmed case; 
3. Direct care for a patient with probable or confirmed COVID-19 disease without 
using proper personal protective equipment; OR 
4. Other situations as indicated by local risk assessments. 
Note: for confirmed asymptomatic cases, the period of contact is measured as the 2 days 
before through the 14 days after the date on which the sample was taken which led to 
confirmation.


2018N382441_03
CONFIDENTIAL
209493
183
10.13.
Appendix 13: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).
Amendment 2 15-MAY-2020
Overall Rationale for the Amendment: The purpose of this amendment is to include an 
Appendix related to COVID-19 Pandemic and Clinical Trial Continuity. This appendix 
will replace the previous Appendix 11, and “Protocol Amendment History,” will be 
included as Appendix 12.
Section # and Name
Description of Change
Brief Rationale
Section 6.2 
Preparation/Handling/
Storage/Accountability
Section 6.6.1.1. Oral 
Bridging 
Section 8. Study 
assessments and 
procedures
Section 8.5. Adverse 
Events and Serious 
Adverse Events
Added reference to 
COVID-19 Section 10.11, 
Appendix 11 
To link Appendix 11 to the main 
body of the protocol 
Section 10.11 
Appendix 11: COVID-
19 Pandemic and 
Clinical Trial 
Continuity
Added Appendix 
To summarize COVID-19 related 
patient management updates that 
were previously communicated in 
a memo to investigators 
Amendment 1 02-APR-2019

Overall Rationale for the Amendment: The reasons for this amendment 
include: addition of exclusion criterion regarding known major resistance 
mutations at Screening, clarification of timing for collection of visit length, 
removal of consent requirement for study staff, correction to allowable window 
around the Month 3 dosing visit, clarification of pregnancy testing requirements at 
Screening, clarification of wording to allow a single re-screen per subject, 
removal of color of vial stopper in product description to allow flexibility of 


2018N382441_03
CONFIDENTIAL
209493
184
packaging for cabotegravir and rilpivirine suspension, clarification of ECG 
collection during the study, clarification of wording to allow qualitative analyses 
to be performed by a CRO under GSK oversight.
Section # and 
Name
Description of Change
Brief Rationale
Section 1.2 
Objectives and 
Endpoints and 
Section 3 
Objectives and 
Endpoints
Added time points where 
visit length is collected 
(Month 1, Month 5 and 
Month 11)
To provide specificity when these 
data will be collected
Section 1.3 Overall 
Design
Deleted wording to require 
written consent from study 
staff
Because there is no risk to study staff, 
consent is not required.
Section 1.5 
Schedule of 
Activities
Clarification of footnote 
“b” re: study visit length 
collection not being 
collected following Month 
11, footnote “i” re: dosing 
window and removal of 
consent requirement for 
study staff in Table 4.
Study visit length will not be 
collected after Month 12, the Month 3 
dosing window is corrected to +0/-7 
days from the projected visit date, and 
consent requirement for study staff 
has been removed.
Section 5.1 
Inclusion Criteria
Urine pregnancy test is 
stipulated for females of 
childbearing potential at 
the Screening visit.
Urine pregnancy test is stipulated at 
Screening. Serum pregnancy test 
should be performed if pregnancy is 
suspected.
Section 5.2 
Exclusion Criteria
New Exclusion Criteria 
added. “Any evidence of 
primary resistance based 
on the presence of any 
major known INI or 
NNRTI resistance-
associated mutation, 
except for K103N by any 
historical resistance test 
result
This exclusion criterion has been 
added to prevent subjects with known 
relevant mutations which could affect 
virologic response from being 
included in the study.
Section 5.4 Screen 
Failures and 
Section 8.1 
Screening 
Assessments
Minor wording changes to 
clarify that subjects may be 
re-screened only one time.
Minor wording to clarify rescreening 
requirements.


2018N382441_03
CONFIDENTIAL
209493
185
Section # and 
Name
Description of Change
Brief Rationale
Section 6.1.1.3 and 
Section 6.1.1.4
Color (grey) of rubber vial 
stopper has been removed 
to allow flexibility of 
packaging.  
A color change in vial stopper color is 
anticipated during the course of this 
study.
Section 8.4.1 
Clinical 
Evaluations and 
Section 8.4.4 
Electrocardiograms
ECG requirements have 
been clarified to require 
ECG at Screening and not 
at Day 1
Minor wording modification to clarify 
ECG requirements for study entry.
Section 9.4 
Statistical 
Analyses
Wording added to allow 
qualitative analyses to be 
performed by Evidera or 
other CRO partner under 
GSK’s oversight
This wording has been changed to 
allow flexibility in CRO vendor for 
the qualitative analyses in this study, 
as well as to confirm that all work 
will be carried out under GSK 
oversight.


2018N382441_03
CONFIDENTIAL
209493
186
11.
REFERENCES
Andrade RJ, Robles M, Lucena MI. Rechallenge in drug-induced liver injury: the 
attractive hazard.  Expert Opin Drug Saf.  2009; 8:709-714.
Centers for Disease Control and Prevention (CDC). Revised Surveillance Case Definition 
for HIV Infection – United States, 2014. MMWR 2014; 63 (RR-03);1-10.
Damschroder L, Aron D, Keith R, et al. Fostering implementation of health services 
research findings into practice: a consolidated framework for advancing implementation 
science. Implementation Science. 2009 https://doi.org/10.1186/1748-5908-4-50
Department of Health and Human Services (DHHS). Panel on Antiretroviral Guidelines 
for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-
infected adults and adolescents. Updated October 25, 2018.  Available at: 
https://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf.
Edurant Prescribing Information, February 2018.
GlaxoSmithKline Document Number 2011N112455_03: LAI115428: A Randomized, 
Open Label Study to Investigate the Safety, Tolerability and Pharmacokinetics of Repeat 
Dose Administration of Long-Acting GSK1265744 and Long-Acting TMC278 
Intramuscular and Subcutaneous Injections in Healthy Adult.  Effective Date:  
04Feb2013.
GlaxoSmithKline Document Number 2011N130484_00:  LAI116181: A Phase 1, Open-
Label, Crossover Study to Evaluate the Pharmacokinetics and Safety of GSK1265744 
and Rilpivirine and Dolutegravir and Rilpivirine in Healthy Adult Subjects.  Effective 
Date:  18Jul2012.
GlaxoSmithKline Document Number 2013N168152_05:  20056:  A Phase IIb Study 
Evaluating a Long-Acting Intramuscular Regimen of GSK1265744 plus TMC278 For 
The Maintenance of Virologic Suppression Following an Induction of Virologic 
Suppression on an Oral regimen of GSK1265744 plus Abacavir/Lamivudine in HIV-1 
Infected, Antiretroviral Therapy- Naive Adult Subjects. Effective Date: 13Jun2014.
GlaxoSmithKline Document Number 2014N216014_00: LAI116482:  A Phase IIb, Dose 
Ranging Study of Oral GSK1265744 in Combination with Nucleoside Reverse 
Transcriptase Inhibitors for Induction of HIV-1 Virologic Suppression Followed by an 
Evaluation of Maintenance of Virologic Suppression when Oral GSK1265744 is 
Combined with Oral Rilpivirine in HIV-1 Infected, Antiretroviral Therapy Naive Adult 
Subjects - Week 96 Results.  Effective Date 02Sept2015.
GlaxoSmithKline Document Number 2016N269422_00: 201120: A Phase IIa Study to 
Evaluate the Safety, Tolerability and Acceptability of Long Acting Injections of the HIV 
Integrase Inhibitor, GSK1265744, in HIV Uninfected Men (ÉCLAIR) –Week 81 Results. 
Effective Date: 25Oct2016.


2018N382441_03
CONFIDENTIAL
209493
187
GlaxoSmithKline Document Number RH2009/00003/07: GSK1265744 (Cabotegravir) 
Clinical Investigator's Brochure, Version 07, December 2017.
Hunt CM, Contraceptive Technology. 20th edition.  Atlanta, Georgia: Ardent Media, 
Inc., 2011: 50.  Table 3-2.  Hepatol 2010; 52:2216-2222.
James LP, Letzig L, Simpson PM, et al. Pharmacokinetics of acetaminophen-protein 
adducts in adults with acetaminophen overdose and acute liver failure. Drug Metab 
Dispos 2009;37(8):1779-1784.
Levey AS, Stevens LA, Schmid CH, et.al. A new equation to estimate glomerular 
filtration rate.  Ann Int Med. 2009; 150: 604-612.
Luke, Douglas A., et al. "Peer Reviewed: The Program Sustainability Assessment Tool: 
A New Instrument for Public Health Programs." Preventing Chronic Disease 11 (2014).
Margolis DA, Gonzales-Garcia J, Stellbrink H, et al. Long-acting intramuscular 
cabotegravir and rilpivirine in adults with HIV-1 infection (LATTE-2): 96-week results 
of a randomised, open-label, phase 2b, non-inferiority trial. Lancet. 2017; S0140-
6736(17)31917-7.
Margolis DA, Gonzales-Garcia J, Stellbrink H, et al. Safety, Efficacy and Durability of 
Long-acting Cabotegravir (CAB) and Rilpivirine (RPV) as Two-Drug IM Maintenance 
Therapy for HIV-1 Infection: LATTE-2 Week 160 Results. European AIDS Clinical 
Society (EACS 2018). Oct 28-31, 2018. Glasgow, UK. Abstract P118.
Papay JI, Clines D, Rafi R, et al. Drug-induced liver injury following positive drug 
rechallenge. Regul Tox Pharm. 2009; 54:84-90.
Powell B, Waltz TJ, Chinman M, et al. A refined compilation of implementation 
strategies: results from the Expert Recommendations for Implementing Change (ERIC) 
project. Implementation Science. 2015. 21(10) DOI 10.1186/s13012-015-0209-1
Proctor E, Silmere H, Raghavanet R, et al. Adm Policy Ment Health (2011) 38: 65. 
https://doi.org/10.1007/s10488-010-0319-7
Rilpivirine Clinical Investigator Brochure [RPV IB], Edition Version 11 Addendum 1 
(09-Nov-2018).
Weiner BJ, Lewis CC, Stanick C, et al. Psychometric assessment of three newly 
developed implementation outcome measures. Implementation Science. 2017;12(1):108. 
doi: 10.1186/s13012-017-0635-3
Wensing AM, Calvez V, Günthard HF, et al. 2017 update of the drug resistance 
mutations in HIV-1. Top Antivir Med 2017; 24:132–3.
Woodcock, A. & Bradley, C. (2006). Validation of the revised 10-item HIV Treatment 
Satisfaction Questionnaire status version (HIVTSQs) and new change version 
(HIVTSQc). Value in Health 9: (5) 320-333.